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1.
Nephrol Dial Transplant ; 35(5): 846-853, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30879076

RESUMO

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 >1.5 mL/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 57 years and 57% were female. At baseline, 34% of the included participants had clinically negligible RKF (mean 0.7 ± 0.4 mL/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.

2.
Pediatr Nephrol ; 35(2): 305-312, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31728748

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

3.
Am J Physiol Renal Physiol ; 317(2): F296-F302, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141401

RESUMO

The accumulation of uremic solutes in kidney failure may impair mental function. The present 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 h after sham operation (control; n = 10) or bilateral nephrectomy (n = 10) and analyzed using an established metabolomic platform. Two hundred forty-eight solutes were identified as uremic based on their accumulation in the plasma ultrafiltrate of nephrectomized compared with control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF-to-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 of <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.


Assuntos
Lesão Renal Aguda/líquido cefalorraquidiano , Encefalopatias/líquido cefalorraquidiano , Uremia/líquido cefalorraquidiano , Lesão Renal Aguda/sangue , Lesão Renal Aguda/complicações , Lesão Renal Aguda/fisiopatologia , Animais , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Encefalopatias/sangue , Encefalopatias/etiologia , Encefalopatias/fisiopatologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Progressão da Doença , Rim/metabolismo , Rim/fisiopatologia , Masculino , Metabolômica/métodos , Nefrectomia , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Uremia/sangue , Uremia/etiologia , Uremia/fisiopatologia
4.
Clin J Am Soc Nephrol ; 13(9): 1398-1404, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087103

RESUMO

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.


Assuntos
Colo/metabolismo , Colo/microbiologia , Uremia/urina , Feminino , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade
5.
J Am Soc Nephrol ; 29(7): 1992-1999, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29728422

RESUMO

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.


Assuntos
Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Diálise Renal/métodos , Idoso , Idoso de 80 Anos ou mais , Cresóis/sangue , Feminino , Glutamina/análogos & derivados , Glutamina/sangue , Hipuratos/sangue , Humanos , Indicã/sangue , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica , Ésteres do Ácido Sulfúrico/sangue , Ureia/sangue
6.
PLoS One ; 12(11): e0188315, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29145509

RESUMO

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.


Assuntos
Espectrometria de Massas/métodos , Diálise Renal , Feminino , Humanos , Masculino
7.
Kidney Int ; 92(6): 1484-1492, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28739139

RESUMO

Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors, we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine, and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dl), a twofold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98-1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06-1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.


Assuntos
Doenças Cardiovasculares/sangue , Cresóis/sangue , Indicã/sangue , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Ésteres do Ácido Sulfúrico/sangue , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Feminino , Glutamina/análogos & derivados , Glutamina/sangue , Hipuratos/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Diálise Renal/estatística & dados numéricos , Fatores de Risco , Albumina Sérica/análise , Uremia/sangue , Uremia/complicações
8.
Kidney Int ; 91(5): 1186-1192, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28089366

RESUMO

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.


Assuntos
Cresóis/sangue , Indicã/sangue , Falência Renal Crônica/terapia , Diálise Renal/métodos , Ésteres do Ácido Sulfúrico/sangue , Uremia/sangue , Adulto , Feminino , Humanos , Falência Renal Crônica/sangue , Masculino , Metabolômica , Pessoa de Meia-Idade , Fatores de Tempo
9.
Nephrol Dial Transplant ; 31(8): 1335-41, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27190347

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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]. CONCLUSIONS: 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.


Assuntos
Cresóis/sangue , Soluções para Diálise/farmacocinética , Indicã/sangue , Diálise Renal/métodos , Insuficiência Renal/terapia , Ésteres do Ácido Sulfúrico/sangue , Biomarcadores/sangue , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/sangue
10.
J Am Soc Nephrol ; 27(11): 3469-3478, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27026365

RESUMO

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.


Assuntos
Diálise Renal , Ureia/metabolismo , Feminino , Soluções para Hemodiálise/química , Humanos , Masculino , Pessoa de Meia-Idade , Ureia/análise
11.
PLoS One ; 10(8): e0135657, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26317986

RESUMO

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.


Assuntos
Metaboloma , Insuficiência Renal/sangue , Uremia/sangue , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Indóis/sangue , Masculino , Pessoa de Meia-Idade , Polifenóis/sangue , Diálise Renal
12.
Clin J Am Soc Nephrol ; 9(9): 1603-10, 2014 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-25147155

RESUMO

BACKGROUND AND OBJECTIVES: 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 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. RESULTS: 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). CONCLUSIONS: 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.


Assuntos
Cresóis/sangue , Fibras na Dieta/administração & dosagem , Indicã/sangue , Diálise Renal , Ésteres do Ácido Sulfúrico/sangue , Colo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-Cego
13.
J Am Soc Nephrol ; 25(3): 615-22, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24231664

RESUMO

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.


Assuntos
Cresóis/sangue , Glutamina/análogos & derivados , Hipuratos/sangue , Indicã/sangue , Falência Renal Crônica/sangue , Túbulos Renais/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Glutamina/sangue , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Diálise Renal
14.
Kidney Int ; 84(3): 585-90, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23636170

RESUMO

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.


Assuntos
Cromatografia Líquida/métodos , Cresóis/metabolismo , Hipuratos/metabolismo , Indicã/metabolismo , Rim/metabolismo , Ésteres do Ácido Sulfúrico/metabolismo , Espectrometria de Massas em Tandem/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Nefropatias/metabolismo , Nefropatias/terapia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Ligação Proteica , Diálise Renal
15.
Clin J Am Soc Nephrol ; 7(6): 982-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22490877

RESUMO

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


Assuntos
Cresóis/urina , Dieta Vegetariana , Digestão , Indicã/urina , Carne , Ésteres do Ácido Sulfúrico/urina , Adulto , Biomarcadores/urina , California , Registros de Dieta , Feminino , Humanos , Rim/metabolismo , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
16.
Nephrol Dial Transplant ; 27(4): 1574-9, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22231033

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Soluções para Diálise/administração & dosagem , Soluções para Diálise/metabolismo , Proteínas/metabolismo , Diálise Renal/instrumentação , Diálise Renal/métodos , Ureia/metabolismo , Humanos , Nefropatias/sangue , Nefropatias/terapia , Taxa de Depuração Metabólica , Prognóstico , Ligação Proteica
17.
J Am Soc Nephrol ; 22(9): 1769-76, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21784895

RESUMO

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


Assuntos
Colo/química , Falência Renal Crônica/sangue , Uremia/sangue , Idoso , Idoso de 80 Anos ou mais , Colo/microbiologia , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Diálise Renal
18.
Clin J Am Soc Nephrol ; 6(2): 290-6, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21030575

RESUMO

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


Assuntos
Taxa de Filtração Glomerular , Nefropatias/terapia , Rim/fisiopatologia , Diálise Renal , Adulto , Idoso , Cresóis/sangue , Feminino , Hipuratos/sangue , Humanos , Indicã/sangue , Rim/metabolismo , Nefropatias/sangue , Nefropatias/fisiopatologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Guias de Prática Clínica como Assunto , Ligação Proteica , Ésteres do Ácido Sulfúrico/sangue , Fatores de Tempo , Resultado do Tratamento , Ureia/sangue
19.
Am J Kidney Dis ; 53(6): 1042-9, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19394728

RESUMO

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


Assuntos
Soluções para Diálise/administração & dosagem , Soluções para Diálise/metabolismo , Proteínas/metabolismo , Diálise Renal/instrumentação , Diálise Renal/métodos , Nitrogênio da Ureia Sanguínea , Estudos Cross-Over , Soluções para Diálise/química , Humanos , Nefropatias/sangue , Nefropatias/terapia , Ácido Cinurênico/sangue , Ácido Cinurênico/metabolismo , Taxa de Depuração Metabólica/fisiologia , Projetos Piloto , Ligação Proteica/fisiologia
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