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Plasma p-cresol lowering effect of sevelamer in peritoneal dialysis patients: evidence from a Cross-Sectional Observational Study.

Guida B, Cataldi M, Riccio E, Grumetto L, Pota A, Borrelli S, Memoli A, Barbato F, Argentino G, Salerno G, Memoli B - PLoS ONE (2013)

Bottom Line: Therapeutic strategies to reduce plasma p-cresol levels are highly demanded but not available yet.Patients receiving sevelamer had plasma p-cresol and serum high sensitivity C-reactive protein concentrations significantly lower than those receiving lanthanum or no drug.These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect cardiovascular risk because of its anti-inflammatory effect.

View Article: PubMed Central - PubMed

Affiliation: Division of Physiology, Dept. of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy.

ABSTRACT
p-Cresol is a by-product of the metabolism of aromatic aminoacid operated by resident intestinal bacteria. In patients with chronic kidney disease, the accumulation of p-cresol and of its metabolite p-cresyl-sulphate causes endothelial dysfunction and ultimately increases the cardiovascular risk of these patients. Therapeutic strategies to reduce plasma p-cresol levels are highly demanded but not available yet. Because it has been reported that the phosphate binder sevelamer sequesters p-cresol in vitro we hypothesized that it could do so also in peritoneal dialysis patients. To explore this hypothesis we measured total cresol plasma concentrations in 57 patients with end-stage renal disease on peritoneal dialysis, 29 receiving sevelamer for the treatment of hyperphosphatemia and 28 patients not assuming this drug. Among the patients not assuming sevelamer, 16 were treated with lanthanum whereas the remaining 12 received no drug because they were not hyperphosphatemic. Patients receiving sevelamer had plasma p-cresol and serum high sensitivity C-reactive protein concentrations significantly lower than those receiving lanthanum or no drug. Conversely, no difference was observed among the different groups either in residual glomerular filtration rate, total weekly dialysis dose, total clearance, urine volume, protein catabolic rate, serum albumin or serum phosphate levels. Multiple linear regression analysis showed that none of these variables predicted plasma p-cresol concentrations that, instead, negatively correlated with the use of sevelamer. These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect cardiovascular risk because of its anti-inflammatory effect.

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Related in: MedlinePlus

Box and whiskers plot of serum p-cresol levels in patients assuming Sev, lanthanum or no binder.The bars represent median, 25th and 75th percentile of plasma p-cresol. * p<0.05 vs no binder at Dunn's post-hoc test.
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pone-0073558-g001: Box and whiskers plot of serum p-cresol levels in patients assuming Sev, lanthanum or no binder.The bars represent median, 25th and 75th percentile of plasma p-cresol. * p<0.05 vs no binder at Dunn's post-hoc test.

Mentions: 57 ESRD patients receiving PD and attending the Division of Nephrology of the Federico II University of Naples as outpatients were recruited for the study. Fifteen of them were women (26%) and the remaining 42 men (74%). At the time of study, patients had a mean age of 59.7±14.5 years. Forty-one patients were on continuous ambulatory peritoneal dialysis and 16 on automated peritoneal dialysis. Based on whether they assumed or not phosphate binders and on which binder they assumed, the patients were stratified in three groups: no binder (n = 12), lanthanum (n = 16) and Sev (n = 29). 20 patients (Sev  = 10, Lanthanum  = 5, No binder  = 5) were treated with calcitriol (0.25 µg every other day–0.5 µg/day) and 23 (Sev  = 13, Lanthanum  = 5, No binder  = 5) with paricalcitol (1 µg every other day–1 µg/day). Because the therapy with hypophosphatemic drugs was individually tailored to achieve target plasma PO4 concentrations, Sev and lanthanum were administered at different dosages in different subjects (dosage ranges: 1600–14400 and 750–3000 mg/die for Sev and lanthanum, respectively). There was no significant difference among the different groups neither in mean age at the time of the study, nor in mean body weight, or relative percentage of the two sexes. Also peritoneal dialysis vintage (i.e. the length of time on dialysis in months) was similar in the three groups. Its mean in the whole patient population was 25.4±22.1 months and in all cases it was longer than six months. Six patients in each of the three patient groups were diabetic. No difference was observed among Sev , lanthanum and no binder groups in mean percentage of HbA1c . It was <7% in both groups suggesting that a good glycemic control was obtained both in all patient groups [24]–[25]. All data we reported so far suggest that Sev-treated, lanthanum-treated and no binder patients are very similar in their demographic, clinical and laboratory profile (Table 1 and Table 2). Nevertheless, significant differences emerged when we compared total p-cresol plasma concentrations. Plasma levels of this uremic toxin were significantly lower in Sev than lanthanum or no-binder groups [median and IQR: 3.3 (1.4–6.9) vs 7.9 (4.1–9.8) and 9.2 (4.3–15.9) in Sev, lanthanum and no binder groups, respectively; H = 9.6, p<0.008] (Fig. 1 and Table 2). In addition, in Sev-treated patients plasma p-cresol concentration was linearly related to the dose of the PO4 binder assumed by the patient being higher Sev doses associated to lower concentrations of this uremic toxin (r = −0.319; P = 0.025) (Fig. 2). Another relevant difference was observed in hs-CRP concentrations that were significantly lower in Sev than in lanthanum or no-binder groups (median and IQR: 3.8 (1.2–6.6) vs 6.3 (2.6–10.0) and 5.9 (3.4–8.4) in Sev, lanthanum and no binder groups, respectively; H = 10.2, p<0.006) (Table 2). No significant difference was observed neither in total creatinine clearance, weekly Kt/V, rGFR and urine volume suggesting that residual renal function and dialysis efficiency were similar in these three groups (Table 1). Moreover, also serum albumin concentrations were not significantly different among the three groups suggesting that the differences in the plasma concentration of p-cresol, a uremic toxin that circulates largely bound to serum albumin, could not be explained by a lower protein-bound fraction (Table 2). Considering that Sev therapy was started because of concurrent hyperphosphatemia and that the main pharmacological effect of Sev is to lower PO4, we compared PO4 circulating levels in the three groups (Table 2). No difference among groups was found (Table 2) suggesting that the treatment with the PO4 binder was effective in normalizing PO4 profile.


Plasma p-cresol lowering effect of sevelamer in peritoneal dialysis patients: evidence from a Cross-Sectional Observational Study.

Guida B, Cataldi M, Riccio E, Grumetto L, Pota A, Borrelli S, Memoli A, Barbato F, Argentino G, Salerno G, Memoli B - PLoS ONE (2013)

Box and whiskers plot of serum p-cresol levels in patients assuming Sev, lanthanum or no binder.The bars represent median, 25th and 75th percentile of plasma p-cresol. * p<0.05 vs no binder at Dunn's post-hoc test.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756054&req=5

pone-0073558-g001: Box and whiskers plot of serum p-cresol levels in patients assuming Sev, lanthanum or no binder.The bars represent median, 25th and 75th percentile of plasma p-cresol. * p<0.05 vs no binder at Dunn's post-hoc test.
Mentions: 57 ESRD patients receiving PD and attending the Division of Nephrology of the Federico II University of Naples as outpatients were recruited for the study. Fifteen of them were women (26%) and the remaining 42 men (74%). At the time of study, patients had a mean age of 59.7±14.5 years. Forty-one patients were on continuous ambulatory peritoneal dialysis and 16 on automated peritoneal dialysis. Based on whether they assumed or not phosphate binders and on which binder they assumed, the patients were stratified in three groups: no binder (n = 12), lanthanum (n = 16) and Sev (n = 29). 20 patients (Sev  = 10, Lanthanum  = 5, No binder  = 5) were treated with calcitriol (0.25 µg every other day–0.5 µg/day) and 23 (Sev  = 13, Lanthanum  = 5, No binder  = 5) with paricalcitol (1 µg every other day–1 µg/day). Because the therapy with hypophosphatemic drugs was individually tailored to achieve target plasma PO4 concentrations, Sev and lanthanum were administered at different dosages in different subjects (dosage ranges: 1600–14400 and 750–3000 mg/die for Sev and lanthanum, respectively). There was no significant difference among the different groups neither in mean age at the time of the study, nor in mean body weight, or relative percentage of the two sexes. Also peritoneal dialysis vintage (i.e. the length of time on dialysis in months) was similar in the three groups. Its mean in the whole patient population was 25.4±22.1 months and in all cases it was longer than six months. Six patients in each of the three patient groups were diabetic. No difference was observed among Sev , lanthanum and no binder groups in mean percentage of HbA1c . It was <7% in both groups suggesting that a good glycemic control was obtained both in all patient groups [24]–[25]. All data we reported so far suggest that Sev-treated, lanthanum-treated and no binder patients are very similar in their demographic, clinical and laboratory profile (Table 1 and Table 2). Nevertheless, significant differences emerged when we compared total p-cresol plasma concentrations. Plasma levels of this uremic toxin were significantly lower in Sev than lanthanum or no-binder groups [median and IQR: 3.3 (1.4–6.9) vs 7.9 (4.1–9.8) and 9.2 (4.3–15.9) in Sev, lanthanum and no binder groups, respectively; H = 9.6, p<0.008] (Fig. 1 and Table 2). In addition, in Sev-treated patients plasma p-cresol concentration was linearly related to the dose of the PO4 binder assumed by the patient being higher Sev doses associated to lower concentrations of this uremic toxin (r = −0.319; P = 0.025) (Fig. 2). Another relevant difference was observed in hs-CRP concentrations that were significantly lower in Sev than in lanthanum or no-binder groups (median and IQR: 3.8 (1.2–6.6) vs 6.3 (2.6–10.0) and 5.9 (3.4–8.4) in Sev, lanthanum and no binder groups, respectively; H = 10.2, p<0.006) (Table 2). No significant difference was observed neither in total creatinine clearance, weekly Kt/V, rGFR and urine volume suggesting that residual renal function and dialysis efficiency were similar in these three groups (Table 1). Moreover, also serum albumin concentrations were not significantly different among the three groups suggesting that the differences in the plasma concentration of p-cresol, a uremic toxin that circulates largely bound to serum albumin, could not be explained by a lower protein-bound fraction (Table 2). Considering that Sev therapy was started because of concurrent hyperphosphatemia and that the main pharmacological effect of Sev is to lower PO4, we compared PO4 circulating levels in the three groups (Table 2). No difference among groups was found (Table 2) suggesting that the treatment with the PO4 binder was effective in normalizing PO4 profile.

Bottom Line: Therapeutic strategies to reduce plasma p-cresol levels are highly demanded but not available yet.Patients receiving sevelamer had plasma p-cresol and serum high sensitivity C-reactive protein concentrations significantly lower than those receiving lanthanum or no drug.These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect cardiovascular risk because of its anti-inflammatory effect.

View Article: PubMed Central - PubMed

Affiliation: Division of Physiology, Dept. of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy.

ABSTRACT
p-Cresol is a by-product of the metabolism of aromatic aminoacid operated by resident intestinal bacteria. In patients with chronic kidney disease, the accumulation of p-cresol and of its metabolite p-cresyl-sulphate causes endothelial dysfunction and ultimately increases the cardiovascular risk of these patients. Therapeutic strategies to reduce plasma p-cresol levels are highly demanded but not available yet. Because it has been reported that the phosphate binder sevelamer sequesters p-cresol in vitro we hypothesized that it could do so also in peritoneal dialysis patients. To explore this hypothesis we measured total cresol plasma concentrations in 57 patients with end-stage renal disease on peritoneal dialysis, 29 receiving sevelamer for the treatment of hyperphosphatemia and 28 patients not assuming this drug. Among the patients not assuming sevelamer, 16 were treated with lanthanum whereas the remaining 12 received no drug because they were not hyperphosphatemic. Patients receiving sevelamer had plasma p-cresol and serum high sensitivity C-reactive protein concentrations significantly lower than those receiving lanthanum or no drug. Conversely, no difference was observed among the different groups either in residual glomerular filtration rate, total weekly dialysis dose, total clearance, urine volume, protein catabolic rate, serum albumin or serum phosphate levels. Multiple linear regression analysis showed that none of these variables predicted plasma p-cresol concentrations that, instead, negatively correlated with the use of sevelamer. These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect cardiovascular risk because of its anti-inflammatory effect.

Show MeSH
Related in: MedlinePlus