Protein-bound Uremic Retention Solutes Research Articles

Removal of the Uremic Retention Solute p‐Cresol Using Fractionated Plasma Separation and Adsorption

Removal of protein-bound uremic retention solutes, including p-cresol, by peritoneal dialysis and hemodialysis (HD) is limited. p-Cresol, mainly circulating as sulfate conjugate (p-cresyl sulfate [PCS]), is independently associated with mortality. Fractionated plasma separation and adsorption (FPSA) is a nonbiologic detoxification system for the treatment of liver failure. The FPSA clearance of uremic retention solutes is unknown. We studied PCS clearance by FPSA, using the Prometheus system. The neutral resin adsorbent and the anion exchange adsorbent bind PCS in vitro (reduction ratios [RRs] 37 and 70%). Ex vivo, the adsorbent mass removal (MR) (median 47.5 mg) contributes more than half to total MR (median 89.6 mg). In vivo, PCS RR during FPSA (50%) exceeded the RR during high flux HD (30%). We halted the study after four inclusions due to repeated thrombosis of the arterio-venous conduit. In conclusion, FPSA is a promising technique to improve clearance of protein-bound uremic retention solutes.

Leptin and β2-Microglobulin Kinetics with Three Different Dialysis Modalities

Leptin is a protein produced by fat cells and involved in body weight regulation. In patients with normal kidney function, leptin has been considered an independent predictor of cardiovascular events. In uremic patients, leptin in plasma serum was assumed to be associated with malnutrition, inflammation and atherosclerosis. Because of its molecular weight and characteristics, leptin can be considered as a protein-bound uremic retention solute. Some authors have reported the possibility of decreasing the serum leptin concentration with high flux membranes, but limited data are available on the elimination with medium-flux membranes or alternative dialysis strategies such as hemodiafiltration. We evaluated the kinetics of leptin and beta2m in a study of 18 chronic hemodialysis patients using low-flux, medium-flux and high-flux biocompatible membranes, the last one used in hemodiafiltration (HDF). Blood samples for leptin and beta2m were collected pre- and post-treatment and 30 minutes after the end of treatment, over a 1-week period that included 3 dialysis sessions. Clearances of leptin and beta2m across the dialyzer were also determined directly from the arterial and venous blood concentrations 60 and 210 minutes after starting dialysis. At baseline, all groups showed similar leptin (18.8+/-4.4 ng/mL) and beta2m concentrations (29.2+/-7.1 ng/mL). After a single dialysis session, a reduction of both solutes was observed with HDF (39.8+/-1.9%, 78.1+/-4.9) and medium flux membranes (18.2+/-0.9%, 52.2+/-1.7%), whereas the concentrations remained unchanged with the low-flux membranes. After one-week period, a trend of reduction of plasma pre dialysis leptin and beta2m were observed with HDF and medium flux membranes. At 60 minutes, HDF showed the best instantaneous clearance across the filter for leptin (56.2+/-10.1 ml/min) and beta2m (75.3+/-4.4 ml/min). The magnitude of post dialysis rebound of leptin at 30 min was variable and strongly correlated with the instantaneous clearance of the solute (r2= 0.88). Leptin serum concentration can be influenced by dialysis modalities and membrane permeability; data on rebound suggest a multicompartimental kinetic of leptin similar to beta2m. Leptin removal, as measured by the reduction rate, can be considered as an index of dialysis efficiency for protein-bound uremic retention solutes.

Online Hemodiafiltration

Online hemodiafiltration (HDF) is an extracorporeal technique for solute removal in renal failure, which takes advantage of an enhancement of convective treatment by the large amount of ultrapure nonpyrogen dialysate being used for substitution of the ultrafiltered volume. It offers many advantages aside from its safe inflammatory profile, which is attributable to the use of ultrapure dialysate and highly biocompatible dialysis membranes. Due to an improved convective clearance, significantly increased removal of large or protein-bound uremic retention solutes can be achieved, with a potential benefit on cardiovascular morbidity and mortality. Recent observational data indicate that online HDF offers a survival advantage even after adjustment for comorbidity and dialysis efficiency. Research has been ongoing to maximize further the effectiveness of the technique by new technical innovations such as transmembrane-pressure feedback control or mid-dilution online HDF.

Acarbose treatment lowers generation and serum concentrations of the protein-bound solute p-cresol: A pilot study

Several protein-bound uremic retention solutes (including p-cresol) originate from colonic bacterial fermentation of protein. Higher colonic availability of carbohydrates drives this process towards lower production of toxic metabolites. Small intestinal alpha-glucosidase inhibitors like Acarbose (Glucobay) enhance the amount of undigested carbohydrates reaching the colon. We studied the effect of Acarbose on generation and serum concentrations of p-cresol. Nine healthy volunteers (age 25 (22-36) years) with a creatinine clearance of 89.6 ml/min/1.73 m(2) (85.5-116.4) were treated with Acarbose for 3 weeks. Dose was gradually increased to reach 300 mg/day after 1 week. Blood sampling, 24-h urine and stool collections on 3 consecutive days were performed before and during the last days of the treatment period. p-Cresol generation was estimated from mean 24-h urinary elimination. Gastrointestinal side effects, if present, were mild to moderate. Serum concentrations of p-cresol declined significantly after Acarbose treatment (before: 1.14 mg/l (0.93-3.03); after: 1.11 mg/l (0.31-1.82); P=0.047). Urinary excretion of p-cresol, reflecting its colonic generation rate, was significantly lower after treatment (before: 29.93 mg/day (6.79-75.19); after: 10.54 mg/day (1.08-30.85); P=0.031). The fecal excretion of nitrogen increased after treatment (before: 1.04 g/day (0.47-2.29); after: 1.99 g/day (0.76-3.08); P=0.047). This pilot study suggests that Acarbose treatment lowers generation and serum concentrations of the protein-bound uremic solute p-cresol. Although further confirmation is warranted, the data may point to a novel treatment option for chronic kidney disease patients in view of the potential toxic effects of p-cresol and related substances.

Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients

Based on in vitro data, protein-bound uremic retention solutes have increasingly been recognized to play a pathophysiological role in the uremic syndrome. p-Cresol, a representative of this group of molecules, has been shown to be implicated in uremic immunodeficiency and endothelial dysfunction, potentially linking its serum levels to mortality. Thus far, however, no clinical information on this issue is available. To determine the relationship between p-cresol and all-cause mortality, 175 prevalent hemodialysis (HD) patients were enrolled in a prospective study. At baseline, serum levels of the water-soluble solutes urea, creatinine, and phosphate, the middle molecule beta2-microglobulin, total and free concentrations of the protein-bound solute p-cresol, and several risk factors for mortality were evaluated. During a median follow-up of 34 months, 60 patients died. Baseline comorbidity (Davies score) (hazard ratio (HR), 1.49; 95% confidence interval (95% CI), 1.19-1.86), impaired nutritional status (HR, 4.22; 95% CI, 2.15-8.29), time since initiation of dialysis (HR, 0.98; 95% CI, 0.97-1.00), and higher free concentrations of the protein-bound solute p-cresol (HR, 2.28; 95% CI, 1.12-4.64) were independently associated with mortality (multivariate Cox proportional hazards analysis). Our data suggest that free serum levels of p-cresol, a representative of the protein-bound uremic retention solutes, are associated with mortality in HD patients. These findings may encourage nephrologists to widen their field of interest beyond the scope of small water-soluble uremic solutes and middle molecules.

The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair

Cardiovascular diseases are the major causes of mortality in uremic patients, and the vascular endothelium is dysfunctional in uremia. We hypothesized that uremic retention solutes may be among the factors involved in this endothelial dysfunction. We therefore investigated the in vitro effect of a large panel of uremic retention solutes (guanidino compounds, polyamines, oxalate, myoinositol, urea, uric acid, creatinine, indoxyl sulfate, indole-3-acetic acid, p-cresol, hippuric acid, and homocysteine) on endothelial proliferation. In addition, we tested the effect of uremic solutes that altered proliferation on endothelial wound repair. Human umbilical vein endothelial cells (HUVEC) were incubated with uremic retention solutes at concentrations in the range found in uremic patients. Protein-bound uremic solutes were also tested in the presence of 4% human albumin. Then, we determined the effect of each uremic solute on endothelial proliferation by a 5-bromo-2-deoxy-uridine (BrdU) labeling assay. In addition, confluent endothelial monolayers were injured, incubated with uremic solutes that altered endothelial proliferation, and the surface of the wound was measured at different intervals by image analysis. Endothelial proliferation was inhibited by two protein-bound uremic retention solutes: p-cresol and indoxyl-sulfate. Inhibition of endothelial proliferation by p-cresol was dose-dependent. Moreover, p-cresol and indoxyl sulfate decreased endothelial wound repair. The presence of albumin did not affect the inhibitory effect of these solutes on endothelial proliferation, but the decrease in endothelial wound repair was less marked in the presence of albumin. We demonstrated that both p-cresol and indoxyl sulfate decrease endothelial proliferation and wound repair. These solutes could play a role in endothelial dysfunction observed in uremic patients.

Protein-bound uremic retention solutes

Protein-bound uremic retention solutes are molecules with low molecular weight (MW) but should be considered middle or high MW substances. This article describes the best known substances of this group, which include p-cresol, indoxyl sulfate, hippuric acid, 3-carboxy-4-methyl-5-propyl-2-furan-propionic acid (CMPF), and homocysteine. At concentrations encountered during uremia, p-cresol inhibits phagocyte function and decreases leukocyte adhesion to cytokine-stimulated endothelial cells. CMPF has been implicated in anemia and neurologic abnormalities of uremia. CMPF could alter the metabolism of drugs of inhibiting their binding to albumin and their tubular excretion. Indoxyl sulfate administrated to uremic rats increases the rate of progression of renal failure. Hippuric acid inhibits glucose utilization in the muscle, and its serum concentration is correlated with neurologic symptoms of uremia. Homocysteine predisposes uremic patients to cardiovascular disease throughimpairment of endothelial and smooth muscle cell functions. The removal of protein-bound compounds by conventional hemodialysis is low. Other strategies to decrease their concentrations include increase in dialyze pore size, daily hemodialysis, peritoneal dialysis, reduction of production or acceleration of degradation, and preservation of residual renal function.