Assistant Professor - University Medical Line, Medicine - Nephrology
Associate Program Director, Stanford Nephrology (2021 - Present)
Dialysis Director, VA Palo Alto (2019 - Present)
Fellowship, Stanford University, Nephrology (2011)
Residency, Santa Clara Valley Medical Center, Internal Medicine (2009)
MD, UC San Diego (2006)
BS, UC Berkeley, Chemistry (2002)
Current Research and Scholarly Interests
I conduct translational research focused on uremia and dialysis. I use mass spectrometry to conduct studies testing ways to reduce levels of solutes and examining the contribution of uremic solutes to illness.
Efficacy of Diuretics in Kidney Disease
This study will determine the efficacy of diuretics in patients with chronic kidney disease.
Efficacy of Twice Weekly Hemodialysis in Patients With Residual Kidney Function
The study will determine the efficacy of twice weekly hemodialysis in patients with residual kidney function.
Dialysis stdKt/V Calculator App Description
Palo Alto, CA
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Improving Solute Clearances by Hemodialysis.
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 2021; 32 (9): 2112-2116
Impaired Tubular Secretion of Organic Solutes in Advanced CKD.
Journal of the American Society of Nephrology : JASN
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
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.
2021; 2 (7): 1188-1195
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
Metabolomic analysis of uremic pruritus in patients on hemodialysis.
2021; 16 (2): e0246765
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
Classification of Uremic Toxins and Their Role in Kidney Failure.
Clinical journal of the American Society of Nephrology : CJASN
Advances in our understanding of uremic retention solutes, as well as improvements in hemodialysis membranes and other techniques designed to remove uremic retention solutes, offer opportunities to readdress the definition and classification of uremic toxins. A consensus conference was held to develop recommendations for an updated definition and classification scheme based upon a holistic approach that incorporates physicochemical characteristics, and, dialytic removal patterns of uremic retention solutes and their linkage to clinical symptoms and outcomes. The major focus is on removal of uremic retention solutes by hemodialysis. The identification of representative biomarkers for different classes of uremic retention solutes and their correlation to clinical symptoms and outcomes may facilitate personalized and targeted dialysis prescriptions to improve quality of life, morbidity, and mortality. Recommendations for areas of future research were also formulated, aimed at improving understanding of uremic solutes and improving outcomes in patients with chronic kidney disease.
View details for DOI 10.2215/CJN.02660221
View details for PubMedID 34233920
Impaired Tubular Secretion of Organic Solutes in Acute Kidney Injury.
2020; 1 (8): 724-730
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 2020; 35 (5): 846–53
- Asymmetric dimethylarginine, erythropoietin resistance, and anemia in CKD. Annals of translational medicine 2019; 7 (Suppl 3): S86
Accumulation of Uremic Solutes in the Cerebrospinal Fluid in Experimental Acute Renal Failure.
American journal of physiology. Renal physiology
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
- Blood Microbiome in CKD: Should We Care? CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 2019; 14 (5): 648–49
Timing of blood pressure medications and intradialytic hypotension.
Seminars in dialysis
Intradialytic hypotension (IDH) is a prevalent yet serious complication of hemodialysis, associated with decreased quality of life, inadequate dialysis, vascular access thrombosis, global hypoperfusion, and increased cardiovascular and all-cause mortality. Current guidelines recommend antihypertensive medications be given at night and held the morning of dialysis for affected patients. Despite little evidence to support this recommendation, more than half of patients on dialysis may employ some form of this method. In this article, we will review the available evidence and clinical considerations regarding timing of blood pressure medications and occurrence of IDH, and conclude that witholding BP medications before hemodialysis should not be a routine practice.
View details for DOI 10.1111/sdi.12777
View details for PubMedID 30836447
Plasma pseudouridine levels reflect body size in children on hemodialysis.
Pediatric nephrology (Berlin, Germany)
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
Characteristics of Colon-Derived Uremic Solutes.
Clinical journal of the American Society of Nephrology : CJASN
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.
2018; 10 (6)
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
- Intensive Hemodialysis Fails to Reduce Plasma Levels of Uremic Solutes CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 2018; 13 (3): 361–62
Residual Function Effectively Controls Plasma Concentrations of Secreted Solutes in Patients on Twice Weekly Hemodialysis.
Journal of the American Society of Nephrology : JASN
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
2017; 12 (11): e0188315
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
Obstacles to reducing plasma levels of uremic solutes by hemodialysis.
Seminars in dialysis
2017; 30 (5): 403-408
More intensive hemodialysis has provided limited clinical benefit. The lack of benefit may be due in part to the failure of intensive dialysis to reduce uremic solute levels in plasma. Two well-described factors limiting the reduction in these levels are the intermittency of dialysis treatment and the distribution of solutes in multiple body compartments. Efforts to increase the clearance of large solutes and protein-bound solutes have revealed two other considerations-the presence of nonrenal clearance and increases in solute generation. For β2 microglobulin, a commonly measured large solute, nonrenal clearance limits reduction in its levels. For the bound solute p-cresol sulfate, an increase in generation appears to limit its reduction. A variety of factors likely determine the behavior of different solutes. More data on solute toxicity are needed as is better knowledge of solute kinetics. We will then be better able to design optimal therapeutic interventions. A combination of dialytic and nondialytic strategies may well be needed to reduce the plasma levels of toxic solutes and improve patients' health.
View details for DOI 10.1111/sdi.12609
View details for PubMedID 28558415
Manipulating the microbiome
2017; 91 (2): 274–76
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
Limited reduction in uremic solute concentrations with increased dialysis frequency and time in the Frequent Hemodialysis Network Daily Trial.
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
Indoxyl Sulfate-Review of Toxicity and Therapeutic Strategies
2016; 8 (12)
Indoxyl sulfate is an extensively studied uremic solute. It is a small molecule that is more than 90% bound to plasma proteins. Indoxyl sulfate is derived from the breakdown of tryptophan by colon microbes. The kidneys achieve high clearances of indoxyl sulfate by tubular secretion, a function not replicated by hemodialysis. Clearance by hemodialysis is limited by protein binding since only the free, unbound solute can diffuse across the membrane. Since the dialytic clearance is much lower than the kidney clearance, indoxyl sulfate accumulates to relatively high plasma levels in hemodialysis patients. Indoxyl sulfate has been most frequently implicated as a contributor to renal disease progression and vascular disease. Studies have suggested that indoxyl sulfate also has adverse effects on bones and the central nervous system. The majority of studies have assessed toxicity in cultured cells and animal models. The toxicity in humans has not yet been proven, as most data have been from association studies. Such toxicity data, albeit inconclusive, have prompted efforts to lower the plasma levels of indoxyl sulfate through dialytic and non-dialytic means. The largest randomized trial showed no benefit in renal disease progression with AST-120. No trials have yet tested cardiovascular or mortality benefit. Without such trials, the toxicity of indoxyl sulfate cannot be firmly established.
View details for DOI 10.3390/toxins8120358
View details for Web of Science ID 000389342000012
View details for PubMedID 27916890
View details for PubMedCentralID PMC5198552
Metabolic Profiling of Impaired Cognitive Function in Patients Receiving Dialysis
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2016; 27 (12): 3780-3787
Retention of uremic metabolites is a proposed cause of cognitive impairment in patients with ESRD. We used metabolic profiling to identify and validate uremic metabolites associated with impairment in executive function in two cohorts of patients receiving maintenance dialysis. We performed metabolic profiling using liquid chromatography/mass spectrometry applied to predialysis plasma samples from a discovery cohort of 141 patients and an independent replication cohort of 180 patients participating in a trial of frequent hemodialysis. We assessed executive function with the Trail Making Test Part B and the Digit Symbol Substitution test. Impaired executive function was defined as a score ≥2 SDs below normative values. Four metabolites-4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline-were associated with impaired executive function at the false-detection rate significance threshold. After adjustment for demographic and clinical characteristics, the associations remained statistically significant: relative risk 1.16 (95% confidence interval [95% CI], 1.03 to 1.32), 1.39 (95% CI, 1.13 to 1.71), 1.24 (95% CI, 1.03 to 1.50), and 1.20 (95% CI, 1.05 to 1.38) for each SD increase in 4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline, respectively. The association between 4-hydroxyphenylacetate and impaired executive function was replicated in the second cohort (relative risk 1.12; 95% CI, 1.02 to 1.23), whereas the associations for phenylacetylglutamine, hippurate, and prolyl-hydroxyproline did not reach statistical significance in this cohort. In summary, four metabolites related to phenylalanine, benzoate, and glutamate metabolism may be markers of cognitive impairment in patients receiving maintenance dialysis.
View details for DOI 10.1681/ASN.2016010039
View details for PubMedID 27444566
Kt/Vurea and Nonurea Small Solute Levels in the Hemodialysis Study.
Journal of the American Society of Nephrology
2016; 27 (11): 3469-3478
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
2016; 29 (6): 481-490
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
Effect of a sustained difference in hemodialytic clearance on the plasma levels of p-cresol sulfate and indoxyl sulfate
NEPHROLOGY DIALYSIS TRANSPLANTATION
2016; 31 (8): 1335-1341
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
2016; 27 (7): 2148-2155
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
An Enlarged Profile of Uremic Solutes
2015; 10 (8)
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
Uremic Solutes Produced by Colon Microbes
2015; 40 (4): 306-311
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
Dietary Protein and Fiber in End Stage Renal Disease
SEMINARS IN DIALYSIS
2015; 28 (1): 75-80
Prior to the availability of hemodialysis, dietary protein restriction played a large part in the treatment of uremia. This therapy was based on observations that uremic symptoms increased with high protein intake. Early investigators thus presumed that "uremic toxins" were derived from the breakdown of dietary protein; its restriction improved uremic symptoms but caused malnutrition. After the availability of hemodialysis, protein restriction was no longer recommended. Studies in healthy subjects have shown that an intake of 0.6-0.8 g/kg/day is adequate to prevent protein malnutrition. Guidelines for hemodialysis patients, however, currently recommend higher protein intakes of 1.2 g/kg/day. A downside to higher intake may be increased production of protein-derived uremic solutes that caused the symptoms observed by early investigators. Some of these solutes are produced by colon microbes acting on protein which escapes digestion in the small intestine. Increasing dietary fiber may reduce the production of colon-derived solutes in hemodialysis patients without adverse effects of protein restriction. Fiber comprises carbohydrates and related substances that are resistant to digestion in the small intestine. Upon delivery to the colon, fiber is broken down to short chain fatty acids, providing energy to both the microbes and the host. With an increased energy supply, the microbes can incorporate dietary protein for growth rather than breaking them down to uremic solutes. Increasing fiber intake in hemodialysis patients has been shown to reduce the plasma levels of selected colon-derived solutes. Further studies are needed to test whether this provides clinical benefit.
View details for DOI 10.1111/sdi.12315
View details for Web of Science ID 000351050000016
View details for PubMedID 25319504
Effect of Increasing Dietary Fiber on Plasma Levels of Colon-Derived Solutes in Hemodialysis Patients
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2014; 9 (9): 1603-1610
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
2014; 85 (5): 1214-1224
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
Prominent Accumulation in Hemodialysis Patients of Solutes Normally Cleared by Tubular Secretion
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2014; 25 (3): 615-622
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
2014; 34 (2): 106-117
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
2013; 84 (3): 585-590
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
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