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Background: Cardiovascular disease is the most frequent cause of mortality in chronic renal failure (CRF). Therefore, it is important to identify appropriate treatment measures. The antioxidant N-acetylcysteine (NAC) has been shown to reduce cardiovascular events in hemodialysis patients. Here we examine a possible direct effect of NAC supplementation on uremia-enhanced atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice., Methods: Uremia was induced surgically in 8-week-old female apoE(-/-) mice. Two weeks after creation of CRF mice were randomized to receive either NAC (daily oral gavage with 200 mg/kg for 8 weeks) or placebo. They were compared to a control group of sham-operated apoE(-/-) mice receiving placebo. After 8 weeks of treatment, the mice were sacrificed, and the cross-section surface area of atherosclerotic plaques was measured in aortic root and descending aorta., Results: At 10 weeks following surgery, atherosclerotic lesions were significantly larger in uremic apoE(-/-) mice than in nonuremic controls. This accelerated atherosclerosis was associated with an increase in aortic nitrotyrosine expression and collagen plaque content. NAC treatment inhibited the progression of atherosclerotic lesions and plaque collagen content compared with placebo treatment. In addition, plaques from NAC-treated uremic animals showed a significant decrease in nitrotyrosine expression whereas the degree of macrophage infiltration was comparable in both uremic groups. There was no difference in mean arterial blood pressure between the three groups., Conclusion: We show for the first time that the antioxidant NAC is capable of reducing atheroma progression, in an animal model of uremia-enhanced atherosclerosis, probably via a decrease in oxidative stress.

Background: Urinary crystal precipitation is the necessary initial step in kidney stone formation. However, clinical relevance of crystalluria in the evaluation of stone formers is disputed., Methods: We serially determined crystalluria in first-voided morning urine samples, together with full 24-hour urine biochemistry, in 181 patients with idiopathic calcium nephrolithiasis who had formed at least one calcium-oxalate stone and were followed for at least 3 years under our care. All stone events which occurred prior to referral, then after entry in the study were recorded., Results: As compared with 109 patients who had no evidence of stone recurrence during follow-up, the 72 patients who experienced >/= one recurrent stone event had a lower daily urine volume (1.74 +/- 0.06 vs. 2.26 +/- 0.05 L/day (mean +/- SEM) (P < 0.0001), higher urine calcium and oxalate concentrations, and daily calcium excretion, and they had more frequent crystalluria (68% vs. 23% of urine samples) (P < 0.0001). By multivariate Cox regression analysis, the hazard ratio for stone recurrence was 0.32 (95% CI 0.16-0.62) for 1 L increase in daily urine volume, 1.12 (1.09-1.24) for 1 mmol/L increase in urine calcium concentration, 1.24 (1.02-1.50) for 0.1 mmol/L increase in urine oxalate concentration and 27.8 (10.2-75.6) for crystalluria index., Conclusion: These data provide evidence that crystalluria, when repeatedly found in early morning urine samples, is highly predictive of the risk of stone recurrence in calcium stone formers. Serial search for crystalluria, a simple and cheap method, may be proposed as a useful tool for the monitoring of calcium stone formers, in addition to urine biochemistry.

Background: Lanthanum (La) carbonate has recently been proposed as an alternative, calcium- and aluminum-free phosphate binder for the treatment of hyperphosphatemia of chronic renal failure (CRF). However, the extent to which CRF enhances tissue La accumulation induced by oral La overload above that observed under conditions of normal renal function remains a matter of debate. In the present study, we examined this issue in two different rat models of CRF., Methods: In a first series of experiments, adult male Sprague-Dawley rats received either a diet to which 0.3% adenine (wt% in feed) was added to induce CRF ("chemical CRF,"N= 20), or a diet free of adenine (control, N= 16). In a second series of experiments, adult male Sprague-Dawley rats underwent 5/6 nephrectomy in a two-step procedure ("surgical CRF,"N= 24). Half of all CRF and control rats were exposed to dietary La (3% lanthanum carbonate, wt% in feed) for four weeks (La[+] rats), whereas the other half received a placebo (La[-] rats)., Results: At the end of this time period, creatinine clearance was 1.51 +/- 0.15 (mean +/- SEM) and 1.45 +/- 0.11 mL/min in La[-] control and La[+] control rats, and declined to 0.22 +/- 0.03 and 0.31 +/- 0.03 mL/min in La[+]-adenine-CRF and La[+]-Nx-CRF rats, respectively. Urinary La excretion was 0.025 +/- 0.010 microg/24 hr in La[-] control rats. It increased to 4.9 +/- 1.2, 17 +/- 3.8, and 77 +/- 18 microg/24 hr in La[+] control, La[+]-adenine-CRF, and La[+]-Nx-CRF rats, respectively. However, only the last value was significantly different from control value. Tissue La concentration was increased in La[+] control rats compared with La[-] control rats. More importantly, tissue La concentration was strikingly higher in La[+]-CRF rats than in La[+] control rats. Thus, liver La (ng/g dry wt) was 1173 +/- 148 in La[+]-adenine-CRF and 1742 +/- 158 in La[+]-Nx-CRF rats, respectively, compared with 385 +/- 29 in La[+] control rats (P < 0.001), and 7.0 +/- 1.4 in La[-] control rats; similarly, bone La was 230 +/- 14 and 288 +/- 26 compared with 81 +/- 8, respectively (P < 0.001), versus 27 +/- 4 in La[-] control rats. Comparable differences were observed in the kidney, skeletal muscle, myocardium, lung, and brain, although to different extents in La[+]-adenine-CRF compared with La[+]-Nx-CRF rats. Finally, liver and kidney weight was significantly reduced in La[+]-adenine-CRF rats compared with La[-]-adenine-CRF rats., Conclusion: The oral administration of lanthanum carbonate to normal rats leads to a more than 10-fold increase of tissue La content in at least some organs, including the liver, lung, and kidney. This increase is further enhanced by the uremic state, per se. Plasma levels are a poor indicator of tissue burden. Given the dramatic tissue levels obtained with this rare earth metal given by the oral route, particularly in liver for absolute values, it is probable that the stimulation by CRF is at least partially explained by an increase in intestinal La absorption. The absorptive pathways involved in intestinal La absorption require further study, including possibly enhancing conditions.

Background: We investigated whether the total peroxyl radical-trapping antioxidant potential (TRAP) assay, which has recently been proposed as a gauge of oxidative stress, could serve to evaluate plasma and low density lipoprotein (LDL) antioxidant state in hemodialysis (HD) patients., Methods: TRAP was determined by the lag time of the chemiluminescence reaction induced by azo-initiator-catalyzed linoleic acid peroxidation in the plasma and corresponding LDL preparations of 23 HD patients and 22 healthy subjects. Antioxidant systems, including glutathione peroxidase (GSH-Px), ascorbate, vitamin E, and uric acid, oxidative stress markers including malondialdehyde (MDA), carbonyls, and advanced oxidation protein products (AOPP), and lipids, including cholesterol and triglycerides, were also determined in the plasma., Results: Both plasma and LDL-TRAP were significantly increased in HD patients despite decreased GSH-Px and ascorbate and increased MDA, carbonyl, and AOPP plasma levels. Plasma TRAP values were closely related to both uric acid and AOPP levels, and LDL-TRAP values were related to triglycerides and AOPP levels. In vitro studies showed that: (a) plasma TRAP of control plasma increased regularly with supplementation of uric acid, although not reaching that of HD plasma with similar uric acid levels; (b) the addition of human serum albumin-AOPP also regularly increased control plasma TRAP, but was close to that of HD plasma with similar AOPP levels; and (c) LDL-TRAP was increased following LDL enrichment with triglycerides., Conclusion: Our study demonstrates that TRAP is not a relevant parameter for evaluating plasma or LDL antioxidant capacity in HD patients, due to the high plasma levels of uric acid, triglycerides and AOPP, which by themselves do not exert efficient antioxidant activity in vivo, but in vitro are able to scavenge the peroxyl radicals involved in the TRAP assay.

In a recent study we demonstrated that the PTH/PTHrP receptor (PTH-R) mRNA was markedly down-regulated in the remnant kidney of uremic rats with severe secondary hyperparathyroidism. Among the factors potentially implicated in this down-regulation, to date only PTH has been demonstrated to modulate PTH-R expression. Here, we examined the effect of thyroparathyroidectomy (TPTX) on the renal expression of PTH-R in rats with normal renal function or with chronic renal failure (CRF) induced by 5/6 nephrectomy. Four groups of rats were studied: control, TPTX, CRF, and CRF + TPTX. Moderate-degree renal failure was documented by mean (+/- SD) creatinine clearances (microliter/min/100 g body wt) of 259 +/- 40 and 212 +/- 45 in CRF and CRF + TPTX rats, compared with 646 +/- 123 and 511 +/- 156 in control and TPTX rats, respectively. Plasma phosphorus, calcitriol, and ionized calcium were significantly lower in CRF and CRF + TPTX than in control animals. Plasma ionized calcium and calcitriol were also lower in TPTX than in control rats. Plasma PTH levels (pg/ml) were increased in CRF rats (41.8 +/- 29.4), and markedly decreased in TPTX (10.1 +/- 7.8) and CRF + TPTX (8.0 +/- 3.8) rats compared with control rats (21.7 +/- 7.5). Northern blot analysis showed that the level of the steady-state PTH-R mRNA in the kidney of CRF and CRF + TPTX rats was markedly decreased compared with that of control rats, the ratios of PTH-R mRNA/beta-actin mRNA being 0.28 +/- 0.04 and 0.27 +/- 0.03 versus 0.54 +/- 0.05, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal effects of prostaglandins have been widely investigated in anesthetized animals, but in contrast only few studies have been devoted to healthy and diseased humans. Recently, both prostacyclin and a stable analog of PGE1, misoprostol, have been available for therapeutic purposes in clinical conditions associated with peripheral or renal vasoconstriction; however, the renal effects have not been defined. We have therefore studied the acute renal effects of PGI2 5 ng.kg/min intravenously and of misoprostol, a stable PGE1 analogue, 400 micrograms orally in two groups of respectively 8 and 12 healthy supine subjects on normal sodium diet using sodium, lithium, inulin, PAH and neutral dextran clearances. PGI2 induced a slight natriuretic effect, a systemic and renal vasodilation with a decrease in mean arterial pressure from 85.3 +/- 1.1 to 80.2 +/- 1.6 mm Hg (P < 0.01) and in renal vascular resistance from 94 +/- 6 to 75 +/- 5 mm Hg.min/ml (P < 0.001). GFR did not change whereas fractional clearance of dextran decreased over the 34 to 48 A radius range. Applying these changes on a hydrodynamic model of filtration of macromolecules through water-filled pores, we calculated that PGI2 decreased the glomerular transcapillary pressure gradient from 35 +/- 1 to 32 +/- 1 mm Hg (P < 0.001), decreased nonsignificantly the ultrafiltration coefficient Kf and did not affect the membrane parameters r0 and omega 0. Misoprostol had no natriuretic effect, induced slight renal vasoconstriction and moderate decrease in GFR from 124 +/- 9 to 114 +/- 10 ml/min.1.73 m2 (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypocalcemia, hyperphosphatemia, and resistance to the action of PTH are well characterized features in the setting of advanced chronic renal failure (CRF). Although the underlying mechanisms are ill-understood, clinical and experimental evidence points to both PTH receptor down-regulation and post-receptor abnormalities in their pathogenesis. In the present study we have examined the effect of advanced CRF in rats on the renal expression of PTH/PTHrP receptor (PTH-R). CRF was created by a standard two-step operation (5/6 nephrectomy). Four weeks thereafter, 19 uremic rats were compared with 23 sham-operated rats. Uremic rats had higher mean (+/- SD) plasma creatinine levels than control rats, 164 +/- 107 microM versus 43 +/- 5 microM, respectively. They also had higher plasma phosphorus and iPTH levels, 4.70 +/- 1.71 mM versus 2.59 +/- 0.37 mM and 561 +/- 336 versus 27 +/- 18 pg/ml, respectively. Mean plasma total calcium and blood ionized calcium were significantly lower in uremic than in control rats, 2.13 +/- 0.06 mM versus 2.61 +/- 0.10 mM and 1.07 +/- 0.11 versus 1.31 +/- 0.06 mM, respectively. Mean plasma calcitriol concentration was also significantly lower in uremic than in control rats, 39.8 +/- 14.6 and 80.4 +/- 15.2 pg/ml, respectively. Nine out of the 19 rats were examined for renal PTH-R gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of the present study was to examine the effect of a two day and a five day administration of 22-oxa-calcitriol (OCT) on calcium metabolism in rats with advanced chronic renal failure and severe secondary hyperparathyroidism. A first series of 27 uremic rats received either placebo, OCT or calcitriol (0.3 microgram i.p./rat) 48 and 24 hours before sacrifice. A second series of 18 uremic rats received either placebo, OCT (0.3 microgram i.p./rat) or calcitriol (0.05 microgram i.p./rat) for five days. We found that after 48 hours (series 1) both calcitriol and OCT increased blood ionized calcium (Ca2+) as compared to vehicle (1.23 +/- 0.04 and 1.10 +/- 0.02 mM, P < 0.01 and P < 0.05, respectively vs. control, 1.02 +/- 0.03 mM). Duodenal Ca transport (S/M) using the everted gut sac technique was not stimulated by OCT, even though it increased from 2.8 +/- 0.4 to 7.0 +/- 0.6 (P < 0.01) with calcitriol. In contrast, duodenal calbindin-D9k mRNA expression and protein content increased to a similar extent with OCT and calcitriol. Calcitriol was more potent in reducing plasma iPTH1-34 levels than OCT: 344 +/- 75 pg/ml (calcitriol) versus 632 +/- 46 pg/ml (OCT) compared with 897 +/- 74 pg/ml (control), P < 0.01. In the second series of rats, the injection of OCT (0.3 microgram i.p./rat) over five days was less effective than the lower dose of calcitriol (0.05 microgram i.p./rat) in reducing circulating iPTH: 110 +/- 26 (calcitriol) and 281 +/- 64 (OCT) versus 624 +/- 135 pg/ml (control), P < 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)

Intestinal calcium transport, renal tubular calcium reabsorption, and plasma 1.25 (OH)2 vitamin D3 (calcitriol) levels have all been reported to be diminished in the spontaneously hypertensive rat (SHR) compared with its genetic control the Wistar Kyoto rat (WKY). In the present study, absorptive duodenal and renal tubular epithelia of 12- to 14-week-old male SHR and WKY were examined by electron microscopy to determine whether such disturbances could be related to structural abnormalities. Patchy loss of microvilli in both duodenal and proximal tubular epithelia was observed in the SHR, whereas brush border membrane was entirely normal in the WKY. Irregular spaces were observed between the basal aspects of SHR intestinal epithelial cells and their basement membrane. In addition, the average height of duodenal and renal microvilli was reduced in the SHR. Two specific markers of the brush border membrane, alkaline phosphatase and villin, as well as the cytoplasmic vitamin-D dependent calcium-binding proteins, CaBP9K and CaBP28K were determined. Duodenal alkaline phosphatase activity was reduced in the SHR, compared with the WKY: 0.145 +/- 0.002 vs. 0.186 +/- 0.002 IE/min.microns 3 x 10(3) brush border, mean +/- SEM, N = 10 pairs, P less than 0.001. However, duodenal villin expression was not different from that of the WKY. Duodenal CaBP9K and renal CaBP28K content was diminished in the SHR: 21.0 +/- 0.80 vs. 29.9 +/- 2.19 micrograms/mg protein, N = 6 pairs, P less than 0.01 for duodenum, and 4.47 +/- 0.39 vs. 7.67 +/- 0.54 micrograms/mg protein, N = 6 pairs, P less than 0.001 for kidney. These data showing structural and functional abnormalities of intestinal and kidney cells in the SHR appear to reflect a disorder of transporting epithelia which may be either intrinsic or related to reduced circulating calcitriol.

To investigate mechanisms underlying GFR control in diabetes mellitus, renal hemodynamics and segmental tubular handling of sodium, using lithium clearance, were assessed in 41 insulin-dependent diabetics (IDD) treated by insulin for 11 +/- 8 days, and in 19 normal controls. Average GFR and effective renal plasma flow (ERPF) were slightly but not significantly higher (136 +/- 22 vs. 123 +/- 16 ml/min.1.73 m2) in IDD than in normal subjects. GFR and ERPF were positively and strongly correlated in controls (r = 0.61, P less than 0.001) and in diabetics (r = 0.72, P less than 0.0001) indicating the marked flow dependency of GFR in both populations. After adjustment for ERPF, GFR was significantly higher in diabetics, suggesting a role of increased glomerular capillary pressure and ultrafiltration coefficient in the subset of "hyperfiltering" patients. Both fractional (FPRNa) and absolute (APRNa) proximal sodium reabsorption were significantly higher in IDD and significantly correlated with GFR. The ensuing decrease in sodium distal delivery could deactivate the tubuloglomerular feedback response and thus favor sustained vasodilation and high GFR in some diabetics. The renal effects of acute administration of drugs acting predominantly at either the pre- or the postglomerular resistance using nicardipine (N = 16) or captopril (N = 25) were further evaluated in IDD. The renal response to captopril or nicardipine was different in IDD. Whereas both drugs induced a marked decrease in renal vascular resistance, GFR was slightly decreased by captopril and was unchanged after nicardipine; these results are similar to those observed in normotensive non-diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Parathyroidectomy (PTx) is indicated in hemodialysis (HD) patients who have severe osteitis fibrosa unresponsive to vitamin D therapy or in whom the latter treatment is contraindicated. Immediately after PTx, plasma immunoreactive parathyroid hormone, calcium and phosphorus concentrations decline abruptly. However, little is known in such patients about the short-term effects of PTx on plasma alkaline phosphatase (AP) activity and plasma aluminum (Al) levels. The present, preliminary study was performed to determine such parameters in 37 HD patients, and to correlate them with data of bone histology. Mean plasma AP activity started to increase after PTx from day 4 onwards. Thus, AP values significantly higher than pre-PTx values were observed at day 7 and 14 (415 +/- 54 vs. 619 +/- 77 and 749 +/- 83 IU/liter, means +/- SEM; N = 37; P less than 0.05 and 0.001, respectively). This increase, in the absence of changes in liver function, was mainly due to the bone-specific iso-AP. Moreover, the degree of increase in plasma AP activity was higher in the subgroup with negative (group I, 21 patients) than in that with positive bone Al staining (group II, 16 patients). However, plasma osteocalcin (BGP) did not change after PTx (N = 8). Basal plasma Al levels were significantly higher in group II both before and two weeks after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

The renal effects of carbohydrates (CHO) were studied in two experiments. 1) The effects of CHO-energy restriction was evaluated by comparing uremic growing rats (initial weight: 80 g) fed "ad lib" (L rats) or CHO-restricted (starch and glucose) but receiving identical amounts of all other nutrients (R rats). R rats showed reduced growth, slower increase in plasma creatinine, lower mortality rate, and less histological renal damage than L rats. 2) Two types of CHO restriction, low glucose (R1 rats) or low starch (R2 rats) were compared to "ad lib" feeding (L1 rats) in adult rats (initial weight: 130 g). Growth was identically reduced in R1 and R2 rats. Mean plasma creatinine levels at week four was lower in R1 than in L1 rats. The overall rate mortality was higher for L1 and R2 than in R1 rats (79%, 81%, 53%) but included deaths from other causes than renal failure. Actuarial survival excluding these deaths was 27%, 83% and 10% in L1, R1 and R2 rats, respectively. Diffuse renal lesions were found in 25 of 30 L1, 5 of 15 R1, and 12 of 15 R2 rats (R1 vs. R1 and R2, P less than 0.01). The results show that CHO restriction may preserve the renal parenchyma, and suggest that restriction of "simple" rather than "complex" CHO restriction may be beneficial, a finding which could be of clinical importance if confirmed by further investigations.

The possible mechanisms of the increase in serum triglycerides (TG) and TG-rich lipoproteins were studied in chronically uremic (U) rats by comparison with either ad-lib fed control (C) rats or diet-restricted (DR), sham-operated pair-fed control rats. A first series of animals was studied in the fed state and a second series after a 16-hr fast. In U animals the concentration of serum TG and TG-rich particles was lower than that of C rats in the fed state but significantly higher than that of C and DR rats after a 16-hr fast. Serum glucose and lactate concentrations in the fed or fasted state were unchanged by uremia. Serum insulin concentration was significantly decreased in U rats as compared to C and DR rats in both series. The fast did not increase the concentration of serum nonesterified fatty acids (NEFA) in U or DR animals to the same extent as in C rats, whereas the serum concentration of beta-hydroxybutyrate (BOB), which was higher than that of C rats in the fed state, was significantly lower after a 16-hr fast. In U animals, as compared to control rats of either series, a significant decrease of epididymal lipoprotein lipase (LPL) activity was observed during both nutritional states when expressing the enzymic activity per number of cells. In conclusion, our data provide evidence against hepatic over-production of TG-rich lipoproteins in rats with chronic renal failure and strongly point to an LPL-mediated defect of their peripheral catabolism, probably related to the insulin deficiency state.