No abstract

Our results demonstrate that (1) [Ca(2+)](i), intracellular calcium stores and the capacitative calcium entry were significantly increased already in early stages of CKD; (2) long-term vitamin D(3) supplementation normalized [Ca(2+)](i) without any effect on intracellular calcium reserves or the capacitative calcium entry.

The angiotensin II receptor 1 antagonist losartan (L) inhibited the advanced glycated end-products (AGEs) induced expression of transforming growth factor β₁ in in vitro experiments performed on renal tubuloepithelial cells. To test the pathophysiological importance of these findings, the possible link between serum AGEs levels and angiotensin system was investigated in the model of normotensive subtotally nephrectomized rats(4/6-NX). Concentration of AGEs in serum of placebo administered 4/6-NX rats (n = 7, 1.09±0.09 U/l) increased slightly in comparison with sham-operated healthy controls (CTRL, n = 8, 0.94±0.10 U/l, p<0.02) as measured by competitive ELISA. Treatment of 4/6-NX rats with L over 12 weeks ameliorated the rise in serum AGEs concentration (1.00±0.12 U/l, n = 15 <0.005) almost to the level observed for CTRL. This effect was further corroborated by the observation, that the impaired renal excretion of AGEs in 4/6-NX-placebo rats (0.07±0.02 U/µmol creatinine) was significantly restored by L (0.09±0.02 U/µmol creatinine, <0.009) and resembled that of the CTRL (0.10±0.03 U/µmol creatinine). Administration of L to 4/6-NX rats significantly improved renal function as evaluated by a smaller rise in serum creatinine and urea concentration. In spite of the improvement in renal function, there were no differences in concentrations of transforming growth factor β₁ in serum and in urine among the two groups. These effects were independent of blood pressure. Our data give first evidence, that long-term treatment with angiotensin II receptor 1 antagonist may exert salutary effects on AGEs levels in the rat remnant kidney model, probably due to improved renal function.

Hippurate (Hip), an endogenous conjugate, belongs to the group of uremic toxins. Hip stimulates P-independent glutaminase (PIG) localized at the proximal luminal membrane, desamidating glutamine with the formation of ammonia, a dominant and adaptive elimination product of H+. This appears to be important because metabolic acidosis (MAC) does not stimulate PIG. Moreover, Hip inhibits ammonia production by P-dependent mitochondrial glutaminase (PDG) that is primarily stimulated by MAC. By this mechanism, it shifts the ammonia production from mitochondria to proximal tubular lumen. MAC stimulates Hip synthesis in the liver and kidney and increases Hip plasma concentration and even fractional excretion by the kidney, which creates an effective regulatory loop of ammoniagenesis. Thus, it appears that Hip by its participation in the correction of MAC possesses the modulatory function.

Patients with advanced renal failure suffer from almost constant insulin resistance (IR) which is a major risk factor of atherosclerosis and very probably also of glomemlosclerosis. However, data on IR in kidney disease patients with mild-to-moderate kidney function decrease are lacking. A group of 52 patients with various kidney diseases and decreased kidney function of different degree but not with advanced renal failure was evaluated. Almost half of them suffered from IR though they did not differ from insulin-sensitive patients in age, sex, prevalence of various kidney diseases, hypertension, clearance of endogenous creatinine, serum creatinine, urea, uric acid, hippurate or pseudouridine concentrations. They did not differ in the prevalence and degree of metabolic acidosis or in the concentration of plasma and total and free magnesium in erythrocytes. They were just slightly more obese and their serum TG and VLDL concentrations were increased and HDL concentration decreased. It is concluded that IR and dyslipoproteinemia develop in the early stages of kidney diseases and could participate in kidney disease progression since the beginning of kidney disease. It is suggested that early treatment of these alterations could decrease the progression of kidney disease more effectively than their treatment in advanced stages.