Timothy Meyer

All Publications

• Twice Weekly Versus Thrice Weekly Hemodialysis - A Pilot Cross-Over Equivalence Trial. Clinical journal of the American Society of Nephrology : CJASN Lee, S., Pham, N. M., Montez-Rath, M. E., Bolanos, C. G., Bonde, S. S., Meyer, T. W., Sirich, T. L. 2024

  Abstract

  The 2015 Update of the Kidney Disease Outcomes Quality Initiative (KDOQI) Guideline for Hemodialysis Adequacy increased the contribution of residual kidney function in calculating standard Kt/V urea (stdKt/V urea ). However, no study has assessed the effect of prescribing twice weekly hemodialysis according to this guideline on patients' quality of life or uremic solute levels.Twenty six hemodialysis patients with average residual urea clearance (Kru) 4.7±1.8 ml/min and hemodialysis vintage of 12±15 months (range two months to 4.9 years) underwent a cross-over trial comparing four weeks of twice weekly hemodialysis and four weeks of thrice weekly hemodialysis. Twice weekly hemodialysis was prescribed to achieve stdKt/V urea 2.2 incorporating Kru using the 2015 KDOQI Guideline. Thrice weekly hemodialysis was prescribed to achieve spKt/V urea 1.3 regardless of Kru. Quality of life and plasma levels of secreted uremic solutes and β 2 microglobulin (β 2 m) were assessed at the end of each period.Equivalence testing between twice and thrice weekly hemodialysis based on the Kidney Disease Quality of Life instrument (primary analysis) was inconclusive. Symptoms as assessed by the secondary outcomes Dialysis Symptom Index and post-dialysis recovery time were not worse with twice weekly hemodialysis. StdKt/V urea was adequate during twice weekly HD (2.7±0.5), and ultrafiltration rate and plasma potassium were controlled with minimally longer treatment times (twice weekly: 195±20 vs. thrice weekly: 191±17 minutes). Plasma levels of the secreted solutes and β 2 m were not higher with twice weekly than thrice weekly hemodialysis.Twice weekly hemodialysis can be prescribed using the higher contribution assigned to Kru by the 2015 KDOQI Guideline. With twice weekly hemodialysis, quality of life was unchanged, and the continuous function of the residual kidneys controlled fluid gain and plasma levels of potassium and uremic solutes without substantially longer treatment times.

  View details for DOI 10.2215/CJN.0000000000000507

  View details for PubMedID 38922689

• The Removal of Uremic Solutes by Peritoneal Dialysis. Journal of the American Society of Nephrology : JASN Meyer, T. W., Bargman, J. M. 2023

  Abstract

  Peritoneal dialysis is now commonly prescribed to achieve target clearances for urea or creatinine. The International Society for Peritoneal Dialysis has proposed however that such targets should no longer be imposed. The Society's new guidelines suggest rather that the peritoneal dialysis prescription should be adjusted to achieve well being in individual patients. The relaxation of treatment targets could allow increased use of peritoneal dialysis. Measurement of solute levels in patients receiving dialysis individualized to relieve uremic symptoms could also help us identify the solutes responsible for those symptoms, and then devise new means to limit their accumulation. This possibility has prompted us to review the extent to which different uremic solutes are removed by peritoneal dialysis.

  View details for DOI 10.1681/ASN.0000000000000211

  View details for PubMedID 37553867

• Increasing the Clearance of Protein Bound Solutes by Recirculating Dialysate through Activated Carbon. Kidney360 Meyer, T. W., Lee, S., Whitmer, L. C., Blanco, I. J., Suba, J. K., Sirich, T. L. 2023

  Abstract

  BACKGROUND: Conventional hemodialysis provides limited clearance of uremic solutes that bind to plasma proteins. No studies however have tested testing whether increasing the clearance of bound solutes provides clinical benefit. Practical means to increase the dialytic clearance of bound solutes are required to perform such studies.METHODS: Artificial plasma was dialyzed using two dialysis systems in series. In the first recirculating system a fixed small volume of dialysate flowed rapidly through an activated carbon block before passing through two large dialyzers. In a second conventional system a lower flow of fresh dialysate was passed through a single dialyzer. Chemical measurements tested the ability of the recirculating system to increase the clearance of selected solutes. Mathematical modeling predicted the dependence of solute clearances on the extent to which solutes were taken up by the carbon block and were bound to plasma proteins.RESULTS: By itself, the conventional system provided clearances of the tightly bound solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) of only 18±10 and 19±11 ml/min, respectively (mean±sd). Because these solutes were effectively adsorbed by the carbon block, the recirculating system by itself provided PCS and IS clearances of 45±11 and 53±16 ml/min. It further raised their clearances to 54±12 ml/min and 61±17 ml/min when operating in series with the conventional system (p < 0.002 vs conventional clearance both solutes). Modeling predicted that the recirculating system would increase the clearances of bound solute even if their uptake by the carbon block was incomplete.CONCLUSIONS: When added to a conventional dialysis system, a recirculating system employing a carbon block sorbent, a single pump, and standard dialyzers can greatly increase the clearance of protein-bound uremic solutes.

  View details for DOI 10.34067/KID.0000000000000155

  View details for PubMedID 37211642

• A Limited Effect of Chronic Renal Insufficiency on the Colon Microbiome. Journal of the American Society of Nephrology : JASN Guthrie, L., Sonnenburg, J. L., Fischbach, M. A., Meyer, T. W. 2023

  View details for DOI 10.1681/ASN.0000000000000064

  View details for PubMedID 36753629

• Removal of Uremic Solutes from Dialysate by Activated Carbon. Clinical journal of the American Society of Nephrology : CJASN Lee, S., Sirich, T. L., Blanco, I. J., Plummer, N. S., Meyer, T. W. 2022

  Abstract

  BACKGROUND AND OBJECTIVES: Adsorption of uremic solutes to activated carbon provides a potential means to limit dialysate volumes required for new dialysis systems. The ability of activated carbon to take up uremic solutes has, however, not been adequately assessed.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Graded volumes of waste dialysate collected from clinical hemodialysis treatments were passed through activated carbon blocks. Metabolomic analysis assessed the adsorption by activated carbon of a wide range of uremic solutes. Additional experiments tested the ability of the activated carbon to increase the clearance of selected solutes at low dialysate flow rates.RESULTS: Activated carbon initially adsorbed the majority, but not all, of 264 uremic solutes examined. Solute adsorption fell, however, as increasing volumes of dialysate were processed. Moreover, activated carbon added some uremic solutes to the dialysate, including methylguanidine. Activated carbon was particularly effective in adsorbing uremic solutes that bind to plasma proteins. In vitro dialysis experiments showed that introduction of activated carbon into the dialysate stream increased the clearance of the protein-bound solutes indoxyl sulfate and p-cresol sulfate by 77%±12% (mean±SD) and 73%±12%, respectively, at a dialysate flow rate of 200 ml/min, but had a much lesser effect on the clearance of the unbound solute phenylacetylglutamine.CONCLUSIONS: Activated carbon adsorbs many but not all uremic solutes. Introduction of activated carbon into the dialysate stream increased the clearance of those solutes that it does adsorb.

  View details for DOI 10.2215/CJN.01610222

  View details for PubMedID 35835518

• Impact of a 7-day homogeneous diet on interpersonal variation in human gut microbiomes and metabolomes. Cell host & microbe Guthrie, L., Spencer, S. P., Perelman, D., Van Treuren, W., Han, S., Yu, F. B., Sonnenburg, E. D., Fischbach, M. A., Meyer, T. W., Sonnenburg, J. L. 2022

  Abstract

  Gut microbiota metabolism of dietary compounds generates a vast array of microbiome-dependent metabolites (MDMs), which are highly variable between individuals. The uremic MDMs (uMDMs) phenylacetylglutamine (PAG), p-cresol sulfate (PCS), and indoxyl sulfate (IS) accumulate during renal failure and are associated with poor outcomes. Targeted dietary interventions may reduce toxic MDM generation; however, it is unclear if inter-individual differences in diet or gut microbiome dominantly contribute to MDM variance. Here, we use a 7-day homogeneous average American diet to standardize dietary precursor availability in 21 healthy individuals. During dietary homogeneity, the coefficient of variation in PAG, PCS, and IS (primary outcome) did not decrease, nor did inter-individual variation in most identified metabolites; other microbiome metrics showed no or modest responses to the intervention. Host identity and age are dominant contributors to variability in MDMs. These results highlight the potential need to pair dietary modification with microbial therapies to control MDM profiles.

  View details for DOI 10.1016/j.chom.2022.05.003

  View details for PubMedID 35643079

• Improving Solute Clearances by Hemodialysis. Blood purification Lee, S., Sirich, T. L., Meyer, T. W. 2022: 1-12

  Abstract

  The adequacy of hemodialysis is now assessed by measuring the removal of the single-solute urea. The urea clearance provided by contemporary dialysis is a large fraction of the blood flow through the dialyzer and therefore cannot be increased much further. Other solutes however likely contribute more than urea to the residual uremic illness suffered by hemodialysis patients. We here review methods which could be employed to increase the clearance of nonurea solutes. We will separately consider the clearances of free low-molecular-mass solutes, free larger solutes, and protein-bound solutes. New clinical studies will be required to test the extent to which increasing the clearance on nonurea solutes with these various characteristics can improve patients' health.

  View details for DOI 10.1159/000524512

  View details for PubMedID 35613554

• Barriers to Reducing Hemodialysis Time and Frequency in Patients with Residual Kidney Function. Journal of the American Society of Nephrology : JASN Meyer, T. W., Blanco, I. J., Grimm, J. C., Leypoldt, J. K., Sirich, T. L. 2021; 32 (9): 2112-2116

  View details for DOI 10.1681/ASN.2021030361

  View details for PubMedID 34465606

• Impaired Tubular Secretion of Organic Solutes in Advanced CKD. Journal of the American Society of Nephrology : JASN Mair, R., Lee, S., Plummer, N., Sirich, T., Meyer, T. 2021

  Abstract

  Background The clearance of solutes removed by tubular secretion may be altered out of proportion to the glomerular filtration rate (GFR) in chronic kidney disease (CKD). Recent studies have described considerable variability in the secretory clearance of waste solutes relative to the GFR in patients with CKD. Methods To test the hypothesis that secretory clearance relative to GFR is reduced in patients approaching dialysis, we used metabolomic analysis to identify solutes in simultaneous urine and plasma samples from 16 CKD patients with an estimated GFR of 7±2 ml/min per 1.73m2 and 16 control participants. Fractional clearances were calculated as the ratios of urine to plasma levels of each solute relative to those of creatinine and urea in CKD patients and to those of creatinine in controls. Results Metabolomic analysis identified 39 secreted solutes with fractional clearance >3.0 in control participants. Fractional clearance values in CKD patients were reduced on average to 65%±27% of those in controls. These values were significantly lower for 18 of 39 individual solutes and significantly higher for only one. Assays of the secreted anions phenylacetyl glutamine, p-cresol sulfate, indoxyl sulfate, and hippurate confirmed variable impairment of secretory clearances in advanced CKD. Fractional clearances were markedly reduced for phenylacetylglutamine (4.2±0.6 for controls versus 2.3±0.6 for CKD patients, P<0.001), p-cresol sulfate (8.6±2.6 for controls versus 4.1±1.5 for CKD patients, P<0.001), and indoxyl sulfate (23.0±7.3 versus 7.5±2.8, P<0.001), but not for hippurate (10.2±3.8 versus 8.4±2.6, P=0.13). Conclusions Secretory clearances for many solutes are reduced more relative to the reduction in GFR in advanced CKD. Impaired secretion of these solutes might contribute to uremic symptoms as patients approach dialysis.

  View details for DOI 10.1681/ASN.2021030336

  View details for PubMedID 34408065

• Association of Plasma Uremic Solute Levels with Residual Kidney Function in Children on Peritoneal Dialysis. Clinical journal of the American Society of Nephrology : CJASN Ganesan, L., O'Brien, F., Sirich, T., Plummer, N., Sheth, R., Fajardo, C., Brakeman, P., Sutherland, S., Meyer, T. 2021

  Abstract

  Background and objectives. Residual native kidney function confers health benefits in dialysis patients. It can facilitate control of extracellular volume and inorganic ion concentrations. Residual kidney function can also limit the accumulation of uremic solutes. This study assessed whether lower plasma concentrations of uremic solutes were associated with residual kidney function in pediatric patients on peritoneal dialysis. Design, setting, participants, and measurements. Samples were analyzed from 29 pediatric peritoneal dialysis patients including 13 without residual kidney function and 10 with residual kidney function. Metabolomic analysis by untargeted mass spectrometry compared plasma solute levels in patients with and without residual kidney function. Dialytic and residual clearances of selected solutes were also measured by assays employing chemical standards. Results. Metabolomic analysis showed that plasma levels of 256 uremic solutes in patients with residual kidney function averaged 64 (51-81 IQR) percent of the values in patients without residual kidney function who had similar total Kt/Vurea The plasma levels were significantly lower for 59 of the 256 solutes in the patients with residual kidney function and significantly higher for none. Assays employing chemical standards showed that residual kidney function provides a higher portion of the total clearance for non-urea solutes than it does for urea. Conclusions. Concentrations of many uremic solutes are lower in peritoneal dialysis patients with residual kidney function than in those without residual kidney function receiving similar treatment as assessed by Kt/Vurea.

  View details for DOI 10.2215/CJN.01430121

  View details for PubMedID 34233922

• Improving Clearance for Renal Replacement Therapy. Kidney360 Lee, S., Sirich, T. L., Meyer, T. W. 2021; 2 (7): 1188-1195

  Abstract

  The adequacy of hemodialysis is now assessed by measuring the removal of a single solute, urea. The urea clearance provided by current dialysis methods is a large fraction of the blood flow through the dialyzer, and, therefore, cannot be increased much further. However, other solutes, which are less effectively cleared than urea, may contribute more to the residual uremic illness suffered by patients on hemodialysis. Here, we review a variety of methods that could be used to increase the clearance of such nonurea solutes. New clinical studies will be required to test the extent to which increasing solute clearances improves patients' health.

  View details for DOI 10.34067/kid.0002922021

  View details for PubMedID 35355887

  View details for PubMedCentralID PMC8786098

• Precision medicine in transplantation and hemodialysis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Oberbauer, R., Meyer, T. W. 2021; 36 (Supplement_2): 31-36

  Abstract

  In kidney transplantation, precision medicine has already entered clinical practice. Donor and recipient human leucocyte antigen (HLA) regions are genotyped in two class 1 and usually three class 2 loci, and the individual degree of sensitization against alloimmune antigens is evaluated by the detection of anti-HLA donor-specific antibodies. Recently, the contribution of non-HLA mismatches to outcomes such as acute T- and B-cell-mediated rejection and even long-term graft survival was described. Tracking of specific alloimmune T- and B-cell clones by next generation sequencing and refinement of the immunogenicity of allo-epitopes specifically in the interaction with HLA and T- and B-cell receptors may further support individualized therapy. Although the choices of maintenance immunosuppression are rather limited, individualization can be accomplished by adjustment of dosing based on these risk predictors. Finally, supplementing histopathology by a transcriptomics analysis allows for a biological interpretation of the histological findings and avoids interobserver variability of results. In contrast to transplantation, the prescription of hemodialysis therapy is far from precise. Guidelines do not consider modifications by age, diet or many comorbid conditions. Patients with residual kidney function routinely receive the same treatment as those without. A major barrier hitherto is the definition of 'adequate' treatment based on urea removal. Kt/Vurea and related parameters neither reflect the severity of uremic symptoms nor predict long-term outcomes. Urea is poorly representative for numerous other compounds that accumulate in the body when the kidneys fail, yet clinicians prescribe treatment based on its measurement. Modern technology has provided the means to identify other solutes responsible for specific features of uremic illness and their measurement will be a necessary step in moving beyond the standardized prescription of hemodialysis.

  View details for DOI 10.1093/ndt/gfaa367

  View details for PubMedID 34153984

• Metabolomic analysis of uremic pruritus in patients on hemodialysis. PloS one Bolanos, C. G., Pham, N. M., Mair, R. D., Meyer, T. W., Sirich, T. L. 2021; 16 (2): e0246765

  Abstract

  Pruritus is a common debilitating symptom experienced by hemodialysis patients. Treatment is difficult because the cause of uremic pruritus is not known. This study addressed the hypothesis that pruritus is caused by solutes that accumulate in the plasma when the kidneys fail. We sought to identify solutes responsible for uremic pruritus using metabolomic analysis to compare the plasma of hemodialysis patients with severe pruritus versus mild/no pruritus. Pruritus severity in hemodialysis patients was assessed using a 100-mm visual analogue scale (VAS), with severe pruritus defined as >70 mm and mild/no pruritus defined as <10 mm. Twelve patients with severe pruritus (Itch) and 24 patients with mild/no pruritus (No Itch) were included. Pre-treatment plasma and plasma ultrafiltrate were analyzed using an established metabolomic platform (Metabolon, Inc.). To identify solutes associated with pruritus, we compared the average peak area of each solute in the Itch patients to that of the No Itch patients using the false discovery rate (q value) and principal component analysis. Dialysis vintage, Kt/Vurea, and serum levels of calcium, phosphorus, PTH, albumin, ferritin, and hemoglobin were similar in the Itch and No Itch patients. Metabolomic analysis identified 1,548 solutes of which 609 were classified as uremic. No difference in the plasma or plasma ultrafiltrate levels of any solute or group of solutes was found between the Itch and No Itch patients. Metabolomic analysis of hemodialysis patients did not reveal any solutes associated with pruritus. A limitation of metabolomic analysis is that the solute of interest may not be included in the metabolomic platform's chemical library. A role for uremic solutes in pruritus remains to be established.

  View details for DOI 10.1371/journal.pone.0246765

  View details for PubMedID 33577623

• Impaired Tubular Secretion of Organic Solutes in Acute Kidney Injury. Kidney360 O'Brien, F. J., Mair, R. D., Plummer, N. S., Meyer, T. W., Sutherland, S. M., Sirich, T. L. 2020; 1 (8): 724-730

  Abstract

  Impairment of kidney function is routinely assessed by measuring the accumulation of creatinine, an organic solute cleared largely by glomerular filtration. We tested whether the clearance of solutes that undergo tubular secretion is reduced in proportion to the clearance of creatinine in humans with AKI.Four endogenously produced organic solutes (phenylacetylglutamine [PAG], hippurate [HIPP], indoxyl sulfate [IS], and p-cresol sulfate [PCS]) were measured in spot urine and plasma samples from ten patients with AKI and 17 controls. Fractional clearance relative to creatinine was calculated to assess tubular secretion. Fractional clearance values were calculated in terms of the free, unbound levels of HIPP, IS, and PCS that bind to plasma proteins.Fractional clearance values for PAG, HIPP, IS, and PCS were >1.0 in patients with AKI as well as controls, indicating that these solutes were still secreted by the tubules of the injured kidneys. Fractional clearance values were, however, significantly lower in patients with AKI than controls, indicating that kidney injury reduced tubular secretion more than glomerular filtration (AKI versus control: PAG, 2.1±0.7 versus 4.6±1.4, P<0.001; HIPP, 10±5 versus 15±7, P=0.02; IS, 10±6 versus 28±7, P<0.001; PCS, 3.3±1.8 versus 10±3, P<0.001). Free plasma levels rose out of proportion to total plasma levels for each of the bound solutes in AKI, so that calculating their fractional clearance in terms of their total plasma levels failed to reveal their impaired secretion.Tubular secretion of organic solutes can be reduced out of proportion to glomerular filtration in AKI. Impaired secretion of protein-bound solutes may be more reliably detected when clearances are expressed in terms of their free, unbound levels in the plasma.

  View details for DOI 10.34067/kid.0001632020

  View details for PubMedID 35252876

  View details for PubMedCentralID PMC8815732

• Contribution of 'clinically negligible' residual kidney function to clearance of uremic solutes NEPHROLOGY DIALYSIS TRANSPLANTATION Toth-Manikowski, S. M., Sirich, T. L., Meyer, T. W., Hostetter, T. H., Hwang, S., Plummer, N. S., Hai, X., Coresh, J., Powe, N. R., Shafi, T. 2020; 35 (5): 846–53

  View details for DOI 10.1093/ndt/gfz042

  View details for Web of Science ID 000562472600018

• Twice-Weekly Hemodialysis Is an Option for Many Patients in Times of Dialysis Unit Stress. Journal of the American Society of Nephrology : JASN Meyer, T. W., Hostetter, T. H., Watnick, S. 2020

  View details for DOI 10.1681/ASN.2020030361

  View details for PubMedID 32300069

• The Uremic Syndrome CHRONIC RENAL DISEASE, 2ND EDITION Dobre, M. A., Meyer, T. W., Hostetter, T. H., Kimmel, P. L., Rosenberg, M. E. 2020: 199–210

  View details for DOI 10.1016/B978-0-12-815876-0.00014-0

  View details for Web of Science ID 000489824100014

• Why Is the GFR So High? Implications for the Treatment of Kidney Failure. Clinical journal of the American Society of Nephrology : CJASN Meyer, T. W., Hostetter, T. H. 2020

  Abstract

  The high GFR in vertebrates obligates large energy expenditure. Homer Smith's teleologic argument that this high GFR was needed to excrete water as vertebrates evolved in dilute seas is outdated. The GFR is proportional to the metabolic rate among vertebrate species and higher in warm-blooded mammals and birds than in cold-blooded fish, amphibians, and reptiles. The kidney clearance of some solutes is raised above the GFR by tubular secretion, and we presume secretion evolved to eliminate particularly toxic compounds. In this regard, high GFRs may provide a fluid stream into which toxic solutes can be readily secreted. Alternatively, the high GFR may be required to clear solutes that are too large or too varied to be secreted, especially bioactive small proteins and peptides. These considerations have potentially important implications for the understanding and treatment of kidney failure.

  View details for DOI 10.2215/CJN.14300920

  View details for PubMedID 33303581

• Accumulation of Uremic Solutes in the Cerebrospinal Fluid in Experimental Acute Renal Failure. American journal of physiology. Renal physiology Mair, R. D., Nguyen, H., Huang, T., Plummer, N. S., Sirich, T. L., Meyer, T. W. 2019

  Abstract

  The accumulation of uremic solutes in kidney failure may impair mental function. This study profiled the accumulation of uremic solutes in the cerebrospinal fluid (CSF) in acute renal failure. CSF and plasma ultrafiltrate were obtained from rats at 48 hours after sham operation (control, n=10) or bilateral nephrectomy (nephrectomy, n=10) and analyzed using an established metabolomic platform. 248 solutes were identified as uremic based on their accumulation in plasma ultrafiltrate of nephrectomized compared to control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF/plasma ultrafiltrate concentration ratios. Levels of many of the uremic solutes were normally lower in the CSF than in the plasma ultrafiltrate indicating exclusion of these solutes from the brain. CSF levels of the great majority of the uremic solutes increased in renal failure. The increase in the CSF was however relatively less than in the plasma ultrafiltrate for most solutes. In particular, for the 31 uremic solutes with CSF to plasma ultrafiltrate ratios less than 0.25 in control rats, the average CSF to plasma ultrafiltrate ratio decreased from 0.13 ± 0.07 in control rats to 0.09 ± 0.06 in nephrectomized rats revealing sustained ability to exclude these solutes from the brain. In summary, levels of many uremic solutes are normally kept lower in the CSF than in the plasma ultrafiltrate by the action of the blood-brain and blood-CSF barriers. These barriers remain functional but cannot prevent accumulation of uremic solutes in the CSF when the kidneys fail.

  View details for DOI 10.1152/ajprenal.00100.2019

  View details for PubMedID 31141401

• Contribution of 'clinically negligible' residual kidney function to clearance of uremic solutes. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Toth-Manikowski, S. M., Sirich, T. L., Meyer, T. W., Hostetter, T. H., Hwang, S., Plummer, N. S., Hai, X., Coresh, J., Powe, N. R., Shafi, T. 2019

  Abstract

  BACKGROUND: Residual kidney function (RKF) is thought to exert beneficial effects through clearance of uremic toxins. However, the level of native kidney function where clearance becomes negligible is not known.METHODS: We aimed to assess whether levels of nonurea solutes differed among patients with 'clinically negligible' RKF compared with those with no RKF. The hemodialysis study excluded patients with urinary urea clearance >1.5mL/min, below which RKF was considered to be 'clinically negligible'. We measured eight nonurea solutes from 1280 patients participating in this study and calculated the relative difference in solute levels among patients with and without RKF based on measured urinary urea clearance.RESULTS: The mean age of the participants was 57years and 57% were female. At baseline, 34% of the included participants had clinically negligible RKF (mean 0.7±0.4mL/min) and 66% had no RKF. Seven of the eight nonurea solute levels measured were significantly lower in patients with RKF than in those without RKF, ranging from -24% [95% confidence interval (CI) -31 to -16] for hippurate, -7% (-14 to -1) for trimethylamine-N-oxide and -4% (-6 to -1) for asymmetric dimethylarginine. The effect of RKF on plasma levels was comparable or more pronounced than that achieved with a 31% higher dialysis dose (spKt/Vurea 1.7 versus 1.3). Preserved RKF at 1-year follow-up was associated with a lower risk of cardiac death and first cardiovascular event.CONCLUSIONS: Even at very low levels, RKF is not 'negligible', as it continues to provide nonurea solute clearance. Management of patients with RKF should consider these differences.

  View details for PubMedID 30879076

• Plasma pseudouridine levels reflect body size in children on hemodialysis. Pediatric nephrology (Berlin, Germany) O'Brien, F. J., Sirich, T. L., Taussig, A. n., Fung, E. n., Ganesan, L. L., Plummer, N. S., Brakeman, P. n., Sutherland, S. M., Meyer, T. W. 2019

  Abstract

  Dialysis in children as well as adults is prescribed to achieve a target spKt/Vurea, where Vurea is the volume of distribution of urea. Waste solute production may however be more closely correlated with body surface area (BSA) than Vurea which rises in proportion with body weight. Plasma levels of waste solutes may thus be higher in smaller patients when targeting spKt/Vurea since they have higher BSA relative to body weight. This study measured levels of pseudouridine (PU), a novel marker solute whose production is closely proportional to BSA, to test whether prescription of dialysis to a target spKt/Vurea results in higher plasma levels of PU in smaller children.PU and urea nitrogen (ureaN) were measured in plasma and dialysate at the midweek hemodialysis session in 20 pediatric patients, with BSA ranging from 0.65-1.87m2. Mathematical modeling was employed to estimate solute production rates and average plasma solute levels.The dialytic clearance (Kd) of PU was proportional to that of ureaN (average KdPU/KdUreaN 0.69 ± 0.13, r2 0.84, p < 0.001). Production of PU rose in proportion with BSA (r2 0.57, p < 0.001). The pretreatment plasma level of PU was significantly higher in smaller children (r2 0.20, p = 0.051) while the pretreatment level of ureaN did not vary with size.Prescribing dialysis based on urea kinetics may leave uremic solutes at higher levels in small children. Measurement of a solute produced proportional to BSA may provide a better index of dialysis adequacy than measurement of urea.

  View details for DOI 10.1007/s00467-019-04369-6

  View details for PubMedID 31728748

• Inflammation and Immunity Pathways Regulate Genetic Susceptibility to Diabetic Nephropathy DIABETES Gurley, S. B., Ghosh, S., Johnson, S. A., Azushima, K., Sakban, R., George, S. E., Maeda, M., Meyer, T. W., Coffman, T. M. 2018; 67 (10): 2096–2106

  Abstract

  Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide, but its molecular pathogenesis is not well defined, and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. In this study, we describe a mouse model combining type 1 diabetes with activation of the renin-angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension, and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy; the 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice early in the course of their disease. We find dramatic differences in regulation of immune and inflammatory pathways, with upregulation of proinflammatory pathways in the susceptible (129) strain and coordinate downregulation in the resistant (C57BL/6) strain. Many of these pathways are also upregulated in rat models and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and RAS activation, may be critical early determinants of susceptibility to DN.

  View details for PubMedID 30065034

  View details for PubMedCentralID PMC6152345

• Characteristics of Colon-Derived Uremic Solutes CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Mair, R. D., Sirich, T. L., Plummer, N. S., Meyer, T. W. 2018; 13 (9): 1398–1404

  View details for DOI 10.2215/CJN.03150318

  View details for Web of Science ID 000448995400015

• Characteristics of Colon-Derived Uremic Solutes. Clinical journal of the American Society of Nephrology : CJASN Mair, R. D., Sirich, T. L., Plummer, N. S., Meyer, T. W. 2018

  Abstract

  BACKGROUND AND OBJECTIVES: Colon microbial metabolism produces solutes that are normally excreted in the urine and accumulate in the plasma when the kidneys fail. This study sought to further identify and characterize human colon-derived uremic solutes.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Colon-derived solutes normally excreted in the urine were identified by comparing urine from controls (n=17) and patients with total colectomies (n=12), using an established metabolomic platform. Colon-derived solutes that accumulate in kidney failure were then identified by comparing the plasma of the control patients with that of patients on dialysis (n=14).RESULTS: Ninety-one urinary solutes were classified as colon-derived on the basis of the finding of a urine excretion rate at least four-fold higher in control patients than in patients with total colectomies. Forty-six were solutes with known chemical structure, 35 of which had not previously been identified as colon-derived. Sixty of the colon-derived solutes accumulated in the plasma of patients with ESKD to a degree greater than urea and were therefore classified as uremic. The estimated urinary clearance for 27 out of the 32 colon-derived solutes for which clearance could be calculated exceeded that of creatinine, consistent with tubular secretion. Sulfatase treatment revealed that 42 out of the 91 colon-derived solutes detected were likely conjugates.CONCLUSIONS: Metabolomic analysis identified numerous colon-derived solutes that are normally excreted in human urine. Clearance by tubular secretion limits plasma levels of many colon-derived solutes.

  View details for PubMedID 30087103

• Uremic Toxin Clearance and Cardiovascular Toxicities. Toxins Mair, R. D., Sirich, T. L., Meyer, T. W. 2018; 10 (6)

  Abstract

  Uremic solutes contribute to cardiovascular disease in renal insufficiency. In this review we describe the clearance of selected uremic solutes, which have been associated with cardiovascular disease. These solutes-indoxyl sulfate (IS), p-cresol sulfate (PCS), phenylacetylglutamine (PAG), trimethylamine-n-oxide (TMAO), and kynurenine-exemplify different mechanisms of clearance. IS and PCS are protein-bound solutes efficiently cleared by the native kidney through tubular secretion. PAG and TMAO are not protein-bound but are also cleared by the native kidney through tubular secretion, while kynurenine is not normally cleared by the kidney. Increases in the plasma levels of the normally secreted solutes IS, PCS, TMAO, and PAG in chronic kidney disease (CKD) are attributable to a reduction in their renal clearances. Levels of each of these potential toxins are even higher in patients on dialysis than in those with advanced chronic kidney disease, which can be accounted for in part by a low ratio of dialytic to native kidney clearance. The rise in plasma kynurenine in CKD and dialysis patients, by contrast, remains to be explained. Our ability to detect lower levels of the potential uremic cardiovascular toxins with renal replacement therapy may be limited by the intermittency of treatment, by increases in solute production, and by the presence of non-renal clearance. Reduction in the levels of uremic cardiovascular toxins may in the future be achieved more effectively by inhibiting their production.

  View details for PubMedID 29865226

• Uremic Toxin Clearance and Cardiovascular Toxicities TOXINS Mair, R. D., Sirich, T. L., Meyer, T. W. 2018; 10 (6)

  View details for DOI 10.3390/toxins10060226

  View details for Web of Science ID 000436131800014

• Intensive Hemodialysis Fails to Reduce Plasma Levels of Uremic Solutes CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Sirich, T. L., Meyer, T. W. 2018; 13 (3): 361–62

  View details for PubMedID 29444901

  View details for PubMedCentralID PMC5967662

• Residual Function Effectively Controls Plasma Concentrations of Secreted Solutes in Patients on Twice Weekly Hemodialysis. Journal of the American Society of Nephrology : JASN Leong, S. C., Sao, J. N., Taussig, A. n., Plummer, N. S., Meyer, T. W., Sirich, T. L. 2018

  Abstract

  Background Most patients on hemodialysis are treated thrice weekly even if they have residual kidney function, in part because uncertainty remains as to how residual function should be valued and incorporated into the dialysis prescription. Recent guidelines, however, have increased the weight assigned to residual function and thus reduced the treatment time required when it is present. Increasing the weight assigned to residual function may be justified by knowledge that the native kidney performs functions not replicated by dialysis, including solute removal by secretion. This study tested whether plasma concentrations of secreted solutes are as well controlled in patients with residual function on twice weekly hemodialysis as in anuric patients on thrice weekly hemodialysis.Methods We measured the plasma concentration and residual clearance, dialytic clearance, and removal rates for urea and the secreted solutes hippurate, phenylacetylglutamine, indoxyl sulfate, and p-cresol sulfate in nine patients on twice weekly hemodialysis and nine patients on thrice weekly hemodialysis.Results Compared with anuric patients on thrice weekly dialysis with the same standard Kt/Vurea, patients on twice weekly hemodialysis had lower hippurate and phenylacetylglutamine concentrations and similar indoxyl sulfate and p-cresol sulfate concentrations. Mathematical modeling revealed that residual secretory function accounted for the observed pattern of solute concentrations.Conclusions Plasma concentrations of secreted solutes can be well controlled by twice weekly hemodialysis in patients with residual kidney function. This result supports further study of residual kidney function value and the inclusion of this function in dialysis adequacy measures.

  View details for DOI 10.1681/ASN.2018010081

  View details for PubMedID 29728422

• Untargeted mass spectrometry discloses plasma solute levels poorly controlled by hemodialysis PLOS ONE Sirich, T. L., Aronov, P. A., Fullman, J., Khanh Nguyen, Plummer, N. S., Meyer, T. W. 2017; 12 (11): e0188315

  Abstract

  Many solutes have been reported to remain at higher plasma levels relative to normal than the standard index solute urea in hemodialysis patients. Untargeted mass spectrometry was employed to compare solute levels in plasma and plasma ultrafiltrate of hemodialysis patients and normal subjects. Quantitative assays were employed to check the accuracy of untargeted results for selected solutes and additional measurements were made in dialysate and urine to estimate solute clearances and production. Comparison of peak areas indicated that many solutes accumulated to high levels in hemodialysis patients, with average peak areas in plasma ultrafiltrate of dialysis patients being more than 100 times greater than those in normals for 123 features. Most of these mass spectrometric features were identified only by their mass values. Untargeted analysis correctly ranked the accumulation of 5 solutes which were quantitatively assayed but tended to overestimate its extent. Mathematical modeling showed that the elevation of plasma levels for these solutes could be accounted for by a low dialytic to native kidney clearance ratio and a high dialytic clearance relative to the volume of the accessible compartment. Numerous solutes accumulate to high levels in hemodialysis patients because dialysis does not replicate the clearance provided by the native kidney. Many of these solutes remain to be chemically identified and their pathogenic potential elucidated.

  View details for PubMedID 29145509

• The Effect of Uremic Solutes on the Organic Cation Transporter 2 JOURNAL OF PHARMACEUTICAL SCIENCES Cheung, K., Hsueh, C., Zhao, P., Meyer, T. W., Zhang, L., Huang, S., Giacomini, K. M. 2017; 106 (9): 2551–57

  Abstract

  Chronic kidney disease (CKD) is characterized by the accumulation of uremic solutes; however, little is known about how these solutes affect drug absorption and disposition. The goal of this study is to evaluate the effect of uremic solutes on the organic cation transporter, OCT2, which plays a key role in the renal secretion of many basic drugs. As a second goal, we reviewed the literature to determine whether there was evidence for the effect of CKD on the renal secretion of basic drugs. We first screened 72 uremic solutes as inhibitors of [14C]-labeled metformin uptake by OCT2. Seven were identified as inhibitors and 3 of them were determined to be clinically relevant. Of the 7 solutes, dimethylamine, malondialdehyde, trimethylamine, homocysteine, indoxyl-β-d-glucuronide, and glutathione disulfide were novel OCT2 inhibitors. For 6 drugs that are known OCT2 substrates, both secretory clearance and glomerular filtration rate declined in parallel with progression of CKD from stage 2 to 4, suggesting that selective effects of uremic solutes on net tubular secretion of organic cations do not occur. Further clinical studies are warranted with a broader range of OCT2 substrates to determine whether CKD may differentially affect tubular secretion of drugs especially in patients with advanced CKD.

  View details for PubMedID 28483424

• Serum Asymmetric and Symmetric Dimethylarginine and Morbidity and Mortality in Hemodialysis Patients AMERICAN JOURNAL OF KIDNEY DISEASES Shafi, T., Hostetter, T. H., Meyer, T. W., Hwang, S., Hai, X., Melamed, M. L., Banerjee, T., Coresh, J., Powe, N. R. 2017; 70 (1): 48–58

  Abstract

  Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are putative uremic toxins that may exert toxicity by a number of mechanisms, including impaired nitric oxide synthesis and generation of reactive oxygen species. The study goal was to determine the association between these metabolites and cardiovascular outcomes in hemodialysis patients.Post hoc analysis of the Hemodialysis (HEMO) Study.1,276 prevalent hemodialysis patients with available samples 3 to 6 months after randomization.ADMA and SDMA measured in stored specimens.Cardiac death, sudden cardiac death, first cardiovascular event, and any-cause death. Association with predictors analyzed using Cox regression adjusted for potential confounders (including demographics, clinical characteristics, comorbid conditions, albumin level, and residual kidney function).Mean age of patients was 57±14 (SD) years, 63% were black, and 57% were women. Mean ADMA (0.9±0.2μmol/L) and SDMA levels (4.3±1.4μmol/L) were moderately correlated (r=0.418). Higher dialysis dose or longer session length were not associated with lower predialysis ADMA or SDMA concentrations. In fully adjusted models, each doubling of ADMA level was associated with higher risk (HR per 2-fold higher concentration; 95% CI) of cardiac death (1.83; 1.29-2.58), sudden cardiac death (1.79; 1.19-2.69), first cardiovascular event (1.50; 1.20-1.87), and any-cause death (1.44; 1.13-1.83). Compared to the lowest ADMA quintile (<0.745 μmol/L), the highest ADMA quintile (≥1.07μmol/L) was associated with higher risk (HR; 95% CI) of cardiac death (2.10; 1.44-3.05), sudden cardiac death (2.06; 1.46-2.90), first cardiovascular event (1.75; 1.35-2.27), and any-cause death (1.56; 1.21-2.00). SDMA level was associated with higher risk for cardiac death (HR, 1.40; 95% CI, 1.03-1.92), but this was no longer statistically significant after adjusting for ADMA level (HR, 1.20; 95% CI, 0.86-1.68).Single time-point measurement of ADMA and SDMA.ADMA and, to a lesser extent, SDMA levels are associated with cardiovascular outcomes in hemodialysis patients.

  View details for PubMedID 28089476

  View details for PubMedCentralID PMC5483385

• Manipulating the microbiome KIDNEY INTERNATIONAL Sirich, T. L., Meyer, T. W. 2017; 91 (2): 274–76

  Abstract

  The application of molecular methods has provided a new picture of the colon microbial flora, or microbiome. The microbiome has been found to be a complex ecosystem with multiple influences on its human host. In renal medicine, interest has focused on the microbiome as a source of toxic waste chemicals and a stimulant to unwanted systemic inflammation. Early attempts to manipulate the microbiome have yielded limited benefit, but further research is strongly motivated.

  View details for PubMedID 28087007

• Free and total p-cresol sulfate levels and infectious hospitalizations in hemodialysis patients in CHOICE and HEMO MEDICINE Banerjee, T., Meyer, T. W., Shafi, T., Hostetter, T. H., Melamed, M., Zhu, Y., Powe, N. R. 2017; 96 (6): e5799

  Abstract

  The uremic syndrome is attributed to progressive retention of compounds that, under normal conditions, are excreted by the healthy kidneys. p-cresol sulfate (PCS), a prototype protein-bound uremic retention solute, has been shown to exert toxic effects in vitro. Recent studies have identified relations between increased levels of PCS and indoxyl sulfate (IS) and adverse clinical outcomes in hemodialysis patients. We explored the relationship between free and total PCS and IS with infection-related hospitalizations (IH) and septicemia in 2 cohorts, Choices for Healthy Outcomes in Caring for end-stage renal disease (ESRD) Study (CHOICE) and Hemodialysis Study (HEMO).We measured free and total levels of PCS and IS in stored specimens in CHOICE, a cohort of 464 incident hemodialysis patients enrolled in 1995 to 1998 and followed for an average of 3.4 years and in a prevalent dialysis cohort of 495 patients enrolled in HEMO from 1995 to 2000 and followed for an average of 4.4 years. We measured free PCS and IS using mass spectroscopy. The 2 cohorts were linked to United States Renal Data System (USRDS) Medicare billing records to ascertain IH over follow-up. We examined the association of free and total levels of PCS and IS with IH and septicemia using multilevel Poisson regression models adjusted for demographics, comorbidities, clinical factors, and laboratory tests including residual kidney function. We stratified patients a priori based on gastrointestinal (GI) disease as PCS and IS are produced in colon.In CHOICE, highest tertile of free PCS in multivariable model was associated with 50% higher risk of IH [95% CI = 1.01-2.23] compared with lowest tertile in patients with no-GI disease. A significant trend was noted between greater levels of free PCS and septicemia in no-GI disease group in both cohorts, while no association was noted in GI disease group. Total PCS concentrations were not associated with either IH or septicemia in either cohort. No significant risk of IH or septicemia was noted with higher levels of free or total IS in either GI or no-GI disease group.These results suggest an association between higher concentrations of free PCS and infection-related and sepsis-related hospitalizations in hemodialysis patients. Better methods of dialysis should be developed to evaluate the utility of removing PCS and its effect on the outcome and also therapies to decrease gastrointestinal tract production of uremic solutes.

  View details for PubMedID 28178126

  View details for PubMedCentralID PMC5312983

• Vascular Access for Hemodialysis and Value-Based Purchasing for ESRD JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Mehrotra, R., Cheung, A. K., Meyer, T., Nath, K. A. 2017; 28 (2): 395–97

  View details for PubMedID 28143965

  View details for PubMedCentralID PMC5280029

• Limited reduction in uremic solute concentrations with increased dialysis frequency and time in the Frequent Hemodialysis Network Daily Trial. Kidney international Sirich, T. L., Fong, K., Larive, B., Beck, G. J., Chertow, G. M., Levin, N. W., Kliger, A. S., Plummer, N. S., Meyer, T. W. 2017

  Abstract

  The Frequent Hemodialysis Network Daily Trial compared conventional three-times weekly treatment to more frequent treatment with a longer weekly treatment time in patients receiving in-center hemodialysis. Evaluation at one year showed favorable effects of more intensive treatment on left ventricular mass, blood pressure, and phosphate control, but modest or no effects on physical or cognitive performance. The current study compared plasma concentrations of uremic solutes in stored samples from 53 trial patients who received three-times weekly in-center hemodialysis for an average weekly time of 10.9 hours and 30 trial patients who received six-times weekly in-center hemodialysis for an average of 14.6 hours. Metabolomic analysis revealed that increased treatment frequency and time resulted in an average reduction of only 15 percent in the levels of 107 uremic solutes. Quantitative assays confirmed that increased treatment did not significantly reduce levels of the putative uremic toxins p-cresol sulfate or indoxyl sulfate. Kinetic modeling suggested that our ability to lower solute concentrations by increasing hemodialysis frequency and duration may be limited by the presence of non-dialytic solute clearances and/or changes in solute production. Thus, failure to achieve larger reductions in uremic solute concentrations may account, in part, for the limited benefits observed with increasing frequency and weekly treatment time in Frequent Hemodialysis Daily Trial participants.

  View details for DOI 10.1016/j.kint.2016.11.002

  View details for PubMedID 28089366

• Trimethylamine N-Oxide and Cardiovascular Events in Hemodialysis Patients JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Shafi, T., Powe, N. R., Meyer, T. W., Hwang, S., Hai, X., Melamed, M. L., Banerjee, T., Coresh, J., Hostetter, T. H. 2017; 28 (1): 321–31

  Abstract

  Cardiovascular disease causes over 50% of the deaths in dialysis patients, and the risk of death is higher in white than in black patients. The underlying mechanisms for these findings are unknown. We determined the association of the proatherogenic metabolite trimethylamine N-oxide (TMAO) with cardiovascular outcomes in hemodialysis patients and assessed whether this association differs by race. We measured TMAO in stored serum samples obtained 3-6 months after randomization from a total of 1232 white and black patients of the Hemodialysis Study, and analyzed the association of TMAO with cardiovascular outcomes using Cox models adjusted for potential confounders (demographics, clinical characteristics, comorbidities, albumin, and residual kidney function). Mean age of the patients was 58 years; 35% of patients were white. TMAO concentration did not differ between whites and blacks. In whites, 2-fold higher TMAO associated with higher risk (hazard ratio [95% confidence interval]) of cardiac death (1.45 [1.24 to 1.69]), sudden cardiac death [1.70 (1.34 to 2.15)], first cardiovascular event (1.15 [1.01 to 1.32]), and any-cause death (1.22 [1.09 to 1.36]). In blacks, the association was nonlinear and significant only for cardiac death among patients with TMAO concentrations below the median (1.58 [1.03 to 2.44]). Compared with blacks in the same quintile, whites in the highest quintile for TMAO (≥135 μM) had a 4-fold higher risk of cardiac or sudden cardiac death and a 2-fold higher risk of any-cause death. We conclude that TMAO concentration associates with cardiovascular events in hemodialysis patients but the effects differ by race.

  View details for PubMedID 27436853

  View details for PubMedCentralID PMC5198291

• Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota CELL HOST & MICROBE Devlin, A. S., Marcobal, A., Dodd, D., Nayfach, S., Plummer, N., Meyer, T., Pollard, K. S., Sonnenburg, J. L., Fischbach, M. A. 2016; 20 (6): 709-715

  Abstract

  Renal disease is growing in prevalence and has striking co-morbidities with metabolic and cardiovascular disease. Indoxyl sulfate (IS) is a toxin that accumulates in plasma when kidney function declines and contributes to the progression of chronic kidney disease. IS derives exclusively from the gut microbiota. Bacterial tryptophanases convert tryptophan to indole, which is absorbed and modified by the host to produce IS. Here, we identify a widely distributed family of tryptophanases in the gut commensal Bacteroides and find that deleting this gene eliminates the production of indole in vitro. By altering the status or abundance of the Bacteroides tryptophanase, we can modulate IS levels in gnotobiotic mice and in the background of a conventional murine gut community. Our results demonstrate that it is possible to control host IS levels by targeting the microbiota and suggest a possible strategy for treating renal disease.

  View details for DOI 10.1016/j.chom.2016.10.021

  View details for Web of Science ID 000392843500008

  View details for PubMedID 27916477

  View details for PubMedCentralID PMC5159218

• Can twice weekly hemodialysis expand patient access under resource constraints? Hemodialysis international. International Symposium on Home Hemodialysis Savla, D., Chertow, G. M., Meyer, T., Anand, S. 2016

  Abstract

  The convention of prescribing hemodialysis on a thrice weekly schedule began empirically when it seemed that this frequency was convenient and likely to treat symptoms for a majority of patients. Later, when urea was identified as the main target and marker of clearance, studies supported the prevailing notion that thrice weekly dialysis provided appropriate clearance of urea. Today, national guidelines on hemodialysis from most countries recommend patients receive at least thrice weekly therapy. However, resource constraints in low- and middle-income countries (LMIC) have resulted in a substantial proportion of patients using less frequent hemodialysis in these settings. Observational studies of patients on twice weekly dialysis show that twice weekly therapy has noninferior survival rates compared with thrice weekly therapy. In fact, models of urea clearance also show that twice weekly therapy can meet urea clearance "targets" if patients have significant residual function or if they follow a protein-restricted diet, as may be common in LMIC. Greater reliance on twice weekly therapy, at least at the start of hemodialysis, therefore has potential to reduce health care costs and increase access to renal replacement therapy in low-resource settings; however, randomized control trials are needed to better understand long-term outcomes of twice versus thrice weekly therapy.

  View details for DOI 10.1111/hdi.12501

  View details for PubMedID 27966247

• Kt/Vurea and Nonurea Small Solute Levels in the Hemodialysis Study. Journal of the American Society of Nephrology Meyer, T. W., Sirich, T. L., Fong, K. D., Plummer, N. S., Shafi, T., Hwang, S., Banerjee, T., Zhu, Y., Powe, N. R., Hai, X., Hostetter, T. H. 2016; 27 (11): 3469-3478

  Abstract

  The Hemodialysis (HEMO) Study showed that high-dose hemodialysis providing a single-pool Kt/Vurea of 1.71 provided no benefit over a standard treatment providing a single-pool Kt/Vurea of 1.32. Here, we assessed whether the high-dose treatment used lowered plasma levels of small uremic solutes other than urea. Measurements made ≥3 months after randomization in 1281 patients in the HEMO Study showed a range in the effect of high-dose treatment compared with that of standard treatment: from no reduction in the level of p-cresol sulfate or asymmetric dimethylarginine to significant reductions in the levels of trimethylamine oxide (-9%; 95% confidence interval [95% CI], -2% to -15%), indoxyl sulfate (-11%; 95% CI, -6% to -15%), and methylguanidine (-22%; 95% CI, -18% to -27%). Levels of three other small solutes also decreased slightly; the level of urea decreased 9%. All-cause mortality did not significantly relate to the level of any of the solutes measured. Modeling indicated that the intermittency of treatment along with the presence of nondialytic clearance and/or increased solute production accounted for the limited reduction in solute levels with the higher Kt/Vurea In conclusion, failure to achieve greater reductions in solute levels may explain the failure of high Kt/Vurea treatment to improve outcomes in the HEMO Study. Furthermore, levels of the nonurea solutes varied widely among patients in the HEMO Study, and achieved Kt/Vurea accounted for very little of this variation. These results further suggest that an index only on the basis of urea does not provide a sufficient measure of dialysis adequacy.

  View details for PubMedID 27026365

• More Dialysis Has Not Proven Much Better. Seminars in dialysis O'Brien, F. J., Fong, K. D., Sirich, T. L., Meyer, T. W. 2016; 29 (6): 481-490

  Abstract

  Patients maintained on standard three times weekly hemodialysis have a high mortality rate and a limited quality of life. Some of this illness is due to systemic diseases that have caused kidney failure, and thus may be irreversible. But we presume that imperfect replacement of normal kidney function by dialysis contributes importantly. Patients on hemodialysis are subject to fluctuations in extracellular fluid volume and inorganic ion concentrations and their plasma levels of many organic waste solutes remain very high. It is thus natural to suppose that their health could be improved by increasing the intensity of dialysis treatment. But despite a great deal of work over the past 20 years, evidence that such improvement can be obtained is generally lacking. Specific benefits can indeed be achieved. Patients who cannot control their intradialytic weight gains or plasma phosphate levels with standard therapy can benefit from extending treatment time. But we cannot promise the average patient that longer or more frequent treatment will reduce mortality or improve the quality of life.

  View details for DOI 10.1111/sdi.12533

  View details for PubMedID 27556575

• Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3. Molecular pharmaceutics Hsueh, C., Yoshida, K., Zhao, P., Meyer, T. W., Zhang, L., Huang, S., Giacomini, K. M. 2016; 13 (9): 3130-3140

  Abstract

  One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD.

  View details for DOI 10.1021/acs.molpharmaceut.6b00332

  View details for PubMedID 27467266

• Effect of a sustained difference in hemodialytic clearance on the plasma levels of p-cresol sulfate and indoxyl sulfate NEPHROLOGY DIALYSIS TRANSPLANTATION Camacho, O., Rosales, M. C., Shafi, T., Fullman, J., Plummer, N. S., Meyer, T. W., Sirich, T. L. 2016; 31 (8): 1335-1341

  Abstract

  The protein-bound solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) accumulate to high plasma levels in renal failure and have been associated with adverse events. The clearance of these bound solutes can be altered independently of the urea clearance by changing the dialysate flow and dialyzer size. This study tested whether a sustained difference in clearance would change the plasma levels of PCS and IS.Fourteen patients on thrice-weekly nocturnal hemodialysis completed a crossover study of two periods designed to achieve widely different bound solute clearances. We compared the changes in pre-dialysis plasma PCS and IS levels from baseline over the course of the two periods.The high-clearance period provided much higher PCS and IS clearances than the low-clearance period (PCS: 23 ± 4 mL/min versus 12 ± 3 mL/min, P < 0.001; IS: 30 ± 5 mL/min versus 17 ± 4 mL/min, P < 0.001). Despite the large difference in clearance, the high-clearance period did not have a different effect on PCS levels than the low-clearance period [from baseline, high: +11% (-5, +37) versus low: -8% (-18, +32), (median, 25th, 75th percentile), P = 0.50]. In contrast, the high-clearance period significantly lowered IS levels compared with the low-clearance period [from baseline, high: -4% (-17, +1) versus low: +22% (+14, +31), P < 0.001). The amount of PCS removed in the dialysate was significantly greater at the end of the high-clearance period [269 (206, 312) versus 199 (111, 232) mg per treatment, P < 0.001], while the amount of IS removed was not different [140 (87, 196) versus 116 (89, 170) mg per treatment, P = 0.15].These findings suggest that an increase in PCS generation prevents plasma levels from falling when the dialytic clearance is increased. Suppression of solute generation may be required to reduce plasma PCS levels in dialysis patients.

  View details for DOI 10.1093/ndt/gfw100

  View details for Web of Science ID 000383285500025

  View details for PubMedID 27190347

• Tubular Secretion in CKD JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Suchy-Dicey, A. M., Laha, T., Hoofnagle, A., Newitt, R., Sirich, T. L., Meyer, T. W., Thummel, K. E., Yanez, N. D., Himmelfarb, J., Weiss, N. S., Kestenbaum, B. R. 2016; 27 (7): 2148-2155

  Abstract

  Renal function generally is assessed by measurement of GFR and urinary albumin excretion. Other intrinsic kidney functions, such as proximal tubular secretion, typically are not quantified. Tubular secretion of solutes is more efficient than glomerular filtration and a major mechanism for renal drug elimination, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and improve prediction of adverse outcomes. We estimated secretion function by measuring secreted solute (hippurate, cinnamoylglycine, p-cresol sulfate, and indoxyl sulfate) clearance using liquid chromatography-tandem mass spectrometric assays of serum and timed urine samples in a prospective cohort study of 298 patients with kidney disease. We estimated GFR by mean clearance of creatinine and urea from the same samples and evaluated associations of renal secretion with participant characteristics, mortality, and CKD progression to dialysis. Tubular secretion rate modestly correlated with eGFR and associated with some participant characteristics, notably fractional excretion of electrolytes. Low clearance of hippurate or p-cresol sulfate associated with greater risk of death independent of eGFR (hazard ratio, 2.3; 95% confidence interval, 1.1 to 4.7; hazard ratio, 2.5; 95% confidence interval, 1.0 to 6.1, respectively). Hazards models also suggested an association between low cinnamoylglycine clearance and risk of dialysis, but statistical analyses did not exclude the null hypothesis. Therefore, estimates of proximal tubular secretion function correlate with glomerular filtration, but substantial variability in net secretion remains. The observed associations of net secretion with mortality and progression of CKD require confirmation.

  View details for DOI 10.1681/ASN.2014121193

  View details for Web of Science ID 000378824800028

  View details for PubMedID 26614381

  View details for PubMedCentralID PMC4926962

• Mechanism of Prominent Trimethylamine Oxide (TMAO) Accumulation in Hemodialysis Patients. PloS one Hai, X., Landeras, V., Dobre, M. A., DeOreo, P., Meyer, T. W., Hostetter, T. H. 2015; 10 (12): e0143731

  Abstract

  Large size, protein binding and intracellular sequestration are well known to limit dialytic removal of compounds. In studying the normal renal and dialytic handling of trimethylamine oxide (TMAO), a molecule associated with cardiovascular disease in the general population, we discovered two largely unrecognized additional limitations to sustained reduction of a solute by chronic hemodialysis. We measured solute levels and handling in subjects on chronic hemodialysis (ESRD, n = 7) and compared these with levels and clearance in normal controls (NLS, n = 6). The ESRD patients had much higher peak predialysis plasma levels of TMAO than NLS (77 ± 26 vs 2±1 μM, mean ± SD, p<0.05). For comparison, predialysis BUN levels in ESRD subjects were 45±11 mg/dl and 15±3 mg/dl in NLS. Thus TMAO levels in ESRD average about 40 fold those in NLS while BUN is 3 fold NLS. However, the fractional reduction of TMAO concentration during dialysis, was in fact greater than that of urea (86±3 vs 74±6%, TMAO vs urea, p < 0.05) and its dialytic clearance while somewhat lower than that of urea was comparable to creatinine's. Also production rates were similar (533±272 vs 606 ± 220 μ moles/day, ESRD vs NLS, p>0.05). However, TMAO has a volume of distribution about one half that of urea. Also in NLS the urinary clearance of TMAO was high (219±78 ml/min) compared to the urinary urea and creatinine clearances (55±14 and 119±21 ml/min, respectively). Thus, TMAO levels achieve multiples of normal much greater than those of urea due mainly to 1) TMAO's high clearance by the normal kidney relative to urea and 2) its smaller volume of distribution. Modelling suggests that only much more frequent dialysis would be required to lower levels Thus, additional strategies such as reducing production should be explored. Furthermore, using urea as the sole marker of dialysis adequacy may be misleading since a molecule, TMAO, that is dialyzed readily accumulates to much higher multiples of normal with urea based dialysis prescriptions.

  View details for DOI 10.1371/journal.pone.0143731

  View details for PubMedID 26650937

  View details for PubMedCentralID PMC4674074

• Mechanism of Prominent Trimethylamine Oxide (TMAO) Accumulation in Hemodialysis Patients PLOS ONE Hai, X., Landeras, V., Dobre, M. A., DeOreo, P., Meyer, T. W., Hostetter, T. H. 2015; 10 (12)

  Abstract

  Large size, protein binding and intracellular sequestration are well known to limit dialytic removal of compounds. In studying the normal renal and dialytic handling of trimethylamine oxide (TMAO), a molecule associated with cardiovascular disease in the general population, we discovered two largely unrecognized additional limitations to sustained reduction of a solute by chronic hemodialysis. We measured solute levels and handling in subjects on chronic hemodialysis (ESRD, n = 7) and compared these with levels and clearance in normal controls (NLS, n = 6). The ESRD patients had much higher peak predialysis plasma levels of TMAO than NLS (77 ± 26 vs 2±1 μM, mean ± SD, p<0.05). For comparison, predialysis BUN levels in ESRD subjects were 45±11 mg/dl and 15±3 mg/dl in NLS. Thus TMAO levels in ESRD average about 40 fold those in NLS while BUN is 3 fold NLS. However, the fractional reduction of TMAO concentration during dialysis, was in fact greater than that of urea (86±3 vs 74±6%, TMAO vs urea, p < 0.05) and its dialytic clearance while somewhat lower than that of urea was comparable to creatinine's. Also production rates were similar (533±272 vs 606 ± 220 μ moles/day, ESRD vs NLS, p>0.05). However, TMAO has a volume of distribution about one half that of urea. Also in NLS the urinary clearance of TMAO was high (219±78 ml/min) compared to the urinary urea and creatinine clearances (55±14 and 119±21 ml/min, respectively). Thus, TMAO levels achieve multiples of normal much greater than those of urea due mainly to 1) TMAO's high clearance by the normal kidney relative to urea and 2) its smaller volume of distribution. Modelling suggests that only much more frequent dialysis would be required to lower levels Thus, additional strategies such as reducing production should be explored. Furthermore, using urea as the sole marker of dialysis adequacy may be misleading since a molecule, TMAO, that is dialyzed readily accumulates to much higher multiples of normal with urea based dialysis prescriptions.

  View details for DOI 10.1371/journal.pone.0143731

  View details for Web of Science ID 000366903300025

  View details for PubMedCentralID PMC4674074

• An Enlarged Profile of Uremic Solutes PLOS ONE Tanaka, H., Sirich, T. L., Plummer, N. S., Weaver, D. S., Meyer, T. W. 2015; 10 (8)

  Abstract

  Better knowledge of the uremic solutes that accumulate when the kidneys fail could lead to improved renal replacement therapy. This study employed the largest widely available metabolomic platform to identify such solutes. Plasma and plasma ultrafiltrate from 6 maintenance hemodialysis (HD) patients and 6 normal controls were first compared using a platform combining gas and liquid chromatography with mass spectrometry. Further studies compared plasma from 6 HD patients who had undergone total colectomy and 9 with intact colons. We identified 120 solutes as uremic including 48 that had not been previously reported to accumulate in renal failure. Combination of the 48 newly identified solutes with those identified in previous reports yielded an extended list of more than 270 uremic solutes. Among the solutes identified as uremic in the current study, 9 were shown to be colon-derived, including 6 not previously identified as such. Literature search revealed that many uremic phenyl and indole solutes, including most of those shown to be colon-derived, come from plant foods. Some of these compounds can be absorbed directly from plant foods and others are produced by colon microbial metabolism of plant polyphenols that escape digestion in the small intestine. A limitation of the metabolomic method was that it underestimated the elevation in concentration of uremic solutes which were measured using more quantitative assays.

  View details for DOI 10.1371/journal.pone.0135657

  View details for Web of Science ID 000360299100041

  View details for PubMedCentralID PMC4552739

• An Enlarged Profile of Uremic Solutes. PloS one Tanaka, H., Sirich, T. L., Plummer, N. S., Weaver, D. S., Meyer, T. W. 2015; 10 (8): e0135657

  Abstract

  Better knowledge of the uremic solutes that accumulate when the kidneys fail could lead to improved renal replacement therapy. This study employed the largest widely available metabolomic platform to identify such solutes. Plasma and plasma ultrafiltrate from 6 maintenance hemodialysis (HD) patients and 6 normal controls were first compared using a platform combining gas and liquid chromatography with mass spectrometry. Further studies compared plasma from 6 HD patients who had undergone total colectomy and 9 with intact colons. We identified 120 solutes as uremic including 48 that had not been previously reported to accumulate in renal failure. Combination of the 48 newly identified solutes with those identified in previous reports yielded an extended list of more than 270 uremic solutes. Among the solutes identified as uremic in the current study, 9 were shown to be colon-derived, including 6 not previously identified as such. Literature search revealed that many uremic phenyl and indole solutes, including most of those shown to be colon-derived, come from plant foods. Some of these compounds can be absorbed directly from plant foods and others are produced by colon microbial metabolism of plant polyphenols that escape digestion in the small intestine. A limitation of the metabolomic method was that it underestimated the elevation in concentration of uremic solutes which were measured using more quantitative assays.

  View details for DOI 10.1371/journal.pone.0135657

  View details for PubMedID 26317986

  View details for PubMedCentralID PMC4552739

• Free Levels of Selected Organic Solutes and Cardiovascular Morbidity and Mortality in Hemodialysis Patients: Results from the Retained Organic Solutes and Clinical Outcomes (ROSCO) Investigators PLOS ONE Shafi, T., Meyer, T. W., Hostetter, T. H., Melamed, M. L., Parekh, R. S., Hwang, S., Banerjee, T., Coresh, J., Powe, N. R. 2015; 10 (5): e0126048

  Abstract

  Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney - p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine - with outcomes in hemodialysis patients.We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA.Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17-2.25; p=0.004) and first cardiovascular event (1.60; 1.23-2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18-1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05-3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12-2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses.Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.

  View details for PubMedID 25938230

• Uremic Solutes Produced by Colon Microbes BLOOD PURIFICATION Tanaka, H., Sirich, T. L., Meyer, T. W. 2015; 40 (4): 306-311

  Abstract

  Colon microbes produce a large number of organic compounds that are foreign to mammalian cell metabolism.Some of the compounds made by microbes are absorbed in the colon and then normally excreted by the kidneys. Accumulation of these compounds in the plasma as uremic solutes may contribute to illness in patients whose kidneys have failed. Mass spectrometry is expanding our knowledge of the chemical identity of the colon-derived uremic solutes, and DNA sequencing technologies are providing new knowledge of the microbes and metabolic pathways by which they are made. Because they are made in an isolated compartment by microbes, their production may prove simpler to suppress than the production of other uremic solutes.To the extent that they are toxic, suppressing their production could improve the health of renal failure patients without the need for more intensive or prolonged dialysis.

  View details for DOI 10.1159/000441578

  View details for Web of Science ID 000366734700007

• The Uremic Syndrome CHRONIC RENAL DISEASE Dobre, M. A., Meyer, T. W., Hostetter, T. H., Kimmel, P. L., Rosenberg, M. E. 2015: 83–91

  View details for DOI 10.1016/B978-0-12-411602-3.00008-1

  View details for Web of Science ID 000351158600008

• Glomerular Effects of Age and APOL1. Journal of the American Society of Nephrology : JASN Meyer, T. W., Lenihan, C. R. 2015

  View details for PubMedID 26038527

• Approaches to Uremia JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Meyer, T. W., Hostetter, T. H. 2014; 25 (10): 2151-2158

  Abstract

  The development of dialysis was a dramatic step forward in medicine, allowing people who would soon have died because of lack of kidney function to remain alive for years. We have since found, however, that the "artificial kidney" does not live up fully to its name. Dialysis keeps patients alive but not well. Part of the residual illness that dialysis patients experience is caused by retained waste solutes that dialysis does not remove as well as native kidney function does. New means are available to identify these toxic solutes, about which we currently know remarkably little, and knowledge of these solutes would help us to improve therapy. This review summarizes our current knowledge of toxic solutes and highlights methods being explored to identify additional toxic solutes and to enhance the clearance of these solutes to improve patient outcomes.

  View details for DOI 10.1681/ASN.2013121264

  View details for Web of Science ID 000342403800005

  View details for PubMedID 24812163

  View details for PubMedCentralID PMC4178448

• Effect of Increasing Dietary Fiber on Plasma Levels of Colon-Derived Solutes in Hemodialysis Patients CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Sirich, T. L., Plummer, N. S., Gardner, C. D., Hostetter, T. H., Meyer, T. W. 2014; 9 (9): 1603-1610

  Abstract

  Numerous uremic solutes are derived from the action of colon microbes. Two such solutes, indoxyl sulfate and p-cresol sulfate, have been associated with adverse outcomes in renal failure. This study tested whether increasing dietary fiber in the form of resistant starch would lower the plasma levels of these solutes in patients on hemodialysis.Fifty-six patients on maintenance hemodialysis were randomly assigned to receive supplements containing resistant starch (n=28) or control starch (n=28) daily for 6 weeks in a study conducted between October 2010 and May 2013. Of these, 40 patients (20 in each group) completed the study and were included in the final analysis. Plasma indoxyl sulfate and p-cresol sulfate levels were measured at baseline and week 6.Increasing dietary fiber for 6 weeks significantly reduced the unbound, free plasma level of indoxyl sulfate (median -29% [25th percentile, 75th percentile, -56, -12] for fiber versus -0.4% [-20, 34] for control, P=0.02). The reduction in free plasma levels of indoxyl sulfate was accompanied by a reduction in free plasma levels of p-cresol sulfate (r=0.81, P<0.001). However, the reduction of p-cresol sulfate levels was of lesser magnitude and did not achieve significance (median -28% [-46, 5] for fiber versus 4% [-28, 36] for control, P=0.05).Increasing dietary fiber in hemodialysis patients may reduce the plasma levels of the colon-derived solutes indoxyl sulfate and possibly p-cresol sulfate without the need to intensify dialysis treatments. Further studies are required to determine whether such reduction provides clinical benefits.

  View details for DOI 10.2215/CJN.00490114

  View details for Web of Science ID 000341275200016

  View details for PubMedID 25147155

  View details for PubMedCentralID PMC4152802

• Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study KIDNEY INTERNATIONAL Niewczas, M. A., Sirich, T. L., Mathew, A. V., Skupien, J., Mohney, R. P., Warram, J. H., Smiles, A., Huang, X., Walker, W., Byun, J., Karoly, E. D., Kensicki, E. M., Berry, G. T., Bonventre, J. V., Pennathur, S., Meyer, T. W., Krolewski, A. S. 2014; 85 (5): 1214-1224

  Abstract

  Here we studied plasma metabolomic profiles as determinants of progression to end-stage renal disease (ESRD) in patients with type 2 diabetes (T2D). This nested case-control study evaluated 40 cases who progressed to ESRD during 8-12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics, although controls had slightly higher eGFR and lower levels of urinary albumin excretion than cases. Plasma metabolites at baseline were measured by mass spectrometry-based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid-derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR, or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D.

  View details for DOI 10.1038/ki.2013.497

  View details for Web of Science ID 000335713300030

  View details for PubMedID 24429397

  View details for PubMedCentralID PMC4072128

• FREE INDOXYL SULFATE (INDICAN) LEVELS ARE NOT ASSOCIATED WITH RESTLESS LEGS SYNDROME (RLS) IN HEMODIALYSIS (HD) PATIENTS Banerjee, T., Meyer, T., Shafi, T., Melamed, M., Hostetter, T., Parekh, R., Powe, N. W B SAUNDERS CO-ELSEVIER INC. 2014: A30

  View details for Web of Science ID 000335456600049

• Prominent Accumulation in Hemodialysis Patients of Solutes Normally Cleared by Tubular Secretion JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Sirich, T. L., Funk, B. A., Plummer, N. S., Hostetter, T. H., Meyer, T. W. 2014; 25 (3): 615-622

  Abstract

  Dialytic clearance of urea is efficient, but other small solutes normally secreted by the kidney may be cleared less efficiently. This study tested whether the high concentrations of these solutes in hemodialysis patients reflect a failure of passive diffusion methods to duplicate the efficacy of clearance by tubular secretion. We compared the plasma concentrations and clearance rates of four solutes normally cleared by tubular secretion with the plasma concentrations and clearance rates of urea and creatinine in patients receiving maintenance hemodialysis and normal subjects. The predialysis concentrations (relative to normal subjects) of unbound phenylacetylglutamine (122-fold), hippurate (108-fold), indoxyl sulfate (116-fold), and p-cresol sulfate (41-fold) were much greater than the concentrations of urea (5-fold) and creatinine (13-fold). The dialytic clearance rates (relative to normal subjects) of unbound phenylacetylglutamine (0.37-fold), hippurate (0.16-fold), indoxyl sulfate (0.21-fold), and p-cresol sulfate (0.39-fold) were much lower than the rates of urea (4.2-fold) and creatinine (1.3-fold). Mathematical modeling showed that prominent accumulation of the normally secreted solutes in hemodialysis patients could be accounted for by lower dialytic clearance relative to physiologic clearance combined with the intermittency of treatment. Whether or not more efficient removal of normally secreted solutes improves outcomes in dialysis patients remains to be tested.

  View details for DOI 10.1681/ASN.2013060597

  View details for Web of Science ID 000332150500021

  View details for PubMedID 24231664

  View details for PubMedCentralID PMC3935591

• Protein-Bound Molecules: A Large Family With a Bad Character SEMINARS IN NEPHROLOGY Sirich, T. L., Meyer, T. W., Gondouin, B., Brunet, P., Niwa, T. 2014; 34 (2): 106-117

  Abstract

  Many small solutes excreted by the kidney are bound to plasma proteins, chiefly albumin, in the circulation. The combination of protein binding and tubular secretion allows the kidney to reduce the free, unbound concentrations of such solutes to lower levels than could be obtained by tubular secretion alone. Protein-bound solutes accumulate in the plasma when the kidneys fail, and the free, unbound levels of these solutes increase more than their total plasma levels owing to competition for binding sites on plasma proteins. Given the efficiency by which the kidney can clear protein-bound solutes, it is tempting to speculate that some compounds in this class are important uremic toxins. Studies to date have focused largely on two specific protein-bound solutes: indoxyl sulfate and p-cresyl sulfate. The largest body of evidence suggests that both of these compounds contribute to cardiovascular disease, and that indoxyl sulfate contributes to the progression of chronic kidney disease. Other protein-bound solutes have been investigated to a much lesser extent, and could in the future prove to be even more important uremic toxins.

  View details for DOI 10.1016/j.semnephrol.2014.02.004

  View details for Web of Science ID 000336418200004

  View details for PubMedID 24780467

• Numerous protein-bound solutes are cleared by the kidney with high efficiency KIDNEY INTERNATIONAL Sirich, T. L., Aronov, P. A., Plummer, N. S., Hostetter, T. H., Meyer, T. W. 2013; 84 (3): 585-590

  Abstract

  The kidney clears numerous solutes from the plasma; however, retention of these solutes causes uremic illness when the kidneys fail. We know remarkably little about which retained solutes are toxic and this limits our ability to improve dialysis therapies. To explore this, we employed untargeted mass spectrometry to identify solutes that are efficiently cleared by the kidney. High-resolution mass spectrometry detected 1808 features in the urine and plasma ultrafiltrate of 5 individuals with normal renal function. The estimated clearance rates of 1082 peaks were greater than the creatinine clearance indicating tubular secretion. Further analysis identified 90 features representing solutes with estimated clearance rates greater than the renal plasma flow. Quantitative mass spectrometry with stable isotope dilution confirmed that efficient clearance of these solutes is made possible by the combination of binding to plasma proteins and tubular secretion. Tandem mass spectrometry established the chemical identity of 13 solutes including hippuric acid, indoxyl sulfate, and p-cresol sulfate. These 13 efficiently cleared solutes were found to accumulate in the plasma of hemodialysis patients, with free levels rising to more than 20-fold normal for all but two of them. Thus, further analysis of solutes efficiently cleared by secretion in the native kidney may provide a potential route to the identification of uremic toxins.Kidney International advance online publication, 1 May 2013; doi:10.1038/ki.2013.154.

  View details for DOI 10.1038/ki.2013.154

  View details for Web of Science ID 000323755300022

  View details for PubMedID 23636170

• Retained organic solutes, patient characteristics and all-cause and cardiovascular mortality in hemodialysis: results from the retained organic solutes and clinical outcomes (ROSCO) investigators BMC NEPHROLOGY Melamed, M. L., Plantinga, L., Shafi, T., Parekh, R., Meyer, T. W., Hostetter, T. H., Coresh, J., Powe, N. R. 2013; 14: 134

  Abstract

  Multiple solutes are retained in uremia, but it is currently unclear which solutes are toxic. Small studies suggest that protein-bound solutes, such as p-cresol sulfate and indoxyl sulfate and intracellular solutes, such as methylamine (MMA) and dimethylamine (DMA), may be toxic. Our objective was to test whether elevated levels of these solutes were associated with mortality.We conducted a prospective cohort study in 521 U.S. incident hemodialysis patients to evaluate associations between these solutes and all-cause and cardiovascular mortality. P-cresol sulfate, indoxyl sulfate, MMA and DMA levels were measured from frozen plasma samples obtained 2 to 6 months after initiation of dialysis. Mortality data was available through 2004 using the National Death Index.Elevated (greater than the population median) p-cresol sulfate, MMA or DMA levels were not associated with all-cause or cardiovascular mortality. Elevated indoxyl sulfate levels were associated with all-cause mortality but not cardiovascular mortality (hazard ratio 1.30 (95% confidence interval 1.01, 1.69) p-value 0.043).In this cohort of 521 incident hemodialysis patients, only elevated indoxyl sulfate levels were associated with all-cause mortality. Further research is needed to identify causes of the toxicity of uremia to provide better care for patients with kidney disease.

  View details for DOI 10.1186/1471-2369-14-134

  View details for Web of Science ID 000321126400002

  View details for PubMedID 23806101

  View details for PubMedCentralID PMC3698023

• Searching for Uremic Toxins CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Dobre, M., Meyer, T. W., Hostetter, T. H. 2013; 8 (2): 322-327

  Abstract

  Treatment of uremia by hemodialysis has become widespread over the last 40 years and has improved substantially over that time. However, people treated with this modality continue to suffer from multiple disabilities. Retention of organic solutes, especially those poorly removed by hemodialysis, likely contributes to these disabilities. Certain classes of solutes are removed less well than urea by hemodialysis and by the normal kidney. These include protein-bound solutes, relatively large solutes, sequestered compounds, and substances removed at rates higher than urea by the normal kidney. Several strategies could be used to discover the solutes responsible for residual morbidities in standardly dialyzed people. Rather than continue to focus only on urea removal as an index for dialysis adequacy, finding additional approaches for removing toxic solutes with characteristics different from urea (and the similar small solutes it represents) is a desirable and feasible goal.

  View details for DOI 10.2215/CJN.04260412

  View details for Web of Science ID 000314488800023

  View details for PubMedID 23024165

  View details for PubMedCentralID PMC3562857

• A Zebrafish Model for Uremic Toxicity: Role of the Complement Pathway BLOOD PURIFICATION Berman, N., Lectura, M., Thurman, J. M., Reinecke, J., Raff, A. C., Melamed, M. L., Quan, Z., Evans, T., Meyer, T. W., Hostetter, T. H. 2013; 35 (4): 265-269

  Abstract

  Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 ± 18 vs. 94 ± 6%, p < 0.05, uremic serum vs. control, respectively). Embryos exposed to serum from ESRD subjects fractionated at 50 kDa showed significantly greater toxicity with the larger molecular weight fraction (83 ± 11 vs. 7 ± 17% survival, p < 0.05, <50 vs. >50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 ± 5 vs. 28 ± 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 ± 6 vs. 3 ± 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement.

  View details for DOI 10.1159/000348456

  View details for Web of Science ID 000324018000003

  View details for PubMedID 23689420

• Competition for organic anion transporters in chronic renal disease Reply KIDNEY INTERNATIONAL Meyer, T. W., Hostetter, T. H. 2012; 82 (9): 1033

  View details for DOI 10.1038/ki.2012.291

  View details for Web of Science ID 000309981700014

• The Production of p-Cresol Sulfate and Indoxyl Sulfate in Vegetarians Versus Omnivores CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Patel, K. P., Luo, F. J., Plummer, N. S., Hostetter, T. H., Meyer, T. W. 2012; 7 (6): 982-988

  Abstract

  The uremic solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) are generated by colon bacteria acting on food components that escape absorption in the small bowel. The production of these potentially toxic compounds may thus be influenced by diet. This study examined whether production of PCS and IS is different in vegetarians and omnivores.The production of PCS and IS was assessed by measuring their urinary excretion rates in participants with normal kidney function. Studies were carried out in 15 vegetarians and 11 individuals consuming an unrestricted diet. Participants recorded food intake over 4 days and collected urine over the final 2 days of each of two study periods, which were 1 month apart.Average PCS excretion was 62% lower (95% confidence interval [95% CI], 15-83) and average IS excretion was 58% lower (95% CI, 39-71) in vegetarians than in participants consuming an unrestricted diet. Food records revealed that lower excretion of PCS and IS in vegetarians was associated with a 69% higher (95% CI, 20-139) fiber intake and a 25% lower (95% CI, 3-42) protein intake. PCS and IS excretion rates varied widely among individual participants and were not closely correlated with each other but tended to remain stable in individual participants over 1 month.PCS and IS production rates are markedly lower in vegetarians than in individuals consuming an unrestricted diet.

  View details for DOI 10.2215/CJN.12491211

  View details for Web of Science ID 000304975100016

  View details for PubMedID 22490877

  View details for PubMedCentralID PMC3362314

• Uremic solutes from colon microbes KIDNEY INTERNATIONAL Meyer, T. W., Hostetter, T. H. 2012; 81 (10): 949-954

  Abstract

  There is renewed interest in identifying organic waste solutes that are normally excreted by the kidneys and must be removed by renal replacement therapy when the kidneys fail. A large number of these waste solutes are produced by colon microbes. Mass spectrometry is expanding our knowledge of their chemical identity, and DNA sequencing technologies are providing new knowledge of the microbes and metabolic pathways by which they are made. There is evidence that the most extensively studied of the colon-derived solutes, indoxyl sulfate and p-cresol sulfate, are toxic. Much more study is required to establish the toxicity of other solutes in this class. Because they are made in an isolated compartment by microbes, their production may prove simpler to suppress than the production of other waste solutes. To the extent that they are toxic, suppressing their production could improve the health of renal failure patients without the need for more intensive or prolonged dialysis.

  View details for DOI 10.1038/ki.2011.504

  View details for Web of Science ID 000303543200005

  View details for PubMedID 22318422

• Selectively increasing the clearance of protein-bound uremic solutes NEPHROLOGY DIALYSIS TRANSPLANTATION Sirich, T. L., Luo, F. J., Plummer, N. S., Hostetter, T. H., Meyer, T. W. 2012; 27 (4): 1574-1579

  Abstract

  The toxicity of bound solutes could be better evaluated if we could adjust the clearance of such solutes independent of unbound solutes. This study assessed whether bound solute clearances can be increased while maintaining urea clearance constant during the extended hours of nocturnal dialysis.Nine patients on thrice-weekly nocturnal dialysis underwent two experimental dialysis treatments 1 week apart. The experimental treatments were designed to provide the same urea clearance while providing widely different bound solute clearance. One treatment employed a large dialyzer and high dialyzate flow rate (Qd) of 800 mL/min while blood flow (Qb) was 270 mL/min. The other treatment employed a smaller dialyzer and Qd of 300 mL/min while Qb was 350 mL/min.Treatment with the large dialyzer and higher Qd greatly increased the clearances of the bound solutes p-cresol sulfate (PCS: 27±9 versus 14±6 mL/min) and indoxyl sulfate (IS: 26±8 versus 14±5 mL/min) without altering the clearance of urea (204±20 versus 193±16 mL/min). Increasing PCS and IS clearances increased the removal of these solutes (PCS: 375±200 versus 207±86 mg/session; IS: 201±137 versus 153±74 mg/session), while urea removal was not different.The removal of bound solutes can thus be increased by raising the dialyzate flow and dialyzer size above the low levels sufficient to achieve target Kt/V(urea) during extended treatment. Selectively increasing the clearance of bound solutes provides a potential means to test their toxicity.

  View details for DOI 10.1093/ndt/gfr691

  View details for Web of Science ID 000302310700047

  View details for PubMedID 22231033

  View details for PubMedCentralID PMC3315673

• The Removal of Protein-Bound Solutes by Dialysis JOURNAL OF RENAL NUTRITION Meyer, T. W. 2012; 22 (1): 203-206

  Abstract

  Protein-bound solutes that accumulate in plasma when the kidneys fail are poorly cleared by conventional dialysis. Means have been developed to reduce the levels of such solutes, either by modifying the dialysis procedure to increase their clearance or by limiting their production. A trial testing whether reducing bound solute levels clinically benefits dialysis patients is required to determine whether these measures should be adopted in routine clinical practice.

  View details for DOI 10.1053/j.jrn.2011.10.011

  View details for Web of Science ID 000298638800039

  View details for PubMedID 22200443

• Dialysis Cannot be Dosed SEMINARS IN DIALYSIS Meyer, T. W., Sirich, T. L., Hostetter, T. H. 2011; 24 (5): 471-479

  Abstract

  Adequate dialysis is difficult to define because we have not identified the toxic solutes that contribute most to uremic illness. Dialysis prescriptions therefore cannot be adjusted to control the levels of these solutes. The current solution to this problem is to define an adequate dose of dialysis on the basis of fraction of urea removed from the body. This has provided a practical guide to treatment as the dialysis population has grown over the past 25 years. Indeed, a lower limit to Kt/V(urea) (or the related urea reduction ratio) is now established as a quality indicator by the Centers for Medicare and Medicaid for chronic hemodialysis patients in the United States. For the present, this urea-based standard provides a useful tool to avoid grossly inadequate dialysis. Dialysis dosing, however, based on measurement of a single, relatively nontoxic solute can provide only a very limited guide toward improved treatment. Prescriptions which have similar effects on the index solute can have widely different effects on other solutes. The dose concept discourages attempts to increase the removal of such solutes independent of the index solute. The dose concept further assumes that important solutes are produced at a constant rate relative to body size, and discourages attempts to augment dialysis treatment by reducing solute production. Identification of toxic solutes would provide a more rational basis for the prescription of dialysis and ultimately for improved treatment of patients with renal failure.

  View details for DOI 10.1111/j.1525-139X.2011.00979.x

  View details for Web of Science ID 000296025300001

  View details for PubMedID 21929590

• Colonic Contribution to Uremic Solutes JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Aronov, P. A., Luo, F. J., Plummer, N. S., Quan, Z., Holmes, S., Hostetter, T. H., Meyer, T. W. 2011; 22 (9): 1769-1776

  Abstract

  Microbes in the colon produce compounds, normally excreted by the kidneys, which are potential uremic toxins. Although p-cresol sulfate and indoxyl sulfate are well studied examples, few other compounds are known. Here, we compared plasma from hemodialysis patients with and without colons to identify and further characterize colon-derived uremic solutes. HPLC confirmed the colonic origin of p-cresol sulfate and indoxyl sulfate, but levels of hippurate, methylamine, and dimethylamine were not significantly lower in patients without colons. High-resolution mass spectrometry detected more than 1000 features in predialysis plasma samples. Hierarchical clustering based on these features clearly separated dialysis patients with and without colons. Compared with patients with colons, we identified more than 30 individual features in patients without colons that were either absent or present in lower concentration. Almost all of these features were more prominent in plasma from dialysis patients than normal subjects, suggesting that they represented uremic solutes. We used a panel of indole and phenyl standards to identify five colon-derived uremic solutes: α-phenylacetyl-l-glutamine, 5-hydroxyindole, indoxyl glucuronide, p-cresol sulfate, and indoxyl sulfate. However, compounds with accurate mass values matching most of the colon-derived solutes could not be found in standard metabolomic databases. These results suggest that colonic microbes may produce an important portion of uremic solutes, most of which remain unidentified.

  View details for DOI 10.1681/ASN.2010121220

  View details for Web of Science ID 000295705800024

  View details for PubMedID 21784895

  View details for PubMedCentralID PMC3171947

• Contribution of Residual Function to Removal of Protein-Bound Solutes in Hemodialysis CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Marquez, I. O., Tambra, S., Luo, F. Y., Li, Y., Plummer, N. S., Hostetter, T. H., Meyer, T. W. 2011; 6 (2): 290-296

  Abstract

  This study evaluated the contribution of residual function to the removal of solutes for which protein binding limits clearance by hemdialysis.Solute concentrations were measured in 25 hemodialysis patients with residual urea clearances ranging from 0.1 to 6.2 ml/min per 1.73 m2. Mathematical modeling assessed the effect of residual function on time-averaged solute concentrations.Dialytic clearances of the protein-bound solutes p-cresol sulfate, indoxyl sulfate, and hippurate were reduced in proportion to the avidity of binding and averaged 8±2, 10±3, and 44±13% of the dialytic urea clearance. For each bound solute, the residual clearance was larger in relation to the residual urea clearance. Residual kidney function therefore removed a larger portion of each of the bound solutes than of urea. Increasing residual function was associated with lower plasma levels of p-cresol sulfate and hippurate but not indoxyl sulfate. Wide variation in solute generation tended to obscure the dependence of plasma solute levels on residual function. Mathematical modeling that corrected for this variation indicated that increasing residual function will reduce the plasma level of each of the bound solutes more than the plasma level of urea.In comparison to urea, solutes than bind to plasma proteins can be more effectively cleared by residual function than by hemodialysis. Levels of such solutes will be lower in patients with residual function than in patients without residual function even if the dialysis dose is reduced based on measurement of residual urea clearance in accord with current guidelines.

  View details for DOI 10.2215/CJN.06100710

  View details for Web of Science ID 000287430800009

  View details for PubMedID 21030575

  View details for PubMedCentralID PMC3052218

• Indoxyl Sulfate: Long Suspected But Not Yet Proven Guilty CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Sirich, T., Meyer, T. W. 2011; 6 (1): 3-4

  View details for DOI 10.2215/CJN.10141110

  View details for Web of Science ID 000286452900002

  View details for PubMedID 21148244

• Reduction in Protein-Bound Solutes Unacceptable as Marker of Dialysis Efficacy during Alternate-Night Nocturnal Hemodialysis AMERICAN JOURNAL OF NEPHROLOGY Meijers, B., Toussaint, N. D., Meyer, T., Bammens, B., Verbeke, K., Vanrenterghem, Y., Kerr, P. G., Evenepoel, P. 2011; 34 (3): 226-232

  Abstract

  The uremic retention solutes indoxyl sulfate and p-cresyl sulfate are linked to cardiovascular disease and overall survival. Dialytic clearances are limited, which is principally attributed to tight protein binding. Extending dialysis duration would be expected to substantially increase protein-bound uremic solute removal. The aim of the current study was to study protein-bound uremic retention solute clearances and kinetics during longer-hours nocturnal hemodialysis.In a prospective cohort study of 32 maintenance alternate-night nocturnal hemodialysis patients, we followed serum concentrations, solute removals and solute clearances of p-cresyl sulfate and indoxyl sulfate. Spent dialysate sampling was fractionated to compare solute removals between the first 4 h and next 4 h of nocturnal dialysis. Single-compartment variable volume kinetics were calculated.Dialytic clearances of protein-bound uremic retention solutes are maintained during nocturnal (longer-hours) dialysis. Clearances of indoxyl sulfate exceed those of p-cresyl sulfate, presumably due to less tight protein-binding. Apparent distribution volumes increase substantially during nocturnal dialysis, indicative of multi-compartmental behavior of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate.During nocturnal hemodialysis, serum concentrations of protein-bound solute concentrations are reduced less than predicted. Reduction ratios are not a valid tool to estimate total solute removal of protein-bound uremic retention solutes.

  View details for DOI 10.1159/000330176

  View details for Web of Science ID 000293838000005

  View details for PubMedID 21791919

• Anemia Therapy in ESRD: Time to Move On CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Folkert, V. W., Meyer, T. W., Hostetter, T. H. 2010; 5 (7): 1163–64

  View details for DOI 10.2215/CJN.03680410

  View details for Web of Science ID 000279752700002

  View details for PubMedID 20538832

• Methylamine clearance by haemodialysis is low NEPHROLOGY DIALYSIS TRANSPLANTATION Ponda, M. P., Quan, Z., Melamed, M. L., Raff, A., Meyer, T. W., Hostetter, T. H. 2010; 25 (5): 1608-1613

  Abstract

  Dialysis adequacy is currently judged by measures of urea clearance. However, urea is relatively non-toxic and has properties distinct from large classes of other retained solutes. In particular, intracellularly sequestered solutes are likely to behave differently than urea.We studied an example of this class, the aliphatic amine monomethylamine (MMA), in stable haemodialysis outpatients (n = 10) using an HPLC-based assay.Mean MMA levels pre-dialysis in end-stage renal disease subjects were 76 +/- 15 microg/L compared to 32 +/- 4 microg/L in normal subjects (n = 10) (P < 0.001). Mean urea reduction was 62% while the reduction ratio for MMA was 43% (P < 0.01). MMA levels rebounded in the 1 hour post-dialytic period to 85% of baseline, whereas urea levels rebounded only to 47% of baseline. MMA had a much larger calculated volume of distribution compared to urea, consistent with intracellular sequestration. Measures of intra-red blood cell (RBC) MMA concentrations confirmed greater levels in RBCs than in plasma with a ratio of 4.9:1. Because of the intracellular sequestration of MMA, we calculated its clearance using that amount removed from whole blood. Clearances for urea averaged 222 +/- 41 ml/min and for MMA 121 +/- 14 ml/min, while plasma clearance for creatinine was 162 +/- 20 ml/min (P < 0.01, for all differences). Using in vitro dialysis, in the absence of RBCs, solute clearance rates were similar: 333 +/- 6, 313 +/- 8 and 326 +/- 4 ml/min for urea, creatinine and MMA, respectively. These findings suggest that the lower MMA clearance relative to creatinine in vivo is a result of MMA movement into RBCs within the dialyser blood path diminishing its removal by dialysis.In conclusion, we find that, in conventional haemodialysis, MMA is not cleared as efficiently as urea or creatinine and raise the possibility that RBCs may limit its dialysis not merely by failing to discharge it, but by further sequestering it as blood passes through the dialyser.

  View details for DOI 10.1093/ndt/gfp629

  View details for Web of Science ID 000276994400043

  View details for PubMedID 20019016

  View details for PubMedCentralID PMC2910329

• LOWER GENERATION OF UREMIC SOLUTES P-CRESOL SULFATE AND INDOXYL SULFATE WITH A VEGETARIAN DIET Spring Clinical Meeting of the National-Kidney-Foundation Luo, F., Patel, K., Plummer, N., Steinberg, L., Hostetter, T., Meyer, T. W B SAUNDERS CO-ELSEVIER INC. 2010: A76–A76

  View details for Web of Science ID 000276054500203

• Derivatization of Methylamine and Ethylamine Followed by LC and Fluorescence Detection for Measurement of Urinary Clearance CHROMATOGRAPHIA Quan, Z., Ponda, M., Melamed, M., Raff, A., Berman, N., Scherer, J., Bitzer, M., Meyer, T., Hostetter, T. 2010; 71 (5-6): 411-418

  View details for DOI 10.1365/s10337-009-1464-6

  View details for Web of Science ID 000275787900008

• Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Gurley, S. B., Mach, C. L., Stegbauer, J., Yang, J., Snow, K. P., Hu, A., Meyer, T. W., Coffman, T. M. 2010; 298 (3): F788–F795

  Abstract

  Previous studies have shown that Akita mice bearing the Ins2(+/C96Y) mutation have significant advantages as a type I diabetes platform for developing models of diabetic nephropathy (DN; Gurley SB, Clare SE, Snow KP, Hu A, Meyer TW, Coffman TM. Am J Physiol Renal Physiol 290: F214-F222, 2006). In view of the critical role for genetic factors in determining susceptibility to DN in humans, we investigated the role of genetic background on kidney injury in Akita mice. To generate a series of inbred Akita mouse lines, we back-crossed the Ins2(C96Y) mutation more than six generations onto the 129/SvEv and DBA/2 backgrounds and compared the extent of hyperglycemia and renal disease with the standard C57BL/6-Ins2(+/C96Y) line. Male mice from all three Akita strains developed marked and equivalent hyperglycemia. However, there were significant differences in the level of albuminuria among the lines with a hierarchy of DBA/2 > 129/SvEv > C57BL/6. Renal and glomerular hypertrophy was seen in all of the lines, but significant increases in mesangial matrix compared with baseline nondiabetic controls were observed only in the 129 and C57BL/6 backgrounds. In F1(DBA/2 x C57BL/6)-Ins2(+/C96Y) mice, the extent of albuminuria was similar to the parental DBA/2-Ins2(+/C96Y) line; they also developed marked hyperfiltration. These studies identify strong effects of genetic background to modify the renal phenotype associated with the Ins2(C96Y) mutation. Identification of these naturally occurring strain differences should prove useful for nephropathy modeling and may be exploited to allow identification of novel susceptibility alleles for albuminuria in diabetes.

  View details for DOI 10.1152/ajprenal.90515.2008

  View details for Web of Science ID 000275856000033

  View details for PubMedID 20042456

  View details for PubMedCentralID PMC2838602

• Chronic Kidney Disease and Cognitive Function in Older Adults: Findings from the Chronic Renal Insufficiency Cohort Cognitive Study JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Yaffe, K., Ackerson, L., Tamura, M. K., Le Blanc, P., Kusek, J. W., Sehgal, A. R., Cohen, D., Anderson, C., Appel, L., DeSalvo, K., Ojo, A., Seliger, S., Robinson, N., Makos, G., Go, A. S. 2010; 58 (2): 338-345

  Abstract

  To investigate cognitive impairment in older, ethnically diverse individuals with a broad range of kidney function, to evaluate a spectrum of cognitive domains, and to determine whether the relationship between chronic kidney disease (CKD) and cognitive function is independent of demographic and clinical factors.Cross-sectional.Chronic Renal Insufficiency Cohort Study.Eight hundred twenty-five adults aged 55 and older with CKD.Estimated glomerular filtration rate (eGFR, mL/min per 1.73 m(2)) was estimated using the four-variable Modification of Diet in Renal Disease equation. Cognitive scores on six cognitive tests were compared across eGFR strata using linear regression; multivariable logistic regression was used to examine level of CKD and clinically significant cognitive impairment (score < or =1 standard deviations from the mean).Mean age of the participants was 64.9, 50.4% were male, and 44.5% were black. After multivariable adjustment, participants with lower eGFR had lower cognitive scores on most cognitive domains (P<.05). In addition, participants with advanced CKD (eGFR<30) were more likely to have clinically significant cognitive impairment on global cognition (adjusted odds ratio (AOR) 2.0, 95% CI=1.1-3.9), naming (AOR=1.9, 95% CI=1.0-3.3), attention (AOR=2.4, 95% CI=1.3-4.5), executive function (AOR=2.5, 95% CI=1.9-4.4), and delayed memory (AOR=1.5, 95% CI=0.9-2.6) but not on category fluency (AOR=1.1, 95% CI=0.6-2.0) than those with mild to moderate CKD (eGFR 45-59).In older adults with CKD, lower level of kidney function was associated with lower cognitive function on most domains. These results suggest that older patients with advanced CKD should be screened for cognitive impairment.

  View details for DOI 10.1111/j.1532-5415.2009.02670.x

  View details for Web of Science ID 000274183800017

  View details for PubMedID 20374407

  View details for PubMedCentralID PMC2852884

• p-Cresol Sulfate: Further Understanding of Its Cardiovascular Disease Potential in CKD AMERICAN JOURNAL OF KIDNEY DISEASES Winchester, J. F., Hostetter, T. H., Meyer, T. W. 2009; 54 (5): 792–94

  View details for DOI 10.1053/j.ajkd.2009.06.019

  View details for Web of Science ID 000271485000005

  View details for PubMedID 19853197

• A MULTICENTER RCT OF DECEASED ORGAN DONOR PRE-TREATMENT WITH CORTICOSTEROIDS: RISK FACTORS FOR ARF IN STEROID PRE-TREADED DONORS Wilflingseder, J., Kainz, A., Mitterbauer, C., Gyoeri, G., Perco, P., Meyer, T., Mayer, B., Langer, R., Oberbauer, R. WILEY-BLACKWELL. 2009: 181

  View details for Web of Science ID 000269392800686

• Effect of Increasing Dialyzer Mass Transfer Area Coefficient and Dialysate Flow on Clearance of Protein-Bound Solutes: A Pilot Crossover Trial AMERICAN JOURNAL OF KIDNEY DISEASES Luo, F. J., Patel, K. P., Marquez, I. O., Plummer, N. S., Hostetter, T. H., Meyer, T. W. 2009; 53 (6): 1042-1049

  Abstract

  Protein-bound solutes are poorly cleared by means of conventional hemodialysis because protein binding limits the "free" solute concentration driving diffusion. This study tested the modeled prediction that clearances of bound solutes could be increased by increasing the dialyzer mass transfer area coefficient (K(o)A) and dialysate flow (Q(d)) to greater than the levels used in conventional practice.Pilot crossover trial.6 stable long-term hemodialysis patients.Study participants underwent an experimental dialysis treatment in which K(o)A and Q(d) were increased by using 2 dialyzers in series and supplying each dialyzer with a Q(d) of 800 mL/min by using 2 dialysis machines. Experimental clearances were compared with those during a conventional treatment with a single dialyzer and Q(d) of 800 mL/min supplied by 1 machine.Measured clearances of uremic solutes.Clearances were measured for urea nitrogen and the bound solutes p-cresol sulfate, indoxyl sulfate, kynurenic acid, and hippurate.Clearances for the bound solutes during conventional treatment were lower than for urea nitrogen (clearance values: urea nitrogen, 255 +/- 16 mL/min; p-cresol sulfate, 23 +/- 4 mL/min; indoxyl sulfate, 30 +/- 7 mL/min; kynurenic acid, 43 +/- 4 mL/min; and hippurate, 115 +/- 11 mL/min). Experimental treatment increased clearances of all solutes (clearance values: urea nitrogen, 318 +/- 19 mL/min; p-cresol sulfate, 37 +/- 6 mL/min; indoxyl sulfate, 46 +/- 8 mL/min; kynurenic acid, 73 +/- 7 mL/min; and hippurate, 165 +/- 17 mL/min). The magnitude of the increases in clearance was greater for bound solutes than for urea nitrogen (increase in clearance: urea nitrogen, 25% +/- 6%; p-cresol sulfate, 66% +/- 19%; indoxyl sulfate, 57% +/- 27%; kynurenic acid, 69% +/- 5%; and hippurate, 44% +/- 15%).A longer term study would be required to determine whether increased dialytic clearance of bound solutes leads to a decrease in plasma solute levels.Dialytic clearance of protein-bound solutes can be increased by increasing K(o)A and Q(d) to greater than conventional levels.

  View details for DOI 10.1053/j.ajkd.2009.01.265

  View details for Web of Science ID 000266866600019

  View details for PubMedID 19394728

• Sodium octanoate to reverse indoxyl sulfate and p-cresyl sulfate albumin binding in uremic and normal serum during sample preparation followed by fluorescence liquid chromatography JOURNAL OF CHROMATOGRAPHY A de Loor, H., Meijers, B. K., Meyer, T. W., Bammens, B., Verbeke, K., Dehaen, W., Evenepoel, P. 2009; 1216 (22): 4684-4688

  Abstract

  Indoxyl sulfate and p-cresyl sulfate are protein-bound marker molecules in chronic kidney disease. Recent findings suggest that indoxyl sulfate and p-cresyl sulfate directly contribute to the uremic syndrome. A method for quantification of p-cresyl sulfate and indoxyl sulfate total serum concentrations was developed. We used sodium octanoate as competitor to replace non-covalent binding of p-cresyl sulfate and indoxyl sulfate to albumin. Total, within-run, between-run and between-day imprecision for indoxyl sulfate and p-cresyl sulfate were all below 6%. The limit of quantification was 3.2microM for both analytes. Recovery, tested in hemodialysis patients, was 102% for indoxyl sulfate and 105% for p-cresyl sulfate. Deming regression demonstrated good agreement for indoxyl sulfate between this new method and an external HPLC method. Method comparison for p-cresyl sulfate of the new method with our in-house GC-MS method demonstrated good agreement, whereas method comparison with an external HPLC method revealed a small proportional bias. Sodium octanoate binding competition is a novel sample preparation that allows for direct quantification of indoxyl sulfate and p-cresyl sulfate.

  View details for DOI 10.1016/j.chroma.2009.04.015

  View details for Web of Science ID 000266307900009

  View details for PubMedID 19394619

• New insights into uremic toxicity CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION Raff, A. C., Meyer, T. W., Hostetter, T. H. 2008; 17 (6): 560-565

  Abstract

  Our concept of uremia has expanded to encompass the illness patients begin to suffer as glomerular filtration rate declines long before the onset of end-stage renal disease (ESRD) not explained by known derangements in volume status or metabolic parameters. New insights into the accumulation of uremic toxins and the loss of function of hormones and enzymes provide important information on the etiology of uremia.New data are accumulating on the identity and toxicity of uremic toxins and the syndromes that encompass uremia. rho-Cresol sulfate and indoxyl sulfate are small, protein-bound molecules that are poorly cleared with dialysis. These molecules have been linked to cardiovascular disease and oxidative injury. Impaired immunity plays a central role in the morbidity of ESRD and may be both the result of uremic toxicity and a contributor to oxidative stress in ESRD. Uremic cachexia is an underrecognized uremic syndrome. New insights into disordered feeding circuits in ESRD may lead to novel therapies using hormone agonists.Mortality in ESRD remains unacceptably high. It is hoped that as knowledge emerges on the causes and consequences of uremia, we are embarking on an era not only of new insights but also new and effective treatments for patients with the ill effects of uremia.

  View details for DOI 10.1097/MNH.0b013e32830f45b6

  View details for Web of Science ID 000260818600002

  View details for PubMedID 18941347

• Coated carbon hemoperfusion provides limited clearance of protein-bound solutes ARTIFICIAL ORGANS Dinh, D. C., Recht, N. S., Hostetter, T. H., Meyer, T. W. 2008; 32 (9): 717-724

  Abstract

  This study assessed the capacity of a cartridge containing coated granular carbon to clear protein-bound solutes. Clearances for test solutes were measured while an albumin solution representing plasma was pumped from a 10 L reservoir through the cartridge at a rate of 200 mL/min for 5 h. Clearance values for phenol red, phenytoin, and indican were well below the limit imposed by the plasma flow and declined with time. The clearance of phenol red, which was the most tightly bound solute, fell from 38 +/- 12 to 17 +/- 2 mL/min. Additional studies revealed that the cartridge contained enough carbon to absorb all the protein-bound test solutes, but that the rate of their clearance was limited by the inability of granular carbon to take up solutes rapidly at a low concentration. The rate of solute uptake at low concentration was shown to be much greater when carbon was in powdered rather than granular form. A device in which approximately 50 g of powdered carbon was recirculated in the dialysate compartment of hollow fiber kidneys cleared phenol red and phenytoin more rapidly than the hemoperfusion cartridge containing 300 g of coated granular carbon. These results indicate that hemoperfusion over coated granular carbon provides limited clearance of protein-bound solutes.

  View details for DOI 10.1111/j.1525-1594.2008.00594.x

  View details for Web of Science ID 000259270100007

  View details for PubMedID 18684207

• Relationship of impaired olfactory function in ESRD to malnutrition and retained uremic molecules 40th Annual Meeting of the American-Society-of-Nephrology/Annual Renal Week Raff, A. C., Lieu, S., Melamed, M. L., Quan, Z., Ponda, M., Meyer, T. W., Hostetter, T. H. W B SAUNDERS CO-ELSEVIER INC. 2008: 102–10

  Abstract

  Olfactory function is impaired in patients with end-stage renal disease (ESRD) and may contribute to uremic anorexia. Only limited correlations of olfactory function and nutritional status were reported. This study examines the relationship of impaired olfactory function to malnutrition and levels of the retained uremic solutes monomethylamine, ethylamine, indoxyl sulfate, and P-cresol sulfate.Cross-sectional observational study.31 stable maintenance hemodialysis patients from an urban outpatient dialysis unit and 18 people with normal renal function participated.Nutritional status assigned by using Subjective Global Assessment (SGA) score; SGA score of 7 indicates normal nutritional status; SGA score of 5 to 6, mild malnutrition; and SGA score of 3 to 4, moderate malnutrition.The primary outcome is olfactory function, assessed using the University of Pennsylvania Smell Identification Test. Levels of retained uremic solutes were measured from a predialysis serum sample. Demographic data and laboratory values for nutritional status, adequacy of dialysis, and inflammation were collected.Mean smell scores were 34.9 +/- 1.4 for controls, 33.5 +/- 3.3 for patients with SGA score of 7, 28.3 +/- 5.8 for patients with SGA score of 5 to 6, and 27.9 +/- 4.4 for patients with SGA score of 3 to 4 (P < 0.001 comparing healthy patients with all patients with ESRD). There was no difference in mean smell scores for healthy controls and patients with SGA score of 7. However, patients with lower smell scores had significantly lower SGA scores (P = 0.02) and higher C-reactive protein levels (P = 0.02). Neither smell score nor nutritional status was associated with levels of retained uremic solutes.Small sample size, only cross-sectional associations can be described.Our results suggest an association between poor nutritional status and impaired olfactory function in patients with ESRD. Additional research is needed to discover the uremic toxins mediating these processes.

  View details for DOI 10.1053/j.ajkd.2008.02.301

  View details for Web of Science ID 000257886600014

  View details for PubMedID 18423810

  View details for PubMedCentralID PMC2712939

• Increasing the clearance of protein-bound solutes by increasing dialyzer mass transfer area coefficient (K(o)A) and dialysate flow (Q(d)) Spring Clinical Meeting of the National-Kidney-Foundation Lao, F., Patel, K., Recht, N., Meyer, T. W B SAUNDERS CO-ELSEVIER INC. 2008: A64–A64

  View details for Web of Science ID 000254874400175

• Uremia - Reply NEW ENGLAND JOURNAL OF MEDICINE Meyer, T. W., Hostetter, T. H. 2008; 358 (1): 95

  View details for Web of Science ID 000252031200030

• Removal of the protein-bound solutes indican and p-cresol sulfate by peritoneal dialysis CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Pham, N. M., Recht, N. S., Hostetter, T. H., Meyer, T. W. 2008; 3 (1): 85-90

  Abstract

  Protein-bound solutes are poorly cleared by peritoneal dialysis. We examined the hypothesis that plasma concentrations of bound solutes would therefore rise as residual renal function is lost.Clearances of urea indican and p-cresol sulfate were measured in peritoneal dialysis patients with and without residual function.In patients with residual function, protein binding restricted the peritoneal indican and p-cresol sulfate clearances to 0.3 +/- 0.1 ml/min, as compared to the peritoneal urea clearance of 5.5 +/- 1.1 ml/min. The urinary indican and p-cresol sulfate clearances of 2.7 +/- 2.5 and 1.3 +/- 1.0 ml/min were closer to the urinary urea clearance of 3.9 +/- 2.2 ml/min, reflecting the superior ability of native kidney function to clear bound solutes. Urinary clearance thus provided the majority of the total indican and p-cresol sulfate clearances of 3.0 +/- 2.5 and 1.6 +/- 1.0 ml/min in patients with residual function but the minority of total urea clearance of 9.4 +/- 2.2 ml/min. Loss of residual function lowered the total clearances for indican and p-cresol sulfate to 0.5 +/- 0.2 and 0.4 +/- 0.2 ml/min, whereas the urea clearance fell only slightly. However there was only a modest increase in the plasma indican level and no increase in the plasma p-cresol sulfate level in patients with no residual function because reduction in the daily removal of these solutes accompanied the reduction in their total clearance rates.Reduction in the removal of indican and p-cresol sulfate kept plasma levels from rising markedly when residual function was lost.

  View details for DOI 10.2215/CJN.02570607

  View details for Web of Science ID 000252293000012

  View details for PubMedID 18045861

  View details for PubMedCentralID PMC2390983

• Uremia NEW ENGLAND JOURNAL OF MEDICINE Meyer, T. W., Hostetter, T. H. 2007; 357 (13): 1316-1325

  View details for Web of Science ID 000249711500008

  View details for PubMedID 17898101

• Increasing the clearance of protein-bound solutes by addition of a sorbent to the dialysate JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Meyer, T. W., Peattie, J. W., Miller, J. D., Dinh, D. C., Recht, N. S., Walther, J. L., Hostetter, T. H. 2007; 18 (3): 868-874

  Abstract

  The capacity of sorbent systems to increase solute clearances above the levels that are provided by hemodialysis has not been well defined. This study assessed the extent to which solute clearances can be increased by addition of a sorbent to the dialysate. Attention was focused on the clearance of protein-bound solutes, which are cleared poorly by conventional hemodialysis. A reservoir that contained test solutes and artificial plasma was dialyzed first with the plasma flow set at 46 +/- 3 ml/min and the dialysate flow (Q(d)) set at 42 +/- 3 ml/min using a hollow fiber kidney with mass transfer area coefficients greater than Q(d) for each of the solutes. Under these conditions, the clearance of urea (Cl(urea)) was 34 +/- 1 ml/min, whereas the clearances of the protein-bound solutes indican (Cl(ind)), p-cresol sulfate (Cl(pcs)), and p-cresol (Cl(pc)) averaged only 5 +/- 1, 4 +/- 1, and 14 +/- 1 ml/min, respectively The effect of addition of activated charcoal to the dialysate then was compared with the effect of increasing Q(d) without addition of any sorbent. Addition of charcoal increased Cl(ind), Cl(pcs), and Cl(pc) to 12 +/- 1, 9 +/- 2, and 35 +/- 4 ml/min without changing Cl(urea). Increasing Q(d) without the addition of sorbent had a similar effect on the clearance of the protein-bound solutes. Mathematical modeling predicted these changes and showed that the maximal effect of addition of a sorbent to the dialysate is equivalent to that of an unlimited increase in Q(d). These results suggest that as an adjunct to conventional hemodialysis, addition of sorbents to the dialysate could increase the clearance of protein-bound solutes without greatly altering the clearance of unbound solutes.

  View details for DOI 10.1681/ASN.2006080863

  View details for Web of Science ID 000245873400025

  View details for PubMedID 17251385

• More work to do on renin-angiotensin system blockade CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Lit, Y. Z., Meyer, T. W. 2006; 1 (4): 611–13

  View details for DOI 10.2215/CJN.01670506

  View details for Web of Science ID 000242241700002

  View details for PubMedID 17699265

• Transcriptome analysis of human renal tubule cells indicates significant alterations between proteinuric nephropathies and healthy controls at early stages of kidney disease Rudnicki, M., Eder, S., Perco, P., Enrich, J., Scheiber, K., Koppelstaetter, C., Schratzberger, G., Mayer, B., Oberbauer, R., Meyer, T., Mayer, G. OXFORD UNIV PRESS. 2006: 12

  View details for Web of Science ID 000239919000027

• Managing diabetic nephropathy: recent studies CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION Lit, Y. M., Meyer, T. 2006; 15 (2): 111-116

  Abstract

  This review summarizes recent studies designed to identify improved treatments for diabetic nephropathy.Recent data support the concept that angiotensin converting enzyme inhibitors and angiotensin II receptor blockers have similar renoprotective effects. Aggressive blockade of the renin-angiotensin system appears to have benefits beyond those achieved with conventional doses of single agents. Dual blockade using angiotensin converting enzyme inhibitors and angiotensin II receptor blockers is effective. Aldosterone receptor antagonists may potentiate the effect of these two classes of compounds. It remains unclear, however, whether maximum benefit can be obtained by the combination of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers or aldosterone receptor antagonists as compared to larger doses of single agents. Not enough data are available currently to recommend thiazolidinedione hypoglycemic agents for renal protection. Trials are being conducted with several new classes of agents.Evidence from short-term studies favors aggressive blockade of the renin-angiotensin system. Long-term studies, however, remain to be performed. A multifactorial approach that incorporates established interventions affords our best means to retard the progression of diabetic nephropathy.

  View details for Web of Science ID 000236403100003

  View details for PubMedID 16481875

• Downloadable computer models for renal replacement therapy KIDNEY INTERNATIONAL Walther, J. L., Bartlett, D. W., Chew, W., Robertson, C. R., Hostetter, T. H., Meyer, T. W. 2006; 69 (6): 1056-1063

  Abstract

  Mathematical models can predict solute clearances and solute concentrations during renal replacement therapy. At present, however, most nephrologists cannot use these models because they require mathematical software. In this report, we describe models of solute transport by convection and diffusion adapted to run on the commonly available software program Excel for Macintosh computers and PCs running Windows. Two programs have been created that can be downloaded from http://www.stanford.edu/~twmeyer/ or http://dev.satellitehealth.com/research/journal.asp. The first, called 'Dr Addis Clearance Calculator', calculates clearance values from inputs including the blood flow Q(b), the hematocrit, the ultrafiltration rate Q(f), the dialysate flow rate Q(d), the reflection coefficient sigma and the mass transfer area coefficient K(o)A for the solute of interest, and the free fraction f if the solute is protein bound. Solute concentration profiles along the length of the artificial kidney are displayed graphically. The second program, called 'Dr Coplon Dialysis Simulator', calculates plasma solute concentrations from the clearance values obtained by the first program and from additional input values including the number of treatments per week, the duration of the treatments, and the solute's production rate and volumes of distribution. The program calculates the time-averaged solute concentration and provides a graphic display of the solute concentration profile through a week-long interval.

  View details for DOI 10.1038/sj.ki.5000196

  View details for Web of Science ID 000236340100020

  View details for PubMedID 16528255

• Impact of genetic background on nephropathy in diabetic mice AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Gurley, S. B., Clare, S. E., Snow, K. P., Hu, A., Meyer, T. W., Coffman, T. M. 2006; 290 (1): F214-F222

  Abstract

  With the goal of identifying optimal platforms for developing better models of diabetic nephropathy in mice, we compared renal effects of streptozotocin (STZ)-induced diabetes among five common inbred mouse strains (C57BL/6, MRL/Mp, BALB/c, DBA/2, and 129/SvEv). We also evaluated the renal consequences of chemical and genetic diabetes on the same genetic background (C57BL/6). There was a hierarchical response of blood glucose level to the STZ regimen among the strains (DBA/2 > C57BL/6 > MRL/MP > 129/SvEv > BALB/c). In all five strains, males demonstrated much more robust hyperglycemia with STZ than females. STZ-induced diabetes was associated with modest levels of albuminuria in all of the strains but was greatest in the DBA/2 strain, which also had the most marked hyperglycemia. Renal structural changes on light microscopy were limited to the development of mesangial expansion, and, while there were some apparent differences among strains in susceptibility to renal pathological changes, there was a significant positive correlation between blood glucose and the degree of mesangial expansion, suggesting that most of the variability in renal pathological abnormalities was because of differences in hyperglycemia. Although the general character of renal involvement was similar between chemical and genetic diabetes, Akita mice developed more marked hyperglycemia, elevated blood pressures, and less variability in renal structural responses. Thus, among the strains and models tested, the DBA/2 genetic background and the Akita (Ins2(+/C96Y)) model may be the most useful platforms for model development.

  View details for DOI 10.1152/ajprenal.00204.2005

  View details for Web of Science ID 000233850500024

  View details for PubMedID 16118394

• Transcriptional response in the unaffected kidney after contralateral hydronephrosis or nephrectomy KIDNEY INTERNATIONAL Hauser, P., Kainz, A., Perco, P., Bergmeister, H., Mitterbauer, C., Schwarz, C., Regele, H. M., Mayer, B., Meyer, T. W., Oberbauer, R. 2005; 68 (6): 2497–2507

  Abstract

  Unilateral loss of kidney function is followed by compensatory contralateral growth. The early, genome-wide transcriptional response of the untouched kidney to unilateral ureteral obstruction (UUO) or unilateral nephrectomy is unknown.Twelve adult male Sprague-Dawley rats were subjected to UUO and twelve rats to unilateral nephrectomy. At time points 12, 24, and 72 hours after insult four rats each were sacrificed and the contralateral kidney harvested for genome-wide gene expression analysis, transcription factor analysis, and histomorphology.Microarray studies revealed that the majority of differentially expressed transcripts were suppressed in UUO and unilateral nephrectomy compared to control kidneys. The function of these suppressed genes is predominantly growth inhibition and apoptosis suggesting a net pro-hypertrophic response. Insulin-like growth factor-2 (IGF-2)-binding protein was one of the few activated genes. We observed a distinctly different molecular signature between UUO and unilateral nephrectomy at the three time points investigated. The early response in UUO rats suggests a counterbalance to the nonfiltering kidney by activation of transport pathways such as the aquaporins. Unilateral nephrectomy kidneys, on the other hand, respond immediately to contralateral nephrectomy by activation of cell cycle regulators such as the cyclin family. Several genes with weakly defined function were found to be associated with either UUO or unilateral nephrectomy. Transcription factor analysis of the identified transcripts suggests common regulation at least of some of these genes. All kidneys showed normal histology.Release of growth inhibition by nephrectomy leads to immediate cell cycle activation after unilateral nephrectomy, whereas UUO kidneys counterbalance filtration failure by activation of several transporters.

  View details for DOI 10.1111/j.1523-1755.2005.00725.x

  View details for Web of Science ID 000233204300006

  View details for PubMedID 16316326

• Removal of p-cresol sulfate by hemodialysis JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Martinez, A. W., Recht, N. S., Hostetter, T. H., Meyer, T. W. 2005; 16 (11): 3430-3436

  Abstract

  Protein-bound solutes are poorly cleared by dialysis. Among the most extensively studied of these solutes is p-cresol, which has been shown to be toxic in vitro. This study examined the form in which p-cresol circulates and quantified its removal by hemodialysis. HPLC analysis of plasma from hemodialysis patients contained a peak whose mobility corresponded to synthetic p-cresol sulfate (PCS) but no detectable unconjugated p-cresol. Treatment with sulfatase resulted in recovery of this peak as p-cresol, confirming its identity. Subsequent studies compared the removal of PCS and another protein-bound solute, indican, to the removal of urea during clinical hemodialysis treatments. PCS and indican were 94 +/- 1% and 93 +/- 2% bound to plasma protein, respectively. Protein-binding caused a predictable decrease in measured dialytic clearance, which averaged 20 +/- 4 ml/min for PCS and 25 +/- 5 ml/min for indican as compared with 260 +/- 20 ml/min for urea. Volumes of distribution for the protein-bound solutes were greater than the plasma volume, averaging 15 +/- 7 L for PCS and 14 +/- 3 L for indican as compared with 37 +/- 7 for urea. Solute reduction ratios were 20 +/- 9% for PCS, 30 +/- 7% for indican, and 69 +/- 5% for urea. We conclude that p-cresol circulates in the form of its sulfate conjugate, PCS. PCS is poorly removed by hemodialysis because its clearance is limited by protein binding and the ratio of its volume of distribution to its clearance is high.

  View details for DOI 10.1681/ASN.2005030310

  View details for Web of Science ID 000232847800034

  View details for PubMedID 16120820

• The clearance of protein-bound solutes by hemofiltration and hemodiafiltration KIDNEY INTERNATIONAL Meyer, T. W., Walther, J. L., Pagtalunan, M. E., Martinez, A. W., Torkamani, A., Fong, P. D., Recht, N. S., Robertson, C. R., Hostetter, T. H. 2005; 68 (2): 867-877

  Abstract

  Hemofiltration in the form of continuous venovenous hemofiltration (CVVH) is increasingly used to treat acute renal failure. Compared to hemodialysis, hemofiltration provides high clearances for large solutes but its effect on protein-bound solutes has been largely ignored.Standard clinical systems were used to remove test solutes from a reservoir containing artificial plasma. Clearances of the protein-bound solutes phenol red (C(PR)) and indican (C(IN)) were compared to clearances of urea (C(UREA)) during hemofiltration and hemodiafiltration. A mathematical model was developed to predict clearances from values for plasma flow Q(p), dialysate flow Q(d), ultrafiltration rate Q(f), filter size and the extent of solute binding to albumin.When hemofiltration was performed with Q(p) 150 mL/min and Q(f) 17 mL/min, clearance values were C(PR) 1.0 +/- 0.1 mL/min; C(IN) 3.7 +/- 0.5 mL/min; and C(UREA) 14 +/- 1 mL/min. The clearance of the protein-bound solutes was approximately equal to the solute-free fraction multiplied by the ultrafiltration rate corrected for the effect of predilution. Addition of Q(d) 42 mL/min to provide HDF while Q(p) remained 150 mL/min resulted in proportional increases in the clearance of protein-bound solutes and urea. In contrast, the clearance of protein-bound solutes relative to urea increased when hemodiafiltration was performed using a larger filter and increasing Q(d) to 300 mL/min while Q(p) was lowered to 50 mL/min. The pattern of observed results was accurately predicted by mathematical modeling.In vitro measurements and mathematical modeling indicate that CVVH provides very limited clearance of protein-bound solutes. Continuous venous hemodiafiltration (CVVHDF) increases the clearance of protein-bound solutes relative to urea only when dialysate flow rate and filter size are increased above values now commonly employed.

  View details for Web of Science ID 000230342500049

  View details for PubMedID 16014068

• Alterations in gene expression in cadaveric vs. live donor kidneys suggest impaired tubular counterbalance of oxidative stress at implantation AMERICAN JOURNAL OF TRANSPLANTATION Kainz, A., Mitterbauer, C., Hauser, P., Schwarz, C., Regele, H. M., Berlakovich, G., Mayer, G., Perco, P., Mayer, B., Meyer, T. W., Oberbauer, R. 2004; 4 (10): 1595-1604

  Abstract

  Recipients of live donor transplant kidneys (LIV) exhibit a significantly longer allograft half-life compared with cadaveric donor organs (CADs). The reasons are incompletely understood. Therefore this study sought to elucidate the genome-wide gene expression profiles in microdissected transplant kidney biopsies obtained from five cadaveric and five matched live donors before transplantation. cDNA microarrays were used to determine the transcripts in isolated glomeruli (G) and the tubulointerstitial (TI) compartment. Data were subjected to hierarchical clustering, maxT adjustment and a jackknife procedure to ensure robustness of reported findings; validation was performed by independent analysis of split biopsies and TaqMan-PCR. One hundred and thirteen sequences representing 62 unique genes (17 redundant features), and 34 ESTs separated G from TI. No difference in gene expression was found in G between LIV and CAD kidneys, but nine genes (two represented twice) and three ESTs were abundantly expressed in the CAD TI compared with LIV. The main biological function of these genes is counter regulation of oxidative stress. Promoter analysis of significant features suggested coregulated gene groups. These data suggest that CAD kidneys exhibit a distinctly different set of transcripts in the TI compartment but not in the G compartment when compared with LIV kidneys.

  View details for DOI 10.1111/j.1600-6143.2004.00554.x

  View details for Web of Science ID 000223862300006

  View details for PubMedID 15367214

• Increasing dialysate flow and dialyzer mass transfer area coefficient to increase the clearance of protein-bound solutes JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Meyer, T. W., Leeper, E. C., Bartlett, D. W., Depner, T. A., Lit, Y. Z., Robertson, C. R., Hostetter, T. H. 2004; 15 (7): 1927-1935

  Abstract

  Clinical hemodialysis systems achieve high single pass extraction of small solutes that are not bound to plasma proteins. But they clear protein-bound solutes much less effectively. This study examines the extent to which clearance of a protein-bound test solute is improved by increasing the dialyzer mass transfer area coefficient (KoA) and the dialysate flow rate (Qd). A reservoir containing test solutes and artificial plasma with albumin concentration approximately 4 g/dl was dialyzed with a standard clinical dialysate delivery system. The clearance of phenol red (ClPR) was compared with the clearances of urea and creatinine at a plasma flow rate (Qp) of 200 ml/min with varying values of KoA and Qd. ClPR increased from 11 +/- 2 ml/min to 23 +/- 2 ml/min when KoA for phenol red, KoAPR, was increased from 238 to 640 ml/min and Qd was increased from 286 +/- 6 ml/min to 734 +/- 9 ml/min. Increasing either KoAPR or Qd alone had lesser effects. Clearance values for phenol red were much lower than clearance values for the unbound solutes urea and creatinine, which ranged from 150 to 200 ml/min and were less affected by varying KoA and Qd. A mathematical model was developed to predict ClPR from values of Qp, Qd, the fraction of phenol red bound to albumin (94% +/- 1%) and KoAPR. The model accurately predicts the pattern of measured results and shows further that ClPR can be made to approach Qp only by very large increases in both KoAPR and Qd.

  View details for DOI 10.1097/01.asn.0000131521.62256.f0

  View details for Web of Science ID 000222275600030

  View details for PubMedID 15213283

• Genome-wide gene-expression patterns of donor kidney biopsies distinguish primary allograft function LABORATORY INVESTIGATION Hauser, P., Schwarz, C., Mitterbauer, C., Regele, H. M., Muhlbacher, F., Mayer, G., Perco, P., Mayer, B., Meyer, T. W., Oberbauer, R. 2004; 84 (3): 353-361

  Abstract

  Roughly 25% of cadaveric, but rarely living donor renal transplant recipients, develop postischemic acute renal failure, which is a main risk factor for reduced long-term allograft survival. An accurate prediction of recipients at risk for ARF is not possible on the basis of donor kidney morphology or donor/recipient demographics. We determined the genome-wide gene-expression pattern using cDNA microarrays in three groups of 36 donor kidney wedge biopsies: living donor kidneys with primary function, cadaveric donor kidneys with primary function and cadaveric donor kidneys with biopsy proven acute renal failure. The descriptive genes were characterized in gene ontology terms to determine their functional role. The validation of microarray experiments was performed by real-time PCR. We retrieved 132 genes after maxT adjustment for multiple testing that significantly separated living from cadaveric kidneys, and 48 genes that classified the donor kidneys according to their post-transplant course. The main functional roles of these genes are cell communication, apoptosis and inflammation. In particular, members of the complement cascade were activated in cadaveric, but not in living donor kidneys. Thus, suppression of inflammation in the cadaveric donor might be a cheap and promising intervention for postischemic acute renal failure.

  View details for DOI 10.1038/labinvest.3700037

  View details for Web of Science ID 000222833100010

  View details for PubMedID 14704720

• Reliability of T7-based mRNA linear amplification validated by gene expression analysis of human kidney cells using cDNA microarrays NEPHRON EXPERIMENTAL NEPHROLOGY Rudnicki, M., Eder, S., Schratzberger, G., Mayer, B., Meyer, T., Tonko, M., Mayer, G. 2004; 97 (3): 86-95

  Abstract

  Genome wide gene expression analysis by cDNA microarrays is often limited by minute amounts of starting RNA. We therefore tested an optimized linear RNA amplification protocol using the RiboAmp amplification kit in the setting of cDNA microarrays. We isolated mRNA from a human kidney cell line (HK-2; ATCC) and from Universal Human Reference RNA (STR; Stratagene). After performing one and two rounds of linear RNA amplification, respectively, the amplified RNAs were co-hybridized to cDNA microarrays. Linearity and reproducibility of the individual experiments were then assessed by calculating the Pearson correlation. The intra-amplification consistency showed a correlation of 0.968 for the first round, 0.907 for the second round and 0.912 for two successive rounds of amplification. If the first round was compared to unamplified material, r was 0.925. The second round amplification yielded a correlation of 0.897 if compared to unamplified mRNA. Two rounds of amplification starting from 200 pg of mRNA compared to unamplified material resulted in a correlation of 0.868. These results indicate that linear amplification using RiboAmp kit yields amplified RNA with a high degree of linearity and reproducibility.

  View details for DOI 10.1159/000078642

  View details for Web of Science ID 000223003700002

• Effect of biocompatible and -incompatible membranes on neutrophils using cDNA microarray technology. Hochegger, K., Eder, S., Rudnicki, M. A., Mayer, B., Meyer, T. W., Mayer, G., Rosenkranz, A. R. LIPPINCOTT WILLIAMS & WILKINS. 2003: 727A

  View details for Web of Science ID 000186219103351

• Strain-specific differences in streptozotocin-induced diabetes in the mouse. Gurley, S. B., Clare, S. E., Meyer, T. W., Coffman, T. M. LIPPINCOTT WILLIAMS & WILKINS. 2003: 595A

  View details for Web of Science ID 000186219102757

• Tubular injury in glomerular disease KIDNEY INTERNATIONAL Meyer, T. W. 2003; 63 (2): 774-787

  View details for Web of Science ID 000180419300050

  View details for PubMedID 12631155

• Genome wide gene expression pattern of donor kidney biopsies distinguish primary allograft function. Hauser, P., Schwarz, C., Regele, H. M., Mayer, G., Mayer, B., Lukas, A., Meyer, T. W., Oberbauer, R. AMER SOC NEPHROLOGY. 2002: 359A–360A

  View details for Web of Science ID 000177757501775

• RNA-amplification for gene-expression profiling of microdissected renal tubular epithelial cells (RTEC). Rudnicki, M. A., Schratzberger, G., Meyer, T. W., Oberbauer, R., Mayer, G. AMER SOC NEPHROLOGY. 2002: 125A

  View details for Web of Science ID 000177757500621

• Renal structural abnormalities following recovery from acute puromycin nephrosis KIDNEY INTERNATIONAL Rasch, R., Nyengaard, Marcussen, N., Meyer, T. W. 2002; 62 (2): 496–506

  Abstract

  Rats that recover from acute puromycin nephrosis later develop widespread glomerular and tubulointerstitial injury. The current study sought to identify structural changes present in the recovery phase that could precipitate progressive renal disease.Stereologic studies were performed 10 weeks after administration of puromycin (PAN) or saline (Cont). Serial sections were examined to assess glomerular structure.Rats receiving puromycin developed heavy proteinuria that returned nearly to control levels at 10 weeks. Kidneys in these animals were moderately enlarged and exhibited expansion of the interstitium (PAN, 254 +/- 47 mm3; Cont, 152 +/- 23 mm3; P < 0.05). The average glomerular volume was not different from control (PAN, 1.90 +/- 0.38 x 10(6) microm3; Cont, 2.07 +/- 0.47 x 10(6) microm3), but a subpopulation of glomeruli of about half normal size was found in PAN rats. Serial sections revealed that most of these glomeruli were not connected to normal tubule segments. Serial sections also revealed that more than 90% of glomeruli in rats recovering from nephrosis had synechias joining the tuft to Bowman's capsule. Synechias occupied an average of 8 +/- 11% of the Bowman's capsule surface in PAN animals versus less than 1% of the surface in controls. The appearance of synechias was not associated with a reduction in the mean number of visceral or parietal epithelial cells per glomerulus.Acute puromycin nephrosis does not cause a notable reduction in visceral epithelial cell number. However, widespread glomerular injury characterized by synechia between the tuft and Bowman's capsule is present following remission of proteinuria. Progression of this residual glomerular injury could contribute to the late development of glomerular segmental sclerosis following recovery from acute nephrosis.

  View details for DOI 10.1046/j.1523-1755.2002.00481.x

  View details for Web of Science ID 000176746600014

  View details for PubMedID 12110010

• Effects of antihypertensive therapy on intrarenal angiotensin and bradykinin levels in experimental renal insufficiency KIDNEY INTERNATIONAL Mackie, F. E., Meyer, T. W., Campbell, D. J. 2002; 61 (2): 555-563

  Abstract

  Whereas angiotensin converting enzyme inhibitors and angiotensin type 1 receptor antagonists have beneficial effects in the remnant model of renal failure, calcium channel blockers do not consistently improve renal disease in this model. This study examined whether these different means of blood pressure reduction have different effects on renal levels of angiotensin (Ang) and bradykinin peptides.Rats subjected to five-sixths nephrectomy were divided into groups with similar hypertension and proteinuria at 4 to 5 weeks. They then received either no treatment, or enalapril, losartan or nifedipine for 2 weeks. Following repeat measurements of proteinuria and blood pressure, Ang II and bradykinin peptides were measured in the remnant kidney and renin, Ang II, and aldosterone were measured in the plasma.All three drugs had equivalent blood pressure-lowering effects. Enalapril and losartan reduced proteinuria but nifedipine did not. Reduction of proteinuria in rats treated with enalapril and losartan was associated with a reduction in Ang II levels in both the peri-infarct and intact portions of the remnant kidney. By contrast, nifedipine increased Ang II levels in the intact portion of the remnant kidney. Losartan reduced bradykinin levels in the peri-infarct portion of the remnant kidney while enalapril reduced bradykinin levels in the intact portion of the remnant kidney. Nifedipine had no effect on intrarenal bradykinin levels.The differential effects of enalapril, losartan and nifedipine on proteinuria and intrarenal Ang II and bradykinin levels suggest that the ability of an antihypertensive to decrease proteinuria may depend on its ability to decrease kidney Ang II and bradykinin levels.

  View details for Web of Science ID 000173446600020

  View details for PubMedID 11849396

• Regulation of renal tubular cell apoptosis and proliferation after ischemic injury to a solitary kidney JOURNAL OF LABORATORY AND CLINICAL MEDICINE Oberbauer, R., Schwarz, C., Regele, H. M., Hansmann, C., Meyer, T. W., Mayer, G. 2001; 138 (5): 343–51

  Abstract

  The time course and regulation of apoptosis and cellular regeneration after 30 minutes of acute ischemic injury to a single kidney was elucidated in rats at five time points over 20 weeks. The fraction of apoptotic cells was most prominent at 1 day after the insult in the distal tubule (8% +/- 4% vs 0% +/- 0%, acute renal failure [ARF] vs sham, respectively) and was still elevated at 7 days (2% +/- 2% vs 0% +/- 0%). At that time, the whole kidney mRNA expression of the apoptosis inhibitory genes bcl-xL and bcl-2, as well as that of the apoptosis promotor bax, was significantly reduced. Immunohistochemistry of kidney specimen showed suppression of bcl-2 in the distal tubule but up-regulation in the proximal tubule, whereas bax protein was more strongly expressed in the distal tubule. Cellular proliferation started at day 1 and continued over the following 20 weeks, leading to severe tubular dilation and kidney failure. These data indicate that differential regulation of bcl-2 family members contributes to the early apoptotic clearance of lethally injured tubular epithelial cells after ischemic injury to a solitary kidney.

  View details for DOI 10.1067/mlc.2001.118926

  View details for Web of Science ID 000172280700007

  View details for PubMedID 11709659

• Glomerular injury and tubular loss in adriamycin nephrosis JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Javaid, B., Olson, J. L., Meyer, T. W. 2001; 12 (7): 1391-1400

  Abstract

  Glomerular injury manifested by sustained proteinuria usually leads to tubule injury and reduction of the GFR. The current study explored the link between these processes in rats with adriamycin nephrosis. One group of nephrotic rats received a vasopressin V2 receptor blocker (V2X) from 4 to 16 wk after injection of adriamycin, whereas a second group received no treatment (NoRx). V2 receptor blockade increased urine volume without affecting protein excretion. At 16 wk, both groups of nephrotic rats exhibited a marked reduction in GFR in comparison with normal controls (V2X, 0.22 +/- 0.19 ml/min; NoRx, 0.20 +/- 0.11 ml/min; control, 1.23 +/- 0.11 ml/min). Morphologic studies revealed that the majority of glomeruli in nephrotic rats were no longer connected to normal tubule segments (V2X, 81 +/- 21%; NoRx, 85 +/- 18%; control, 1 +/- 2%). Glomeruli without tubules were not, however, globally sclerosed. Disruption of the glomerular tubular junction was associated with the presence of amorphous material separating damaged tubule cells from the basement membrane. Serial sections revealed that this material spread from extensive areas of adhesion between the glomerular tuft and capsule to invest the tubular neck. Reduction of the GFR was strongly correlated with the fraction of glomeruli not connected to normal tubules (r(2) = 0.82; P < 0.0001). V2 receptor blockade did not preserve renal function or structure. These findings suggest that local extension of glomerular injury to destroy the tubule neck is an important cause of loss of renal function in adriamycin nephrosis.

  View details for Web of Science ID 000169539800008

  View details for PubMedID 11423568

• Intrarenal angiotensin and bradykinin peptide levels in the remnant kidney model of renal insufficiency KIDNEY INTERNATIONAL Mackie, F. E., Campbell, D. J., Meyer, T. W. 2001; 59 (4): 1458-1465

  Abstract

  The remnant kidney model of renal failure is associated with normal or suppressed plasma renin and angiotensin (Ang) II levels when hypertension is established. However, the hypertension responds to angiotensin-converting enzyme (ACE) inhibition and Ang II receptor antagonism, suggesting a role for Ang II in the hypertensive process. Bradykinin (BK) is a potent vasoactive peptide that may also participate in this model.Ang II and BK peptides were measured in the ischemic peri-infarct portion and the intact portion of the remnant kidney at two, five, and seven weeks after surgery. Plasma Ang II, renin, angiotensinogen, and aldosterone levels were also measured.Ang II levels in the peri-infarct portion were higher than in the intact portion at all time points and were higher than in sham-operated kidney at two weeks. Ang II levels in the intact portion were similar to the levels in kidneys of sham-operated rats at two and five weeks and were suppressed at seven weeks. BK levels were increased in the peri-infarct portion at all time points and in the intact portion at two and five weeks. Plasma Ang II and aldosterone levels were also elevated at two weeks.Peri-infarct renal tissue Ang II levels and plasma Ang II and aldosterone levels increase transiently during the evolution of hypertension in the remnant kidney model. Sustained hypertension is associated with an increase in intrarenal BK levels but not with persistent increases in intrarenal or circulating Ang II levels.

  View details for Web of Science ID 000167737200028

  View details for PubMedID 11260408

• Hemodynamic effects of angiotensin II in the kidney RENIN-ANGIOTENSIN SYSTEM AND PROGRESSION OF RENAL DISEASES Toke, A., Meyer, T. W. 2001; 135: 34-46

  View details for Web of Science ID 000172719200003

  View details for PubMedID 11705290

• Effect of angiotensin II blockade on renal injury in mineralocorticoid-salt hypertension HYPERTENSION Sorooshian, M., Olson, J. L., Meyer, T. W. 2000; 36 (4): 569-574

  Abstract

  Kidney function and structure were compared in control rats (group 1) and in 3 groups of rats made hypertensive by administration of aldosterone and saline for 8 weeks (groups 2, 3, and 4). Group 2 rats received only aldosterone and saline, while group 3 also received losartan and group 4 also received enalapril. Rats in all groups were subjected to uninephrectomy before beginning the experiment. Hypertension and proteinuria in rats given aldosterone and saline were not affected by losartan or enalapril (8-week values for blood pressure in mm Hg: 135+/-3 group 1, 193+/-4 group 2, 189+/-4 group 3, 189+/-5 group 4; P<0.05 groups 2, 3, and 4 versus 1; 8-week values for proteinuria in mg/d: 44+/-8 group 1, 278+/-34 group 2, 267+/-37 group 3, 289+/-36 group 4; P<0.05 groups 2, 3, and 4 versus 1). Vascular, glomerular, and tubulointerstitial injury accompanied hypertension and proteinuria at 8 weeks. Losartan and enalapril did not prevent vascular injury, which was characterized by thickening of arterial and arteriolar walls and by fibrinoid necrosis and thrombotic microangiopathy. Likewise, losartan and enalapril did not reduce the prevalence of glomerular segmental sclerosis (1+/-1% group 1, 10+/-2% group 2, 11+/-2% group 3, 13+/-2% group 4; P<0.05 groups 2, 3, and 4 versus 1) or limit tubulointerstitial injury as reflected by the volume fraction of the cortical interstitium (15+/-1% group 1, 20+/-1% group 2, 21+/-1% group 3, 21+/-1% group 4; P<0.05 groups 2, 3, and 4 versus 1). These findings suggest that local angiotensin II activity does not contribute to the development of renal injury in mineralocorticoid-salt hypertension.

  View details for Web of Science ID 000090109900018

  View details for PubMedID 11040237

• Evolution of incipient nephropathy in type 2 diabetes mellitus 31st Annual Meeting of the American-Society-of-Nephrology Lemley, K. V., Abdullah, I., Myers, B. D., Meyer, T. W., Blouch, K., Smith, W. E., Bennett, P. H., Nelson, R. G. NATURE PUBLISHING GROUP. 2000: 1228–37

  Abstract

  We examined the course of glomerular injury in 12 Pima Indians with long-standing (>8 years) type 2 diabetes mellitus, normal serum creatinine, and microalbuminuria. They were compared with a group of 10 Pima Indians in Arizona with new-onset (<5 years) type 2 diabetes, normal renal function, and normoalbuminuria (<30 mg albumin/g creatinine on random urine specimens).A combination of physiological and morphological techniques was used to evaluate glomerular function and structure serially on two occasions separated by a 48-month interval. Clearances of iothalamate and p-aminohippuric acid were used to determine glomerular filtration rate (GFR) and renal plasma flow, respectively. Afferent oncotic pressure was determined by membrane osmometry. The single nephron ultrafiltration coefficient (Kf) was determined by morphometric analysis of glomeruli and mathematical modeling.The urinary albumin-to-creatinine ratio (median + range) increased from 84 (28 to 415) to 260 (31 to 2232) mg/g between the two examinations (P = 0.01), and 6 of 12 patients advanced from incipient (ratio = 30 to 299 mg/g) to overt nephropathy (>/=300 mg/g). A 17% decline in GFR between the two examinations from 186 +/- 41 to 155 +/- 50 mL/min (mean +/- SD; P = 0.06) was accompanied by a 17% decline in renal plasma flow (P = 0.003) and a 6% increase in plasma oncotic pressure (P = 0.02). Computed glomerular hydraulic permeability was depressed by 13% below control values at both examinations, a result of a widened basement membrane and a reduction in frequency of epithelial filtration slits. The filtration surface area declined significantly, however, from 6.96 +/- 2.53 to 5.51 +/- 1.62 x 105 mm2 (P = 0.01), a change that was accompanied by a significant decline in the number of mesangial cells (P = 0.001), endothelial cells (P = 0.038), and podocytes (P = 0.0005). These changes lowered single nephron Kf by 20% from 16.5 +/- 6.0 to 13.2 +/- 3.6 nL/(minutes + mm Hg) between the two examinations (P = 0.02). Multiple linear regression analysis revealed that among the determinants of GFR, only the change in single nephron Kf was related to the corresponding change in GFR.We conclude that a reduction in Kf is the major determinant of a decline in GFR from an elevated toward a normal range as nephropathy in type 2 diabetes advances from an incipient to an overt stage.

  View details for Web of Science ID 000089155700029

  View details for PubMedID 10972685

• Podocyte loss characterizes incipient nephropathy in Pima Indians with type 2 diabetes mellitus Nelson, R. G., Lemley, K. V., Smith, W. E., Meyer, T. W., Bennett, P. H., Myers, B. D. SPRINGER. 2000: A26–A26

  View details for Web of Science ID 000089136700103

• Contribution of angiotensin II to late renal injury after acute ischemia JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Pagtalunan, M. E., Olson, J. L., Meyer, T. W. 2000; 11 (7): 1278-1286

  Abstract

  Rats recovering from acute renal ischemia exhibit tubule loss and interstitial fibrosis followed by development of proteinuria and glomerular sclerosis. The current study assessed the contribution of angiotensin II (AngII) to these processes. The contribution of AngII to early tubule loss and interstitial fibrosis was assessed in rats studied for 35 d after right nephrectomy and transient occlusion of the left renal artery. One group of rats received no treatment, while a second group received losartan beginning at 2 d following ischemia. Studies at 35 d showed that losartan did not improve GFR (2.04 +/- 0.30 ml/min treated, 2.16 +/- 0.21 ml/min untreated), reduce the fraction of glomeruli that were no longer connected to normal tubule segments (42 +/- 9% treated, 42 +/- 13% untreated), or limit expansion of the interstitial volume fraction (25 +/- 3% treated, 25 +/- 4% untreated). The contribution of AngII to progressive glomerular injury following initial recovery from ischemia was assessed in similarly prepared rats studied for 140 d. One group of rats received no treatment, while a second group received enalapril beginning at 35 d following ischemia. Enalapril markedly reduced proteinuria (78 +/- 17 mg/d treated, 229 +/- 52 mg/d untreated) and the prevalence of segmental glomerular sclerosis (14 +/- 9% treated, 45 +/- 10% untreated). Untreated rats developed sclerotic lesions in glomeruli not connected to normal tubules, as well as in glomeruli connected to normal tubules. Enalapril prevented injury in both classes of glomeruli. These results indicate that AngII does not contribute to interstitial fibrosis during recovery from ischemic injury. Reduction of AngII activity, can, however, prevent secondary glomerular injury in kidneys initially damaged by ischemia.

  View details for Web of Science ID 000087816900013

  View details for PubMedID 10864584

• Methods for estimating the volume of individual glomeruli KIDNEY INTERNATIONAL Pagtalunan, M. E., Drachman, J. A., Meyer, T. W. 2000; 57 (6): 2644-2649

  Abstract

  Methods for estimating the volume of individual glomeruli.The Cavalieri and maximal planar area (MPA) methods are commonly used to measure the volume of individual glomeruli. Previous studies have suggested that the MPA method, which is less laborious, yields values that are much greater than those obtained by the Cavalieri method. The current study re-examined the relationship of MPA and Cavalieri values for glomerular volume in humans and rats.Both methods were used to measure the volume of 1201 glomeruli from 58 humans and 281 glomeruli from 15 rats. Tissue was embedded in Epon. Further mathematical analysis was performed to assess the extent to which deviation of glomeruli from spherical shape affects the relationship of values obtained by the MPA and Cavalieri methods.MPA values exceeded Cavalieri values by an average of only 14 +/- 22% in humans and 6 +/- 16% in rats. The relationship of MPA to Cavalieri values was similar in individual humans and rats, with widely varying values for average glomerular volume. Neither the development of sclerosis nor the loss of any connection to a tubule affected the relationship of the MPA and Cavalieri values for the volume of individual glomeruli. Mathematical analysis showed that MPA values would not exceed Cavalieri values if glomeruli had ellipsoidal rather than spherical shape.Similar values for glomerular volume are obtained using the Cavalieri and MPA methods in humans and rats.

  View details for Web of Science ID 000087346100047

  View details for PubMedID 10844635

• Transplant glomerulopathy as a cause of late graft loss AMERICAN JOURNAL OF KIDNEY DISEASES Suri, D. L., Tomlanovich, S. J., Olson, J. L., Meyer, T. W. 2000; 35 (4): 674-680

  Abstract

  Several pathophysiological processes contribute to chronic kidney transplant rejection. Among the most distinctive is transplant glomerulopathy, characterized by widening of the subendothelial space with accumulation of flocculent material and duplication of the basement membrane. The current study assessed the course of graft loss in patients with and without this form of injury. Twenty-five patients with prominent transplant glomerulopathy were identified from biopsies performed at a single center during 4 years. These patients were compared with control patients with a similar degree of renal dysfunction in whom biopsies showed chronic rejection without transplant glomerulopathy. Patients with transplant glomerulopathy showed an increased rate of graft loss after biopsy. Biopsies were performed longer after transplantation in these patients, however, than in control patients with an equal degree of graft dysfunction. Graft survival from the time of transplantation was therefore not different between the two groups. Morphological studies showed that transplant glomerulopathy was not associated with increased severity of chronic vascular injury characterized by arterial and arteriolar intimal thickening or hyalinosis. These findings show that transplant glomerulopathy may develop late after transplantation and separately from chronic vascular rejection. The appearance of transplant glomerulopathy on a biopsy specimen is followed by accelerated graft loss.

  View details for Web of Science ID 000086223700016

  View details for PubMedID 10739789

• Podocyte number predicts long-term urinary albumin excretion in Pima Indians with Type II diabetes and microalbuminuria DIABETOLOGIA Meyer, T. W., Bennett, P. H., Nelson, R. G. 1999; 42 (11): 1341-1344

  Abstract

  The predictive value of glomerular structure on progression of renal disease was examined in patients with Type II (non-insulin-dependent) diabetes and microalbuminuria (urinary albumin-to-creatinine ratio = 30-299 mg/g).Kidney biopsy specimens were obtained from 16 diabetic Pima Indians (6 men, 10 women). Progression of renal disease was assessed by measuring urinary albumin excretion 4 years after the biopsy (UAE(4 years)) and by computing the change in urinary albumin excretion during the study (Delta UAE).At baseline, the duration of diabetes averaged 13.3 years (range = 4.0-23.8 years) and the mean glomerular filtration rate was 159 ml x min(-1) x 1.73 m(-2) (range = 98 - 239 ml x min(-1) x 1.73 m(-2)). Median urinary albumin excretion was 67 mg/g (range = 25-136 mg/g) and it increased to 625 mg/g (range = 9-13471 mg/g) after 4 years; 10 subjects (63 %; 4 men, 6 women) developed macroalbuminuria (urinary albumin-to-creatinine ratio >/= 300 mg/g). Neither mean arterial pressure nor HbA(1 c) changed substantially during follow-up. Among the glomerular morphologic characteristics, the number of visceral epithelial cells, or podocytes, per glomerulus was the strongest predictor of renal disease progression (UAE(4 years), r = -0.49, p = 0.05; DeltaUAE, r = -0.57, p = 0.02), with fewer cells predicting more rapid progression. Glomerular basement membrane thickness did not predict progression (UAE(4 years), r = 0.11, p = 0.67; DeltaUAE, r = 0.09, p = 0.73) and mesangial volume fraction had only a modest effect (UAE(4 years,) r = 0.42, p = 0.11; DeltaUAE, r = 0.48, p = 0.06).Whether lower epithelial cell number per glomerulus among those that progressed was due to cellular destruction, a reduced complement of epithelial cells, or both is uncertain. Nevertheless, these findings suggest that podocytes play an important part in the development and progression of diabetic renal disease. [Diabetologia (1999) 42: 1341-1344]

  View details for Web of Science ID 000083388000009

  View details for PubMedID 10550418

• Effects of eprosartan on glomerular injury in rats with reduced renal mass PHARMACOLOGY Gandhi, M., Meyer, T. W., Brooks, D. P. 1999; 59 (2): 89-94

  Abstract

  The effects of the selective angiotensin AT1 receptor antagonist, eprosartan, were evaluated in experimental renal disease. Five-sixth nephrectomy in male Munich-Wistar rats led to the development of hypertension, proteinuria and remnant glomerulosclerosis. Administration of the AT1 receptor antagonist, eprosartan, for 4 weeks resulted in inhibition of angiotensin II activity as confirmed by a reduced blood pressure response to exogenous angiotensin II challenge. Compared to vehicle treatment, eprosartan normalized blood pressure, reduced proteinuria and limited remnant glomerulosclerosis. These data suggest that eprosartan may provide a new tool in the treatment of progressive renal disease.

  View details for Web of Science ID 000081940300003

  View details for PubMedID 10450063

• Influence of donor factors on early function of graft kidneys JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Suri, D., Meyer, T. W. 1999; 10 (6): 1317-1323

  Abstract

  Factors which influence graft function can be divided into donor factors that affect both kidneys from the same donor equally and postdonor factors that affect each kidney individually. This study assessed the influence of donor factors on graft function early after transplantation. Sixty-one donors who provided kidneys that were transplanted locally into two separate recipients were identified. Recipient creatinine clearance values were estimated from serum creatinine concentrations using a computer model. Pairwise ANOVA showed that donor factors accounted for 35 to 45% of the variation in recipient creatinine clearance from 2 d to 2 wk posttransplantation. Although donor factors had a large aggregate effect during this period, individual factors that influenced graft function could not be identified from analysis of donor medical records. At 6 mo after transplantation, the effect of donor factors on graft function was no longer discernible. These results show that the condition of the donor exerts an important influence on graft function early after transplantation. More detailed study is required to identify individual factors that contribute to this effect.

  View details for Web of Science ID 000080487900019

  View details for PubMedID 10361871

• Late consequences of acute ischemic injury to a solitary kidney JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Pagtalunan, M. E., Olson, J. L., Tilney, N. L., Meyer, T. W. 1999; 10 (2): 366-373

  Abstract

  The sequelae of acute ischemic injury to a solitary kidney were assessed in rats subjected to right nephrectomy and transient occlusion of the left renal artery; control rats underwent right nephrectomy alone. Incomplete recovery from ischemic injury at 2 wk (serum creatinine levels of 1.1 +/- 0.2 versus 0.5 +/- 0.1 mg/dl, P < 0.05 for ischemia versus control) was followed by deterioration of renal function at 20 wk (serum creatinine levels of 1.7 +/- 0.4 versus 0.7 +/- 0.1 mg/dl, P < 0.05 for ischemia versus control). Morphologic studies showed that impairment of function after ischemic injury was associated with widespread tubulointerstitial disease. Some tubule segments were atrophic and others exhibited cystic dilation, so that the tubular cell volume fraction was reduced (37 +/- 4 versus 53 +/- 2%, P < 0.05), while the tubular lumen and interstitial volume fractions were increased (31 +/- 4 versus 23 +/- 2% and 29 +/- 2 versus 20 +/- 1%, respectively, both P < 0.05). Many glomeruli retained open capillary loops but were no longer connected to normal tubule segments (63 +/- 8 versus 15 +/- 7% of glomeruli, P < 0.05). There was a strong inverse correlation between the prevalence of such glomeruli and the GFR at 20 wk after ischemia (r2 = 0.79, P < 0.001). Tubulointerstitial disease at that time was accompanied by proteinuria and widespread segmental glomerular tuft injury. The occurrence of similar processes in human patients could contribute to the loss of graft kidneys that suffer ischemic injury during transplantation.

  View details for Web of Science ID 000078320700020

  View details for PubMedID 10215337

• Contribution of tubular injury to loss of remnant kidney function KIDNEY INTERNATIONAL Gandhi, M., Olson, J. L., Meyer, T. W. 1998; 54 (4): 1157-1165

  Abstract

  The remnant kidney model has been widely used to identify mechanisms responsible for the progression of renal disease. However, the structural changes associated with progressive loss of function in this model have not been well characterized.Kidney function and structure were assessed at 10 weeks (REM 10) and 25 weeks (REM 25) after five-sixths renal ablation and in control rats (Control). Serial sections were examined to relate glomerular and tubular structure in individual nephrons.Remnant kidney function declined between 10 and 25 weeks after ablation (GFR 0.90 +/- 0.34 vs. 0.23 +/- 0.07 ml/min, REM 10 vs. REM 25, P < 0.05). This decline in function was associated with an increase in the prevalence of globally sclerotic glomeruli (14 +/- 10 vs. 0 +/- 0 vs. 0 +/- 0%, REM 25 vs. REM 10 vs. Control, P < 0.05 REM 25 vs. REM 10 and Control). The decline in remnant kidney function between 10 and 25 weeks was also associated with the appearance of glomeruli that were atubular (48 +/- 14 vs. 9 +/- 8 vs. 3 +/- 5%, REM 25 vs. REM 10 vs. Control, P < 0.05 REM 25 vs. REM 10 and Control) or connected to atrophic proximal tubule segments (26 +/- 10 vs. 11 +/- 6 vs. 1 +/- 2%, REM 25 vs. REM 10 vs. Control, P < 0.05 all comparisons). Atubular glomeruli, which usually had open capillary loops available for filtration, were more numerous than globally sclerotic glomeruli at 25 weeks after ablation.These findings indicate that tubular injury contributes to progressive loss of renal function following reduction in nephron number.

  View details for Web of Science ID 000076096900013

  View details for PubMedID 9767531

• Natriuretic effect of adenosine A(1)-receptor blockade in rats NEPHROLOGY DIALYSIS TRANSPLANTATION Oberbauer, R., Schreiner, G. F., Meyer, T. W. 1998; 13 (4): 900–903

  Abstract

  Many effects of adenosine on renal function have been identified. The development of adenosine receptor blockers has made it possible to identify which of these effects are exerted by endogenous adenosine. At least four adenosine receptor subtypes, denoted A1, A2a, A2b, and A3 are currently known. In the present study the selective A1 receptor blocker 1,3-dipropyl-8[2-(5,6-epoxy) norbanyl] xanthine (CVT-117) was used to assess the effect of A1 activation by endogenous adenosine on renal function in rats.Clearance studies were performed before and after administration of 0.1 mg/kg and 0.8 mg/kg of CVT-117 in separate groups of rats and before and after administration of vehicle in time-control rats. Measurements of heart rate before and after administration of exogenous adenosine confirmed effective A1 receptor blockade.At both the lower and higher doses, A1 receptor blockade with CVT-117 increased fractional sodium excretion and urine flow rate without altering GFR. The increase in sodium excretion following A1 blockade was not accompanied by increases in the excretion of phosphate or potassium.These results show that endogenous adenosine promotes sodium retention by activation of A1 receptors.

  View details for DOI 10.1093/ndt/13.4.900

  View details for Web of Science ID 000073055300015

  View details for PubMedID 9568847

• Course of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus Symposium on Progression of Renal Disease - Clinical Patterns, Therapeutic Options and What We Have Learned from Clinical Trials Nelson, R. G., Meyer, T. W., Myers, B. D., Bennett, P. H. NATURE PUBLISHING GROUP. 1997: S45–S48

  Abstract

  The course of renal disease attributable to non-insulin-dependent diabetes mellitus (NIDDM) has been characterized extensively in the Pima Indians of Arizona. Studies in this population indicate that the glomerular filtration rate often increases at the onset of NIDDM and remains elevated as long as normal urinary albumin excretion (< 30 mg albumin/g creatinine) or microalbuminuria (30-299 mg albumin/g creatinine) persist. After the development of macroalbuminuria (> or = 300 mg albumin/g creatinine), the glomerular filtration rate declines at least as rapidly as reported in subjects with insulin-dependent diabetes. Morphologic examination of kidney tissue reveals extensive glomerular sclerosis, mesangial expansion, and widening of epithelial cell foot processes and the glomerular basement membrane in the subjects with macroalbuminuria, but not in those with normo- or microalbuminuria. These findings suggest that substantial structural damage to the kidney occurs at or about the time that macroalbuminuria develops, and the decline in glomerular function in those with macroalbuminuria is due to a loss of ultrafiltration surface area and a reduction in glomerular hydraulic permeability.

  View details for Web of Science ID A1997YJ60500012

  View details for PubMedID 9407420

• Podocyte loss and progressive glomerular injury in type II diabetes JOURNAL OF CLINICAL INVESTIGATION Pagtalunan, M. E., Miller, P. L., JUMPINGEAGLE, S., Nelson, R. G., Myers, B. D., Rennke, H. G., Coplon, N. S., Sun, L. M., Meyer, T. W. 1997; 99 (2): 342-348

  Abstract

  Kidney biopsies from Pima Indians with type II diabetes were analyzed. Subjects were classified clinically as having early diabetes (n = 10), microalbuminuria (n = 17), normoalbuminuria, despite a duration of diabetes equal to that of the subjects with microalbuminuria (n = 12), or clinical nephropathy (n = 12). Subjects with microalbuminuria exhibited moderate increases in glomerular and mesangial volume when compared with those with early diabetes, but could not be distinguished from subjects who remained normoalbuminuric after an equal duration of diabetes. Subjects with clinical nephropathy exhibited global glomerular sclerosis and more prominent structural abnormalities in nonsclerosed glomeruli. Marked mesangial expansion was accompanied by a further increase in total glomerular volume. Glomerular capillary surface area remained stable, but the glomerular basement membrane thickness was increased and podocyte foot processes were broadened. Broadening of podocyte foot processes was associated with a reduction in the number of podocytes per glomerulus and an increase in the surface area covered by remaining podocytes. These findings suggest that podocyte loss contributes to the progression of diabetic nephropathy.

  View details for Web of Science ID A1997WE31100024

  View details for PubMedID 9006003

  View details for PubMedCentralID PMC507802

• In vivo suppression of the renal Na+/P-i cotransporter by antisense oligonucleotides PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Oberbauer, R., Schreiner, G. F., Biber, J., Murer, H., Meyer, T. W. 1996; 93 (10): 4903–6

  Abstract

  A 20-mer phosphorothioate oligonucleotide (AS1) was designed to hybridize to the message for the rat kidney sodium phosphate cotransporter NaPi-2 close to the translation initiation site. Single intravenous doses of this oligonucleotide were given to rats maintained on a low phosphorus diet to increase NaPi-2 expression. At 3 days after oligonucleotide infusion, rats receiving 2.5 micromol of AS1 exhibited a reduction in renal NaPi-2 to cyclophilin mRNA ratio by 40% +/- 17%, and rats receiving 7.5 micromol of AS1 exhibited a reduction in NaPi-2 to cyclophilin mRNA ratio by 46% +/- 21%. Reversed-sequence AS1 was without effect. The higher dose of 7.5 micromol of AS1 also reduced the rate of phosphate uptake into renal brush border membrane vesicles and the expression of NaPi-2 protein detected by Western blotting in these vesicles. Reversed sequence AS1 was again without effect on these parameters. These results suggest that systemically infused oligonucleotides can exert antisense effects in the renal proximal tubule.

  View details for DOI 10.1073/pnas.93.10.4903

  View details for Web of Science ID A1996UL25500070

  View details for PubMedID 8643501

  View details for PubMedCentralID PMC39377

• Atubular glomeruli in patients with chronic allograft rejection TRANSPLANTATION Pagtalunan, M. E., Oberbauer, R., Haas, M., Barlan, M., Mayer, G., Olson, J. L., Meyer, T. W. 1996; 61 (8): 1166–71

  Abstract

  Morphometric studies were performed in 15 patients with chronic renal allograft rejection. Biopsy cores were serially sectioned so that atubular glomeruli could be identified and volumes of individual glomeruli could be measured. Control tissue was obtained from 9 cadaver donors and 8 living donors. Serial sectioning revealed that atubular glomeruli were as common as sclerotic glomeruli in chronic rejection. The prevalence of atubular glomeruli averaged 18 +/- 15% (mean +/- SD) in recipients with chronic rejection, 2 +/- 2% in cadaver donors, and 1 +/- 3% in living donors (P<0.05, recipients vs. donor groups). In comparison, the prevalence of sclerotic glomeruli averaged 19 +/- 13%, 4 +/- 7%, and 7 +/- 10% in the three groups (P<0.05 recipients vs. donor groups). Atubular glomeruli exhibited reduced mean volume (3.1 +/- 0.9 x 10(6)micron(3) vs. 4.5 +/- 1.5 x lO(6)micron(3), atubular vs. open glomeruli in recipients, P < 0.05) but could not be distinguished from open glomeruli by their appearance on single sections. Recipients with chronic rejection exhibited tubular atrophy and interstitial fibrosis with an increase in the interstitial volume fraction to 51 +/- 14% as compared with 29 +/- 6% in cadaver donors and 17 +/- 2% in living donors (P<0.05 recipients vs. donor groups). Similar interstitial expansion was observed in recipients with a high prevalence of atubular glomeruli, recipients with a high prevalence of sclerotic glomeruli, and also in four recipients in whom the predominant form of glomerular injury was transplant glomerulopathy. These results suggest that mechanisms responsible for development of atubular glomeruli are among the processes that contribute to loss of graft function in patients with chronic rejection.

  View details for DOI 10.1097/00007890-199604270-00008

  View details for Web of Science ID A1996UJ00300008

  View details for PubMedID 8610412

• RENAL UPTAKE OF AN 18-MER PHOSPHOROTHIOATE OLIGONUCLEOTIDE KIDNEY INTERNATIONAL OBERBAUER, R., SCHREINER, G. F., MEYER, T. W. 1995; 48 (4): 1226–32

  Abstract

  Renal uptake of a 35S labeled 18-mer phosphorothioate oligodeoxynucleotide (molecular wt approximately 6,000) was evaluated following intravenous infusion into rats. The kidneys contained 21 +/- 3% of the infused dose at five hours after infusion and 3 +/- 1% of the infused dose at four days after infusion. The concentration of oligonucleotide was greater in the kidney than in the liver, spleen, or plasma at both intervals. Urine excretion of oligonucleotide label averaged 17 +/- 1%, 35 +/- 5%, and 64 +/- 3% of the infused dose at five hours, one day, and four days after infusion. Electrophoresis (PAGE) showed that oligonucleotide was retained in the kidney was the intact 18-mer at both five hours and four days after infusion, while full size oligonucleotide was not found in the urine at either interval. Light microscopic autoradiography showed that oligonucleotide uptake was most prominent in the early proximal tubule. Electron microscopic autoradiography indicated that oligonucleotide was not confined to the brush border or endocytic-lysosomal pathway. Micropuncture studies showed that the tubule fluid to plasma concentration ratios of oligonucleotide label averaged 7 +/- 3% in Bowman's space and 6 +/- 2% in the distal tubule. Despite restriction of filtration by plasma protein binding, as indicated by the low Bowman's space to plasma concentration ratio, the calculated tubular reabsorption rate for oligonucleotide was sufficient to account for the large amount of oligonucleotide found in the kidney after intravenous infusion. These results indicate that the proximal tubule plays a prominent role in the disposition of intravenously infused oligonucleotide, and raise the possibility that oligonucleotides could exert antisense effects in this nephron segment.

  View details for DOI 10.1038/ki.1995.406

  View details for Web of Science ID A1995RV92600036

  View details for PubMedID 8569084

• TUBULOINTERSTITIAL INJURY AND IMPAIRED RENAL-FUNCTION AFTER RECOVERY FROM ACUTE PUROMYCIN NEPHROSIS AMERICAN JOURNAL OF PHYSIOLOGY-RENAL FLUID AND ELECTROLYTE PHYSIOLOGY BABOOLAL, K., MEYER, T. W. 1995; 269 (3): F331–F338

  Abstract

  Renal function was assessed at 2 and 8 wk after infusion of puromycin into the left renal artery of Munich Wistar rats. At 2 wk, albumin excretion averaged 90 +/- 12 micrograms/min in the left kidney and 4 +/- 1 microgram/min in the right kidney. Unilateral nephrosis was accompanied by reduction in the glomerular filtration rate (GFR) (left, 0.71 +/- 0.04; right, 1.31 +/- 0.02 ml/min) and by impaired excretion of sodium (FENa; left, 0.025 +/- 0.004; right, 0.064 +/- 0.006%). Reductions in GFR and FENa in the nephrotic kidney were not reversed by acute angiotensin II receptor blockade with losartan. At 8 wk, albumin excretion averaged 6 +/- 1 in the left kidney and 8 +/- 1 microgram/min in the right kidney. Recovery from nephrosis was accompanied by persistent reduction in GFR (left, 1.05 +/- 0.05; right, 1.41 +/- 0.05 ml/min) and impairment of sodium excretion in the previously nephrotic left kidney (left, 0.031 +/- 0.004; right, 0.051 +/- 0.004%). Losartan again did not return GFR and FENa toward normal. The reductions in GFR and FENa in the previously nephrotic left kidney were associated with structural changes, including intratubular casts, an increased fractional volume of the interstitium (left, 25 +/- 1; right, 15 +/- 1%), decreased fractional volume of tubules (left, 66 +/- 2; right, 77 +/- 1%), and glomerular collapse (left, 15 +/- 2; right, 1 +/- 1%). These findings suggest that tubulointerstitial injury can cause persistent reduction in GFR and impairment of sodium excretion after recovery from acute nephrosis.

  View details for Web of Science ID A1995RV40200005

  View details for PubMedID 7573481

• ENDOTHELIAL-CELL INJURY INITIATES GLOMERULAR SCLEROSIS IN THE RAT REMNANT KIDNEY JOURNAL OF CLINICAL INVESTIGATION Lee, L. K., Meyer, T. W., Pollock, A. S., Lovett, D. H. 1995; 96 (2): 953-964

  Abstract

  The development of progressive glomerulosclerosis in the renal ablation model has been ascribed to a number of humoral and hemodynamic events, including the peptide growth factor, transforming growth factor-beta 1 (TGF-beta 1). An important role has also been attributed to angiotensin II (AII), which, in addition to its hemodynamic effects, can stimulate transcription of TGF-beta 1. We postulated that increased glomerular production of AII, resulting from enhanced intrinsic angiotensinogen expression, stimulates local TGF-beta 1 synthesis, activating glomerular matrix protein synthesis, and leads to sclerosis. Using in situ reverse transcription, the glomerular cell sites of alpha-1 (IV) collagen, fibronectin, laminin B1, angiotensinogen, and TGF-beta 1 mRNA synthesis were determined at sequential periods following renal ablation. The early hypertrophic phase was associated with global, but transient, increases in the mRNA for alpha-1 (IV) collagen. No changes were noted for fibronectin, TGF-beta 1, and angiotensinogen mRNAs. At 24 d after ablation, at which time sclerosis is not evident, endothelial cells, particularly in the dilated capillaries at the vascular pole, expressed angiotensinogen and TGF-beta 1 mRNAs, as well as fibronectin and laminin B1 RNA transcripts. By 74 d after ablation angiotensinogen and TGF-beta 1 mRNAs were widely distributed among endothelial and mesangial cells, and were particularly prominent in regions of evolving sclerosis. These same regions were also notable for enhanced expression of matrix protein mRNAs, particularly fibronectin. All receptor blockade inhibited angiotensinogen, TGF-beta 1, fibronectin, and laminin B1 mRNA expression by the endothelium. We conclude that, as a result of hemodynamic changes, injured or activated endothelium synthesizes angiotensinogen, triggering a cascade of TGF-beta 1 and matrix protein gene expression with resultant development of the segmental glomerular sclerotic lesion.

  View details for Web of Science ID A1995RM46600037

  View details for PubMedID 7635988

  View details for PubMedCentralID PMC185283

• THE EFFECT OF HYPERGLYCEMIA ON GLOMERULAR FUNCTION IN OBESE ZUCKER RATS JOURNAL OF LABORATORY AND CLINICAL MEDICINE PARK, S. K., MEYER, T. W. 1995; 125 (4): 501–7

  Abstract

  Studies were carried out in two groups of obese male Zucker rats with hereditary insulin resistance. Group 1 rats were made hyperglycemic by reducing beta-cell reserve with streptozotocin. Group 2 rats served as controls. Group 1 rats exhibited hyperglycemia (blood glucose concentration, 263 +/- 14 mg/dl) whereas insulin levels remained greater than those observed in lean rats (plasma insulin concentrations: group 1,508 +/- 89 mU/ml; lean rats, 91 +/- 23 mU/ml). In group 2 rats more marked hyperinsulinemia (plasma insulin concentration, 1096 +/- 234 mU/ml) maintained normoglycemia (blood glucose concentration, 75 +/- 4 mg/dl). Studies at 5 weeks showed that hyperglycemic group 1 rats exhibited increases in kidney weight (group 1, 2.78 +/- 0.11 gm; group 2, 2.16 +/- 0.07 gm; p < 0.05) and glomerular filtration rate (GFR) (group 1, 1.83 +/- 0.08 ml/min; group 2, 1.55 +/- 0.10 ml/min; p < 0.05). Micropuncture revealed that the increase in GFR in hyperglycemic rats was attributable to increases in the single-nephron plasma flow rate (group 1, 225 +/- 16 nl/min; group 2, 172 +/- 14 nl/min; p < 0.05) and the glomerular ultrafiltration coefficient (group 1, 2.49 +/- 0.17 nl/min/mm Hg; group 2, 2.02 +/- 0.14 nl/min/mm Hg; p < 0.05), which were not accompanied by an increase in glomerular transcapillary hydraulic pressure (group 1, 49 +/- 1 mm Hg; group 2, 48 +/- 1 mm Hg). Morphologic studies revealed that the increase in GFR in group 1 was associated with an increase in glomerular volume (group 1, 3.46 +/- 0.15 x 10(6) m3; group 2, 2.99 +/- 0.14 x 10(6) m3; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1995QQ63100013

  View details for PubMedID 7706906

• MORPHOMETRIC ANALYSIS OF EFFECTS OF ANGIOTENSIN-II ON GLOMERULAR STRUCTURE IN RATS AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY Pagtalunan, M. E., Rasch, R., Rennke, H. G., Meyer, T. W. 1995; 268 (1): F82-F88

  Abstract

  Micropuncture and morphometric studies related the effects of angiotensin II (ANG II) on glomerular function and structure. Compared with control animals, rats receiving an intrarenal infusion of ANG II at 40 ng.kg-1.min-1 exhibited a marked reduction in the glomerular ultrafiltration coefficient (Kf) (0.84 +/- 0.13 vs. 1.43 +/- 0.05 microliters.s-1.mmHg-1, ANG II vs. control), which caused a decrease in glomerular filtration rate (GFR) (1.04 +/- 0.11 vs. 1.27 +/- 0.11 ml/min) despite an increase in glomerular transcapillary hydraulic pressure difference (46 +/- 1 vs. 40 +/- 1 mmHg). Morphometric studies showed that these hemodynamic changes were not associated with any reduction in glomerular volume (1.27 +/- 0.05 vs. 1.31 +/- 0.07 x 10(6) microns3, ANG II vs. control), glomerular capillary volume (4.25 +/- 0.36 vs. 4.41 +/- 0.33 x 10(5) microns3), or glomerular peripheral capillary surface area (2.24 +/- 0.11 vs. 2.29 +/- 0.30 x 10(5) microns2). Higher-power electron micrographs showed that ANG II also did not alter mean foot process width (478 +/- 14 vs. 491 +/- 18 nm, ANG II vs. control), reduce the total filtration slit length overlying the peripheral capillary wall (7.0 +/- 0.6 vs. 6.6 +/- 0.5 x 10(5) microns), or reduce the average width of individual filtration slits (45 +/- 2 vs. 43 +/- 2 nm). ANG II infusion thus caused a 40% reduction in the value of Kf without causing detectable changes in epithelial cell or filtration slit structure.

  View details for Web of Science ID A1995QB70200010

  View details for PubMedID 7840251

• THE EFFECT OF ACUTE ANGIOTENSIN-II BLOCKADE ON RENAL-FUNCTION IN RATS WITH REDUCED RENAL MASS KIDNEY INTERNATIONAL BABOOLAL, K., MEYER, T. W. 1994; 46 (4): 980–85

  Abstract

  The effect of acute Ang II blockade on renal function in rats with reduced nephron number was assessed in micropuncture studies. The Ang II receptor blocker, losartan, was administered at a dose of 10 mg i.v. at two intervals following five-sixths renal ablation. At eight weeks following ablation, Ang II blockade (Ang IIX) increased sodium excretion [UNa V, Ang IIX 2.2 +/- 0.4 microEq/min; time control (TC) 1.0 +/- 0.3 microEq/min; P < 0.05] but did not reduce mean arterial pressure (AP, Ang IIX 142 +/- 6 mm Hg; TC 151 +/- 6 mmHg), glomerular transcapillary pressure (delta P, Ang IIX 50 +/- 1 mm Hg; TC 50 +/- 1 mm Hg), or urine albumin excretion (UAlb V: Ang IIX 149 +/- 18 micrograms/min; TC 168 +/- 20 micrograms/min). Similarly, at two weeks following ablation, Ang II blockade increased UNa V (Ang IIX 2.8 +/- 0.4 microEq/min; TC 0.5 +/- 0.2 microEq/min; P < 0.05) without reducing AP (Ang IIX 132 +/- 6 mm Hg; TC 140 +/- 7 mm Hg), delta P (Ang IIX 50 +/- 3 mm Hg; TC 48 +/- 2 mm Hg), or UAlb V (Ang IIX 32 +/- 3 micrograms/min; TC 36 +/- 10 micrograms/min). These findings indicate that within the remant kidney, Ang II promotes sodium retention but does not have an acutely reversible effect on glomerular pressure or permselectivity.

  View details for DOI 10.1038/ki.1994.357

  View details for Web of Science ID A1994PH78600004

  View details for PubMedID 7861724

• GLOMERULAR-PERMEABILITY BARRIER IN THE RAT - FUNCTIONAL ASSESSMENT BY IN-VITRO METHODS JOURNAL OF CLINICAL INVESTIGATION DANIELS, B. S., DEEN, W. M., MAYER, G., MEYER, T., HOSTETTER, T. H. 1993; 92 (2): 929–36

  Abstract

  The formation of glomerular ultrafiltrate is dependent on the prevailing hemodynamic forces within the glomerular microcirculation and the intrinsic properties of the filtration barrier. However, direct assessment of the permeability barrier is difficult with most available techniques. We used confocal microscopy to image 1-micron thick optical cross-sections of isolated intact glomeruli and glomeruli denuded of cells and quantitated dextran (70,000 mol wt) diffusion from the capillary lumen. Dextran permeance was 11 times greater for the acellular filtration barrier than the intact peripheral capillary. Consideration of the basement membrane and cells as series resistors demonstrated that cells of the filtration barrier contribute 90% of the total resistance to macromolecular permeance. Using a different approach, dextran sieving coefficients for acellular glomeruli consolidated as a multilayer sheet in a filtration cell were similar to those for intact glomeruli in vivo at radii 30-36 A and approximately 50 times greater at a dextran radius of 60 A. The presence of cells significantly reduced hydraulic permeability determined on consolidated intact or acellular glomeruli in an ultrafiltration cell with 50 mmHg applied pressure. The glomerular basement membrane does restrict macromolecular permeability but cells are important determinants of the overall macromolecular and hydraulic permeability of the glomerulus.

  View details for DOI 10.1172/JCI116668

  View details for Web of Science ID A1993LT16900051

  View details for PubMedID 7688767

  View details for PubMedCentralID PMC294932

• THE EFFECTS OF BLOOD-PRESSURE REDUCTION ON CYCLOSPORINE NEPHROTOXICITY IN THE RAT JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Lafayette, R. A., Mayer, G., Meyer, T. W. 1993; 3 (12): 1892-1899

  Abstract

  The effects of blood pressure reduction on cyclosporine nephrotoxicity were studied over 12 months in four groups of rats. Group 1 received no drugs and served as controls. Groups 2, 3, and 4 received cyclosporine (CyA), approximately 9 mg/kg.day, in their food. In addition, Group 3 received enalapril and Group 4 received minoxidil, hydrochlorothiazide, and reserpine. Time-averaged monthly systolic blood pressure was equal in Groups 1 and 2 (136 +/- 1 and 135 +/- 1 mm Hg, respectively). Antihypertensive agents reduced average systolic blood pressure in Groups 3 and 4 (116 +/- 1 and 117 +/- 1 mm Hg, respectively). Morphometric studies showed that 12 months of CyA treatment caused interstitial fibrosis with an increase in the fractional volume of cortical interstitium (VvInt: Group 2, 20 +/- 1%; Group 1, 11 +/- 1%) and a reduction in mean glomerular volume (VG. Group 2, (2.00 +/- 0.06) x 10(6) mu 3; Group 1, (2.48 +/- 0.06) x 10(6) mu 3). These structural changes were accompanied by a significant reduction in GFR (Group 2, 2.27 +/- 0.10 mL/min; Group 1, 2.76 +/- 0.10 mL/min). Cotreatment with enalapril reduced interstitial fibrosis (VvInt, 14 +/- 1%) and maintained VG (2.23 +/- 0.08 x 10(6) mu 3) and GFR (2.56 +/- 0.08 mL/min) at near-normal values in Group 3. In contrast, the combination antihypertensive regimen increased the extent of interstitial fibrosis (VvInt, 24 +/- 1%) and further lowered VG (1.72 +/- 0.05 x 10(6) mu 3) and GFR (1.72 +/- 0.05 mL/min) in Group 4. These results show that sustained treatment with a moderate dose of CyA causes interstitial fibrosis and impairs renal function in rats. The administration of enalapril, but not minoxidil, reserpine, and hydrochlorothiazide, limits renal injury in this model.

  View details for Web of Science ID A1993LJ29800007

  View details for PubMedID 8338921

• 45 YEAR FOLLOW-UP AFTER UNINEPHRECTOMY KIDNEY INTERNATIONAL NARKUNBURGESS, D. M., NOLAN, C. R., NORMAN, J. E., PAGE, W. F., MILLER, P. L., MEYER, T. W. 1993; 43 (5): 1110–15

  Abstract

  This study examined the consequences of nephrectomy in United States Army personnel who lost a kidney due to trauma during World War II (WWII). Records of 62 servicemen who underwent nephrectomy at an average age of 25 years were obtained. Mortality was compared with that of WWII servicemen of the same age. Medical records of 28 deceased subjects were reviewed for evidence of kidney disease. Medical histories were obtained and blood pressure and kidney function were assessed in 28 living subjects. Two subjects could not be located, and four subjects declined to participate. Mortality at 45 years was not increased in nephrectomized subjects. Kidney disease present in six of 28 deceased subjects was attributable to causes other than prior nephrectomy. Glomerular sclerosis was not increased in 10 subjects who had autopsy examinations. The prevalence of hypertension was not increased in living subjects. Five of 28 living subjects had abnormal renal function manifested by proteinuria greater than 250 mg/day in four cases (range: 377 to 535 mg/day) and serum creatinine levels greater than 1.5 mg/dl in three cases (range: 1.7 to 1.9 mg/dl). Conditions other than nephrectomy could have contributed to impairment of renal function in each of these subjects. These findings suggest that uninephrectomy in young adults has few major adverse consequences over 45 years.

  View details for DOI 10.1038/ki.1993.156

  View details for Web of Science ID A1993KX28900017

  View details for PubMedID 8510390

• EFFECTS OF ANGIOTENSIN-II RECEPTOR BLOCKADE ON REMNANT GLOMERULAR PERMSELECTIVITY KIDNEY INTERNATIONAL Mayer, G., Lafayette, R. A., Oliver, J., Deen, W. M., Myers, B. D., Meyer, T. W. 1993; 43 (2): 346-353

  Abstract

  This study examined the mechanisms by which angiotensin II (Ang II) receptor blockade improves glomerular barrier function in rats with reduced nephron number. Proteinuria was measured at four weeks after 5/6 renal ablation, and rats were then divided into a group which received the Ang II receptor blocker MK954 and a group which received no treatment. Studies performed one week later showed that Ang II receptor blockade reduced proteinuria without altering GFR in renal ablated rats. Micropuncture studies showed that Ang II blockade reduced both mean arterial pressure (142 +/- 7 mm Hg, ablation without treatment; 105 +/- 2 mm Hg, ablation with treatment) and glomerular transcapillary pressure (54 +/- 3 mm Hg, ablation without treatment; 43 +/- 1 mm Hg, ablation with treatment). Dextran sieving studies showed that untreated rats developed a size-selective defect characterized by increased transglomerular passage of neutral dextrans with radii 54 to 76 A and a charge-selective defect characterized by an increased transglomerular passage of anionic dextran sulfate with a radius of approximately 18 A. Ang II blockade reduced fractional clearance values for large neutral dextrans near to values observed in normal rats but had no effect on the fractional clearance of dextran sulfate (0.68 +/- 0.11, ablation without treatment; 0.66 +/- 0.08, ablation with treatment; 0.46 +/- 0.05, normal rats). These findings indicate that reducing Ang II activity improves size-selectivity without affecting charge-selectivity in injured remnant glomeruli.

  View details for Web of Science ID A1993KH90700009

  View details for PubMedID 7680077

• THE EFFECTS OF FRUCTOSE FEEDING ON GLOMERULAR STRUCTURE IN THE RAT JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY PARK, S. K., MEYER, T. W. 1992; 3 (6): 1330–32

  View details for Web of Science ID A1992KD27000017

  View details for PubMedID 1477329

• MORE LESSONS FROM THE REMNANT KIDNEY JOURNAL OF LABORATORY AND CLINICAL MEDICINE MEYER, T. W. 1992; 120 (6): 814–15

  View details for Web of Science ID A1992KA90900001

  View details for PubMedID 1453098

• ANGIOTENSIN-II RECEPTOR BLOCKADE LIMITS GLOMERULAR INJURY IN RATS WITH REDUCED RENAL MASS JOURNAL OF CLINICAL INVESTIGATION Lafayette, R. A., Mayer, G., Park, S. K., Meyer, T. W. 1992; 90 (3): 766-771

  Abstract

  The effects of angiotensin II (AII) blockade were compared with the effects of angiotensin converting enzyme inhibition in rats with reduced nephron number. Rats were subjected to five-sixths renal ablation and divided into four groups with similar values for blood pressure and serum creatinine after 2 wk. Group 1 then served as untreated controls, while group 2 received the AII receptor antagonist MK954 (which has previously been designated DuP753), group 3 received the converting enzyme inhibitor enalapril, and group 4 received a combination of reserpine, hydralazine, and hydrochlorothiazide. Micropuncture and morphologic studies were performed 10 wk later. Converting enzyme inhibition, AII receptor blockade, and the combination regimen were equally effective in reversing systemic hypertension (time-averaged systolic blood pressure: group 1, 185 +/- 5 mmHg; group 2, 125 +/- 2 mmHg; group 3, 127 +/- 2 mmHg; group 4, 117 +/- 4 mmHg). Micropuncture studies showed that glomerular transcapillary pressure was reduced significantly by converting enzyme inhibition and by AII blockade but not by the combination regimen (delta P: group 1, 49 +/- 1 mmHg; group 2, 42 +/- 1 mmHg; group 3, 40 +/- 2 mmHg, group 4, 47 +/- 1 mmHg). Reduction of systemic blood pressure was associated with the development of markedly less proteinuria and segmental glomerular sclerosis in rats receiving enalapril and MK954 but not in rats receiving the combination regimen (prevalence of glomerular sclerotic lesions: group 1, 41 +/- 4%; group 2, 9 +/- 1%; group 3, 9 +/- 1%; group 4, 33 +/- 6%). These results indicate that the effects of converting enzyme inhibition on remnant glomerular function and structure depend on reduction in AII activity and are not attributable simply to normalization of systemic blood pressure.

  View details for Web of Science ID A1992JN95900012

  View details for PubMedID 1522231

• CALMODULIN TRAPPING BY CALCIUM-CALMODULIN DEPENDENT PROTEIN-KINASE SCIENCE Meyer, T., Hanson, P. I., Stryer, L., Schulman, H. 1992; 256 (5060): 1199-1202

  Abstract

  Multifunctional calcium-calmodulin-dependent protein kinase (CaM kinase) transduces transient elevations in intracellular calcium into changes in the phosphorylation state and activity of target proteins. By fluorescence emission anisotropy, the affinity of CaM kinase for dansylated calmodulin was measured and found to increase 1000 times after autophosphorylation of the threonine at position 286 of the protein. Autophosphorylation markedly slowed the release of bound calcium-calmodulin; the release time increased from less than a second to several hundred seconds. In essence, calmodulin is trapped by autophosphorylation. The shift in affinity does not occur in a site-directed mutant in which threonine at position 286 has been replaced by a non-phosphorylatable amino acid. These experiments demonstrate the existence of a new state in which calmodulin is bound to CaM kinase even though the concentration of calcium is basal. Calmodulin trapping provides for molecular potentiation of calcium transients and may enable detection of their frequency.

  View details for Web of Science ID A1992HV19200035

  View details for PubMedID 1317063

• GLOMERULAR HYPERTROPHY ACCELERATES HYPERTENSIVE GLOMERULAR INJURY IN RATS AMERICAN JOURNAL OF PHYSIOLOGY Miller, P. L., Rennke, H. G., Meyer, T. W. 1991; 261 (3): F459-F465

  Abstract

  Micropuncture and morphological studies were performed in four groups of rats that received subcutaneous infusions of saline or angiotensin II (ANG II) for 8 wk. Group 1 rats received saline; group 2 rats were subjected to uninephrectomy and then received saline; group 3 rats received ANG II (100 ng/min); and group 4 rats were subjected to uninephrectomy and then received ANG II (50 ng/min). In comparison with group 1 rats, group 2 rats exhibited no increase in mean arterial pressure (MAP) (group 2, 102 +/- 6 mmHg; group 1, 104 +/- 10 mmHg) or glomerular capillary pressure (PGC) (group 2, 56 +/- 3 mmHg; group 1, 55 +/- 4 mmHg). In the absence of glomerular hypertension, an increase in glomerular volume (VG) was not associated with glomerular sclerosis in group 2 rats. In contrast to group 2 rats, group 3 rats exhibited increases in MAP (161 +/- 13 mmHg) and PGC (70 +/- 7 mmHg) without any increase in VG. Glomerular hypertension was associated with development of increased albuminuria and glomerular sclerosis in group 3. Group 4 rats exhibited increases in MAP (157 +/- 18 mmHg), PGC (69 +/- 6 mmHg), and VG. These rats also developed glomerular sclerosis and significantly more albuminuria than would have been expected from simple combination of effects of uninephrectomy and ANG II infusion. Additional morphological studies were performed in two groups of rats that received ANG II for 12 wk. Over this period, uninephrectomized group 6 rats infused with ANG II (50 ng/min) developed markedly greater albuminuria and glomerular sclerosis than intact group 5 rats infused with ANG II (100 ng/min).(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1991GE63800097

  View details for PubMedID 1887907

• Effects of tissue preparation on glomerular volume and capillary structure in the rat. Laboratory investigation; a journal of technical methods and pathology Miller, P. L., Meyer, T. W. 1990; 63 (6): 862-866

  Abstract

  The effect of tissue preparation on glomerular volume in normal rats was assessed. In group 1 rats (N = 8), kidney tissue was obtained by immersion-fixation of needle biopsy cores and excised slices from the left kidney and by perfusion-fixation of the remaining right kidney at close to ambient arterial pressure. In group 2 rats (N = 8), tissue was obtained by kidney perfusion at a supernormal pressure (approximately 165 mm Hg). Studies in group 1 showed that mean glomerular volume (VG) was not different in biopsy cores (1.07 +/- 0.13 x 10(6) mu 3) and in kidney slices fixed by immersion (0.92 +/- 0.09 x 10(6) mu 3). A significantly higher value for VG (1.51 +/- 0.18 x 10(6) mu 3) was obtained in kidneys perfusion-fixed at close to ambient arterial pressure. Morphometric studies showed that reduced VG in immersion-fixed tissue was associated with lowered values for peripheral capillary wall surface area (225 +/- 21 x 10(3) mu 2 versus 159 +/- 27 x 10(3) mu 2, p less than 0.05) and reduced mean capillary radius (4.5 +/- 6 mu versus 2.7 +/- 3 mu, p less than 0.05) compared with perfusion-fixed tissue. The data suggest that glomerular capillaries contract when tissue is immersion-fixed and shows that values for mean peripheral capillary wall surface area/glomerulus and mean glomerular capillary radius obtained in immersion- and perfusion-fixed tissue cannot be directly compared. Studies in group 2 showed that VG was not altered by perfusion at a supernormal pressure (1.40 +/- 0.16 x 10(6) mu 3) as compared with perfusion at ambient pressure (1.51 +/- 0.18 x 10(6) mu 3). Further studies in group 1, however, showed that values for VG obtained in paraffin-embedded tissue were approximately 40% lower than values for VG obtained in methacrylate-embedded tissue from the same kidneys.

  View details for PubMedID 2255192

• CONVERTING ENZYME-INHIBITION AND GLOMERULAR SIZE SELECTIVITY IN DIABETIC NEPHROPATHY SATELLITE SYMP OF THE 1989 ANNUAL MEETING OF THE AMERICAN SOC OF NEPHROLOGY Meyer, T. W., Morelli, E., LOON, N., Peters, W., Myers, B. D. WILLIAMS & WILKINS. 1990: S64–S68

  Abstract

  Differential solute clearances were used to examine the effects of enalapril on glomerular barrier function in 16 proteinuria patients with diabetic glomerulopathy. In these patients, a 90-day course of enalapril reduced arterial pressure without lowering renal plasma flow or glomerular filtration rate. Glomerular clearances of dextrans of broad size distribution (28 to 60 A) were lowered significantly. Theoretical analysis of the dextran clearance profiles revealed that enalapril shifted glomerular pore size distribution to a smaller size. This change in barrier size selectivity was associated with a reduction in fractional albumin and immunoglobulin G clearances during enalapril therapy; urinary protein excretion tended to decrease in parallel. These results indicate that converting enzyme inhibition diminishes glomerular permeability to proteins in diabetic nephropathy by enhancing barrier size selectivity. Because enalapril therapy did not alter the renal plasma flow rate or glomerular filtration rate, these results further suggest that the primary action of enalapril may be to modulate the intrinsic membrane properties of the glomerular barrier.

  View details for Web of Science ID A1990FT10100005

  View details for PubMedID 16989068

• REVERSAL OF GLOMERULAR HYPERFILTRATION AND RENAL HYPERTROPHY BY BLOOD-GLUCOSE NORMALIZATION IN DIABETIC RATS DIABETES Stackhouse, S., Miller, P. L., Park, S. K., Meyer, T. W. 1990; 39 (8): 989-995

  Abstract

  Two groups of rats with streptozocin-induced diabetes and one group of nondiabetic control rats were studied. Group 1 diabetic rats received daily insulin to maintain blood glucose levels at 300-400 mg/dl for 44 wk. Group 2 diabetic rats received the same insulin regimen for 37 wk and then received an increased dose of insulin to return blood glucose levels close to normal for 7 wk. Group 3 nondiabetic rats were age-matched controls. Glomerular filtration rate (GFR) and kidney weight were elevated in moderately hyperglycemic group 1 rats compared with group 3 rats. Normalization of blood glucose returned both GFR (group 1, 1.83 +/- 0.04 ml/min; group 2, 1.36 +/- 0.05 ml/min; group 3, 1.45 +/- 0.07 ml/min) and kidney weight (group 1, 2.55 +/- 0.06 g; group 2, 1.82 +/- 0.05 g; group 3, 1.72 +/- 0.06 g) to normal in group 2 rats. Despite a sustained increase in GFR, group 1 rats did not exhibit any increase in glomerular volume (group 1, 2.77 +/- 0.09 x 10(6) microns3; group 2, 2.69 +/- 0.09 x 10(6) microns3; group 3, 2.81 +/- 0.7 x 10(6) microns3). Group 1 rats did, however, exhibit a significant increase in glomerular mesangial volume (group 1, 0.31 +/- 0.02 x 10(6) microns3; group 2, 0.28 +/- 0.02 x 10(6) microns3; group 3, 0.21 +/- 0.01 x 10(6) microns3), which was not reversed by normalization of blood glucose in group 2. These findings show that normalization of blood glucose can reverse established glomerular hyperfiltration and renal hypertrophy in moderately hyperglycemic diabetic rats. They further indicate that mesangial expansion is associated with sustained moderate hyperglycemia in this disease model.

  View details for Web of Science ID A1990DQ94300018

  View details for PubMedID 2373266

• HYPERTENSION AND PROGRESSIVE GLOMERULAR INJURY CAUSED BY FOCAL GLOMERULAR ISCHEMIA AMERICAN JOURNAL OF PHYSIOLOGY Miller, P. L., Rennke, H. G., Meyer, T. W. 1990; 259 (2): F239-F245

  Abstract

  Sprague-Dawley rats received infusions of 55-microns microspheres (groups 1 and 3) or dextrose (groups 2 and 4) into both renal arteries. Groups 1 and 2 rats were studied over 7 mo. In group 1 rats renal embolization increased the mean arterial pressure (group 1, 140 +/- 4 mmHg; group 2, 118 +/- 2 mmHg) without reducing the glomerular filtration rate (GFR; group 1, 4.69 +/- 0.16 ml/min; group 2, 4.57 +/- 0.22 ml/min). Micropuncture studies showed that systemic hypertension was accompanied by an increase in the glomerular capillary pressure of functioning nephrons in group 1 rats. Morphological studies showed that renal embolization caused both glomerular ischemia (group 1, 11.8 +/- 1.9% of glomeruli; group 2, 0.1 +/- 0.1% of glomeruli) and glomerular segmental sclerosis (group 1, 15.0 +/- 1.0% of glomeruli; group 2, 3.3 +/- 0.2% of glomeruli). Groups 3 and 4 rats were studied over 2 mo. Renal embolization again increased the mean arterial pressure without reducing the GFR in group 3 rats. Morphological studies showed that at 2 mo renal embolization caused glomerular ischemia without glomerular segmental sclerosis. These studies show that focal glomerular ischemia can cause systemic and glomerular capillary hypertension in the absence of a reduction in the GFR. They further show that focal glomerular ischemia can cause progressive sclerotic injury in the remaining, nonischemic portion of the glomerular population.

  View details for Web of Science ID A1990DU95400083

  View details for PubMedID 2386205

• MECHANISMS OF PROTEINURIA IN DIABETIC RENAL-DISEASE SEMINARS IN NEPHROLOGY Meyer, T. W. 1990; 10 (3): 194-202

  View details for Web of Science ID A1990DD85900003

  View details for PubMedID 2190277

• GLOMERULAR HYPERTROPHY AGGRAVATES EPITHELIAL-CELL INJURY IN NEPHROTIC RATS JOURNAL OF CLINICAL INVESTIGATION Miller, P. L., Scholey, J. W., Rennke, H. G., Meyer, T. W. 1990; 85 (4): 1119-1126

  Abstract

  Glomerular function and structure were assessed after reduction of nephron number and restriction of protein intake in rats with adriamycin nephrosis. Rats received an injection of adriamycin and were divided into three groups with similar values for albuminuria after 4 wk. Group 1 rats then served as controls, group 2 rats were subjected to four-fifths renal ablation, and group 3 rats were placed on a low protein diet (8% protein) while group 1 and group 2 rats remained on a standard diet (24% protein). Micropuncture and morphometric studies were performed 10 d later. Estimated single-nephron albuminuria (SNalb) was increased by renal ablation in group 2 and decreased by protein restriction in group 3 (group 1, 20 +/- 2 micrograms/d; group 2, 68 +/- 7 micrograms/d; group 3, 12 +/- 1 microgram/d, P less than 0.05 groups 2 and 3 vs. 1). Increased SNalb was associated with increased glomerular volume in group 2 and reduced SNalb was associated with reduced glomerular volume in group 3. (group 1, 1.44 +/- 0.04 x 10(6) microns 3; group 2, 1.66 +/- 0.08 x 10(6) microns 3; group 3, 1.26 +/- 0.03 x 10(6) microns 3, P less than 0.05 groups 2 and 3 vs. 1). Increased SNalb in group 2 was not associated with an increase in glomerular transcapillary hydraulic pressure. The area of epithelial cell detachment from the peripheral capillary wall was markedly increased in group 2 but not perceptibly altered in group 3 (group 1, 16 +/- 5 x 10(2) microns 2; group 2, 65 +/- 17 x 10(2) microns 2; group 3, 18 +/- 5 x 10(2) microns 2; P less than 0.05 group 2 vs. 1). These studies show that glomerular hypertrophy is associated with increased epithelial cell detachment from the peripheral capillary wall and with increased remnant nephron albuminuria after reduction of nephron number in rats with established nephrosis.

  View details for Web of Science ID A1990CX97700018

  View details for PubMedID 2318969

• EFFECTS OF CONVERTING-ENZYME INHIBITION ON BARRIER FUNCTION IN DIABETIC GLOMERULOPATHY DIABETES Morelli, E., LOON, N., Meyer, T., Peters, W., Myers, B. D. 1990; 39 (1): 76-82

  Abstract

  Differential solute clearances were used to examine the effects of a 90-day course of enalapril on glomerular barrier function in 16 proteinuric patients with diabetic glomerulopathy. By day 90, plasma renin and prorenin became elevated, and arterial pressure declined. Transglomerular passage of dextrans of broad size distribution (radii 28-60 A) was lowered significantly. In a subset of 8 patients, withdrawal of enalapril was followed after an additional 30 days by a return of renin levels and arterial pressure to pretreatment levels. The dextran-sieving profile also returned to baseline, becoming uniformly elevated above treated day-90 levels. A theoretical analysis of the serial dextran-sieving profiles indicated that enalapril shifted glomerular pore size distribution to smaller size. These changes in barrier size selectivity were associated with a reduction in fractional albumin and IgG clearances during enalapril therapy and a subsequent rise in these quantities after its withdrawal; urinary protein excretion rate tended to vary in parallel. We conclude that inhibition of converting enzyme in humans with established diabetic glomerulopathy diminishes glomerular permeability to proteins by enhancing barrier size selectivity. Because neither enalapril therapy nor its withdrawal influenced the glomerular filtration or renal plasma flow rates significantly, we propose that the primary action of enalapril may be to modulate the intrinsic membrane properties of the glomerular barrier.

  View details for Web of Science ID A1990CG67100012

  View details for PubMedID 1698674

• ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS IN THE TREATMENT OF DIABETIC GLOMERULOPATHY SATELLITE SYMP ON ACE INHIBITORS AND THE KIDNEY Myers, B. D., Meyer, T. W. KARGER. 1990: 27–29

  Abstract

  Continuous therapy with an angiotensin-converting enzyme (ACE) inhibitor has been shown to have a glomerular vasodepressor effect in the newly diabetic rat and to largely prevent subsequent development of severe sclerosing glomerular injury. Preliminary studies in humans with established diabetic glomerular injury reveal that ACE inhibitor therapy has an antiproteinuric effect and may also slow the decline in glomerular filtration rate that usually attends this disorder. Although promising, the human studies are inconclusive because of short duration and other limitations in experimental technique and study design. Additional trials are required to confirm more positively this amelioration of human diabetic glomerular injury by ACE inhibitor therapy.

  View details for Web of Science ID A1990DB92700005

  View details for PubMedID 2345590

• ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS IN THE PREVENTION OF EXPERIMENTAL DIABETIC GLOMERULOPATHY AMERICAN JOURNAL OF KIDNEY DISEASES Myers, B. D., Meyer, T. W. 1989; 13 (1): 20-24

  Abstract

  Continuous therapy with an angiotensin-converting enzyme (ACE) inhibitor has been shown to have a glomerular vasodepressor effect in the newly diabetic rat and to largely prevent the subsequent development of a severe, sclerosing glomerular injury. Preliminary studies in humans with established diabetic glomerular injury (DGI) reveal that ACE inhibitor therapy has an antiproteinuric effect and may also show the decline in glomerular filtration rate that usually attends this disorder. Although promising, the human studies are inconclusive because of short duration and other limitations in experimental technique and study design. Additional trials are needed to confirm a specific effect of ACE inhibitor therapy to ameliorate human diabetic glomerular injury.

  View details for Web of Science ID A1989R802700007

  View details for PubMedID 2643307

• INCREASED SINGLE-NEPHRON PROTEIN EXCRETION AFTER RENAL ABLATION IN NEPHROTIC RATS AMERICAN JOURNAL OF PHYSIOLOGY Meyer, T. W., Rennke, H. G. 1988; 255 (6): F1243-F1248

  Abstract

  The effects of reducing nephron number in rats with established nephrosis were investigated. Rats received an injection of adriamycin and were divided into three groups with similar values for proteinuria after 4 wk. Group 1 rats were then subjected to sham operation. Group 2 rats were subjected to four-fifths renal ablation, and group 3 rats were subjected to four-fifths renal ablation and then maintained on enalapril. Micropuncture and morphological studies were performed 3 wk later. During this 3-wk period, proteinuria increased slightly in each group. Increased proteinuria in groups 2 and 3 reflected a dramatic increase in remnant nephron proteinuria after renal ablation in nephrotic rats. Increased remnant nephron proteinuria in groups 2 and 3 was associated with increased single-nephron glomerular filtration rate (group 1, 30 +/- 2 nl/min; group 2, 54 +/- 3 nl/min; group 3, 41 +/- 4 nl/min) and increased glomerular volume (group 1, 0.93 +/- 0.05 x 10(6) micron 3; group 2, 1.30 +/- 0.09 x 10(6) micron 3; group 3, 1.27 +/- 0.05 x 10(6) micron 3). The increase in single-nephron glomerular filtration rate after renal ablation in both group 2 and 3 rats was attributable to an increase in glomerular plasma flow (group 1, 119 +/- 14 nl/min; group 2, 217 +/- 18 nl/min; group 3, 183 +/- 13 nl/min) without a significant increase in glomerular transcapillary hydraulic pressure (group 1, 45 +/- 1 mmHg; group 2, 48 +/- 3 mmHg; group 3, 44 +/- 2 mmHg). Group 2 exhibited an increase in systemic blood pressure that was prevented by enalapril treatment in group 3. These studies show that an increase in remnant nephron proteinuria accompanies glomerular hypertrophy and hyperfiltration when nephron number is reduced in nephrotic rats. This increase in remnant nephron proteinuria is not attributable to elevation of systemic or glomerular capillary pressure.

  View details for Web of Science ID A1988R495800098

  View details for PubMedID 3202187

• PLASMA-PROTEIN CONCENTRATION AND COLLOID OSMOTIC-PRESSURE IN NEPHROTIC RATS KIDNEY INTERNATIONAL Miller, P. L., Meyer, T. W. 1988; 34 (2): 220-223

  Abstract

  Colloid osmotic pressure (COP) was related to plasma total protein concentration in rats with adriamycin nephrosis. Nephrotic rats were divided into three groups on the basis of plasma albumin concentration. Measured values for COP were 6 to 8 mm Hg below those predicted by the Landis-Pappenheimer equation in group 3 plasma samples with albumin concentrations 0.5 to 1.0 g/dl. In contrast, measured values for COP were only slightly below those predicted by the Landis-Pappenheimer equation in group 2 plasma samples with albumin concentrations 1.0 to 1.5 g/dl and in group 1 plasma samples with albumin concentrations 1.5 to 2.0 g/dl. The reduction in concentration of albumin was accompanied by an increase in the concentration of non-albumin proteins in each group of nephrotic rats. COP exerted by these non-albumin proteins partially offset the reduction in COP attributable to reduced albumin concentration. Results show that the Landis-Pappenheimer equation significantly overestimates COP only in nephrotic rats whose plasma albumin concentration is very markedly reduced.

  View details for Web of Science ID A1988P347600009

  View details for PubMedID 3184597

• PROGRESSIVE GLOMERULAR INJURY AFTER LIMITED RENAL INFARCTION IN THE RAT AMERICAN JOURNAL OF PHYSIOLOGY Meyer, T. W., Rennke, H. G. 1988; 254 (6): F856-F862

  Abstract

  Wistar Munich rats subjected to partial renal ablation were compared with intact rats. Group 1 rats were subjected to bilateral segmental infarction of 40% of their total renal mass. Group 2 rats underwent uninephrectomy. Group 3 rats underwent sham operation. Micropuncture and morphological studies were performed in each group at 28 wk after operation. In group 1, glomerular capillary pressure was elevated by 7 mmHg and systemic blood pressure was elevated by 31 mmHg despite reduction of nephron number by only 40% and reduction of glomerular filtration rate (GFR) by only 10%. Progressive albuminuria and segmental glomerular sclerosis were associated with elevation of glomerular capillary pressure in this group. In group 2, single-nephron glomerular filtration rate (SNGFR) was higher than in group 1, but systemic and glomerular capillary pressure remained normal. Group 2 rats developed markedly less albuminuria and glomerular sclerosis than group 1 rats despite more pronounced remnant nephron hyperfiltration. These studies support the view that glomerular hypertension is the major hemodynamic derangement contributing to remnant glomerular injury and show that capillary hypertension can initiate remnant glomerular injury even when the majority of the renal mass remains intact.

  View details for Web of Science ID A1988N862500071

  View details for PubMedID 3381887