Decrease In Inulin Clearance Research Articles

Physical Training Is a Potential Modifier of Risk for Contrast-Induced Acute Kidney Injury in Diabetes Mellitus.

Background Iodinated contrast (IC) is a leading cause of hospital-based acute kidney injury (AKI). Contrast-induced acute kidney injury (CI-AKI) is a decline in renal function due to iodinated contrast administration and occurs more frequently in individuals with increasingly common risk factors, such as diabetes mellitus (DM). Physical training (PT) can have renoprotective effects on CI-AKI in diabetic nephropathy. The aim of this study was to evaluate the injury in kidneys of diabetic rats submitted to treatment with IC, evaluating the impact of PT on hemodynamics and renal function in addition to oxidative profile in diabetic rats submitted to IC-AKI. Materials and Methods Adult male Wistar rats are randomized into four groups: citrate (n = 7): control group, citrate buffer (streptozotocin-STZ vehicle), intravenous tail (iv), single dose; DM (n = 7): STZ, 60 mg/kg, iv, single dose; DM+IC (n = 7): DM rats treated with IC (sodium meglumine ioxithalamate, 6 mL/kg, intraperitoneal (ip), single dose); DM+IC+PT (n = 7): DM rats treated with IC as mentioned and submitted to physical training. Renal function parameters (inulin clearance, neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine, and urinary albumin), hemodynamics (renal blood flow and renal vascular resistance), and oxidative profile (urinary peroxides, urinary TBARS, urinary nitric oxide, and renal tissue thiols) were evaluated. Results It was possible to observe a decrease in inulin clearance, renal blood flow, and thiols in renal tissue accompanied by an increase in urinary flow, serum creatinine, urinary albumin, renal vascular resistance, urinary peroxides, urinary nitrate, and TBARS in the DM group compared to the citrate group. The DM+IC group showed a reduction in inulin clearance, and the renal dysfunction was also seen by the increased NGAL. Renal hemodynamics and oxidative profile compared were also worsened in the DM group. PT improved renal function by increasing renal blood flow and thiol levels in renal tissue and reduced renal vascular resistance, metabolites of reactive oxygen, nitrogen species, and lipid peroxidation in the DM+IC+PT group compared to DM+IC. Conclusions Our results confirmed that DM induction increases renal vulnerability to the toxicity of IC and an association between DM with IC predisposes to severe AKI with reduced renal function alongside with renal hemodynamic alterations and oxidative mechanism of injury. The PT showed a renoprotective effect in DM animals subjected to damage with IC by modulating renal hemodynamics and oxidative profile, confirming a potential to modify the risk of CI-AKI when diabetes mellitus is present.

Heparanase mediates renal dysfunction during early sepsis in mice

Heparanase, a heparan sulfate-specific glucuronidase, mediates the onset of pulmonary neutrophil adhesion and inflammatory lung injury during early sepsis. We hypothesized that glomerular heparanase is similarly activated during sepsis and contributes to septic acute kidney injury (AKI). We induced polymicrobial sepsis in mice using cecal ligation and puncture (CLP) in the presence or absence of competitive heparanase inhibitors (heparin or nonanticoagulant N-desulfated re-N-acetylated heparin [NAH]). Four hours after surgery, we collected serum and urine for measurement of renal function and systemic inflammation, invasively determined systemic hemodynamics, harvested kidneys for histology/protein/mRNA, and/or measured glomerular filtration by inulin clearance. CLP-treated mice demonstrated early activation of glomerular heparanase with coincident loss of glomerular filtration, as indicated by a >twofold increase in blood urea nitrogen (BUN) and a >50% decrease in inulin clearance (P < 0.05) in comparison to sham mice. Administration of heparanase inhibitors 2 h prior to CLP attenuated sepsis-induced loss of glomerular filtration rate, demonstrating that heparanase activation contributes to early septic renal dysfunction. Glomerular heparanase activation was not associated with renal neutrophil influx or altered vascular permeability, in marked contrast to previously described effects of pulmonary heparanase on neutrophilic lung injury during sepsis. CLP induction of renal inflammatory gene (IL-6, TNF-α, IL-1β) expression was attenuated by NAH pretreatment. While serum inflammatory indices (KC, IL-6, TNF-α, IL-1β) were not impacted by NAH pretreatment, heparanase inhibition attenuated the CLP-induced increase in serum IL-10. These findings demonstrate that glomerular heparanase is active during sepsis and contributes to septic renal dysfunction via mechanisms disparate from heparanase-mediated lung injury.

Outcomes 18 Months after the First Human Partial Face Transplantation

Background: We performed the first human partial face allograft on November 27, 2005. Here we report outcomes up to 18 months after transplantation. Methods: The postsurgical induction immunosuppression protocol included thymoglobulins combined with tacrolimus, mycophenolate mofetil, and prednisone. Donor hematopoietic stem cells were infused on postoperative days 4 and 11. Sequential biopsy specimens were taken from a sentinel skin graft, the facial skin, and the oral mucosa. Functional progress was assessed by tests of sensory and motor function performed monthly. Psychological support was provided before and after transplantation. Results: Sensitivity to light touch, as assessed with the use of static monofilaments, and sensitivity to heat and cold had returned to normal at 6 months after transplantation. Motor recovery was slower, and labial contact allowing complete mouth closure was achieved at 10 months. Psychological acceptance of the graft progressed as function improved. Rejection episodes occurred on days 18 and 214 after transplantation and were reversed. A decrease in inulin clearance led to a change in immunosuppressive regimen from tacrolimus to sirolimus at 14 months. Extracorporeal photochemotherapy was introduced at 10 months to prevent recurrence of rejection. There have been no subsequent rejection episodes. At 18 months, the patient is satisfied with the aesthetic result. Conclusions: In this patient who underwent the first partial face transplantation, the functional and aesthetic results 18 months after transplantation are satisfactory.

Long-term caffeine consumption exacerbates renal failure in obese, diabetic, ZSF1 (fa-facp) rats

Our preliminary studies indicate that chronic caffeine consumption has adverse renal effects in nephropathy associated with high blood pressure and insulin resistance. The purpose of this study was to investigate the effects of early (beginning at 8 weeks of age) and long-term (30 weeks) caffeine treatment (0.1% solution) on renal function and structure in obese, diabetic ZSF1 rats. Metabolic and renal function measurements were performed at six-week intervals and in a subset of animals (N = 6 per group) heart rate (HR) and mean arterial blood pressure (MABP) were monitored by a radiotelemetric technique. At the end of the study acute, measurements of renal hemodynamics and excretory function were conducted in anesthetized animals. Caffeine produced a very mild increase (4 to 5%) of MABP and HR, but greatly augmented proteinuria (P < 0.001), reduced creatinine clearance (P < 0.05) and had a mixed effect on metabolic status in obese ZSF1 rats. Caffeine significantly reduced body weight, glycosuria, fasting glucose and insulin levels and improved glucose tolerance, had no effect on elevated plasma triglycerides levels and significantly increased plasma cholesterol level (P < 0.001). Acute measurements of renal function revealed increased renal vascular resistance (95.1 +/- 11 vs. 50.7 +/- 2.4 mm Hg/mL/min/g kidney, P < 0.01) and decreased inulin clearance (0.37 +/- 0.11 vs. 0.97 +/- 0.13 mL/min/g kidney, P < 0.002) in caffeine-treated versus control animals, respectively. Caffeine potentiated the development of more severe tubulointerstitial changes (P < 0.05) and increased focal glomerulosclerosis (14.7 +/- 1.7 vs. 6.5 +/- 0.9%, caffeine vs. control, P < 0.002). The present study provides the first evidence that caffeine (despite improving insulin sensitivity) exacerbates renal failure in obese, diabetic ZSF1 rats. Further mechanistic studies of adverse renal effects of caffeine in chronic renal failure associated with metabolic syndrome are warranted.

Trimethoprim-Sulfamethoxazole (Tmp/Smx) Potentiates Indinavir Nephrotoxicity

Indinavir is a widely prescribed protease inhibitor in the treatment of HIV infection. It has been associated with nephrolithiasis, crystalluria and tubulointerstitial nephritis. Nelfinavir is another protease inhibitor used successfully in AIDS treatment. The objective of this study was to evaluate the effect of both indinavir and nelfinavir individually, and in association with trimethoprim-sulfamethoxazole (TMP/SMX), on renal function in Wistar rats. Doses of indinavir (80 mg/kg body weight [BW] daily), nelfinavir (75 mg/kg BW daily) and TMP/SMX (100 mg TMP/kg BW daily) were given by gavage for 15 days. Seven groups were studied: control, vehicle, TMP/SMX, indinavir, indinavir+TMP/SMX, nelfinavir, and nelfinavir+TMP/SMX. No changes were observed in body weight, urine volume and blood pressure. The vehicle group did not differ from the control group. TMP/SMX induced a small decrease in inulin clearance with no tubular alterations. Indinavir decreased inulin clearance (indinavir: 0.48 +0.03 vs control: 0.93 +/- 0.08, P < 0.001) and renal blood flow (indinavir: 6.2 +/- 0.2 vs control: 8.0 +/- 0.3, P < 0.05). These effects were potentiated by TMP/SMX, which produced high vasoconstriction associated with alterations in tubular functions, characterised by increased fractional excretion of sodium (indinavir+TMP/SMX: 1.14 +/- 0.16 vs control: 0.39 +/- 0.07, P < 0.01). Nelfinavir either alone or in combination with TMP/SMX did not change the renal function of the rats. These results suggest that indinavir nephrotoxicity in rats is potentiated by TMP/SMX and that nelfinavir alone or in combination with TMP/SMX is not nephrotoxic.

Effects of sodium artesunate, a new antimalarial drug, on renal function

Sodium artesunate is currently used in malaria treatment. Adverse effects of this drug have not been described, probably because they cannot be differentiated from malaria-related effects. The effects on renal function of an acute infusion of sodium artesunate (12 mg/kg body weight) were studied in the rat with clearance techniques. We also evaluate the effect of sodium artesunate on chloride lumen-bath flux (Cl Jlb) in the isolated thick ascending limb of the loop of Henle (TALH) microperfused in vitro. Acute infusion of artesunate to the rat decreased inulin clearance, despite an increase in renal blood flow. These effects were associated with an increase in urinary excretion of sodium, chloride, potassium, and nitric oxide metabolites (NO(2)/NO(3)). In water-loaded animals, artesunate increased sodium and water distal delivery and decreased free water clearance (C(H(2)O)) factored for sodium and water delivery. Following hypertonic NaCl infusion, artesunate decreased free water excretion (Tc(H(2)O)) corrected by clearance of osmolarity (C(Osm)). In vitro, artesunate 10(-6) and 10(-3) mol/L added to bath solution decreased chloride lumen-bath flux in isolated rabbit TALH in a dose-dependent manner, with the threshold effect at 10(-4) mol/L. This effect was completely blocked by N(G)-nitroL-arginine-metilester (L-NAME) 5 mmol/L. Artesunate 10(-4) mol/L added to the perfusion solution did not change Cl Jlb. These findings suggest that artesunate decreases glomerular filtration rate and increases renal blood flow and urinary excretion of Na, Cl, and K. These effects were due, at least in part, to the inhibition of Cl transport across cortical and medullary TALH, and were mediated by local production of nitric oxide, since it is associated with an increase in NO(2)/NO(3) urinary excretion and it is blocked by L-NAME in vitro.

Effect of venovenous bypass on perioperative renal function in liver transplantation: Results of a randomized, controlled trial

Although venovenous bypass (VVBP) has been suggested to protect the kidneys during liver transplantation and its systematic use has therefore been recommended, this beneficial effect of VVBP has not been clearly demonstrated. In a prospective, randomized, controlled trial, 77 patients receiving liver transplants for chronic liver disease were allocated to be supported with VVBP (group 1, 38 patients) or not (group 2, 39 patients). Both groups were similar in relation to preoperative clinical and laboratory data and operative transfusion requirements. Inulin clearance and urinary beta2-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) excretion (to determine glomerular filtration rate and tubular damage, respectively) were measured at different perioperative periods (anesthesia induction, hepatectomy, anhepatic phase, biliary anastomosis, and 24 hours after surgery). A significant decrease in inulin clearance and increase in tubular damage markers were observed in the anhepatic phase, which only partly improved in the subsequent phases. No significant differences were observed between groups 1 and 2 at any perioperative phase, except during the anhepatic phase, in which a more marked renal function impairment occurred in group 2 patients. However, renal function on the 7th postoperative day and the need for hemodialysis/ hemofiltration during the 1st week were similar in both groups. Among 40 variables analyzed, only low mean arterial pressure at anesthesia induction was identified as an independent predictor for early postoperative severe renal failure (inulin clearance < 10 mL/min/1.73 m2 at the 24th postoperative hour), with no significant relationship between this complication and the use of venovenous bypass. Renal function markedly deteriorates during liver transplantation, and renal impairment persists during the early postoperative period. Because VVBP support is not associated with any clear benefit in renal function, its systematic use does not seem to be justified. (Hepatology 1996 Jun;23(6):1418-28)

Acute and Chronic Effects of Nonsteroidal Antiinflammatory Drugs on Glomerular Filtration Rate in Elderly Patients

To assess the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on glomerular filtration rate (GFR) in elderly patients with and without renal insufficiency, we conducted an open-label, randomized, prospective three-period cross-over study. Twenty-nine patients at least 65 years old were assigned to groups with preserved GFR (> 1.16 mL/s [70 mL/min]) or with renal insufficiency (GFR 0.50-1.16 mL/s [30-70 mL/min]). Patients received 800 mg ibuprofen three times daily, 20 mg piroxicam daily, or 200 mg sulindac twice daily for 1 month. Three-hour inulin and two-day creatinine clearances were measured before and after the first and last doses of NSAIDs. Ibuprofen, piroxicam, and sulindac decreased inulin clearance after single-doses in both groups of patients. In patients with renal insufficiency, creatinine clearance did not change after administration of ibuprofen for 1 month (0 +/- 0.06 mL/s, mean +/- standard error), but was decreased similarly with administration of either piroxicam or sulindac (-0.12 +/- 0.06 mL/s [-7.2 +/- 3.6 mL/min], P < 0.02). One patient with preserved GFR, but with other risk factors for NSAID-associated renal impairment, met our criteria for withdrawal by experiencing at least a 40 mumol/L (0.5 mg/dL) increase in serum creatinine above their baseline value. Our data indicate that NSAIDs do not adversely affect GFR in patients with preserved renal function unless they have another risk factor for NSAID-associated renal impairment. In contrast, patients with renal insufficiency may have significant chronic decrements in GFR with long-acting NSAIDs such as piroxicam and sulindac, but not with short-acting ibuprofen. Such patients should have renal function monitored while being treated with long-acting NSAIDs.

Role of nitric oxide (EDRF) in radiocontrast acute renal failure in rats.

This study was undertaken to examine the possible role of endothelium-derived relaxing factor (EDRF), identified as nitric oxide (NO), in the pathogenesis of radiocontrast-induced acute renal failure in rats. Normal and salt-depleted rats were monitored for 60 min or 24 h after radiocontrast administration. The administration of L-arginine to normal rats abolished the immediate decrease in p-aminohippurate clearance (CPAH) and attenuated the decrease in inulin clearance (CIn). The administration of NO synthase inhibitor to the salt-depleted animals resulted in a significantly more pronounced decrease in CPAH compared with both the control and the L-arginine-treated animals. The recovery of CIn 24 h after radiocontrast administration to the salt-depleted rats was significantly better in the L-arginine-treated rats than in either the control or inhibitor-treated groups. The administration of radiocontrast material resulted in a significant decrease in urinary guanosine 3',5'-cyclic monophosphate as well as NO2 + NO3 excretion. This decrease was significantly attenuated by L-arginine. Our results 1) suggest that NO plays a major role in the pathogenesis of radiocontrast-induced acute renal failure and 2) suggest a novel therapeutic approach, i.e., the use of L-arginine in this form of acute renal failure.

Renal effects of captopril and nitrendipine in transgenic rats with an extra renin gene.

We investigated the acute effects of captopril and nitrendipine on renal function and sodium excretion in hypertensive, male, heterozygous transgenic rats harboring a mouse renin gene [TGR (mRen-2)27]. Both drugs reduced blood pressure dose dependently in conscious transgenic rats. The oral ED20 for captopril was 0.5 mg/kg and 2.7 mg/kg for nitrendipine. In orally salt-loaded (20 mL/kg saline) transgenic rats captopril (0.3 to 3.0 mg/kg) reduced sodium excretion by approximately 90% in the 6 hours after administration, whereas equally antihypertensive doses of nitrendipine increased sodium excretion by approximately 100%. The antinatriuretic effect of captopril was accompanied by a reduction in creatinine clearance and a decrease in the excretion of cyclic GMP. In orally water-loaded (20 mL/kg water) transgenic rats captopril also reduced sodium excretion by more than 90%, and nitrendipine slightly increased sodium excretion. In control Sprague-Dawley rats the effects were opposite; namely, captopril tended to increase natriuresis, and nitrendipine caused a small but distinct decrease in sodium excretion. Intravenous captopril in anesthetized transgenic rats caused an antinatriuresis with a decrease in inulin clearance but not in Sprague-Dawley rats. To control for non-renin-related effects of captopril, we gave transgenic rats oral losartan. Losartan also decreased urinary sodium excretion. The results suggest a role for the renin-angiotensin system in the maintenance of glomerular filtration rate and sodium excretion in transgenic TGR (mRen-2)27 rats.

Long‐term cyclosporin A nephrotoxicity in the rat

Cyclosporin A (CyA) nephrotoxicity was examined in Spraque-Dawley rats given CyA (12.5 (n = 45) or 25 (n = 45) mg/kg/day perorally for 16 weeks. Control rats (n = 45) received CyA vehicle. All rats were given either isradipine (ISRA) 1 or 5 mg/kg/day orally, or isradipine vehicle. Fifteen rats died from interstitial pneumonia caused by Staphylococcus xylosus. A predefined morphological CyA nephrotoxicity scoring system, based on semiquantitative scores for basophilic tubules and for interstitial fibrosis, performed on hematoxylin-eosin-stained tissue, yielded mean scores for basophilic tubules of 0.2 (range 0-1) in controls, 1.4 (range 0-3) in rats given CyA 12.5 mg/kg/day (p < 0.001), and 1.7 (range 0-3) in CyA 25 mg/kg/day rats (p < 0.001 as compared to controls). Rats given CyA were grouped according to their score for interstitial fibrosis: 0.2 (range 0-1) in CyA 12.5 mg/kg/day and 1.7 (range 0-3) in CyA 25 mg/kg/day rats (p < 0.001). When scores for basophilic tubules and interstitial fibrosis were pooled, none of the control rats had a score above 1, while 47% of the low-dose and 95% of the high-dose rats scored above 1. Thus, this CyA nephrotoxicity scoring system provided an easy, efficacious, and reproducible identification of rats with morphological CyA nephrotoxicity, and may be of clinical interest in the assessment of CyA nephrotoxicity. Kidney tissue from rats not treated with isradipine was further investigated with periodic acid-Schiff (PAS) with and without diastase treatment, and with Sirius Red. The latter confirmed the increase in connective tissue following tubular atrophy in CyA-treated rats. PAS reaction disclosed diastase-resistant positivity in the glomerular arterioles (score in controls: mean 0.4, range 0-1, in CyA 12.5 mg/kg/day mean 2.2, range 1-3, p < 0.001 as compared to controls; in CyA 25 mg/kg/day mean 1.1, range 0-2, p < 0.005 as compared to controls, p < 0.05 as compared to CyA 12.5 mg/kg/day). Furthermore, the straight part of the distal tubules of rats given the highest CyA dose contained considerable amounts of glycogen. The significance of this finding is unknown. Renal functional studies confirmed previous results since CyA decreased inulin clearance (Cin) from 1.2 +/- 0.5 to 0.8 +/- 0.3 ml/min/g kidney weight (kW) (p < 0.05), and lithium clearance (CLi) was reduced from 263 +/- 113 to 119 +/- 61 microliters/min/gKW (p < 0.001). Isradipine had no significant effect.

23Na‐NMR detects hypoxic injury in intact kidney: Increases in sodium inhibited by DMSO and DMTU

Hypoxic injury in the isolated perfused rat kidney (IPRK) was monitored using 23Na-NMR in the presence or absence of 1.5 and 15 mM dimethylthiourea (DMTU) or 15 mM dimethylsulphoxide (DMSO) before and after inducing hypoxia. Hypoxia induced a prompt exponential increase in total renal 23Na+, renal vascular resistance, and sodium excretion and decreased inulin clearance and adenine nucleotides and reduced glutathione concentrations. Lipid peroxide metabolites were unaltered. The increase in 23Na+ was significantly reduced (P < 0.001) by both DMTU and DMSO although hypoxic perturbations of function and biochemical parameters were not. Posthypoxic increases in renal 23Na+ include approximately 10% from the intratubular compartment, but principally reflect the intracellular and interstitial compartments. The results demonstrate that 23Na-NMR is a sensitive indicator of hypoxic renal injury in intact kidney and suggest that DMTU and DMSO protect against hypoxic injury by a mechanism independent of free radical-binding.

Percutaneous Reduction of Cyst Volume of Polycystic Kidney Disease: Effects on Renal Function

Percutaneous reduction of cyst volume was performed in 10 patients with autosomal dominant polycystic kidney disease and its effects on renal function were studied. Although creatinine clearance, urinary excretion of β2-microglobulin and N-acetyl-β-D-ghicosaminidase, and renal uptake of 99mtechnetium-dimercaptosuccinic acid did not change significantly, a transient increase in urinary protein and a decrease in inulin clearance were observed. Complications, such as hematuria, fever and decreases in hematocrit, were slight and transient in most patients. This procedure holds little promise for altering the course of polycystic kidney disease.

Acute Effects of Ciclosporin on Renal Hemodynamics and Urinary Protein Excretion in Patients with the Nephrotic Syndrome

The possibility that the renal hemodynamic abnormalities associated with ciclosporin (CS) administration are enhanced in nephrotic patients (NP), leading to severe impairment of renal function and/or to modifications in proteinuria, has not hitherto been tested. Ten NP and 8 healthy subjects (NC) were examined before and after oral CS administration (10 mg/kg body weight in NP and 12 mg/kg body weight in NC: a lower dosage was adopted in NP because of edema overestimating the actual body weight) under water diuresis by standard renal clearance methods. Basal blood volume was lower in NP. Blood CS levels were not significantly different in the two groups. Basal glomerular filtration rate (GFR) was similar in NP and NC, while renal plasma flow (RPF) was lower in NP. After CS, both GFR and RPF significantly decreased in the two groups, but the percent decrease in inulin clearance was greater in NP. Filtration fraction increased only in NC. Basal renal vascular resistances were greater in NP, and significantly increased after CS in both groups. Basal fractional sodium excretion (FENa) was lower in NP: after CS FENa decreased only in NC. Neither plasma renin activity, nor plasma aldosterone changed after CS. When urinary protein excretion (UP) was corrected by GFR, no change was observed after CS; by contrast, selectivity of proteinuria (as assessed by the CIgG/CTransferrin ratio) markedly increased. Our data indicate that CS induces a greater fall in the GFR in hypovolemic NP than in healthy subjects, probably because in the former GFR becomes extremely plasma flow dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-DNA antibodies bind directly to renal antigens and induce kidney dysfunction in the isolated perfused rat kidney.

The pathogenesis of SLE is commonly attributed to the deposition of circulating immune complexes consisting of DNA and anti-DNA autoantibodies. However, recent work has shown multiple cross-reactions between anti-DNA antibodies and a variety of cellular and extracellular Ag. To test the possibility that these antibodies interact directly with glomerular Ag and induce kidney dysfunction, we applied mouse and human anti-DNA IgG to the isolated perfused rat kidney. The NZB/NZW mouse monoclonal anti-DNA bound to glomerular Ag with a concomitant induction of proteinuria and a decrease in inulin clearance. The albumin excretion was 2301 +/- 734 micrograms/min at 160 min of perfusion, as compared with 85 +/- 21 micrograms/min in controls (p less than 0.001). The inulin clearance was reduced to 0.17 +/- 0.02 ml/min as compared with 0.28 +/- 0.09 ml/min in controls (p less than 0.05). Polyclonal anti-DNA IgG obtained from patients with lupus nephritis bound to rat glomeruli and induced albumin excretion of 542 +/- 217 micrograms/min at 160 min of perfusion, as compared with 163 +/- 77 micrograms/min in controls (p = NS). The addition of plasma as a source of C to the human IgG increased the proteinuria markedly (albumin excretion of 1115 +/- 195 micrograms/min at 160 min of perfusion, p less than 0.02), probably due to C activation. Preincubation of the reactive mouse and human IgG with DNA completely abolished their binding to renal tissue and its physiologic consequences. These results suggest that direct binding of anti-DNA antibodies to renal Ag may play an important role in the induction of lupus nephritis.

Direct nephrotoxicity of Russell's viper venom demonstrated in the isolated perfused rat kidney.

Envenoming by Russell's Viper (Vipera russelli) is an important cause of acute renal failure. The mechanism of renal damage is unresolved. It is difficult to obtain evidence of a direct nephrotoxic action because of the coincidental disturbance to the systemic circulation. We studied the action of Russell's Viper venom on the function of the isolated perfused rat kidney. Direct nephrotoxic action was indicated by a dose dependent decrease in inulin clearance and an increase in fractional excretion of sodium seen at venom concentrations down to 50 ng/ml, a concentration likely to be achieved in the human circulation after envenoming. The isolated perfused kidney was also used to assess the efficiency of antivenom and for a comparison with snake venoms from the Thai cobra (Naja kauothia) and the Nigerian Saw-Scaled Viper (Echis ocellatus).

Effect of Potassium Depletion on Ischemic Renal Failure

The present study was carried out to examine the effect of potassium depletion in rat kidneys subjected to a temporary ischemic event produced by clamping of left renal artery. The postischemic kidneys of rats on a normal diet with adequate potassium intake showed an increase in H2O, Na and K excretion, with no change in inulin clearance whereas significant differences were found in potassium-deprived rats. Potassium depletion was brought about by dietary K deprivation for 10 days. K-depleted rats (serum K = 2.5 +/- 0.1 mEq/l) had a decrease in inulin clearance of the postischemic kidney from 1.01 +/- 0.10 to 0.43 +/- 0.05 ml/min (p less than 0.01), and a greater increase in fractional excretion of H2O, Na and K when compared to normal rats. The postischemic kidney from both normal and hypokalemic rats showed a decrease in Na-K-ATPase of the inner stripe of the outer medulla. These data indicate that short-term ischemia produces polyuria, increases natriuresis and kaliuresis, associated, at least in part, with a decrease in Na-K-ATPase in the inner stripe of the outer medulla (probably the thick ascending limb of Henle) and that K depletion potentiates ischemic renal failure.

Dose‐response effects of pressor doses of arginine vasopressin on renal haemodynamics in the rat.

1. Dose-response effects of arginine vasopressin on renal haemodynamics were studied in conscious and in pentobarbitone-anaesthetized rats infused with 77 mM-NaCl at 5.2 and 2.6 ml h-1 respectively. 2. Vasopressin at 0.8 pmol h-1 (100 g body weight)-1 did not have a significant effect on arterial blood pressure in conscious or anaesthetized rats. Increasing the dose to 2.5 pmol h-1 (100 g body weight)-1 induced a pressor effect in conscious rats but not in anaesthetized rats. A pressor response was observed in the latter at a dose of 10 pmol h-1 (100 g body weight)-1. 3. Pressor doses of vasopressin of 100 pmol h-1 (100 g body weight)-1 and less did not significantly alter the clearance of p-aminohippurate (PAH) in either conscious or anaesthetized rats. A dose of 1000 pmol h-1 (100 g body weight)-1 significantly decreased PAH clearance in both conscious and anaesthetized animals. 4. Inulin clearance was unchanged by non-pressor doses of vasopressin in both conscious and anaesthetized rats. Moderately pressor doses decreased inulin clearance in conscious animals only. The highest dose administered (1000 pmol h-1 (100 g body weight)-1) decreased inulin clearance in both conscious and anaesthetized rats. 5. Pressor doses of vasopressin had a biphasic effect on the filtration fraction in conscious rats. The filtration fraction decreased with doses of vasopressin at the lower end of the pressor range but increased with the highest dose of 1000 pmol h-1 (100 g body weight)-1. In contrast the filtration fraction did not change significantly with moderate pressor doses in anaesthetized rats but was increased by doses of 100 and 1000 pmol h-1 (100 g body weight)-1. 6. It is concluded that pressor doses of vasopressin lower than 100 pmol h-1 (100 g body weight)-1 do not decrease renal plasma flow rate in conscious or pentobarbitone-anaesthetized rats. The results suggest that the inconsistent effects of vasopressin on renal blood flow reported in the literature are due, at least in part, to the wide range of doses used.

Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity.

In ischemic acute renal failure oxygen free radicals may mediate injury. In addition, iron appears to play a critical role in hydroxyl radical formation and lipid peroxidation during reperfusion of ischemic kidneys. To determine whether iron may play a similar role in pigment (heme protein)-induced acute renal failure, we studied the effects of the iron chelator deferoxamine in two experimental models of pigment-induced acute renal failure, intramuscular glycerol injection and intravenous hemoglobin infusion without and with concurrent ischemia in the rat. Intramuscular injection of 50% glycerol (5 ml/kg) caused inulin clearance to fall to 0.13 +/- 0.03 (SE) ml/min (normal value, 1.0-1.2 ml/min). Continuous infusion of deferoxamine beginning at the time of glycerol injection significantly attenuated this renal dysfunction. Deferoxamine-treated animals had an inulin clearance of 0.37 +/- 0.06 ml/min (P less than 0.01). Glycerol injection was also associated with significant lipid peroxidation, measured as renal malondialdehyde content. Deferoxamine-treated glycerol-injected rats had renal malondialdehyde content not significantly different from control animals. In another model of heme pigment-induced renal injury, hemoglobin was infused to produce hemoglobinuria. Inulin clearance 1 h after hemoglobin infusion was significantly reduced to 0.84 +/- 0.5 ml/min (P less than 0.025). Infusion of deferoxamine after hemoglobin prevented the hemoglobin-induced decrease in inulin clearance. Thirty minutes of renal ischemia followed by infusion of hemoglobin resulted in more severe renal dysfunction with inulin clearance of 0.54 +/- 0.08 ml/min. Deferoxamine infused at the time of reperfusion attenuated the fall in glomerular filtration rate after ischemia and hemoglobin infusion:inulin clearance 1.04 +/- 0.07 (P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

A renorenal suppression in response to atrial natriuretic peptide in the unilateral ischaemic rat.

1. The present study was carried out to investigate the haemodynamic and natriuretic effects of atrial natriuretic peptide (ANP) in normal rats and in rats with unilateral ischaemia. 2. Twenty-four hour unilateral ureter occlusion gave rise to a marked vasoconstriction in the ipsilateral kidney after its release. Intravenous infusion of ANP doubled p-aminohippurate clearance and inulin clearance and elicited massive natriuresis in the hydronephrotic kidney, while in the contralateral kidney these clearance values were decreased and there was a lack of natriuresis. The responses in the latter kidney were also different from those in the normal rat, in which significant natriuresis was elicited by ANP even though a decrease in p-aminohippurate clearance occurred. 3. After the control kidney in the unilateral hydronephrotic rat was denervated either mechanically or by pretreatment with prazosin, ANP induced a natriuresis in both kidneys. Furthermore, the renal denervation prevented the decrease in inulin clearance in the control kidney after ANP administration. 4. These findings suggest that the renal response to ANP may depend on the vascular tone before administration, and that renal nerve activity may modify the effects of ANP on renal haemodynamics and sodium excretion.