Assistant Professor of Medicine, Stanford (1984 - 1992)
Associate Professor of Medicine, Stanford (1992 - 2001)
Professor of Medicine, Stanford (2001 - Present)
MD, Harvard, Medicine (1975)
BA, Harvard College, Chemistry (1971)
Current Research and Scholarly Interests
Inadequate removal of uremic solutes contributes to widespread illness in the more than 350,000 Americans maintained on hemodialysis. But we know remarkably little about these solutes. Dr. Meyer's research efforts are focused on identifying which uremic solutes are toxic, how these solutes are made, and how their production could be decreased or their removal could be increased. We should be able to improve treatment if we knew more about what we are trying to remove.
Searching for Uremic Toxins
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2013; 8 (2): 322-327
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
The Production of p-Cresol Sulfate and Indoxyl Sulfate in Vegetarians Versus Omnivores
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2012; 7 (6): 982-988
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
2012; 81 (10): 949-954
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
2012; 27 (4): 1574-1579
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
2012; 22 (1): 203-206
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
2011; 24 (5): 471-479
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
2011; 22 (9): 1769-1776
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
2011; 6 (2): 290-296
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 2011; 6 (1): 3-4
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
2009; 53 (6): 1042-1049
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
New insights into uremic toxicity
CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION
2008; 17 (6): 560-565
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
2008; 32 (9): 717-724
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
Removal of the protein-bound solutes indican and p-cresol sulfate by peritoneal dialysis
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2008; 3 (1): 85-90
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 2007; 357 (13): 1316-1325
Increasing the clearance of protein-bound solutes by addition of a sorbent to the dialysate
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2007; 18 (3): 868-874
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
Managing diabetic nephropathy: recent studies
CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION
2006; 15 (2): 111-116
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
2006; 69 (6): 1056-1063
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
Removal of p-cresol sulfate by hemodialysis
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2005; 16 (11): 3430-3436
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
2005; 68 (2): 867-877
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
Increasing dialysate flow and dialyzer mass transfer area coefficient to increase the clearance of protein-bound solutes
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2004; 15 (7): 1927-1935
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
- Tubular injury in glomerular disease KIDNEY INTERNATIONAL 2003; 63 (2): 774-787
Effects of antihypertensive therapy on intrarenal angiotensin and bradykinin levels in experimental renal insufficiency
2002; 61 (2): 555-563
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
Intrarenal angiotensin and bradykinin peptide levels in the remnant kidney model of renal insufficiency
2001; 59 (4): 1458-1465
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 2001; 135: 34-46
Effect of angiotensin II blockade on renal injury in mineralocorticoid-salt hypertension
2000; 36 (4): 569-574
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
NATURE PUBLISHING GROUP. 2000: 1228–37
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
Contribution of angiotensin II to late renal injury after acute ischemia
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2000; 11 (7): 1278-1286
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
2000; 57 (6): 2644-2649
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
2000; 35 (4): 674-680
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
1999; 42 (11): 1341-1344
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
1999; 59 (2): 89-94
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
1999; 10 (6): 1317-1323
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
1999; 10 (2): 366-373
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
1998; 54 (4): 1157-1165
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
Podocyte loss and progressive glomerular injury in type II diabetes
JOURNAL OF CLINICAL INVESTIGATION
1997; 99 (2): 342-348
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
ANGIOTENSIN-II RECEPTOR BLOCKADE LIMITS GLOMERULAR INJURY IN RATS WITH REDUCED RENAL MASS
JOURNAL OF CLINICAL INVESTIGATION
1992; 90 (3): 766-771
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
View details for PubMedCentralID PMC329928
CALMODULIN TRAPPING BY CALCIUM-CALMODULIN DEPENDENT PROTEIN-KINASE
1992; 256 (5060): 1199-1202
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
1991; 261 (3): F459-F465
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
1990; 63 (6): 862-866
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
WILLIAMS & WILKINS. 1990: S64–S68
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
1990; 39 (8): 989-995
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
1990; 259 (2): F239-F245
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 1990; 10 (3): 194-202
GLOMERULAR HYPERTROPHY AGGRAVATES EPITHELIAL-CELL INJURY IN NEPHROTIC RATS
JOURNAL OF CLINICAL INVESTIGATION
1990; 85 (4): 1119-1126
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
1990; 39 (1): 76-82
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
KARGER. 1990: 27–29
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
1989; 13 (1): 20-24
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
1988; 255 (6): F1243-F1248
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
1988; 34 (2): 220-223
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
1988; 254 (6): F856-F862
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