Does the Administration of Sevelamer or Nicotinamide Modify Uremic Toxins or Endotoxemia in Chronic Hemodialysis Patients?

International audienceBackgroundHyperphosphatemia control is a major issue in hemodialysis patients. Both sevelamer and nicotinamide are prescribed for this purpose. In addition, they exert pleiotropic effects such as an improvement of inflammatory status and potentially enhanced clearance of uremic toxins. In the present secondary analysis of the NICOREN trial, we investigated the impact of sevelamer and nicotinamide on uremic toxins, toxin precursors, and endotoxemia in chronic hemodialysis patients.MethodsCirculating uremic toxins (including phenylacetylglutamine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, kynurenine, hippuric acid, indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, kynurenic acid, and p-cresyl glucuronide) and precursors were measured by ultra-performance liquid chromatography-tandem mass spectrometry, and urea, uric acid, phosphate, C-reactive protein, and intact parathyroid hormone by routine biochemistry methods. Serum endotoxin (evaluated by lipopolysaccharide levels) and C-terminal fibroblast growth factor-23 levels were measured using enzyme-linked immunosorbent assay kits.ResultsOne hundred hemodialysis patients were randomized to receive either nicotinamide or sevelamer treatment. Among them, 63% were male, mean (standard deviation) age was 65 +/- 14years, 47% had diabetes mellitus, and 51% had a history of cardiovascular disease. In the sevelamer group, but not the nicotinamide group, serum levels of urea, uric acid, and fibroblast growth factor-23 were significantly reduced after 6months of treatment. The other circulating uremic toxins and toxin precursors remained unchanged in response to either phosphate-lowering agent. Sevelamer treatment led to a marked decrease in serum lipopolysaccharide (p<0.001) whereas nicotinamide treatment induced an only modest decrease of borderline significance (p=0.057). There was no change in C-reactive protein levels.Conclusion p id=Par4 In contrast to sevelamer, nicotinamide did not reduce circulating levels of low-molecular-weight uremic toxins other than phosphate, and neither agent reduced circulating uremic toxins of high-molecular-weight or protein-bound toxins. Sevelamer, but not nicotinamide, reduced serum endotoxin levels. Despite no change in serum C-reactive protein, the endotoxin-lowering effect of sevelamer may help to attenuate the inflammatory status of patients with chronic kidney disease

Does p-cresylglucuronide have the same impact on mortality as other protein-bound uremic toxins?

BACKGROUND: Uremic toxins are emerging as important, non-traditional cardiovascular risk factors in chronic kidney disease (CKD). P-cresol has been defined as a prototype protein-bound uremic toxin. Conjugation of p-cresol creates p-cresylsulfate (PCS) as the main metabolite and p-cresylglucuronide (PCG), at a markedly lower concentration. The objective of the present study was to evaluate serum PCG levels, determine the latter's association with mortality and establish whether the various protein-bound uremic toxins (i.e. PCS, PCG and indoxylsulfate (IS)) differed in their ability to predict mortality. METHODOLOGY/PRINCIPAL FINDINGS: We studied 139 patients (mean ± SD age: 67±12; males: 60%) at different CKD stages (34.5% at CKD stages 2-3, 33.5% at stage 4-5 and 32% at stage 5D). A recently developed high-performance liquid chromatography method was used to assay PCG concentrations. Total and free PCG levels increased with the severity of CKD. During the study period (mean duration: 779±185 days), 38 patients died. High free and total PCG levels were correlated with overall and cardiovascular mortality independently of well-known predictors of survival, such as age, vascular calcification, anemia, inflammation and (in predialysis patients) the estimated glomerular filtration rate. In the same cohort, free PCS levels and free IS levels were both correlated with mortality. Furthermore, the respective predictive powers of three Cox multivariate models (free PCS+other risk factors, free IS+other risk factors and free PCS+other risk factors) were quite similar--suggesting that an elevated PCG concentration has much the same impact on mortality as other uremic toxins (such as PCS or IS) do. CONCLUSIONS: Although PCG is the minor metabolite of p-cresol, our study is the first to reveal its association with mortality. Furthermore, the free fraction of PCG appears to have much the same predictive power for mortality as PCS and IS do

The clinical impact of plasma leptin levels in a cohort of chronic kidney disease patients

Background. Recent research has clarified the relationship between adipokines, metabolic syndrome (MS) and cardiovascular disease (CVD). The results of animal and clinical studies have revealed a positive relationship between leptin and vascular smooth muscle cell counts and calcification, arterial rigidity, carotid thickness and the incidence of CVD. However, despite leptin fulfilling the definition of a uremic toxin, its exact role in chronic kidney disease (CKD) has yet to be determined. Methods. One hundred and forty-two CKD patients (stages 2–5D) participated in this study, and were followed for a minimum of 20 months at Amiens University Medical Center. Results. Leptin was negatively correlated with the glomerular filtration rate (GFR), total adiponectin (TAdip) and high-molecular weight adiponectin and positively correlated with age, waist circumference, body mass index (BMI), aortic calcification score (ACS), C-reactive protein (CRP), triglycerides, insulin and parathormone (PTH). Leptin and insulin were significantly correlated with the MS score. The BMI, insulin, MS score and PTH were independent predictors of leptin levels (P = 0.002, 0.016, 0.028 and 0.017, respectively). Leptin, insulin and TAdip were independent predictors of the presence of MS (P = 0.05, 0.04 and 0.04). However, leptin levels were not significantly predictive of the clinical outcomes. Conclusions. Our study was the first to demonstrate a significant, independent link between leptin and MS (but not clinical outcomes) and PTH in patients at different CKD stages. Future studies will have to assess the involvement of leptin in MS and clinical outcomes in CKD, and the potential modulation of leptin by PTH

Efficacy and safety of nicotinamide in haemodialysis patients: the NICOREN study

International audienceBackground: Nicotinamide (NAM) has been proposed as an alternative treatment to phosphate binders for hyperphosphataemia in chronic kidney disease. Methods: The NICOREN multicentre, open-label and randomized study was designed to examine non-inferiority and safety of NAM when compared with sevelamer (SEV) in chronic haemodialysis patients. One hundred patients were randomized to either NAM or SEV treatment for 24 weeks. Serum biochemistry and NAM's main metabolite, N-methyl-2-pyridone-5-carboxamide (2PY), were measured to assess compliance, efficacy and safety. Results: After 24 weeks, we observed a comparable decrease in serum phosphorus in the NAM and SEV treatment arms, from 2.1 +/- 0.4 to 1.8 +/- 0.5 and 2.3 +/- 0.5 to 1.7 +/- 0.5 mM (P = not significant), respectively. The criterion for non-inferiority was, however, not met due to a more limited number of patients being included than planned. Treatment discontinuation due to adverse events was 1.6 times higher in the NAM than in the SEV group with only 55% of study completers in the NAM arm versus 90% in the SEV arm. Thrombocytopenia was observed in four NAM-treated patients. Serum 2PY levels were comparable at baseline, but increased markedly in the NAM group, but not in the SEV group, at 24 weeks (P < 0.0001). Conclusions: Thus, both drugs are equally effective in lowering serum phosphorus, but patients' tolerance of NAM was largely inferior to that of SEV. Extremely high 2PY levels may contribute to NAM's side effects

Harrell’s C index according to the Cox models (Model 1: Ln free PCS+aortic calcification+CRP+Hb; Model 2: Ln free IS +aortic calcification+CRP+Hb; Model 3: Ln free PCG +aortic calcification+CRP+Hb).

<p>Harrell’s C index according to the Cox models (Model 1: Ln free PCS+aortic calcification+CRP+Hb; Model 2: Ln free IS +aortic calcification+CRP+Hb; Model 3: Ln free PCG +aortic calcification+CRP+Hb).</p

Mortality and free p-cresylglucuronide levels (A) Kaplan–Meier estimates of overall mortality as a function of free p-cresylglucuronide levels relative to the median; p = 0.002 in a log-rank comparison of the curves.

<p>(B) Kaplan–Meier estimates of cardiovascular mortality as a function of free p-cresylglucuronide levels relative to the median; p = 0.01 in a log-rank comparison of the curves.</p

Biochemical characteristics of the study population.

<p>Data are expressed as means ± SD and (median) for variables with a non-Gaussian distribution. PTH: parathyroid hormone; GFR: glomerular filtration rate; LDL: low-density lipoprotein.</p>§<p>calculated for patients at CKD stages 2 to 5 (n = 96).</p

Univariate and multivariate Cox regression analysis of risk factors at baseline for all-cause mortality, with free p-cresylglucuronide entered as a continuous variable in all patients (n = 139).

<p>RR: risk ratio; CI: confidence interval.</p