Effect of fluoride on bone and bone cells in ovariectomized rats.

To evaluate whether treatment with a mitogenic agent may increase bone formation and bone mass in osteopenia induced by estrogen deficiency, we determined the effect of oral fluoride treatment on bone and bone cells in ovariectomized rats. Sodium fluoride (NaF) was administered to 3-month-old ovariectomized rats 1 day after ovariectomy (OVX) for 1, 3, and 6 months. NaF was given in drinking water at the dose of 1 mg/kg body weight per day. Fluoride administration led to a partial prevention of the bone loss induced by OVX as shown by histologic analysis of tibial metaphysis and by evaluation of femoral calcium content. These beneficial effects of fluoride were more striking at early time points (1 and 3 months postovariectomy) than after 6 months of treatment. The increase in trabecular bone volume in OVX rats treated with fluoride was associated with a rise in the osteoblast surface, which was increased by 60, 72, and 235% at 1, 3, and 6 months postovariectomy compared to untreated OVX rats. In OVX rats and in sham-operated rats plasma osteocalcin was increased in correlation with the osteoblast surface. However, these two parameters were not correlated in OVX rats treated with fluoride. The heat-labile bone-specific alkaline phosphatase in plasma was decreased in OVX rats treated with fluoride compared to OVX rats, suggesting that both the number and the activity of osteoblasts were affected by NaF treatment. To examine the effect of fluoride on the osteocalcin production and the proliferative capacity of bone cells, osteoblastic cells were isolated by collagenase digestion from the bone surface of tibia in treated and untreated OVX rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vitamin D, desferrioxamine and aluminum-induced bone disease in uremic rats

The effect of 100 ng 1 alpha-OH vitamin D/week alone and in combination with desferrioxamine (DFO), 150 mg/week, was evaluated in aluminum loaded uremic rats. Vitamin D (Vit D) caused an increase of Al in muscle and a decrease in serum Al. Bone histology showed mineralization defect and an increase in bone mass, due to an increase in unmineralized bone, induced both by Al and Vit D administration. Treatment with DFO enhanced urinary Al excretion and lowered tissue Al, without inducing major changes of static bone histology. It is concluded that in Al-loaded uremic rats Vit D can redistribute body Al and that both Al and Vit D can cause a mineralization defect. A 6-week treatment with DFO lowers tissue Al without changing significantly static bone parameters.     

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.     

Improvement of anemia with deferoxamine in hemodialysis patients with aluminum-induced bone disease

As microcytic anemia is a feature of aluminium intoxication, we prospectively studied the hematologic effects of deferoxamine in 10 hemodialysis patients with aluminum-induced bone disease. Comparing the mean monthly results of a 4 month period before and during deferoxamine therapy, we observed an important decrease of the transfusion needs (alpha less than 0.025) and an increase of hematocrit (p less than 0.02), hemoglobin (p less than 0.02), MCV (p less than 0.02) and MCH (p less than 0.05); the number of red blood cells remained unchanged. Our results show that deferoxamine treatment of dialysis patients with aluminum bone disease can markedly improve their anemia, even in the absence of recent aggravation, microcytosis and hypochromia. They also suggest that aluminum could participate in the anemia of dialysis patients even if it is normocytic.     

Spectrum of renal bone disease in end-stage renal failure patients not yet on dialysis.

BACKGROUND: During the last few years the spectrum of renal osteodystrophy (ROD) in dialysis patients has been studied thoroughly and the prevalence of the various types of ROD has changed considerably. Whereas until a decade ago most patients presented with secondary hyperparathyroidism (HPTH), adynamic bone (ABD) has become the most common lesion within the dialysis population over the last few years. Much less is known about the spectrum of ROD in end-stage renal failure (ESRF) patients not yet on dialysis. METHODS: Transiliac bone biopsies were taken in an unselected group of 84 ESRF patients (44 male, age 54+/-12 years) before enrolment in a dialysis programme. All patients were recruited within a time period of 10 months from various centres (n=18) in Macedonia. Calcium carbonate was the only prescribed medication in patients followed up by the outpatient clinic. RESULTS: HPTH was found in only 9% of the patients, whilst ABD appeared to be the most frequent renal bone disease as it was observed in 23% of the cases next to normal bone (38%). A relatively high number of patients (n=10; 12%) fulfilled the criteria of osteomalacia (OM). Mixed osteodystrophy (MX) was diagnosed in 18% of the subjects. There was no significant difference between groups in age, creatinine, or serum and bone strontium and aluminium levels. Patient characteristics associated with ABD included male gender and diabetes, whilst OM was associated with older age (>58 years). CONCLUSIONS: In an unselected population of ESRF patients already, 62% of them have an abnormal bone histology. ABD is the most prevalent type of ROD in this population. In the absence of aluminium or strontium accumulation the relatively high prevalence of a low bone turnover as expressed by either normal bone or ABD and OM is striking.     

Effect of chronic renal failure on bone turnover and bone alkaline phosphatase isoforms.

BACKGROUND: Biochemical markers of bone turnover are used to monitor metabolic bone disease associated with renal failure. We have applied a comprehensive panel of markers to patients with chronic renal failure (CRF), with particular focus on the isoforms of bone alkaline phosphatase (BALP). METHODS: Twenty CRF patients undergoing hemodialysis (N = 9) and peritoneal dialysis (N = 11) were measured for serum parathyroid hormone (PTH), osteocalcin, total ALP, and four BALP isoforms (B/I, B1x, B1, and B2) by high-performance liquid chromatography. These BALP isoforms were also compared with BALP measured by three commercial immunoassays (Alkphase-B, Tandem-R Ostase, and Tandem-MP Ostase). Type I collagen turnover was assessed by serum samples using the type I procollagen intact amino- and carboxy-terminal propeptides (PINP and PICP) and two fragments (ICTP and CrossLaps) derived from the carboxy-terminal telopeptide of mature matrix collagen by different degradative pathways. RESULTS: Mean levels of bone turnover markers were elevated in CRF, with marked increases in those markers, osteocalcin, ICTP, and CrossLaps, cleared by the kidney. Total ALP activities were increased corresponding to elevated B/I and B2 isoform levels. The B1 isoform level was not significantly different from healthy controls. B1x was detected in 60% of the patients but was not resolved in healthy individuals. Kendall's tau rank correlation showed that B1x correlated significantly (P < 0.05) with B1 (0.53) and PINP (0.55), and was the only marker to correlate with PTH (0.49). B1x was not significantly correlated with any of the commercial BALP immunoassays. Interestingly, the immunoassay calibrators contained high activities of the B/I peak (39 to 80%) compared with human serum (4%). CONCLUSION: There are selective differences between the BALP isoforms in CRF compared with healthy adults. The commercial BALP immunoassays are comparable with each other but are unable to distinguish the BALP isoform-specific differences in CRF patients.     

High fluoride intakes cause osteomalacia and diminished bone strength in rats with renal deficiency

Renal insufficiency is known to increase plasma fluoride levels, which may increase the risk of fluorosis and osteomalacia. The purpose of this study was to determine the effects of fluoride on skeletal fragility and mineralization in renal-deficient animals. We evaluated the skeleton of rats with surgically induced renal deficiency (4/5 nephrectomy) that were chronically exposed to fluoridated water at concentrations of 0, 5, 15, and 50 ppm for a period of 6 months. The chosen fluoride doses caused plasma fluoride levels equivalent to those in humans consuming fluoridated water levels of 0, 1, 3, and 10 ppm, respectively. Animals with renal deficiency drank about 60% more water and excreted 85% more urine than control animals. Glomerular filtration rate (GFR) was decreased 68% and plasma BUN was increased fourfold in rats with renal deficiency. Plasma fluoride was strongly correlated with 1/GFR and was greatly increased by renal deficiency in all animals consuming fluoridated water. There was a strong positive, nonlinear relationship between plasma fluoride and bone fluoride levels, suggesting nonlinear binding characteristics of fluoride to bone. The amount of unmineralized osteoid in the vertebral bone was related to the plasma fluoride levels. Vertebral osteoid volume was increased over 20-fold in animals with renal deficiency that received 15 or 50 ppm fluoride, suggesting osteomalacia. Should osteomalacia be defined as a tenfold increase in osteoid volume, there appeared to be a threshold plasma fluoride level of about 20 μmol/L, above which osteomalacia was observed consistently. This plasma fluoride level was not achieved in control rats regardless of fluoride intake, nor was it achieved in renal-deficient rats receiving 0 or 5 ppm fluoride. A fluoride concentration of 50 ppm reduced femoral bone strength by 11% in control rats and by 31% in renal-deficient rats. Vertebral strength also was decreased significantly in renal-deficient rats given 50 ppm fluoride. In conclusion, fluoridated water in concentrations equivalent to 3 and 10 ppm in humans, caused osteomalacia and reduced bone strength in rats with surgically-induced renal deficiency.     

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.     

Inhibitory effect of fluoride on renal stone formation in rats.

The effect of fluorine (F) on stone formation induced by ethylene glycol (EG) was studied in rats. For different groups, the drinking water was supplemented with EG, sodium fluoride (NaF), EG+NaF, or nothing as control. An isotope-tracing method was used to evaluate experimental stone formation in the kidneys by introducing 45Ca intraperitoneally into rats and then measuring the radioactivity of the kidney. At the end of the 4-week experiment, rats of the EG+NaF group showed a significantly lower incidence of gross urinary stones and lower 45Ca activity in their kidneys compared to the EG group of rats. Both the EG group and EG+NaF group had markedly increased urinary oxalate excretion, with the latter significantly lower than the former (p less than 0.05). Urinary oxalate excretion was relatively lower in the NaF group than in the control group. This study indicates that NaF can inhibit renal stone formation induced by EG by decreasing oxalate synthesis and urinary oxalate excretion, and suggests a possible clinical therapeutic value of NaF in the prevention of oxalate kidney stones.     

Effect of experimentally induced renal failure on testicular testosterone synthesis in rats.

Renal insufficiency is responsible for gonadal impairment, but the pathogenesis of testicular dysfunction remains unresolved. This study examines the possible role of the endocrine disturbance and angiotensin II-induced physiological abnormality for the pathogenesis of gonadal dysfunction of two different types of chronic renal failure. Chronic renal insufficiency was induced in rats given an adenine-excessive diet or in 5/6 nephrectomized animals. Circulating levels of blood urea nitrogen, creatinine, renin-angiotensin-aldosterone (R-A-A) system androstenedione, 17 alpha-hydroxy progesterone (17 alpha-OHP), testosterone, luteinizing hormone, and follicle-stimulating hormone were assayed. Systolic blood pressure, renal blood flow, and testicular blood flow were also determined. High serum levels of 17 alpha-OHP, androstenedione, and low testosterone were noted in the normotensive group. Enhanced R-A-A system decreased testicular blood flow and low testosterone were seen in the hypertensive group. The data provide evidence that gonadal dysfunction in adenine-induced renal failure appears to be caused by the suppression of 17 beta-hydroxysteroid oxydoreductase activity, and gonadal impairment in 5/6 nephrectomized uremia can be evoked by enhanced renin-angiotensin-aldosterone system and hypertension.     

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.     

Effect of magnesium lithospermate B in rats with sodium-induced hypertension and renal failure.

To evaluate the antihypertensive effect of magnesium lithospermate B isolated from Salviae miltiorrhizae radix, determinations of blood pressure and urinary excretions of sodium, potassium, prostaglandin E2 (PGE2) and kallikrein, which have been proposed to play an important role in the regulation of blood pressure, were made in rats with sodium-induced hypertension and renal failure. In rats given magnesium lithospermate B, blood pressure was significantly decreased, whereas urinary excretion of electrolytes was significantly increased. Urinary PGE2 excretion following administration of magnesium lithospermate B increased as the dose of the compound was stepped up. The activity of kallikrein in urine was also increased by the treatment. From these results, the blood pressure-lowering action of magnesium lithospermate B may be due in part to enhancement of the kallikrein-prostaglandin system.     

Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function, and bone in rats with renal failure

BACKGROUND: Hyperphosphatemia and disturbances in calcium or parathyroid hormone (PTH) metabolism contribute to the high incidence of cardiovascular disease and renal osteodystrophy in chronic renal failure (CRF). We evaluated the effect of hyperphosphatemia on the cardiovascular system, on renal function, and on bone in experimental uremia. METHODS: Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx) with minipump implantation, delivering 1-34 rat PTH (physiologic rate), or were sham-operated and received vehicle. Only phosphorus content (low-phosphorus (LP) 0.2%; high-phosphorus (HP) 1.2%) differentiated diets. We divided the groups as follows: PTx +Nx +LP; sham + LP; PTx + Nx + HP; and sham + HP. Tail-cuff pressure and weight were measured weekly. After 2 months, biochemical, arterial, and myocardial histology and bone histomorphometry were analyzed. RESULTS: Heart weight normalized to body weight (heart weight/100 g body weight) was higher in PTx + Nx + HP rats (PTx + Nx + HP = 0.36 +/- 0.01 vs. sham + HP = 0.29 +/- 0.01, PTx + Nx + LP = 0.32 +/- 0.01, sham + LP = 0.28 +/- 0.01) (P < 0.05). Serum creatinine levels were higher in PTx + Nx + HP rats than in PTx + Nx + LP rats (1.09 +/- 0.13 vs. 0.59 +/- 0.03 mg/dL) (P < 0.05). Levels of PTH did not differ significantly between the groups. Myocardial and arterial histology detected no vascular calcification or fibrosis. Bone histomorphometry revealed an association, unrelated to uremia, between HP diets and decreased trabecular connectivity. CONCLUSION: Myocardial hypertrophy, impaired renal function, and adverse effects on bone remodeling were associated with hyperphosphatemia and were not corrected by PTH replacement. Although no vascular calcification was observed in this model, we cannot rule out an adverse effect of hyperphosphatemia on the vascular bed. Our finding underscores the importance of phosphorus control in reducing morbidity and mortality in CRF patients.     

Expression of bone type 1 PTH receptor in rats with chronic renal failure

Some researchers have speculated that a decrease in bone type 1 PTH receptor (PTH1R) may be among the causes of “skeletal resistance” in chronic renal failure (CRF). Indeed, the down-regulation of PTH1R mRNA has been identified in uremic bones. However, few studies have identified the patterns of PTH1R protein expression. In this article we compare the bone expression of PTH1R protein and mRNA under control and CRF conditions. Sprague–Dawley rats underwent 5/6 nephrectomies (Nx) or sham operations (control), and were killed 16 weeks later. Blood urea nitrogen (BUN), serum Cr, P, and parathyroid hormone (PTH) were higher in the Nx group than in the controls, while serum Ca and 1,25(OH)₂D₃ were lower in the Nx group. Immunohistochemical images of lumbar bone samples were analyzed by an image processing system. PTH1R was essentially identified in all osteoblasts. The expression of osteoblast PTH1R protein was quantified based on the gray value of PTH1R staining. The mean gray scale of osteoblasts was 25% lower in Nx rats than in control rats (P < 0.01), whereas osteoblast cell counts and cell sizes were not significantly different between the two groups. Thus, down-regulation of PTH1R protein expression under the CRF condition appeared likely. Total RNA extracted from the bone samples was reverse transcribed for real-time polymerase chain reaction (PCR). PTH1R mRNA expression was 33% lower in the Nx group than in the control group in the quantitative PCR analysis (P < 0.05). Our findings suggested that osteoblast PTH1R expression is down-regulated at both the protein and mRNA levels in the steady state of CRF.     

Effect of dietary sodium on atrial natriuretic factor released in rats with chronic renal failure.

Studies were done in partially nephrectomized rats to examine the effect of dietary sodium intake on atrial natriuretic factor (ANF) released by the atria. Experiments were done in four groups of male Wistar rats. Group 1 (n = 10) and 3 (m = 10) rats were sham-operated. Group 2 and 4 were 5/6 nephrectomized. Group 1 and 2 were fed a sodium-supplemented diet. Group 3 and 4 received a sodium-deficient diet. Renal functions were similar between group 2 and 4. Plasma ANF level was raised in group 2 (182 +/- 17 pg/ml). Circulating ANF levels in group 1,3 and 4 were 95 +/- 5, 90 +/- 5 and 95 +/- 4 pg/ml, respectively. Atrial ANF contents were higher in partially nephrectomized rats after receiving a sodium-supplemented diet. A reduction in atrial ANF contents occurred when fed a sodium-deficient diet. In vitro studies were done to assess the rate of ANF released. ANF secretory rates were highest in group 2 (11 +/- 1.5 pg/min/mg). There was no difference between group 1,3 and 4. A positive correlation was found between plasma ANF and ANF released in all groups examined. Thus, plasma ANF levels were a good reflection of ANF secretory rates. A significant correlation existed between plasma ANF and sodium excretion in chronic renal failure rats (r = 0.78; p less than 0.01). A dissociation between plasma ANF and water excretion was seen. These results suggest that in chronic renal failure rats, ANF played a role in sodium adaptation.     

Effect of eicosapentaenoic acid on the progression of chronic renal failure in rats.

Eicosapentaenoic acid (EPA) can induce a shift in prostaglandin and leukotriene synthesis. The effects of EPA supplementation of the diet on the progression of chronic renal failure (CRF) were evaluated in a model of 5/6 renal mass ablation in rats. After 30 or 60 days of CRF, elevation in single-nephron glomerular filtration rate due to an increase in glomerular plasma flow and hydraulic pressure was observed. These hemodynamic alterations were followed by a rise in proteinuria and glomerular sclerosis. EPA treatment for 30 or 60 days did not substantially modify the hemodynamic or morphological profiles induced by renal mass ablation. In the present non-immune model of CRF, preglomerular vasodilation with glomerular hyperperfusion and hypertension were responsible, at least in part, for the presence of proteinuria and glomerular sclerosis. No additional vasodilation was observed in the present model of CRF, and, thus, hemodynamic effects induced by EPA did not modify renal damage, in contrast to the EPA effects observed in immune-mediated models of CRF.     

Studies on the precursor of methylguanidine in rats with renal failure.

Each of creatinine (Cr), guanidinoacetic acid (GAA) and arginine (Arg) was administered intraperitoneally to rats with renal failure, and the levels of methylguanidine (MG) in the serum, liver, kidney, muscle and urine were determined at certain intervals. The levels of MG in the serum, liver, kidney, muscle and urine after Cr administration increased markedly with time. The amount of total MG at 24 h was estimated to be 114 micrograms/100 g body weight, which accounted for 0.46% of the Cr dose. In contrast, changes in MG levels after administration of GAA or Arg were only slight in comparison with those after Cr administration. Thus, MG was proved to be produced mainly from Cr.