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Hyperphosphatemia has been associated with higher mortality risk in CKD 5 patients receiving dialysis. Here, we determined the association between the use of single and combined phosphate-binding agents and survival in 6797 patients of the COSMOS study: a 3-year follow-up, multicenter, open-cohort, observational prospective study carried out in 227 dialysis centers from 20 European countries. Patient phosphate-binding agent prescriptions (time-varying) and the case-mix-adjusted facility percentage of phosphate-binding agent prescriptions (instrumental variable) were used as predictors of the relative all-cause and cardiovascular mortality using Cox proportional hazard regression models. Three different multivariate models that included up to 24 variables were used for adjustments. After multivariate analysis, patients prescribed phosphate-binding agents showed a 29 and 22% lower all-cause and cardiovascular mortality risk, respectively. The survival advantage of phosphate-binding agent prescription remained statistically significant after propensity score matching analysis. A decrease of 8% in the relative risk of mortality was found for every 10% increase in the case-mix-adjusted facility prescription of phosphate-binding agents. All single and combined therapies with phosphate-binding agents, except aluminum salts, showed a beneficial association with survival. The findings made in the present association study need to be confirmed by randomized controlled trials to prove the observed beneficial effect of phosphate-binding agents on mortality.

Aristolochic acid contamination in herbal remedies leads to interstitial fibrosis, tubular atrophy, and renal failure in humans. To study the cellular mechanisms contributing to the pathophysiology of this renal disease, we studied Wistar rats treated with aristolochic acid and measured tubular and interstitial cell proliferation, epithelial/mesenchymal cell marker expression, tubular membrane integrity, myofibroblast accumulation, oxidative stress, mitochondrial damage, tubular apoptosis, and fibrosis. Oxidative stress, a loss of cadherin concomitant with vimentin expression, basement membrane denudation with active caspase-3 expression, and mitochondrial injury within tubular cells were evident within 5 days of administration of the toxin. During the chronic phase, interstitial mesenchymal cells accumulated in areas of collagen deposits. Impaired regeneration and apoptosis of proximal tubular cells resulted in tubule atrophy with a near absence of dedifferentiated cell transmembrane migration. We suggest that resident fibroblast activation plays a critical role in the process of renal fibrosis during aristolochic acid toxicity.

Background: Patients with end-stage renal disease (ESRD) undergoing hemodialysis have severe alterations in cell-mediated immunity (CMI) that increases their risk of contracting chronic hepatitis B virus (HBV) infection and decreases their protective responses to HBV vaccine. In an effort to improve the humoral response to an accelerated HBV vaccine protocol in these patients, the ability of an immunomodulator, AM3, to improve seroconversion was investigated., Methods: A total of 269 patients were enrolled in a multicenter trial. All patients received a DNA recombinant vaccine (40 microg HBsAg/dose/day) on days 0, 10, 21, and 90. AM3 or placebo (3 g/day) was given orally for 30 consecutive days beginning 15 days prior to the first vaccine dose. Anti-HBsAg titers were measured on days 120 and 270 after the beginning of the trial., Results: After one month, 207 patients could be evaluated and 132 patients after six months. The placebo and AM3-treated groups had comparable seroconversion and protective response rates one month after the final vaccine dose. The AM3 treatment group, but not the placebo group, maintained these protective titers up to six months after the final vaccine dose. At this time, the percentage of high responders (anti-HBsAg>100 IU/L) and mean anti-HBsAg titers in the AM3 group was significantly higher than in the placebo group., Conclusions: AM3 is a safe and easily tolerated oral agent that potentiates long-term serological immunity to hepatitis B in hemodialysis patients after vaccination.

The effect of a six-month peritoneal amino acid administration on muscle metabolism at rest and during exercise was examined in 12 patients (4 control and 8 amino acid treated) on continuous ambulatory peritoneal dialysis. 31P-magnetic resonance spectroscopy was used to measure several high-energy phosphates (PCr, Pi) in resting muscle and during exercise and recovery. At rest, no significant changes were detected between the non-treated (control) and the amino acid treated (experimental) group. Before the administration of amino acids, the exercise-induced fall in [PCr], the increase in [ADP] and [Pi] and the pH were not significantly different in the control and experimental group. The initial rate of PCr recovery and the calculated maximal rate of ATP-synthesis (Qmax) for the control subjects was not significantly different at the onset and the end of the study. In the treated group, however, the fall in [PCr] and increase in [ADP] after exercise were significantly lower after than before treatment, while [Pi] and pH were identical. The initial rate of PCr recovery and Qmax were also significantly improved. These changes indicate an improved oxidative phosphorylation under the treatment and suggest that the impaired oxidative metabolism of the dialysis patients could be the result of their bad nutritional state.

Two similar cases of rapidly progressive fibrosing interstitial nephritis in young women who followed the same slimming regimen prompted us to conduct an epidemiological survey of the nephrology centres of Brussels and to further investigate the exact nature of this slimming treatment. Seven other women under the age of 50 in terminal or preterminal renal failure were admitted for dialysis in 1991 and 1992. They had all followed a slimming regimen in the same medical clinic. Renal biopsy samples in eight of the nine cases showed extensive interstitial fibrosis without glomerular lesions. Two of the patients were seen for the first time in terminal renal failure and were started immediately on dialysis. For the seven other women, the nephropathy was characterised by a rapid deterioration in renal function, with initial serum creatinine doubling within about 3 months. The clinic had specialised in slimming treatments for the previous 15 years without any problems. In May, 1990, therapy was changed, with the introduction of two Chinese herbs (Stephania tetrandra and Magnolia officinalis). In June, 1992, three of twenty-five randomly selected women who had followed the same regimen during at least 3 months from 1990 had impaired renal function. Chemical analysis of some brands of these Chinese herbs did not show nephrotoxic contaminants of fungal or plant origin (ochratoxin or aristolochic acid) or adulteration by diuretics or antiinflammatory drugs. However, the medicinal preparation of the capsules taken by patients had different alkaloid profiles from those expected in Chinese plants. The striking relation between a specific type of fibrosing interstitial nephritis in young women and a slimming treatment involving Chinese herbs adds support to the arguments against uncontrolled therapy with herbal preparations.

Methods are described for the determination of aluminium in serum and in diluted urine by means of graphite furnace atomic absorption spectrometry. For the analysis of serum, thermal decomposition of the sample in the furnace, using a ramp charring program, was found to be necessary in order to eliminate the organic material. The precision of the method was 10%. For urine the relative deviation was 9%. The precision was markedly improved by the use of an automatic sample injector (5.3%). Since large contamination problems make the determination of Al at the parts per billion (ppb) level very difficult, special attention was paid to the precautions to be taken in order to avoid external aluminum contamination.

Aluminum (Al) loaded rats were injected chronically with either desferrioxamine (DFO) or saline. Six rats of each treatment group were sacrificed before and after one, three, and nine months of treatment for determination of tissue and serum Al, and for histological localization of bone Al. Urinary Al was measured during one week before sacrifice. Al loading caused significant elevations of bone (136.2 +/- 22.0 micrograms/g) and liver (114.4 +/- 41.9 micrograms/g) aluminum. Serum Al in DFO-treated animals was not different from their controls (216.4 +/- 80.5 and 226.9 +/- 42.9 micrograms/liter after one month; 151.0 +/- 20.8 and 138.0 +/- 63.9 micrograms/liter after three months; 72.1 +/- 40.7 and 61.6 +/- 14.2 micrograms/liter after nine months in control and DFO-treated animals respectively). Urinary Al excretion in the DFO-treated group was increased at all times as compared to the control rats. A decrease of muscle Al occurred after one month of DFO treatment, but no significant differences of liver and bone Al could be shown between DFO-treated rats and their controls. Al decreased to a comparable degree in all tissues of both DFO and control rats after nine months of treatment. Histomorphometric examination of the bones showed that after one and three months of treatment, significantly less Al was localized at the calcification front of DFO-treated rats compared to their controls (75.6 +/- 6.9% and 53.4 +/- 20.9% after one month; 52.3 +/- 10.2% and 34.8 +/- 10.6% after three months in control and DFO rats respectively).(ABSTRACT TRUNCATED AT 250 WORDS)