Foscarnet nephrotoxicity: mechanism, incidence and prevention

Foscarnet is a pyrophosphate analogue that has been successfully used in severe cytomegalovirus (CMV) infections. Little is known of the incidence and mechanisms of foscarnet-induced nephrotoxicity as most data comes from recipients of renal allografts or from patients with severe underlying disease or with other nephrotoxic drugs. We have retrospectively analyzed the evolution of renal function after 56 courses of foscarnet. In addition, we have prospectively studied the protective effects of hydration on foscarnet nephrotoxicity (2.5 liters of saline/day during the night before the foscarnet therapy and throughout the course of treatment). Foscarnet-induced acute renal failure was defined as a rise in serum creatinine of at least 25% from the basal value. An increase in serum creatinine occurred in 37 cases out of the 56 courses of foscarnet (66%). The mean serum creatinine prior to foscarnet was 80.5 +/- 3.3 mumol/l and the mean increase was 190 +/- 28.3 mumol/l (range 80-1,000). Peak serum creatinine was higher than 200 and 300 mumol/l in 16 and 13 patients, respectively. Kidney obtained at autopsy from a 30-year-old male with AIDS, CMV pneumonitis and acute renal failure secondary to foscarnet administration showed an extensive tubular necrosis. In the group which was prospectively hydrated only 1 patient had an acute renal failure. The mean serum creatinine at the peak (96 +/- 4 mumol/l) and at the end of the treatment (83 +/- 4 mumol/l) was significantly lower (p less than 0.05) than in non hydrated patients. In conclusion, foscarnet is a highly nephrotoxic drug which induces acute tubular necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adult minimal change glomerulopathy with acute renal failure

Oliguric acute renal failure occurs in some adult patients with minimal change glomerulopathy. To look for clinical and pathologic factors that increase the risk for developing acute renal failure, 21 adults with minimal change glomerulopathy and a serum creatinine greater than 177 mumol/L (mean, 486 mumol/L; range, 194 to 1,344 mumol/L) (greater than 2.0 mg/dL [mean, 5.5 mg/dL; range, 2.2 to 15.2 mg/dL]) were compared with 50 adults with minimal change glomerulopathy and a serum creatinine less than 133 mumol/L (mean, 88 mumol/L; range, 53 to 124 mumol/L) (less than 1.5 mg/dL [mean, 1.0 mg/dL; range, 0.6 to 1.4 mg/dL]). Minimal change glomerulopathy patients with acute renal failure were older (59.5 v 40.3 years, P less than 0.001), and had higher systolic blood pressure (158 v 138 mm Hg, P = 0.001), more proteinuria (13.5 v 7.9 g/24 h, P = 0.01), and more arteriosclerosis in the renal biopsy specimen (1.7 + v 0.7 + on a scale of 0 to 4+, P = 0.005). Tubular epithelial simplification identical to that observed with ischemic acute renal failure (acute tubular necrosis) was observed in 71% of the patients with serum creatinine greater than 177 mumol/L (greater than 2.0 mg/dL) and 0% of those with less than 133 mumol/L (less than 1.5 mg/dL). All 18 patients with renal failure for whom follow-up data were available had recovery of function (mean creatinine, 539 +/- 301 mumol/L [6.1 +/- 3.4 mg/dL] at the time of biopsy and 106 +/- 27 mumol/L [1.2 +/- 0.3 mg/dL] at last follow-up), but sometimes only after weeks of dialysis support.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of sevoflurane preconditioning on ischaemia/reperfusion injury in the rat kidney in vivo

BACKGROUND AND OBJECTIVE: Whereas the protective effect of anaesthetic and ischaemic preconditioning has been described for several organs, it is uncertain whether this mechanism is also effective in the kidney. We compared the effect of preconditioning with sevoflurane and preconditioning with short episodes of ischaemia on renal ischaemia/reperfusion injury in the rat in vivo. METHODS: Fourteen days after right-sided nephrectomy, anaesthetized male Wistar rats were randomly assigned to a sham-operated group (no arterial occlusion, n = 5) or underwent 45 min of left renal artery occlusion (control group, n = 9) followed by 3 days of reperfusion. Two further experimental groups of animals were preconditioned prior to ischaemia either by administering 1 MAC sevoflurane for 15 min followed by 10 min of washout (sevoflurane group, n = 10) or by subjecting the animals to three short episodes of renal ischaemia (ischaemia-preconditioned group, n = 8). Blood creatinine was measured during reperfusion and morphological damage was assessed by histological examination. RESULTS: Baseline creatinine values were similar in all four groups (0.7 +/- 0.2 mg dL-1; mean +/- SD) and remained unchanged in the sham-operated animals after 3 days (0.8 +/- 0.2 mg dL-1). Creatinine levels increased in the ischaemic preconditioning group (3.3 +/- 1.2 mg dL-1) and sevoflurane preconditioning group (4.0 +/- 1.1 mg dL-1) compared to the control group (1.6 +/- 0.6 mg dL-1). Morphological damage was less severe in the control group, i.e. in animals without preconditioning, than in both preconditioning groups. CONCLUSION: Neither sevoflurane nor ischaemic preconditioning preserves renal function or attenuates cell damage in the rat in vivo.     

Renal and systemic oxygen consumption in patients with normal and abnormal renal function.

Systemic and renal oxygen consumption and hemodynamics were studied in patients with normal renal function (NI; serum creatinine concentration (Screat), 1.0 +/- 0.04 mg/dL) and those with moderate chronic renal failure with diabetes mellitus Screat, 2.7 +/- 0.2 mg/dL) or without diabetes mellitus (Screat, 2.4 +/- 0.1 mg/dL). Patients with chronic renal failure were anemic and had normal systemic oxygen consumption (NI, 10,564 +/- 277; chronic renal failure, 9,669 +/- 362 mumol of O2/min) and elevated systemic oxygen extraction (NI, 22.9 +/- 1; chronic renal failure, 30.9 +/- 1.2%) (P less than 0.02). Cardiac output and index and arterial oxygen saturation were equivalent in normal patients and in patients with chronic renal failure. Patients with chronic renal failure had higher renal oxygen extraction (NI, 7.3 +/- 0.8; chronic renal failure, 13.9 +/- 1%), lower RBF (NI, 572 +/- 146; chronic renal failure, 197 +/- 20 mL/min/kidney), and lower renal oxygen consumption per kidney (NI, 391 +/- 101; chronic renal failure, 177 +/- 20 mumol of O2/min/kidney) than did normal patients (P less than 0.02). There was a linear relationship between hemoglobin and RBF (r = 0.47, P less than 0.02). Patients with chronic renal failure and diabetes had lower RBF (diabetes mellitus, 146 +/- 23; without diabetes, 242 +/- 28 mL/min/kidney) and renal oxygen consumption per kidney (diabetes mellitus, 131 +/- 21; without diabetes, 218 +/- 29 mumol of O2/min/kidney (P less than 0.03) but equivalent renal oxygen extraction when compared with patients without diabetes. Patients with chronic renal failure without diabetes mellitus had higher renal oxygen consumption when expressed per 100 mL of creatinine clearance (diabetes mellitus, 1,016 +/- 150; without diabetes mellitus, 1,453 +/- 175 mumol of O2/min/100 mL of creatinine clearance; P less than 0.03). There was a significant linear relationship (P less than 0.005, r = 0.38) between calculated creatinine clearance and renal oxygen consumption with a y intercept representing basal renal oxygen consumption (115 mumol of O2/min/kidney) and a slope of 2.3 mumol of O2/mL. Patients with moderate chronic renal failure have normal systemic oxygen consumption but reduced RBF and renal oxygen consumption. The latter parameters are even lower in patients with chronic renal failure and diabetes. Renal hypermetabolism is more likely to exist in nondiabetic than diabetic renal disease. Basic human renal physiology and pathophysiology are described by the relationships between renal oxygen consumption, blood flow, oxygen extraction, and creatinine clearance in patients with normal and abnormal renal function of varied cause.     

N-acetylcysteine attenuates NSAID-induced rat renal failure by restoring intrarenal prostaglandin synthesis.

BACKGROUND: Renal failure is a threatening side-effect of NSAID administration, consequent to NSAID-mediated abrogation of prostaglandin synthesis and resultant renal ischaemia. N-acetylcysteine (NAC) has renoprotective properties. We examined effects of NAC in a rat model of NSAID-induced renal failure. METHODS: Renal failure was generated in 80 rats by 6-day water deprivation and 3-day 15 mg/kg/day diclofenac injection. The rats were concomitantly treated, or not, by NAC, 40 mg/kg/day. Renal function was evaluated by cystatin C, creatinine and urea. Intrarenal blood flow was measured by laser Doppler. The kidneys were subjected to pathological examination or evaluation of intrarenal NO, H2O2 and PGE2. RESULTS: NAC significantly attenuated deterioration of renal function in diclofenac-treated rats: cystatin C dropped from 2.8+/-0.35 to 2.2+/-0.67 mg/l, P=0.016; creatinine from 1.2+/-0.97 to 0.96+/-0.19 mg/dl, P=0.02; urea from 208.4+/-57.9 to 157.6+/-33.7 mg/dl, P=0.028. Diclofenac-inflicted hystopathological damage was significantly reduced following NAC treatment. Intrarenal medullar blood flow dropped by 51+/-12.4% in diclofenac-treated rats, but only by 14+/-3.39% in those receiving NAC after diclofenac injection (P<0.001). H2O2 was elevated in renal tissues of diclofenac-receiving rats, while decreased in NAC-treated animals. PGE2 release by diclofenac-treated rats dropped significantly, but was restored after NAC administration both in renal cortices (144.7+/-10.4 vs 19.7+/-1.5 pmol/ml, P<0.001) and medullae (148.5+/-7.3 vs 66.6+/-7.3 pmol/ml, P<0.001). CONCLUSIONS: In this model of renal failure induced by NSAID administration combined with water deprivation, NAC treatment successfully attenuated the deterioration of renal function by inducing renal vasodilatation, decreasing oxidative stress via inhibition of intrarenal ROS content and restoration of intrarenal PGE2 release back to the basal levels.     

Amelioration of postischaemic acute renal failure in conscious dogs by human atrial natriuretic peptide

We studied the effect of human ANP (alpha-hANP)-99-126 on the course of postischaemic acute renal failure in unilaterally nephrectomised, conscious dogs subjected to 120 min of renal ischaemia. In contrast to a control group A (n = 7), the investigational group B (n = 9) received an intra-aortic bolus injection of 100 micrograms/kg alpha-hANP and an additional continuous infusion of 0.3 micrograms/kg per min x 180 min immediately after ischaemia. On days 1 and 2 after ischaemia, only the bolus injection was repeated. Administration of hANP resulted in a marked restoration of GFR (29 +/- 2 vs 18 +/- 4 ml/min, P less than or equal to 0.01), diuresis (0.8 +/- 0.1 vs 0.5 +/- 0.1 ml/min, P less than or equal to 0.05), and natriuresis (44 +/- 7 vs 25 +/- 4 mumol/min, P less than or equal to 0.05) on the first postischaemic day, which was mirrored by a reduction in nitrogen retention (Purea: 8 +/- 1 vs 12 +/- 2 mmol/l P less than or equal to 0.05, Pcrea: 137 +/- 20 vs 204 +/- 37 mumol/l). Renal perfusion, however, was only slightly improved on day 1 after ischaemia (198 +/- 20 vs 163 +/- 27 ml/min, N.S.). Our data clearly demonstrate that repeated bolus applications of hANP ameliorate postischaemic acute renal failure in conscious dogs. We assume that the observed beneficial effect on GFR might be the consequence of an increase in glomerular capillary pressure rather than an improvement of renal perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Furosemide and dopamine in malarial acute renal failure

The effects of furosemide and furosemide with dopamine on renal function were studied in 23 patients with acute renal failure due to falciparum malaria whose serum creatinine ranged from 230 to 947 mumol/l. Furosemide given intravenously at the dosage of 200 mg 6 hourly for a period of 4 days did not alter the clinical course of renal failure. Intravenous administration of furosemide (200 mg 6 hourly) with dopamine (1 microgram/kg/min) for 4 days increased creatinine clearance and arrested the progress of renal failure when the serum creatinine was less than 400 mumol/l, but failed to alter the course of renal failure when the serum creatinine exceeded 600 mumol/l.     

Renal accumulation of ammonia: the cause of post-ischaemic functional loss and the "blue line"

The "blue line", a dark discoloration at the corticomedullary junction, is a constant finding after a significant period of renal ischaemia. In this study, it has been shown to be caused by packing of all of the peritubular capillaries at the corticomedullary junction with red blood cells. Five rats and 10 dogs were alkalinised by replacing their drinking water with 2% sodium bicarbonate for 2 weeks pre-operatively, in order to inhibit the glutaminase enzyme system and thereby decrease ammonia accumulation during ischaemia. Five rats and 6 dogs were used as unprotected controls. All animals were subjected to 60 min warm ischaemia. Renal function was significantly protected in the alkalinised rats (P less than 0.002) and dogs (P less than 0.001), with the serum creatinine rising to a maximum of 0.21 +/- 0.03 mmol/l in the alkalinised rats and 0.18 +/- 0.04 mmol/l in the alkalinised dogs. There was no "blue line" in the alkalinised animals. It is suggested that the "blue line" plays a central role in post-ischaemic renal failure. Prevention of ammonia formation by alkalinisation protects against ischaemic renal damage and the formation of the "blue line".     

Effects of verapamil in the prevention of warm ischaemia induced acute renal failure in dogs

Acute renal failure in the immediate postoperative period remains a significant complication of renal transplantation. A major factor in the pathogenesis may be warm ischaemia (WI). Recent evidence implicates a calcium mediated mechanism as a final common pathway in certain models of acute renal failure. This study was undertaken to evaluate the effects of Verapamil, a calcium antagonist, in the prevention of warm ischaemia-induced acute renal failure following renal autotransplantation in the dog. Twenty-one mongrel dogs were randomly allocated to three groups. Group 1 (control, 8 dogs) received 20 ml normal saline before a standardized 60 min warm ischaemic insult to the left kidney. Group 2 (6 dogs) received Verapamil (0.3 mg/kg) by intravenous injection and Group 3 (7 dogs) received Verapamil (0.3 mg/kg) by intra-arterial injection into the left renal artery prior to the same ischaemic insult. The left kidney was heterotopically grafted to the right iliac fossa in the warm ischaemic period. Contralateral nephrectomy was performed. The dogs were followed up to 7 days after operation by serial creatinine estimation. Histological examination of some autografts was performed. Of the eight controls, six showed marked renal impairment (serum creatinine greater than 800, or death in renal failure). Three of the six dogs given intravenous Verapamil showed marked renal impairment. None of the seven dogs receiving intra-arterial Verapamil showed marked renal impairment (P = 0.013, chi 2 test). The mean rate of serum creatinine rise for each group was analysed by multivariate analyses of variance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Superficial nephron obstruction and medullary congestion after ischemic injury: effect of protective treatments

90 min of renal artery occlusion in previously unilaterally nephrectomized rats produce acute renal failure (ARF) (plasma creatinine at 48 h after ischemia: 636 +/- 44 vs. 133 +/- 9 mumol/l in controls). Between 1 and 48 h after releasing the occlusion, two populations of superficial nephrons could be observed, one with dilated tubules and elevated proximal tubular pressures (PTP: 39 +/- 1 vs. 12 +/- 1 mm Hg in controls) and the other with collapsed tubules and decreased PTP (9 +/- 1 mm Hg). Proximal tubular passage time (PPT) could not be determined with the Lissamine green technique. Seven methods of pretreatment were tested, 5 of which provided partial functional protection (DOCA/NaCl/NaCl, furosemide infusion, inosine bolus, mannitol bolus and the combination of the last two). Neither renal renin levels nor urinary NaCl excretion were consistently correlated with protection. Functionally protected rats consistently showed no PTP increase and normal PPT in the tubules at the kidney surface. However, plasma creatinine at 48 h differed markedly within the 5 protected groups, ranging from 168 +/- 18 to 398 +/- 35 mumol/l. Extensive medullary congestion was seen at 1-6 h after ischemia only in those rats with obstructed, high pressure nephrons at the kidney surface. To conclude: (1) Functional protection from ischemic ARF, both with and without an accompanying increase in solute excretion, was achieved by the abolition of tubular obstruction. (2) Despite similar degrees of restoration of superficial nephron function, the persisting impairment of whole kidney function differed markedly between the protected groups. (3) Impairment of deeper nephron function must therefore play a major role, perhaps through persisting obstruction in the long loops of Henle. (4) High pressure nephrons may compromise medullary venous outflow in the outer zone of the outer medulla.     

Effects of famotidine, a new histamine H2-receptor antagonist, on renal function

The effects of famotidine on renal function were investigated. Eight healthy men (N) and 8 renal patients with varying degrees of renal failure (R.F.) participated in the trial. They were given either famotidine (40 mg) or cimetidine (800 mg) for 7 days. Cimetidine produced a significant decrease in creatinine clearance (from 131.6 +/- 12.9 to 107.7 +/- 3.4 ml/min (N), and 22.2 +/- 3.9 to 18.1 +/- 3.5 ml/min (R.F.], and increase in serum creatinine (from 0.96 +/- 0.05 to 1.09 +/- 0.04 mg/dl (N), and 3.46 +/- 0.62 to 3.86 +/- 0.51 mg/dl (R.F.], and a decrease in creatinine excretion (from 24.0 +/- 1.1 to 22.6 +/- 0.8 mg/kg/24 hr (N], respectively, although the reduction in creatinine excretion in the renal failure group was small. On the other hand, the famotidine treatment produced no significant changes in renal function in both subjects (creatinine clearance, 136.5 +/- 5.7 to 133.6 +/- 6.0 ml/min (N), and 21.9 +/- 3.6 to 20.9 +/- 4.1 ml/min (R.F.); serum creatinine, 0.98 +/- 0.02 to 0.99 +/- 0.02 mg/dl (N), and 3.24 +/- 0.43 to 3.46 +/- 0.55 mg/dl (R.F.); and urinary creatine, 25.1 +/- 1.0 to 25.3 +/- 1.0 mg/kg/24 hr (N), and 17.2 +/- 1.4 to 16.6 +/- 1.5 mg/kg/24 hr (R.F.]. There were no changes in the percent sodium excretion, or the serum and urinary beta 2-microglobulin in both groups.     

Acute renal failure following hemorrhagic shock: protective and aggravating factors.

Acute renal failure following hemorrhagic shock was studied in awake rats. The animals were bled to maintain the mean arterial blood pressure between 40 and 60 mm Hg during 180 min. After this period, the blood was reinfused and the rats were studied 24 h later. Hemorrhagic shock caused a less intensive renal injury than 60-min bilateral renal artery clamping. Renal function in the latter model was worse (p less than 0.05) as shown by serum creatinine (SCr) (0.75 +/- 0.10 vs 1.2 +/- 0.2 mg/dL), blood urea nitrogen (BUN) (26.0 +/- 2.8 vs 53.0 +/- 8.5 mg/dL), fractional excretion of sodium (FENa, %) (0.3 +/- 0.1 vs 1.8 +/- 1.0) and potassium (FEK, %) (41.4 +/- 5.7 vs 76.3 +/- 14.2) and urine/plasma creatine (U/PCr (86.4 +/- 15.7 vs 38.8 +/- 15.5). The rats which received verapamil (10 micrograms/kg/min) prior and during the HS did not show increase in SCr (0.5 +/- 0.06 vs 0.75 +/- 0.1 mg/dL, p less than 0.05). This effect was also observed in the rats which received intravenous allopurinol (40 mg/kg) before HS, SCr did not increase (0.5 +/- 0.04 vs 0.75 +/- 0.1 mg/dL, p = 0.05), suggesting a protective effect of those substances in HS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chloroquine influences renal function in rural Zimbabweans with acute transient fever

To establish the effects of chloroquine on kidney function we monitored renal parameters in age and sex matched control subjects and patients who presented with acute transient fever. The patients were immediately treated with chloroquine diphosphate in the recommended dosage. Blood samples for creatinine, urea, Na+ and K+ determinations were collected before treatment (Day 0), on the 3rd day of treatment (Day 3) and two days after the last dose of chloroquine (Day 5). 24 h urine collections were collected for five consecutive days from the second day of treatment. Spot urine samples showed the absence of blood cells, bilirubin, glucose, protein and ketones. Examination of thick blood smears over three days did not reveal any forms of malaria parasites. Urinary tract infection in the patients was also excluded. Therefore, these patients were a suitable group to assess the effects of chloroquine on renal function. The blood pressure in females and males decreased significantly after two days of chloroquine treatment compared with Day 0. The plasma concentration of creatinine in females and females was increased by chloroquine 2 days after the last dose by comparison with the Day 0 (females, 66 +/- 2 mumol/L versus 83 +/- 2 mumol/L n = 20, p < 0.01 and males, 78 +/- 6 mumol/L versus 81 +/- 9 mumol/L, n = 20, p < 0.01). This was paralleled by a reduction in urinary creatinine excretion during the same period (females 15 +/- 1 mg/kg body weight/24 h versus 12 +/- 1 mg/kg body weight/24 h and males 23 +/- 3 mg/kg/24 h versus 18 +/- 2 mg/kg/24 h, p < 0.01 in both instances). Urinary urea excretion in females was reduced from 290 +/- 6 mumol/kg/24 h to 215 +/- 5 mumol/kg/24 h 2 days after treatment. The results of the study suggest that the effects of chloroquine in patients with acute transient fever include lowered urinary urea and creatinine excretion.     

Prevention of cold ischaemia-reperfusion injury by an endothelin receptor antagonist in experimental renal transplantation.

BACKGROUND: Endothelin (ET) is known to play a role in the pathogenesis of warm ischaemic renal damage, however, little is known about its involvement in renal cold ischaemia. This study was designed to investigate the response of ET after kidney cold ischaemia, and to assess the potential protective effect of bosentan, a dual, non-selective ET(A)/ET(B) receptor antagonist, against cold ischaemia reperfusion injury in a rat model of syngeneic renal transplantation. METHODS: Kidneys from Lewis rats were transplanted, either immediately or after 5 h of cold preservation. After 48 h, contralateral nephrectomy was performed. Rats were organized into three groups: Tr-NoISC, no cold ischaemia; Tr-ISC, 5 h cold ischaemia; and Tr-BOS, 5 h cold ischaemia plus bosentan (100 mg/kg/day, from the day before transplantation until the seventh day post-transplantation). On day 7, plasma and tissue immunoreactive ET (irET), as well as ET mRNA tissue expression, were evaluated. Renal function was measured by means of serum creatinine on days 3, 4, 5 and 7, and by creatinine clearance on day 7. Conventional histology was performed. RESULTS: The ischaemic group had significantly higher plasma irET levels than the non-ischaemic group and significantly lower levels than the bosentan group. Tissue irET levels and ET mRNA expression were similar in the ischaemic and bosentan groups and were higher than in the non-ischaemic group. Throughout the follow-up, serum creatinine was significantly higher in the ischaemic group than in the bosentan group. Moreover, creatinine decreased rapidly in the bosentan group after nephrectomy, whereas it continued to increase for 48 h in the ischaemic group. Kidneys from the ischaemic group showed a higher degree of tubular-cell necrosis and epithelial-cell detachment than kidneys from the bosentan group. CONCLUSIONS: We conclude that cold ischaemia and preservation damage induces an increase in renal ET mRNA and irET expression in the reperfusion phase, contributing both to the deterioration of renal function and to tubular necrosis. Bosentan is effective in protecting kidneys from this cold ischaemia reperfusion damage. Non-selective ET(A)/ET(B) receptor antagonists might be potentially useful in clinical renal transplantation.     

Secondary hyperoxalemia caused by vitamin C supplementation in regular hemodialysis patients

Oxalosis can be a problem in renal failure. As vitamin C is a precursor of oxalate in patients on regular hemodialysis, we have measured plasma levels of vitamin C, oxalate, pyridoxine, thiamine and creatinine twice before and 4 weeks after a change of vitamin C dosage in 49 dialysis patients who had been receiving 500 mg of oral vitamin C daily for more than 6 months. Ten unsupplemented dialysis patients served as controls. The mean plasma levels of vitamin C and oxalate were 3.3 +/- 0.3 mg/dl and 50.4 +/- 8.2 mumol/l respectively. Four weeks after the vitamin C dosage was changed from 500 to 100, 50 and 0 mg, plasma oxalate levels were 34.1 +/- 1.4, 33.3 +/- 3.7, and 25.7 +/- 3.9 mumol/l respectively. There was a strong correlation between plasma vitamin C and oxalate levels (r = 0.755, p less than 0.01) but none between pyridoxine and oxalate. A significant correlation was also noted between the duration of hemodialysis and plasma oxalate levels (r = 0.582, p less than 0.01). Our results suggest that hyperoxalemia in regular hemodialysis patients is aggravated by routine vitamin C supplementation. The administration of vitamin C should be restricted to a dose necessary to correct vitamin C deficiency.     

Treatment of azotemic, nonoliguric, anemic patients with human recombinant erythropoietin raises whole-blood viscosity proportional to hematocrit.

It has been reported that patients with azotemia have reduced red blood cell (RBC) deformability. Since this is a major determinant of whole-blood viscosity (WBV) and rigid RBCs increase WBV disproportionately relative to the level of hematocrit, it is conceivable that sustained improvement of hematocrit with recombinant human erythropoietin (rhEPO) therapy in azotemic patients might result in abnormally raised WBV. To address this concern, WBV and plasma viscosity (PV) were measured in 9 adult patients (4 men, 5 women) with anemia (mean hematocrit 29.2 +/- 2.7%) and azotemia [mean serum creatinine concentration 339.85 +/- 102.44 mumol/l (3.8 +/- 1.1 mg/dl)] before and after 6 months of treatment with rhEPO (50-175 U/kg given intravenously thrice weekly). Baseline and post-treatment hematocrit, WBV and PV were compared to values derived in 50 normal adult subjects with normal renal function [25 women, 25 men; mean serum creatinine concentration 79.56 +/- 8.84 mumol/l (0.9 +/- 0.1 mg/dl), mean hematocrit 42.4 +/- 3.7%]. To compare rheologic factors at subnormal hematocrits, blood from subjects with normal renal function was diluted with autologous plasma to achieve a range of hematocrits from 20 to 50%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of radiocontrast agents in rats: a new model of acute renal failure

The objectives of this study were first to develop a reproducible and reversible model of acute renal failure following contrast medium infusion in the rat; second to use that method to compare the nephrotoxicity of low- and high-osmolar contrast agents. Contrast media or saline were perfused in the aorta while a clamp was applied on the aorta just above the renal artery. Three minutes of renal ischemia with or without infusion of isotonic saline induced no change in serum creatinine and a slight and transient decrease in creatinine clearance at 24 h. Urinary N-acetyl glucosaminidase (NAG) excretion was not modified in this control group. All 17 kidneys which were examined were normal. 2,100 mosm/kg hypertonic saline induced a significant increase in serum creatinine and a significant decrease in creatinine clearance (from 1.8 +/- 0.1 to 0.8 +/- 0.1 and 1.0 +/- 0.2 ml/min at 24 and 48 h, respectively). Urinary NAG excretion increased from 23 +/- 18 to 48 +/- 20 and 8 +/- 4 mumol h-1/mmol creatinine at 24 and 48 h, respectively (p less than 0.05). Histologic analysis of 5 kidneys revealed acute tubular necrosis (n = 3) and no histologic abnormalities (n = 2). Diatrizoate induced an acute and reversible renal failure. Creatinine clearance decreased from 1.6 +/- 0.1 to 0.4 +/- 0.1 and 0.8 +/- 0.1 ml/min at 24 and 48 h, respectively (p less than 0.01). Urinary NAG excretion increased also significantly from 43 +/- 9 to 352 +/- 79 and 64 +/- 23 mumol h-1/mmol creatinine at 24 and 48 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of Nva2-cyclosporine on glomerular filtration rate and renal blood flow in the rat

The effects of Nva2-cyclosporine on glomerular filtration and renal blood flow in rats were studied and compared with those of cyclosporine. An infusion of Nva2-cyclosporine (20 mg/kg) caused a 53% fall in glomerular filtration rate (1.0 +/- 0.08 to 0.47 +/- 0.09; P less than 0.001) and renal plasma flow (3.2 +/- 0.4 to 1.6 +/- 0.4; P less than 0.005). Nva2-cyclosporine when infused in a dose of 10 mg/kg caused a nearly identical fall in inulin clearance and renal plasma flow. By comparison an infusion of cyclosporine (20 mg/kg) caused a 50% decrease in inulin clearance and a fall in renal plasma flow from 2.6 +/- 0.3 to 0.9 +/- 0.3. Nva2-cyclosporine or cyclosporine was given chronically in a dose of 20 mg/kg intraperitoneally for seven days. Cyclosporine produced a 27% fall in creatinine clearance, whereas Nva2-cyclosporine produced a 19% decrease in creatinine clearance (NS). These studies suggest that Nva2-cyclosporine has adverse effects on renal blood flow and glomerular filtration rate similar to those seen with cyclosporine.     

Chronic amphotericin B nephrotoxicity in the rat, protective effect of prophylactic salt loading

Amphotericin B (AMPHO) is the most effective and widely used antifungal agent for the treatment of systemic fungal disease in man. Its use is frequently limited by the development of nephrotoxicity, including renal vasoconstriction with depressed glomerular filtration rate (GFR) and renal plasma flow (RPF), inability to concentrate the urine, and renal potassium wasting. We investigated the effects of oral NaCl loading during chronic administration of AMPHO, on renal function in the rat. Rats were provided 150 mmol/L NaCl (AMPHO plus NaCl) or tap water (AMPHO plus H2O) as drinking water, 3 days prior to, and during chronic AMPHO (5 mg/kg/d intraperitoneal [IP] for 21 days). At the end of the experimental period, renal functional parameters were determined, including serum creatinine, urinary volume and electrolyte excretion rates, ability to maximally concentrate the urine after water deprivation, and renal hemodynamics. NaCl supplementation prevented the rise in serum creatinine (AMPHO plus NaCl, initial v final, 0.39 +/- 0.03 v 0.40 +/- 0.03 mg/dL [34.6 +/- 2.7 v 35.4 +/- 2.7 mumol/L], P = NS) seen in AMPHO plus H2O (0.34 +/- 0.01 v 0.51 +/- 0.04 mg/dL [30.0 +/- 0.9 v 45.2 +/- 3.5 mumol/L], P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Uninephrectomy does not potentiate contrast media nephrotoxicity in the streptozotocin-induced diabetic rat

We studied the effect of radiographic contrast media on renal function in both streptozotocin-induced diabetic rats and normoglycemic rats with reduced renal functional mass. Male Sprague-Dawley induced-diabetic rats and weight-matched controls were divided into unilaterally nephrectomized and intact groups prior to an intravenous challenge with sodium diatrizoate (Urografin) at two dose levels, 1,300 and 2,600 mg iodine/kg. Serum creatinine concentration did not change on the 1st and 3rd day after a dose of 1,300 mg/kg of iodine in normal or induced-diabetic rats. Consequent to a dose of 2,600 mg/kg of iodine, induced-diabetic rats had a significant increase in serum creatinine levels to 0.9 +/- 0.45 mg/dl (control 0.68 +/- 0.11 mg/dl). The observed increase in serum creatinine concentration after treatment with sodium diatrizoate was significantly correlated with the degree of hyperglycemia, but not with prior unilateral nephrectomy. Unilateral nephrectomy, prior to administration of sodium diatrizoate did not potentiate the risk of radiocontrast agent injury in induced-diabetic rats. From these findings, we infer that: (1) streptozotocin-induced diabetes in the rat confers a risk for the development of radiocontrast-induced acute renal failure and (2) as judged by the rise in serum creatinine concentration after exposure, there is an increased risk of acute renal failure associated with a higher dose of radiocontrast material.