Role of dietary phosphorus in the progression of renal failure

Dietary phosphorus is thought to be a factor that impairs the residual renal function in patients with chronic renal failure. To determine the effect of dietary phosphorus on the prognosis of chronic renal failure, low-phosphorus milk was prepared from normal cow's milk using boehmite, a synthetic phosphate-ion absorbent. Regular diet, normal cow's milk, and low-phosphorus milk were then given to 5/6-nephrectomized rats and the serum levels of inorganic phosphorus, calcium, creatinine, and blood urine nitrogen in the rats in each group were compared. The serum levels of inorganic phosphorus and calcium were not different among the groups, despite a significant difference in phosphorus intakes. On the other hand, serum levels of creatinine (Cr) and blood urine nitrogen (BUN) in the rats fed low-phosphorus milk were significantly lower (Cr, 0.54+/-0.054mg/dl; BUN, 29.2+/-3.90mg/dl) than those in the rats fed a regular diet (Cr, 0.64+/-0.057mg/dl; BUN, 37.4+/-3.55mg/dl) or normal milk (Cr, 0.61+/-0.040mg/dl; BUN, 34.5+/-3.59mg/dl). No beneficial effect of protein restriction was observed when residual renal functions in rats fed a regular diet and those fed normal milk were compared. The results suggest that dietary phosphorus plays a major role in the progression of renal failure.     

Role of Toll-like receptor 4 in endotoxin-induced acute renal failure

Toll-like receptor 4 (TLR4) is present on monocytes and other cell types, and mediates inflammatory events such as the release of TNF after exposure to LPS. C3H/HeJ mice are resistant to LPS-induced mortality, due to a naturally occurring mutation in TLR4. We therefore hypothesized that LPS-induced acute renal failure (ARF) requires systemic TNF release triggered by LPS acting on extrarenal TLR4. We injected C3H/HeJ mice and C3H/HeOuJ controls with 0.25 mg of LPS, and sacrificed them 6 h later for analysis of blood urea nitrogen (BUN) and kidney tissue (n = 8 per group). In contrast to C3H/HeOuJ controls, C3H/HeJ mice were completely resistant to LPS-induced ARF (6-h BUN of 32.3 +/- 1.1 vs 61.7 +/- 5.6 mg/dl). C3H/HeJ mice released no TNF into the circulation at 2 h (0.00 vs 1.24 +/- 0.16 ng/ml), had less renal neutrophil infiltration (6.4 +/- 1.0 vs 11.4 +/- 1.3 neutrophils per high power field), and less renal apoptosis, as assessed by DNA laddering. Transplant studies showed that C3H/HeJ recipients of wild-type kidneys (n = 9) were protected from LPS-induced ARF, while wild-type recipients of C3H/HeJ kidneys (n = 11) developed severe LPS-induced ARF (24-h BUN 44.0 +/- 4.1 vs 112.1 +/- 20.0 mg/dl). These experiments support our hypothesis that LPS acts on extrarenal TLR4, thereby leading to systemic TNF release and subsequent ARF. Renal neutrophil infiltration and renal cell apoptosis are potential mechanisms by which endotoxemia leads to functional ARF.     

葛根素对甘油致急性肾功能衰竭兔血液流变学和肾血流量的影响

目的 肌注甘油复制急性肾功能衰竭(ARF)兔模型,观察葛根素(Pue)对ARF兔血液流变学和肾血流量的影响.方法 健康雄性日本大耳白兔30只,随机分为正常组、ARF模型组、Pue 1组(20 mg/kg)、Pue 2组(40mg/kg)、Pue 3组(80 mg/kg).各组于不同时间点测量其肾血流量、血液流变学指标和肾功能指标(Cr、BUN),并观察肾组织形态学改变.结果 与模型组比较,Pue 2组和Pue 3组治疗后各时间点Cr、BUN降低(P＜0.05),血液流变学指标降低明显(P＜0.05),肾血流量增加差异具有统计学意义(P＜0.05).Pue 2组和Pue 3组肾小管上皮细胞肿胀减轻,管型少见.结论 葛根素可明显改善急性肾功能衰竭兔血液流变性,增加肾血流量,进而达到改善、减轻肾小管损害的作用.     

Renal function and fractional clearances of American river otters (Lutra canadensis)

The finely lobulated kidneys of American river otters (Lutra canadensis) are not visualized on plain abdominal radiographs. Similar values for blood urea nitrogen (BUN), creatinine, and uric acid were obtained on different analytical systems used in 1984 and 1985. The mean +/- SD for measured plasma osmolalities (309.80 +/- 8.86 mOsmol/kg) of otters in 1985 was significantly (P less than 0.01) less than that of calculated serum osmolalities in the same 1985 specimens (321.61 +/- 5.64 mOsmol/kg) and in 1984 specimens (322.20 +/- 7.16 mOsmol/kg). Urine specific gravities and osmolalities were highly correlated (r = 0.92). On routine urinalysis, protein and bilirubin were frequent chemical findings, and urobilinogen was present in all urine samples. White and red blood cells and epithelial cells were frequent findings on urine microscopic examinations. Proteus mirabilis was cultured from four of four female otters with genitourinary infections. The mean +/- SD creatinine values for paired serum and urine samples (n = 13) were serum creatinine (Scr) 0.66 +/- 0.09 mg/dl and urine creatinine (Ucr) 186.9 +/- 55.6 mg/dl. Corresponding values for serum electrolytes (Se) and urine electrolytes (Ue) yielded mean +/- SD calculated renal fractional clearances (FC = Ue/Se x Scr/Ucr) of sodium 9.65 +/- 5.81 x 10(-4), potassium 4.15 +/- 2.01 x 10(-2), chloride 10.81 +/- 5.33 x 10(-4), calcium 4.52 +/- 4.46 x 10(-3), and phosphate 6.58 +/- 3.44 x 10(-3).     

Induction of nephrotoxicity by high doses of gentamicin in diabetic rats

Rats with streptozotocin-induced diabetes mellitus (DM) are resistant to aminoglycoside (AG) nephrotoxicity presumably because of defective transport and accumulation of drug by proximal tubular cells. To test this hypothesis we injected DM rats with saline or with gentamicin, 100, 200, and 400 mg/kg per day for 6 days, to determine if the renal cortical concentration of gentamicin could be raised to toxic levels. Nephrotoxicity was assessed by monitoring for evidence of accelerated lipid peroxidation in the renal cortex, for elevation of the serum creatinine concentration, and for evidence of proximal tubular cell injury and necrosis by light and electron microscopy. At 100 mg/kg per day renal cortical gentamicin was 454 +/- 85 micrograms/g. Except for an increase in renal cortical phospholipids these rats manifested no evidence of accelerated lipid peroxidation or elevation of serum creatinine. At 200 mg/kg per day renal cortical gentamicin rose to 636 +/- 20 micrograms/g. These rats manifested mild functional and morphological evidence of toxicity. At 400 mg/kg renal cortical gentamicin rose to 741 +/- 43 micrograms/g. These rats developed severe nephrotoxic injury as manifested by a marked increase of lipid peroxidation evident by an increase of malondialdehyde from a control level of 0.48 +/- 0.02 to 1.72 +/- 0.12 nmole/mg protein, a shift from unsaturated to saturated fatty acids esterified in renal cortical phospholipids, depression of superoxide dismutase and catalase, and a shift from reduced to oxidized glutathione. The serum creatinine rose from a baseline level of 0.24 +/- 0.01 to 0.46 +/- 0.05 mg/dl. Light and electron microscopy revealed enlarged lysosomes distended with typical myeloid bodies and extensive proximal tubular cell necrosis. These observations provide compelling evidence in support of the view that the resistance of DM rats to AG nephrotoxicity is causally linked to the low rate of drug uptake by renal proximal tubular cells. When the renal cortical concentration reaches a critical level, it elicits a pattern of toxic injury indistinguishable from that of nondiabetic rats. Thus, there is nothing inherent to the diabetic state that prevents AGs from causing their usual adverse effects on the metabolism of renal proximal tubular cells once they gain access in sufficient quantity into these cells.     

Role of the kidney in the metabolism of apolipoprotein A-IV: influence of the type of proteinuria

Increased plasma concentrations of apolipoprotein A-IV (apoA-IV) in chronic renal disease suggest a metabolic role of the kidney for this antiatherogenic protein. Therefore, we investigated patients with various forms of proteinuria and found increased serum concentrations of apoA-IV in 124 nephrotic patients compared with 274 controls (mean 21.9 +/- 9.6 vs. 14.4 +/- 4.0 mg/dl; P < 0.001). Decreasing creatinine clearance showed a strong association with increasing apoA-IV levels. However, serum albumin levels significantly modulated apoA-IV levels in patients with low creatinine clearance, resulting in lower levels of apoA-IV in patients with low compared with high albumin levels (21.4 +/- 8.6 vs. 29.2 +/- 8.4 mg/dl; P = 0.0007). Furthermore, we investigated urinary apoA-IV levels in an additional 66 patients with a wide variety of proteinuria and 30 controls. Especially patients with a tubular type of proteinuria had significantly higher amounts of apoA-IV in urine than those with a pure glomerular type of proteinuria and controls (median 45, 14, and 0.6 ng/mg creatinine, respectively). We confirmed these results in affected members of a family with Dent's disease, who are characterized by an inherited protein reabsorption defect of the proximal tubular system. In summary, our data demonstrate that the increase of apoA-IV caused by renal impairment is significantly modulated by low levels of serum albumin as a measure for the severity of the nephrotic syndrome. From this investigation of apoA-IV in urine as well as earlier immunohistochemical studies, we conclude that apoA-IV is filtered through the normal glomerulus and is subsequently reabsorbed mainly by proximal tubular cells.     

Glomerular filtration rate and blood pressure monitoring in awake baboons

Minimally invasive techniques were used to collect urine with an external catheter together with automated intermittent monitoring of arterial blood pressure in awake male baboons. Using endogenous creatinine, 24-hour creatinine clearances were measured for 2 to 3 consecutive days in four intact and in four uninephrectomized baboons. Despite large differences in urinary volume and sodium excretion, reproducibility of 24-hour creatinine clearances was within 15% in 15 of 19 studies obtained from 6 of 8 animals. Arterial blood pressure was monitored intermittently at 30 to 60 minute intervals over 24 hours with a Dinamap monitor and recorder. Mean blood pressure averaged 71 +/- 4.4 to 89 +/- 5.5 mm Hg in different animals. Blood pressure tended to be lower at night than during the day. In separate studies using 15 to 60 minute urine collection periods, inulin clearance was compared in awake and in anesthetized animals with endogenous or exogenous creatinine clearance measured simultaneously. The clearance of creatinine systematically exceeded the clearance of inulin, even in intact animals with a normal serum creatinine. The creatinine-to-inulin clearance ratio averaged 1.16 +/- 0.03 at a serum concentration of 0.7 to 0.8 mg/dl; 1.27 +/- 0.03 at a serum creatinine of 1.0 to 1.1 mg/dl and 1.56 +/- 0.04 at a serum creatinine greater than 10 mg/dl. All values exceed unity significantly (p less than 0.001). Thus, renal function, including inulin clearance, can be measured in awake baboons. Duplicate or triplicate 24-hour urine collections are needed to assess the reliability of creatinine excretion. However, creatinine clearance overestimates glomerular filtration rate, as it does in humans.     

Beneficial effect of verapamil in ischemic acute renal failure in the rat

To investigate the possible protective effect of Ca2+ blockers in ischemic acute renal failure (ARF), verapamil, in a dose of 10 micrograms/kg body wt/min was administered for 100 min, starting 15 min before the total occlusion of the left renal artery after right nephrectomy in rats. Mean 24-hr creatinine clearance, blood urea, and serum creatinine levels, 24 hr after declamping, were used as a measure of kidney function. These values which were 135 +/- 1.9 microliter/min, 231 +/- 22 mg%, and 2.25 +/- 0.22 mg%, respectively, in the untreated rats, were found to be significantly different, i.e., 326.3 +/- 33.2 microliter/min, P less than 0.001, 112 +/- 25 mg%, P less than 0.001, and 1.26 +/- 0.28 mg%, P less than 0.01, respectively, in the verapamil-treated animals. Increased 24-hr total urine creatinine, sodium, osmolality, and a lower fractional excretion of sodium were also observed in the verapamil-treated rats with ARF. The combination of propranolol 1 mg/kg body wt/min and verapamil 10 micrograms/kg body wt/min for 100 min had no additive effect on renal function. In another group of ARF rats in which verapamil was started after declamping, no alleviating effect was observed. It is concluded that verapamil, an inhibitor of cellular membrane transport, when given prior to the renal ischemia, offers a partial but significant protection in this model of ischemic ARF.     

Transgenic expression of a soluble complement inhibitor protects against renal disease and promotes survival in MRL/lpr mice

To investigate the role of complement in lupus nephritis, we used MRL/lpr mice and a transgene overexpressing a soluble complement regulator, soluble CR1-related gene/protein y (sCrry), both systemically and in kidney. Production of sCrry in sera led to significant complement inhibition in Crry-transgenic mice relative to littermate transgene negative controls. This complement inhibition with sCrry conferred a survival advantage to MRL/lpr mice. In a total of 154 animals, 42.5% transgene-negative animals had impaired renal function (blood urea nitrogen > 50 mg/dl) compared with 16.4% mice with the sCrry-producing transgene (p < 0.001). In those animals that died spontaneously, MRL/lpr mice with the sCrry-producing transgene did not die of renal failure, while those without the transgene did (blood urea nitrogen values of 46.6 +/- 9 and 122 +/- 29 mg/dl in transgene-positive and transgene-negative animals, respectively; p < 0.001). Albuminuria was reduced in those transgenic animals in which sCrry expression was maximally stimulated (urinary albumin/creatinine = 12.4 +/- 4.3 and 36.9 +/- 7.7 in transgene-positive and transgene-negative animals, respectively; p < 0.001). As expected in the setting of chronic complement inhibition, there was less C3 deposition in glomeruli of sCrry-producing transgenic mice compared with transgene-negative animals. In contrast, there was no effect on glomerular IgG deposition, levels of anti-dsDNA Ab and rheumatoid factor, or spleen weights between the two groups. Thus, long-term complement inhibition reduces renal disease in MRL/lpr mice, which translates into improved survival. MRL/lpr mice in which complement is inhibited still have spontaneous mortality, yet this is not from renal disease.     

CARDIOGENIC ACUTE RENAL FAILURE (CARF) FOLLOWING OPEN-HEART SURGERY

Although previous reports have attributed acute renal failure (ARF) following cardiovascular surgery to acute tubular necrosis (ATN), little emphasis has been placed on renal failure due to congestive heart failure (CARF). Of 100 cases of ARF studied prospectively over an 18-month period, 36 occurred after open-heart surgery. Nineteen of these cases were associated with heart failure. The remaining 17 had ATN as manifested by high urinary sodium, low urine/plasma creatinine, and abnormal urinary sediment. At the onset of CARF, intravascular volume expansion was universally present, and oliguria with pulmonary edema was common. Urinary chemistries were (mean +/- SD): sodium (mEq/L) 8 +/- 7, U/P creatinine 72 +/- 45, and FENa (%) 0.1 +/- 0.1. Therapy consisted of digoxin, furosemide (F), vasopressors (V), and, when indicated, intraaortic balloon counterpulsation. Survivors of CARF responded more frequently to F and required less V. Ultimately, survival depended upon improvement in cardiac performance. All oliguric ATN patients failed to respond to F. Mortality for the CARF group was 52%. In contrast, 82% of the oliguric ATN group expired, whereas overall ATN mortality was 60%. Cardiogenic acute renal failure is a frequent cause of ARF after open-heart surgery in our institution. It is characterized by prerenal urinary chemistries, has a high mortality, and may be reversible.     

Effects of the anaesthetic/tranquillizer treatments on selected plasma biochemical parameters in NZW rabbits

In order to assess the response of plasma biochemical parameters to anaesthesia, 40 New Zealand White (NZW) rabbits were assigned to four treatment groups (n = 10): control (1 ml i.v. saline solution), fentanyl-droperidol (FD) (0.4 ml/kg s.c. of 'thalamonal' solution; 2.5 mg/ml droperidol, 0.05 mg/ml fentanyl), ketamine (K) (10 mg/kg i.v.) with either xylazine (X) (3 mg/kg i.v.) or diazepam (D) (2 mg/kg i.v.). Blood samples were obtained from the central ear artery at six time points: before injection, and at 10, 30, 60, 120 min and 24 h after injection of the anaesthetics/saline. Plasma ALT, AST, ALP, GGT, BUN, creatinine, phosphate and potassium levels were measured by the Hitachi 747 autoanalyser. The administration of K-X increased (P < 0.05) plasma ALT (from 11.4 +/- 0.9 to 20.2 +/- 1.7 IU/l, at 10 min), AST (from 10.5 +/- 3.3 to 34 +/- 2.1 IU/l, at 120 min), BUN (from 17.2 +/- 0.9 to 25.8 +/- 1.8 mg/dl, at 60 min) and creatinine concentrations (from 1 +/- 0.1 to 1.6 +/- 0.2 mg/dl, at 10 min). After K-D administration, we observed an increase (P < 0.05) in plasma ALT (from 11.4 +/- 0.9 to 20.2 +/- 1.1 IU/l, at 10 min), AST (from 11.4 +/- 1.6 to 28 +/- 3.7 IU/l, at 10 min), BUN (from 15.8 +/- 0.8 to 30 +/- 1.5 mg/dl, at 10 min) and creatinine levels (from 1 +/- 0.08 to 2.2 +/- 0.2 mg/dl, at 120 min). No significant changes were seen in the FD group. We conclude that K-X and K-D may affect plasma concentration of select serum enzymes and biochemical parameters. These results should be taken into account when blood samples are evaluated in treated rabbits.     

Effects of oxygen free radical scavengers on uranium-induced acute renal failure in rats

Study was made to determine whether oxygen free radicals mediate uranium-induced acute renal failure (ARF). Superoxide dismutase (SOD), a superoxide anion scavenger, did not prevent uranium acetate (UA) (5 mg/kg, i.v.)-induced renal injury 48 h after injection. In contrast, dimethylthiourea (DMTU), a hydroxyl radical scavenger, significantly attenuated UA-induced rise in serum creatinine concentration (1.11 ± 0.05 (DMTU) vs. 1.40 ± 0.06 mg/dl (control), p < .05), and tubular necrosis. Dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, decreased UA-induced tubular damage. UA injection caused no increase in renal cortical malondialdehyde (MDA) content. DMTU and DMSO did not modify intrarenal MDA content. UA administration brought about significant increase in plasma renin activity but not in renal cortical renin content. Treatment with DMTU and DMSO had no effect on plasma renin activity or intrarenal renin content. It follows from these findings that DMTU and DMSO may attenuate UA-induced renal injury. Such a protective effect would not be mediated through modulation of lipid peroxidation or renin activity.     

The protection against gentamicin nephrotoxicity in the streptozotocin-induced diabetic rat is not related to gender.

Since gender can influence the renal toxicity of a drug in a given species, the present study was undertaken to evaluate the role of sex in the protection against gentamicin (G)-induced nephrotoxicity afforded by diabetes mellitus (DM) in the rat. We have compared the effects of administration of G (40 mg/kg/day, for 14 days) on male and female DM Sprague-Dawley rats. Non-diabetic animals of both sexes receiving identical doses of G served as controls. At the end of the experiment on day 14, both female (F) and male (M) control groups had similar and marked evidence of nephrotoxicity: elevation of plasma creatinine (F 1.7 +/- 0.7; M 2.8 +/- 0.6 mg/dl), decrease in endogenous 24-h creatinine clearance (Ccr) (F0.3 +/- 0.1; M 0.2 +/- 0.1 ml/min/100 g BW), and histological evidence of severe acute tubular necrosis. In marked contrast, the DM rats showed no functional or morphological evidence of renal damage throughout the study regardless of their gender (day 14: plasma creatinine: F 0.2 +/- 0.03; M 0.2 +/- 0.02; Ccr: F 1.2 +/- 0.1; M 1.6 +/- 0.1 ml/min/100 g BW), and they also accumulated less G in their kidney cortex than the C rats. The male controls exhibited higher renal cortex accumulation of G than the female controls (p < 0.05), whereas the opposite occurred in the DM groups (p < 0.01). Because the validity of using Ccr for the evaluation of GFR changes in experimental nephrotoxicity has been questioned, we have compared, in a separate experiment, three different methods of estimation of GFR (simultaneous short clearances of inulin and Ccr, and 24-h Ccr) in conscious female Sprague-Dawley rats undergoing the same treatment with G described above. At no time during the study did the method used for estimation of the GFR influence the results. We conclude that male and female Sprague-Dawley rats with diabetes are functionally and morphologically equally protected against G. Furthermore, no gender-related differences in the magnitude of G-induced nephrotoxicity was demonstrated in the non-diabetic control animals.     

Measurement of urinary clusterin as an index of nephrotoxicity.

Measurements of tissue immunoassayable clusterin, a protein associated with programmed cell death and tissue reorganization, were performed in rats treated with nephrotoxic doses of gentamicin sulfate. Adult Lewis rats were treated with 100 mg/kg/day of gentamicin sulfate for 12 days. Urine, serum, and tissue levels of clusterin protein were measured, as were urinary N-acetyl beta-glucosaminidase (NAG) and serum creatinine levels. Induction of renal injury by gentamicin was detectable within 4 days by increased levels of urinary N-acetyl beta-glucosaminidase (from 280 +/- 66 (mean +/- SD) to 910 +/- 210 nmol/mg creatinine), and within 9 days of initiating gentamicin treatment by increased serum creatinine (from 0.5 +/- 0.1 to 1.2 +/- 0.4 mg/dl). Paralleling these changes, renal, urinary, and serum levels of clusterin increased 10-, 116-, and 3-fold (P less than 0.05). Treatment with gentamicin sulfate did not increase clusterin levels in the seminal vesicle, ventral prostate, testis, or epididymis. The measurement of urinary or serum clusterin may play a role in the early detection of renal injury.     

Protection against ischemic acute renal failure by prostaglandin infusion

We have shown that intravenous infusion of epinephrine (4ug/kg/min for 6 hours) into mongrel dogs consistently produces renal hemodynamic and histopathologic characteristics of ischemic acute renal failure (ARF). This study describes renal responses that were modified by intravenous infusion of prostaglandin E (PGE₂)(10 ug/min) one hour before and during a 6 hour infusion of epinephrine (4 ug/kg/min). Two groups of animals were studied: Group I (epinephrine alone) and Group II (epinephrine + PGE₂). Urine volume, glomerular filtration rate, urinary sodium excretion rate, urine osmolality, and serum urea nitrogen were measured. Renal tissues were studied using light and electron microscopy. While urine volume or glomerular filtration rate decreased significantly in both groups, they were slightly but significantly better in Group II than Group I. Urine osmolality significantly decreased in Group I but significantly increased in Group II. Group I animals became azotemic (mean serum urea nitrogen, 27 ± 1 mg/dl), whereas Group II animals showed serum urea nitrogen at the upper limits of normal (mean 20 ± 2 mg/dl). The difference was significant (P <.01). Severe acute tubular lesions were a consistent feature in Group I. Tubular lesions were less severe and infrequent in Group II animals. While mitochondrial dark bodies (electron microscopy) characterized tubular lesions in Group I, fewer mitochondria contained dark bodies in Group II animals. These dark bodies appear to be calcium and constitute a definitive sign of ischemia. Therefore, this study indicates that PGE₂ attenuates epinephrine-induced tubular ischemia and injury and ARF which may be attributed to excessive solute excretion or to inhibition of calcium influx into tubular mitochondria.     

Microdissection studies of the structural alterations induced in rat kidneys by experimental postischemic acute renal failure

A unique opportunity presented itself for a morphologic study of experimental unilateral acute renal failure (ARF) in male rats. The ARF had been induced in the rats by temporary occlusion (1h) of the left renal artery. Twenty-nine rats were divided into subsets as follows: 2-3 h, 24 h, 1 week, 2, 4, 8, and 12 weeks following release of occlusion. Microdissection showed a heterogeneous population of abnormally structured proximal tubules in which the regressive lesions of tubular necrosis were combined with the progressive reaction of repair. The lesions demonstrated are reminiscent of those which have been described in ARF in the human and in experimental animals. Many proximal tubules in the 2- to 3-hour subset presented 1-3 disruptive lesions (DLs) while greater numbers of proximal tubules from the 24-hour group presented 1-5 DLs. Many proximal tubules presented no DLs, but nearly all from the 24-hour subset (97-100%) displayed a squamate appearance which paralleled and was caused by acute tubular necrosis. At 1 week, a dilated pars recta was common, but by this time, the squamate pattern had disappeared. Many casts were present. At 2 weeks, many fewer casts were present in proximal tubules and none were seen at 4, 8 or 12 weeks. The nephrons, particularly the proximal tubules, presented a variety of structural alterations at 2, 4, 8 and 12 weeks. Changes of special interest include (1) the presence of swan-necks; (2) a distinctive squamate appearance of the proximal tubules in the animals killed at 24 h; (3) a spiral, curled appearance caused by differential hyperplasia in animals at 4, 8 and 12 weeks, and (4) a tendency for ischemic lesions to involve all layers of the renal cortex.     

ET(A) receptor blockade prevents renal dysfunction in salt-sensitive hypertension induced by sensory denervation

To test the hypothesis that activation of the endothelin type A (ET(A)) receptor contributes to decreased renal excretory function and increased blood pressure in sensory nerve-degenerated rats fed a high-salt diet, neonatal Wistar rats were given vehicle or capsaicin (CAP, 50 mg/kg s.c.) on the first and second day of life. After being weaned, vehicle or CAP-treated rats were fed a normal (NS, 0.5%) or a high- (HS, 4%) sodium diet for 2 wk with or without ABT-627 (5 mg x kg(-1) x day(-1), a selective ET(A) receptor antagonist). Systolic blood pressure increased in CAP-treated rats fed a HS diet (CAP-HS) compared with vehicle-treated rats fed a HS diet (CON-HS, 145 +/- 7 vs. 89 +/- 5 mmHg, P < 0.05). Creatinine clearance and fractional sodium excretion (FE(Na)) decreased in CAP-HS rats compared with CON-HS rats (creatinine clearance, 0.54 +/- 0.05 vs. 0.81 +/- 0.09 ml x min(-1) x 100 g body wt(-1); FE(Na), 8.68 +/- 0.99 vs. 12.53 +/- 1.47%, respectively; P < 0.05). Water and sodium balance increased in CAP-HS rats compared with CON-HS (water balance, 20.2 +/- 1.5 vs. 15.5 +/- 1.9 ml/day; sodium balance, 11.9 +/- 3.1 vs. 2.4 +/- 0.3 meq/day, respectively; P < 0.05). The endothelin (ET)-1 levels in plasma and isolated glomeruli increased by about twofold in CAP-HS rats compared with CON-HS rats (P < 0.05). ABT-627 prevented the decrease in creatinine clearance and FE(Na), the increase in water and sodium balance, and the increase in blood pressure in CAP-HS rats (P < 0.05). Therefore, the blockade of the ET(A) receptor ameliorates the impairment of renal excretory function and prevents the elevation in blood pressure in salt-sensitive hypertension induced by degeneration of sensory nerves, indicating that the activation of the ET(A) receptor impairs renal function and contributes to the development of a salt-induced increase in blood pressure in this model.     

Effects of vitamin E on microsomal Ca(2+) -ATPase activity and calcium levels in streptozotocin-induced diabetic rat kidney

Vitamin E treatment has been found to be beneficial in preventing or reducing diabetic nephropathy. Increased tissue calcium and abnormal microsomal Ca(2+)-ATPase activity have been suggested as contributing factors in the development of diabetic nephropathy. This study was undertaken to test the hypothesis that vitamin E reduces lipid peroxidation and can prevent the abnormalities in microsomal Ca(2+)-ATPase activity and calcium levels in kidney of streptozotocin (STZ)-induced diabetic rats. Male rats were rendered diabetic by a single STZ injection (55 mg x kg(-1) i.p.). After diabetes was verified, diabetic and age-matched control rats were untreated or treated with vitamin E (400-500 IU kg(-1) x day(-1), orally) for 10 weeks. Ca(2+)-ATPase activity and lipid peroxidation (MDA) were determined spectrophotometrically. Blood glucose levels increased approximately five-fold (> 500 mg x dl(-1)) in untreated-diabetic rats but decreased to 340+/-27 mg x dl(-1) in the vitamin E treated-diabetic group. Kidney MDA levels did not significantly change in the diabetic state. However, vitamin E treatment markedly inhibited MDA levels in both control and diabetic animals. Ca(2+)-ATPase activity was 0.483+/-0.008 U l(-1) in the control group and significantly increased to 0.754+/-0.010 U l(-1) in the STZ-diabetic group (p < 0.001). Vitamin E treatment completely prevented the diabetes-induced increase in Ca(2+)-ATPase activity (0.307+/-0.025 U l(-1), p < 0.001) and also reduced the enzyme activity in normal control rats. STZ-diabetes resulted in approximately two-fold increase in total calcium content of kidney. Vitamin E treatment led to a significant reduction in kidney calcium levels of both control and diabetic animals (p < 0.001). Thus, vitamin E treatment can lower blood glucose and lipid peroxidation, which in turn prevents the abnormalities in kidney calcium metabolism of diabetic rats. This study describes a potential biochemical mechanism by which vitamin E supplementation may delay or inhibit the development of cellular damage and nephropathy in diabetes.     

An elevation of BUN/creatinine ratio in patients with hyperthyroidism

Blood urea nitrogen (BUN/creatinine ratio was abnormally high (24.8 +/- 0.6) in untreated hyperthyroid patients due to both increase in BUN and decrease in creatinine concentration. BUN, creatinine and BUN/creatinine ratio were all completely normalized after restoration of euthyroid status. On the other hand, BUN/creatinine ratio was slightly suppressed in hypothyroidism before treatment and it was reversed by thyroxine treatment (12.6 +/- 4.0 and 16.3 +/- 3.3, before and after treatment, respectively). An age-related increase in BUN/creatinine ratio, which was primarily due to an age-related increase in BUN, was also found in hyperthyroid subjects (21.9 +/- 2.8 vs 27.7 +/- 9.0; first vs fifth decade) and in normal controls (13.7 +/- 2.8 vs 16.0 +/- 2.9; first vs fifth decade). To elucidate reasons for abnormal increase in BUN/creatinine ratio in hyperthyroidism, measurement of cardiac output and kinetic analysis on urea nitrogen (UN) and creatinine were performed. The results indicated a marked increase in cardiac output. Serum creatine concentration was clearly increased in hyperthyroid patients. Thus, serum creatinine concentration was suppressed due to a decrease in creatinine synthesis and an increase in renal creatinine excretion. BUN was high, primarily due to an increase in UN production secondary to excessive protein catabolism together with insufficient excretion of UN.     

Parameters of tubulo-glomerular function in anesthetized rabbits with acute kidney insufficiency

We have induced acute renal failure (ARF) in barbiturate anesthetized rabbits, through warm ischaemia of 30 or 60 min duration caused by transient bilateral occlusion of renal arteries. In this model we have monitored some renal performance parameters, before and 4 hours after reperfusion, aiming to characterize ARF in this animal species. Glomerular filtration rate (determined by the inulin clearance technique) was of 9.74 +/- 0.48 ml min-1 in 4 rabbits before injury and declined by 91% (60 min ischemia) during the first reperfusion hour. In 6 rabbits undergoing 30 min occlusion, pre-ARF values of 10.70 +/- 0.98 ml min-1 declined by 47%. In both groups no recovery was observed in the following hours. Tubular enzymes (alanine-amino-peptidase, AAP and N-acetyl-beta-glucosaminidase, NAG) were released into urines before injury at the rate of 1.11 +/- 0.18 and 1.32 +/- 0.41 mU min-1, respectively, in the 30 min model (3 animals/group). During ARF, maximal AAP output was five-fold increased (5.83 +/- 0.35 mU min-1), whereas NAG was unmodified. On the other hand, renal haemodynamics in 5 rabbits did not change after the ischaemic procedure: total renal blood flow (44 +/- 5 ml min-1) and renal vascular resistances (225 +/- 26 Pa ml-min) displayed less than 10% variations throughout the reperfusion period. We concluded that ARF in rabbits can be reliably and reproducibly monitored and that the pathogenesis of the disease, in our situation, is attributable mainly to tubular cell damage and not to impairment of the vascular component of renal performance.