Uremic Toxins Overload Accelerates Renal Damage in a Rat Model of Chronic Renal Failure

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Uremic toxins have been suggested to promote progression of chronic renal failure by damaging tubular cells. Previous in vitro studies have indicated that some uremic toxins induce oxidative stress and activate NF-ĸB to upregulate plasminogen activator inhibitor-1 in tubular cells. These mechanisms may promote tubulointerstitial fibrosis. The present study examined whether uremic toxins induce glomerular and tubulointerstitial damage in vivo. Two uremic toxins, hippuric acid (HA) or indoleacetic acid (IAA), were tested in two independent experiments (HA-treated rats vs. non-HA-treated controls, IAA-treated rats vs. non-IAA-treated controls). The uremic toxins were administered to subtotally nephrectomized rats. Renal functions were measured periodically and glomerular sclerosis and interstitial fibrosis were examined at the end of the experimental period (18 and 24 weeks, respectively, after subtotal nephrectomy for HA and IAA treatments). Glomerular filtration rate (inulin clearance) at the end of the study period was significantly lower in uremic toxin-treated rats than in control rats (HA-treated rats: 0.090 ± 0.004 ml/min/100 g body weight vs. non-HA-treated controls: 0.125 ± 0.013, IAA-treated rats: 0.068 ± 0.006 versus non-IAA-treated controls: 0.100 ± 0.013; both p < 0.05). Beta-N-acetyl-glucoseamidase excretion was significantly higher in uremic toxin-treated rats than in control rats (HA-treated: 0.55 ± 0.05 U/day vs. control: 0.39 ± 0.04 at week 18, IAA-treated: 0.35 ± 0.02 vs. control: 0.26 ± 0.07 at week 16; both p < 0.05). Glomerular sclerosis index was significantly higher in uremic toxin-treated rats than in control rats (HA-treated: 0.85 ± 0.16 versus control: 0.48 ± 0.10, IAA-treated: 1.13 ± 0.25 vs. control: 0.57 ± 0.10; both p < 0.05). Significant enlargement of interstitial fibrosis was observed in indoleacetic acid-treated rats. These results indicate that overload of uremic toxins accelerates the loss of kidney function, glomerular sclerosis and tubulointerstitial injury in a rat model of chronic renal failure. The present study suggests the potential benefit of early intervention to remove various uremic toxins in delaying the onset of end-stage renal failure in patients with progressive renal disease.

Related collections

Most cited references 4

Record: found
Abstract: found
Article: not found

Expression cloning and characterization of a novel multispecific organic anion transporter.

M Hosoyamada, H Endou, T Sekine … (1997)

Numerous drugs and endogenous compounds are efficiently excreted from the renal proximal tubule via carrier-mediated pathways. Transepithelial excretion of organic anions occurs via their accumulative transport from the blood into the proximal tubule cells across the basolateral membrane and subsequent secretion into the urine through the apical membrane. Here we report on the isolation of a novel complementary DNA from rat kidney that encodes a 551-amino acid residue protein (OAT1) with 12 putative membrane-spanning domains. When expressed in Xenopus laevis oocytes, OAT1 mediated sodium-independent para-aminohippurate (PAH) uptake (Km = 14.3 +/- 2.9 microM). The uptake rate of PAH was increased by the outwardly directed dicarboxylate gradient, consisting with the idea that OAT1 is an organic anion/dicarboxylate exchanger. OAT1 displayed remarkably wide substrate selectivity, covering endogenous substrates such as cyclic nucleotides, a prostaglandin and uric acid, and a variety of drugs with different structures (e.g. antibiotics, a nonsteroidal anti-inflammatory drug, diuretics, an antineoplastic drug, and a uricosuric drug). The Northern blot analysis and in situ hybridization revealed that OAT1 is exclusively expressed in the particular segment of the proximal tubule in the kidney. These data suggest that OAT1 is a multispecific organic anion transporter at the basolateral membrane of the proximal tubule. Isolation of OAT1 will facilitate elucidation of the molecular basis of drug kinetics and the development of new drugs lacking unwanted side effects.

0 comments Cited 43 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Identical decline of residual renal function in high-flux biocompatible hemodialysis and CAPD.

Benjamin N. Greenwood, Ken Farrington, James Tattersall … (2001)

Patients on conventional hemodialysis lose residual renal function more rapidly than patients on continuous ambulatory peritoneal dialysis (CAPD). The effect of dialysis using synthetic membranes and ultrapure water is less clear. The decline of urea clearance was compared in a cohort of 475 incident end-stage renal failure patients who received treatment with CAPD (N=175) or hemodialysis (HD) utilizing high-flux polysulphone membranes, ultrapure water, and bicarbonate as the buffer (N=300). CAPD patients were significantly younger, fitter (lower comorbidity severity score), less dependent (higher Karnofsky performance score) and less likely to have presented late than HD patients. There was no difference in the mean urea clearance in each group at dialysis initiation, or at any 6-month time point during the ensuing 48 months. This was true even after exclusion of patients who had died in the first year after initiation, those transferred to another dialysis modality, or those who had been transplanted. Only age and chronic interstitial disease predicted retention of urea clearance at one year. The rate of decline of urea clearance was similar in pre- and post-dialysis initiation phases, though there may have been a step-decline of about 2 mL/min at initiation, which requires further investigation. In hemodialysis using high-flux biocompatible membranes and ultrapure water, residual renal function declines at a rate indistinguishable from that in CAPD. This may have important implications, since preservation of residual renal function has major benefits and is a valid therapeutic goal.