Dose-dependent effects of strontium on bone of chronic renal failure rats

BACKGROUND: We previously reported on increased bone strontium (Sr) levels in dialysis patients with osteomalacia versus those presenting other types of renal osteodystrophy. A causal role of strontium in the development of osteomalacia was established in a chronic renal failure (CRF) rat model. METHODS: In the present study we investigated whether the effect of Sr on bone was related to dosage. Four groups of CRF rats were studied: a control group (control-CFR; N=6) not receiving strontium and three groups of animals loaded orally with Sr during 18 weeks by adding the element as the SrCl2. H20 compound to the drinking water at concentrations of 0.03 g/100mL (Sr-30; N=6), 0.075 g/100mL (Sr-75; N=6), or 0.15 g/100mL (Sr-150; N=6) respectively. A fifth group consisting of seven animals with intact renal function (control-NRF), not receiving Sr served as controls for the effect of CRF on bone histology. RESULTS: As compared to the control-NRF and control-CRF groups, Sr administration resulted in a dose-dependent increase in bone and serum Sr levels. No difference in body weight and biochemical serum and urinary parameters [i.e., calcium (Ca), phosphorus (P), and creatinine] was noted between the various CRF groups. At sacrifice, intact parathyroid hormone (iPTH) levels of CRF groups were significantly (P < 0.05) higher than the values measured in the control-NRF group indicating the development of hyperparathyroidism secondary to the installation of the CRF. This is further supported by the differences in bone histomorphometry between the control-CRF and control-NRF animals, which, respectively, showed an increased amount of osteoid (mean +/- SEM 3.4 +/- 1.2% vs. 0.37 +/- 0.14%, P < 0.05) in combination with a distinct osteoblastic activity (35 +/- 11% vs. <2%, P < 0.05) and an increased bone formation rate [(BFR), 677 +/- 177 microm 2/mm2/day vs. 130 +/- 50 microm 2/mm2/day, P < 0.05]. Bone surface area and erodic perimeter did not differ between the various study groups. In the Sr-30 group, Sr loading went along with a dramatic reduction of the BFR as indicated by the total absence of double tetracyclin labels and osteoblastic activity, which in the presence of a low to normal amount of osteoid (2.7 +/- 1.9%) points to the development of the adynamic type of renal osteodystrophy. Interestingly, compared to the control-CRF group, histodynamic and histologic parameters of the Sr-75 group did not differ significantly and a substantial osteoblastic activity (7.6 +/- 4.0%) was seen also. In the Sr-150 group, the various osteoid parameters were significantly (P < 0.05) increased vs. all other groups and were accompanied by a reduced BFR and mineral apposition rate (MAR) and an increased mineralization lag time (MLT), indicating a mineralization defect and the development of osteomalacia. CONCLUSIONS: Our findings indicate that the role of Sr in the development of bone lesions in renal failure is complex and that, depending on the dose, the element may act via multiple pathways.     

异丙酚对急性心肌梗死大鼠心脏功能的影响

目的 观察异丙酚对急性心肌梗死大鼠血液动力学影响的量-效关系以及心肌梗死范围和心肌超微结构的变化。方法 将急性心肌梗死模型的大鼠随机分为5组（n=8）,对照组（Ⅰ）,其余大鼠分别持续静脉输注30（Ⅱ）、45（Ⅲ）、60（Ⅳ）、75（Ⅴ）mg·kg-1·h-1异丙酚30min。测定输注异丙酚30min血药浓度,观察血液动力学、心肌梗死范围和心肌超微结构的变化。结果 血药浓度为（3.4±0.9）～（12.9±2.4）μg/ml时,平均动脉压（MAP）、心率（HR）、左室收缩压（LVSP）、左室内压力变化最大速率（±dp/dtmax）、心肌耗氧指数（MOCI）均呈剂量依赖性下降（P<0.05）,左心室舒张末压（LVEDP）无明显变化（P>0.05）,心肌梗死面积为23.7％～29.2％（P>0.05）,心肌超微结构无显著性差异。结论 在血药浓度（3.4±0.9）～（12.9±2.4）μg/ml范围内,异丙酚对血液动力学及心收缩功能呈剂量依赖性抑制,对心肌梗死范围和心肌细胞超微结构无明显影响。     

Endotoxin-induced acute renal failure in rats: effects of L-arginine and nitric oxide synthase inhibition on renal function

BACKGROUND: The regulation of renal hemodynamics is closely related to the L-arginine (L-Arg)/nitric oxide (NO) pathway. NO - metabolized from L-Arg - is capable of improving renal function in ischemic and toxic acute renal failure (ARF), while NO synthase (NOS) inhibition induces deterioration in renal function. The mortality rate in patients with septic shock is increased when treated with a non-selective NOS inhibitor, while the incidence of ARF requiring renal replacement therapy is unaffected. To date, there are no studies on the impact of NOS substrate (L-Arg) and inhibitor (L-NMMA) on renal function in early lipopolysaccharide (LPS)-induced ARF. METHODS: ARF was induced by intravenous (i.v.) LPS. Animals were treated with L-Arg, L-NMMA (NOS substrate and inhibitor), a combination of both or saline. Glomerular filtration rate (GFR), urine flow, fractional sodium excretion, excretion of NO metabolism stable end products and blood pressure (BP) were recorded at baseline, after ARF induction, during drug infusion and thereafter. RESULTS: L-Arg induced better GFR during infusion. Excretion of the NO metabolism end products was highest in the L-Arg group and lowest in the NOS inhibitor group. L-Arg administration had no influence on BP, while L-NMMA induced a slight elevation. CONCLUSIONS: We conclude that exogenous L-Arg exerts beneficial effects in early LPS-induced ARF in rats during drug infusion, while NOS inhibition has no influence on GFR. Subcellular compartmentalization of the L-Arg pool in cytoplasma and the rapid utilization of exogenous L-Arg in such a micro-environment could explain this effect, which has been observed in other ARF models and was called the "L-Arg paradox". In further studies the effects of early and prolonged administration of L-Arg in endotoxinemia should be investigated.     

高血磷对慢性肾衰竭大鼠血管钙化的影响

目的 研究高血磷对慢性肾衰竭大鼠血管钙化的影响。 方法 44只Wistar雄性大鼠分别行5/6肾切除（n=24，模型组）或假手术（n=20，对照组），39只大鼠术后4周开始给予高磷或低磷饮食10周。动物分4组：模型组+高磷饮食(CHP)，模型组+低磷饮食(CLP)，对照组+高磷饮食(NHP)，对照组+低磷饮食(NLP)。高磷饮食配方：磷（P）1.2%, 钙（Ca）1.6%，维生素D 1 IU/kg；低磷饮食配方：P 0.2%, Ca 0.5%，维生素D 1 IU/kg。特定饮食开始（基线）和结束时称体质量；检测Scr、血P、血Ca、1,25(OH)2D3、全段甲状旁腺激素（iPTH）。特定饮食结束时处死大鼠，取胸主动脉组织，采用Von Kossa染色和钙含量测定判断血管钙化程度，同时检测核心结合因子α1（Cbfα-1）mRNA的表达。 结果 术后第4周特定饮食开始时，模型组大鼠Scr水平显著高于对照组大鼠 [（94.4±17.6）比（36.4±0.6）μmol/L，P < 0.05]，余各项指标组间差异无统计学意义。特定饮食10周时，4组间体质量差异无统计学意义；各组各时间点血Ca水平差异均无统计学意义；血1,25(OH)2D3水平除了在NLP组显著增高外，余3组间差异均无统计学意义；CHP组血P和iPTH水平显著增高，出现严重血管钙化、程度3～4级；胸主动脉钙含量明显增高，同时Cbfa-1 mRNA表达显著上调。血P水平对胸主动脉钙含量的影响比iPTH水平更强（β ＝ 0.832>0.267）。血P水平与胸主动脉钙含量、Cbfα-1 mRNA表达量呈直线正相关（r = 0.672～0.73，P < 0.05）。 结论 高血磷是导致慢性肾衰竭大鼠血管钙化的重要因素。 Cbfα-1的表达上调可能是其导致血管钙化的机制之一。     

Effect of dietary salt restriction on tubular hypertrophy in rats with early-stage chronic renal failure

OBJECTIVE: Because salt restriction minimizes the occurrence of glomerular hypertrophy and tubular damage, we examined the effect of such restriction in rats with chronic renal failure (CRF). MATERIAL AND METHODS: Male Sprague-Dawley rats were fed either a low-salt rat chow (65 mg sodium/100 g) or a normal salt diet (390 mg sodium/100 g) and underwent either 4/5 nephrectomy or a sham operation. Thus, there were four study groups (10 rats in each): a low-salt nephrectomy group (L-Nx); a normal diet nephrectomy group (N-Nx); a low-salt sham operation group (L-S); and a normal diet sham operation group (N-S). At the end of 8 weeks, all the rats were killed. RESULTS: Urinary sodium output, urinary protein excretion and blood pressure in L-Nx were significantly decreased in comparison to the values in N-Nx. Body weight, urine volume and glomerular filtration rate were similar between L-Nx and N-Nx. Histologically, the planar area of glomeruli and the smallest diameter of the proximal tubules in L-Nx were significantly reduced in comparison to those in N-Nx: 8.8+/-0.3 x 10(-3) vs 9.7+/-0.3 x 10(-3) mm2 (p < 0.01) and 6.7+/-0.1 x 10(-2) vs 7.4+/-0.1 x 10(-2) mm (p < 0.01). There were no statistically significant differences between L-S and N-S with the exception of urinary sodium output. CONCLUSION: Salt restriction in nephrectomized rats minimized the occurrence of proximal tubular hypertrophy independently of renal function. This suggests that salt restriction directly delays the occurrence of both tubular hypertrophy and glomerular hypertrophy in the presence of CRF.     

Somatic and renal effects of growth hormone in rats with chronic renal failure

Recombinant human growth hormone (rhGH) has been widely used to improve growth in children with chronic renal failure (CRF). However, there has been great concern that GH may aggravate renal disease and hasten the progression to end-stage renal failure. We therefore investigated the effect of prolonged administration of rhGH at various doses on somatic growth and renal function and structure in rats with CRF, divided into four groups based on rhGH dose (vehicle, 0.4, 2.0, and 10.0 IU/day). rhGH was administered subcutaneously daily for 8 weeks. The mean growth was significantly greater in rats treated with high-dose rhGH (10.0 IU) than those treated with low-dose rhGH (P = 0.0089) or vehicle (P = 0.0011). Body weight gain increased in parallel with body length (Creatinine clearance at the end of the experiment was significantly lower in rats on high or medium-dose rhGH than those on low-dose rhGH and controls (P <0.05). The glomerular sclerosing index was greater in rats treated with higher doses of rhGH. There were significant differences between rats treated with high-dose rhGH and controls (P = 0.0144) and also between rats on medium-dose rhGH and controls (P = 0.0065). Although there was no significant difference, rats treated with higher doses of rhGH tended to excrete more protein. Renal insulin-like growth factor-I (IGF-I) content and circulating IGF-I and IGF-II levels did not significantly differ among groups. We conclude that: (1) GH improves somatic growth failure in rats with CRF, but prolonged administration of GH dose-dependently induces deterioration in renal function and structure and (2) this effect was induced neither via circulating IGF-I and IGF-II nor by local production of IGF-I, but seems to be direct. Received June 7, 1996; received in revised form and accepted November 19, 1996     

Effects of erythropoietin, bromocryptine and hydralazine on testicular function in rats with chronic renal failure

Summary. We evaluated the effects of chronic renal failure (CRF) on testicular function and semen physiology. A CRF model was created in 48 male rats by performance of five-sixths nephrec-tomies in two-stage procedures, and a control (group A) by two-stage sham operation on six male rats. Seven weeks later, serum urea and creatinine concentrations were assessed, and the nephrectomized rats were then equally divided into four groups, B, C, D and E, and treated with saline, erythropoietin, bromocryptine and hydralazine, respectively. Seventeen weeks after the first surgical procedure, the number of fertile rats, the mean values of epididymal sperm content and motility, the outcome of in vitro fertilization, and peripheral serum testosterone concentrations and responses to human chorionic gonadotropin were significantly higher ( P <0.05) in groups A, G and D than in groups B and E. Serum prolactin concentration was significantly higher ( P <0.05) in all groups of nephrectomized rats than in group A. Our results indicate that bromocryptine and erythropoetin improve Leydig cell function, sper-matogenesis, epididymal sperm maturation, and sperm fertilizing capacity in rats with CRF.     

The effects of acute renal failure on long-term renal function

The relationship between acute renal failure (ARF) and long-term renal function remains unknown. We therefore undertook a study of patients at the Baltimore VA Hospital to examine the effects of a bout of acute renal injury on long-term renal function. We retrospectively reviewed the relationship between serum creatinine and time of observation for 6058 individuals who had values greater than 1.4 mg/dL in any two consecutive years. Individuals were stratified according to total years of observation with a minimum of two years. Severity of acute renal injury was divided into mild, moderate, and severe with elevations in baseline creatinine of < 50%, 50-300% and > 300% respectively. Sporadic elevations in creatinine were evident in 8-15% of the population. There were a total of 1328 episodes of acute renal failure in 916 patients that were suitable for analysis. Mild ARF on a substrate of normal or mildly abnormal renal function resolved without long-term sequelae. Moderate and severe ARF occurred more frequently on a background of reduced renal function but baseline function was retained in at least 60% of patients. We conclude that ARF is more frequent in patients with chronic kidney disease but it is not invariably associated with an accelerated course to end-stage renal disease or death. Overall, the majority of ARF events resolved without adverse long-term effects suggesting appropriate management in the majority of instances.     

Effect of fluoride on aluminum-induced bone disease in rats with renal failure.

Aluminum (Al) accumulation in renal failure is an etiological factor in the pathogenesis of low turnover bone disease. Aluminum-induced impairment of mineralization has been related to a reduced extent of active bone-forming surface. The present study investigated the effect of fluoride, a potent stimulator of osteoblast number, on the toxicity of aluminum in rats with renal failure (Nx). Following a large parenteral aluminum load (3.2 mg/kg x day) over a period of nine weeks, bone histomorphometry of vertebral cancellous bone revealed a severe low-turnover osteodystrophy as evidenced by a fall in osteoblastic osteoid surfaces and mineral apposition rates. Concurrent administration of fluoride [20 mg/liter (F20) or 40 mg/liter (F40) supplied with the drinking water] resulted in a significant increase in the number of osteoblasts (Nx+Al+F40 vs. Nx+Al, 33.75 +/- 2.83 vs. 1.81 +/- 0.43 mm-1, P less than 0.001) together with an overall reduced deposition of aluminum in bone (469.3 +/- 24.6 vs. 592.2 +/- 28.3 micrograms/g, P less than 0.01). However, there was an increase in the fraction of osteoid surface exhibiting stainable aluminum at the bone-osteoid interface (70.7 +/- 7.1 vs. 44.3 +/- 6.0%, P less than 0.005). Fluoride-exposed rats accumulated a significantly larger osteoid volume, suggesting an exacerbation of the osteomalacic lesion, and furthermore, dynamic histomorphometric parameters remained depressed. These results indicate that fluoride has a distinct effect on the pattern of aluminum deposition in bone. In addition, fluoride antagonizes the aluminum-induced reduction in osteoblast number but provides no amelioration of the impaired mineralization in aluminum-intoxicated rats. Thus, in this model a decrease in the extent of osteoblast surface does not account for the development of aluminum-related bone disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial hypertrophy in rats with renal insufficiency

Increased defatted dry wt of the heart and increased heart calcium content were observed in subtotally nephrectomized male Sprague-Dawley rats compared with sham-operated pairfed controls. Increased heart wt contrasted with no change of the weight of viscera (liver, spleen) and markedly decreased weight of striated muscle. Heart wt was unchanged after 5 days of renal insufficiency, but significantly increased after 14 or 21 days. Increased heart wt persisted despite effective beta adrenoreceptor blockade (2 X 10 mg metroprolol/kg/day i.p.) or effective alpha-1-adrenoreceptor blockade (2 X 2 mg prazosin/kg/day i.p.). Increased heart wt was also demonstrable despite normalization of basal blood pressure (intraarterial blood pressure measurement in conscious animals): blood pressure was lowered in one series with hydralazine/nadolol in drinking water (calculated to deliver 20 and 2 mg/kg/day, respectively) and in another series with furosemide in drinking water (15 mg/kg/day) combined with metoprolol (2 X 10 mg/kg/day i.p.). Increased heart wt was also noted despite correction of anemia by blood transfusion (Hct greater than 40%) and after parathyroidectomy in animals kept eucalcemic with high dietary calcium. Micromorphometry of left ventricular myocardium in perfusion-fixed tissue showed no significant change of the relative proportion of connective tissue and myocardial fibers. Myocardial isomyosin pattern was changed with an increase of fast-migrating V1 isomyosin in animals with renal insufficiency compared to sham-operated pairfed controls.     

Protective effects of melatonin on renal failure in pinealectomized rats

AIM: The purpose of the current study was to investigate the effects melatonin on renal function. METHODS: The histological appearance of the kidney and malondialdehyde, nitric oxide, glutathione and superoxide dismutase contents were determined. Serum creatinine and blood urea nitrogen levels were also assayed. Rats were divided as: Sham, pinealectomized (Px) and pinealectomized and treated with melatonin. RESULTS: In Px group, malondialdehyde and nitric oxide levels were elevated when compared with the sham group. The Px group exhibited reduced superoxide dismutase activity and glutathione content. All of these harmful changes were restored by melatonin. Melatonin also ameliorated serum creatinine and blood urea nitrogen levels related to renal injury. The score for glomerular, tubular and interstitial changes was significantly higher in the Px group. Melatonin supplementation significantly reduced these parameters. CONCLUSIONS: This protective effect may be associated with both melatonin's lipophilic and hydrophilic effects, thus providing on-site protection against free radical mediated damage.     

Chronic effects of tertatolol on renal function in hypertensive patients with mild chronic renal failure.

To assess the potential benefit of drug-induced renal haemodynamic changes in patients with chronic renal failure, we have evaluated the effects of the beta-blocking agent tertatolol on blood pressure, glomerular filtration rate, and renal plasma flow. Inulin and PAH clearances were performed before and after 3 months treatment and oral tertatolol, 5 mg daily in eight hypertensive patients with moderate chronic renal failure. After 3 months of treatment, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increased significantly by 10% and 13% respectively, whereas renal vascular resistance decreased by 16% and the filtration fraction was unchanged. These results indicate that tertatolol possesses novel renal haemodynamic properties in hypertensive patients with chronic renal failure. However, the long-term benefit of such a therapy is yet to be confirmed.     

Adverse effects on cerebral perfusion of prostacyclin administered directly into patients with fulminant hepatic failure and acute renal failure.

Prior to commencing renal replacement therapy, 8 patients with fulminant hepatic failure and acute renal failure were treated with an infusion of prostacyclin, 5 ng/kg/min, for 30 min, administered directly into the femoral vein. During this period, several adverse effects were noted. There was a reduction in mean arterial blood pressure from a median of 82 (range 65-93) to 67 mm Hg (55-80), p less than 0.01; and an increase in intracranial pressure from a median of 14 (6-33) to 17 mm Hg (6-42), p less than 0.05; with a consequent reduction in cerebral perfusion pressure from a median of 63 (43-77) to 43 mm Hg (15-74), p less than 0.05. There was a reduction in arterial oxygen tension from a median of 19 (13-28) to 16 kPa (12-27), p less than 0.05; and no change in cardiac output, from a median of 6.7 (4.9-11.2) to 6.5 l/min/m2 (3.8-11.0), p greater than 0.05). The administration of prostacyclin into this group of critically ill patients, at risk of death due to cerebral oedema/hypoxia, produced both a reduction in cerebral perfusion pressure and a reduction in total cerebral oxygen delivery.     

Effect of bone morphogenetic protein-7 transfected bone marrow mesenchymal stem cells on renal injury in rats with chronic renal failure

Objective To observe the bone marrow mesenchymal stem cells (BMSCs) modified by bone morphogenetic protein-7 (BMP-7) gene on the expression of renal BMP-7, transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF), further to explore its protective mechanism on renal injury in rats with chronic renal failure (CRF). Methods BMSCs with high expression of BMP-7 gene (BMSCs-BMP-7) and empty vector-BMSCs (BMSCs-EV) were obtained by lentiviral-mediated gene transfection. Thirty male Sprague-Dawley (SD) rats were randomly divided into 5 groups, 6 in each group: normal control (CON) group; PBS intervention (CRF with PBS infusion, CRF+PBS) group; BMSCs intervention (CRF with BMSCs infusion, CRF+BMSCs) group; BMSCs-EV intervention (CRF with BMSCs-empty vector infusion, CRF+BMSCs-EV) group and BMSCs-BMP-7 intervention (CRF with BMSCs-BMP-7 infusion, CRF+BMSCs-BMP-7) group. The CRF model was established by 5/6 nephrectomy. The CON group was a sham operation group. The corresponding 12-weeks interventions of each experimental group were performed after 2 weeks of modeling, the rats in the CON group and the CRF+PBS group were injected with 1 ml of PBS through the tail vein, and the other three groups were injected with 1 ml of the corresponding cell suspension once a week. At the time of sacrifice, blood and renal tissue samples were reserved. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured by routine biochemical methods, and the expression of BMP-7, VEGF, TGF-β1 in kidney was assayed by Western blotting. Results At the time of sacrifice, the levels of Scr and BUN in the CRF+PBS group were significantly higher than those in the CON group (all P＜0.01); Compared with the CRF+PBS group, the Scr and BUN of the CRF+BMSCs group, CRF+BMSCs-EV group and CRF+BMSCs-BMP-7 group were decreased to different extents, the differences were statistically significant (all P＜0.01); the Scr and BUN of the CRF+BMSCs-BMP-7 group were significantly lower than CRF+BMSCs group and CRF+BMSCs-EV group (all P＜0.05). The expression of BMP-7 and VEGF were the lowest in the CRF+PBS group. Compared with the CRF+PBS group, the expression of BMP-7 and VEGF in the CRF+BMSCs group, CRF+BMSCs-EV group and CRF+BMSCs-BMP-7 group were significantly increased respectively (all P＜0.05). The expression of the BMP-7 and VEGF in the CRF+BMSCs-BMP-7 group were higher than those in the CRF+BMSCs group and CRF+BMSCs-EV group (P＜0.01). Compared with the CON group, the expression of TGF-β1 in the CRF+PBS group was significantly increased (P＜0.01); compared with the CRF+PBS group, the expression of TGF-β1 in the CRF+BMSCs group, CRF+BMSCs-EV and CRF+BMSCs-BMP-7 group was significantly decreased (all P＜0.01); the expression of TGF-β1 in the CRF+BMSCs-BMP-7 group was lower than the CRF+BMSCs and CRF+BMSCs-EV group (both P＜0.01). Conclusions BMSCs modified by BMP-7 has a protective effect on CRF rats; its protective mechanism may be related to antagonizing TGF-β1 and up-regulation of renal VEGF expression.     

Extreme hyperphosphatemia and acute renal failure after a phosphorus-containing bowel regimen

Phosphate intoxication, manifested by hypocalcemic tetany and acute renal failure, may complicate bowel-cleansing preparations which contain phosphate. These preparations are commonly used to prepare patients for various gastrointestinal procedures. Often, patients who receive these regimens are at increased risk of phosphate intoxication from diseases which slow gastrointestinal transit or decrease renal excretion (renal insufficiency). We present a patient who developed oliguric acute renal failure from severe phosphate intoxication associated with a phosphate-containing bowel-cleansing regimen.     

Echocardiographic assessment of global ventricular function using the myocardial performance index in rats with hypertrophy

Myocardial hypertrophy is the hallmark of chronic pressure overload and the myocardial performance index (MPI) is an easily recordable measurement of Doppler time intervals. In this study, the utility of using MPI to assess the progression of hypertrophy in the aortic-banded rat model was evaluated. Male Wistar rats (70-90 g) underwent ascending aorta constriction (n = 4) or a sham operation (n = 5). High-resolution echocardiography was performed 4, 7, 10, and 12 weeks after the surgery. Over this follow-up interval, animals in the aortic-banded group demonstrated an increase in their mean left ventricular (LV) mass and MPI compared with controls. MPI reflects ventricular performance in small animals with LV hypertrophy, showing alterations early after aorta constriction.     

Effects of efficient phosphate binding on bone in chronic renal failure rats

BACKGROUND: We recently reported that administration of high doses of lanthanum carbonate (1000 mg/kg/day) to chronic renal failure (CRF) rats can result in a mineralization defect. Our results suggested, however, that the impaired mineralization was not due to a direct toxic action of lanthanum on the bone, but rather was an indirect consequence of a phosphate depletion resulting from the compound's high phosphate-binding capacity. To further substantiate these results, in the present study, the effects of lanthanum carbonate on bone were compared to the effects of sevelamer, a nonabsorbed, non-metal-containing polymeric phosphate-binding agent. METHODS: Male Wistar rats underwent a 5/6th nephrectomy to induce chronic renal failure, after which they were treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) by oral gavage for 12 weeks. RESULTS: CRF animals treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) developed a phosphate depletion after 4 weeks of treatment, as evidenced by a marked reduction in phosphaturia. At sacrifice after 12 weeks of treatment, bone histomorphometry showed that a mineralization defect had developed in two out of six animals in the lanthanum-carbonate-treated group, in four out of seven animals in the 1000 mg/kg/ day sevelamer group, and in one out of nine animals in the 500 mg/kg/day sevelamer group. CONCLUSIONS: These results corroborate our previous findings that the administration of a powerful phosphate-binding agent to CRF rats can induce phosphate depletion, resulting in a mineralization defect.     

Acute effects of paracetamol on prostaglandin synthesis and renal function in normal man and in patients with renal failure

The effects of oral dosing with paracetamol (40 mg/kg/day for 3 days) on serum thromboxane B2 (TXB2), glomerular filtration rate (GFR), sodium homeostasis, urinary excretion of prostaglandin E2 (PGE2) and on some other renal function parameters were investigated in 10 healthy young controls aged 23-26 years, 9 healthy elderly persons with normal renal function aged 66-78 years and 9 patients with chronic stable impaired renal function. Plasma paracetamol concentration was unaffected by age and GFR, whereas the sulphate and glucuronide metabolites of paracetamol accumulated substantially in patients with renal failure, and to a lesser degree in elderly controls. Serum TXB2 was significantly reduced 1 and 4 hours after oral ingestion of a single dose of paracetamol (18 mg/kg), but the values were normalized after 12 hours. Urinary sodium excretion was reduced by 23.4% on the first treatment day in elderly controls, but unchanged in young controls and in patients with renal failure. Urinary excretion of PGE2 was unchanged in young controls, but reduced by 35.9% on the first day on paracetamol treatment in elderly controls and from 22-29% on the 3 days on paracetamol in patients with impaired renal function. Paracetamol was without effect on potassium homeostasis or on the excretion of glandular kallikrein or proteins in urine. Our study indicates that oral treatment with paracetamol in therapeutic doses reversibly reduces serum TXB2 for at least 4 hours after ingestion both in healthy controls and in patients with impaired renal function. Our data also suggest that paracetamol effects renal PGE2 excretion, especially in patients with impaired renal function. Renal glomerular and tubular function parameters were unchanged by paracetamol.