Bio

Academic Appointments


Professional Education


  • MD, UC San Diego (2006)
  • BS, UC Berkeley, Chemistry (2002)

Research & Scholarship

Clinical Trials


  • Efficacy of Twice Weekly Hemodialysis in Patients With Residual Kidney Function Recruiting

    The study will determine the efficacy of twice weekly hemodialysis in patients with residual kidney function.

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Publications

All Publications


  • Asymmetric dimethylarginine, erythropoietin resistance, and anemia in CKD ANNALS OF TRANSLATIONAL MEDICINE Sirich, T. L., Chertow, G. M. 2019; 7
  • Accumulation of Uremic Solutes in the Cerebrospinal Fluid in Experimental Acute Renal Failure. American journal of physiology. Renal physiology Mair, R. D., Nguyen, H., Huang, T., Plummer, N. S., Sirich, T. L., Meyer, T. W. 2019

    Abstract

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

    View details for DOI 10.1152/ajprenal.00100.2019

    View details for PubMedID 31141401

  • Blood Microbiome in CKD: Should We Care? CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Mair, R. D., Sirich, T. L. 2019; 14 (5): 648?49
  • Blood Microbiome in CKD: Should We Care? Clinical journal of the American Society of Nephrology : CJASN Mair, R. D., Sirich, T. L. 2019

    View details for PubMedID 30962188

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

    Abstract

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

    View details for PubMedID 30879076

  • Timing of blood pressure medications and intradialytic hypotension. Seminars in dialysis Wang, K. M., Sirich, T. L., Chang, T. I. 2019

    Abstract

    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) O'Brien, F. J., Sirich, T. L., Taussig, A., Fung, E., Ganesan, L. L., Plummer, N. S., Brakeman, P., Sutherland, S. M., Meyer, T. W. 2019

    Abstract

    Dialysis in children as well as adults is prescribed to achieve a target spKt/Vurea, where Vurea is the volume of distribution of urea. Waste solute production may however be more closely correlated with body surface area (BSA) than Vurea which rises in proportion with body weight. Plasma levels of waste solutes may thus be higher in smaller patients when targeting spKt/Vurea since they have higher BSA relative to body weight. This study measured levels of pseudouridine (PU), a novel marker solute whose production is closely proportional to BSA, to test whether prescription of dialysis to a target spKt/Vurea results in higher plasma levels of PU in smaller children.PU and urea nitrogen (ureaN) were measured in plasma and dialysate at the midweek hemodialysis session in 20 pediatric patients, with BSA ranging from 0.65-1.87m2. Mathematical modeling was employed to estimate solute production rates and average plasma solute levels.The dialytic clearance (Kd) of PU was proportional to that of ureaN (average KdPU/KdUreaN 0.69?▒?0.13, r2 0.84, pá

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

    View details for PubMedID 31728748

  • Asymmetric dimethylarginine, erythropoietin resistance, and anemia in CKD. Annals of translational medicine Sirich, T. L., Chertow, G. M. 2019; 7 (Suppl 3): S86

    View details for DOI 10.21037/atm.2019.04.22

    View details for PubMedID 31576295

    View details for PubMedCentralID PMC6685898

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

    Abstract

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

    View details for PubMedID 30087103

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

    Abstract

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

    View details for PubMedID 29865226

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

    View details for PubMedID 29444901

    View details for PubMedCentralID PMC5967662

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

    Abstract

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

    View details for DOI 10.1681/ASN.2018010081

    View details for PubMedID 29728422

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

    Abstract

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

    View details for PubMedID 29145509

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

    Abstract

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

    View details for PubMedID 28087007

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

    Abstract

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

    View details for DOI 10.1016/j.kint.2016.11.002

    View details for PubMedID 28089366

  • Obstacles to reducing plasma levels of uremic solutes by hemodialysis. Seminars in dialysis Sirich, T. L. 2017; 30 (5): 403?8

    Abstract

    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 ?2 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 PubMedID 28558415

  • Indoxyl Sulfate-Review of Toxicity and Therapeutic Strategies TOXINS Leong, S. C., Sirich, T. L. 2016; 8 (12)

    Abstract

    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 Tamura, M. K., Chertow, G. M., Depner, T. A., Nissenson, A. R., Schiller, B., Mehta, R. L., Liu, S., Sirich, T. L. 2016; 27 (12): 3780-3787

    Abstract

    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 Meyer, T. W., Sirich, T. L., Fong, K. D., Plummer, N. S., Shafi, T., Hwang, S., Banerjee, T., Zhu, Y., Powe, N. R., Hai, X., Hostetter, T. H. 2016; 27 (11): 3469-3478

    Abstract

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

    View details for PubMedID 27026365

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

    Abstract

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

    View details for DOI 10.1111/sdi.12533

    View details for PubMedID 27556575

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

    Abstract

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

    View details for DOI 10.1093/ndt/gfw100

    View details for Web of Science ID 000383285500025

    View details for PubMedID 27190347

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

    Abstract

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

    View details for DOI 10.1681/ASN.2014121193

    View details for Web of Science ID 000378824800028

    View details for PubMedID 26614381

    View details for PubMedCentralID PMC4926962

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

    Abstract

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

    View details for DOI 10.1371/journal.pone.0135657

    View details for Web of Science ID 000360299100041

    View details for PubMedCentralID PMC4552739

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

    Abstract

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

    View details for PubMedID 26317986

  • Dietary Protein and Fiber in End Stage Renal Disease SEMINARS IN DIALYSIS Sirich, T. L. 2015; 28 (1): 75-80

    Abstract

    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

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

    Abstract

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

    View details for DOI 10.1159/000441578

    View details for Web of Science ID 000366734700007

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

    Abstract

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

    View details for DOI 10.2215/CJN.00490114

    View details for Web of Science ID 000341275200016

    View details for PubMedID 25147155

    View details for PubMedCentralID PMC4152802

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

    Abstract

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

    View details for DOI 10.1038/ki.2013.497

    View details for Web of Science ID 000335713300030

    View details for PubMedID 24429397

    View details for PubMedCentralID PMC4072128

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

    Abstract

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

    View details for DOI 10.1681/ASN.2013060597

    View details for Web of Science ID 000332150500021

    View details for PubMedID 24231664

    View details for PubMedCentralID PMC3935591

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

    Abstract

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

    View details for DOI 10.1016/j.semnephrol.2014.02.004

    View details for Web of Science ID 000336418200004

    View details for PubMedID 24780467

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

    Abstract

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

    View details for DOI 10.1038/ki.2013.154

    View details for Web of Science ID 000323755300022

    View details for PubMedID 23636170

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

    Abstract

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

    View details for DOI 10.1093/ndt/gfr691

    View details for Web of Science ID 000302310700047

    View details for PubMedID 22231033

    View details for PubMedCentralID PMC3315673

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