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Ischemia results in the marked reduction of renal proximal tubule function which is manifested by decreased Na+ and H2O reabsorption. In the present studies the possibility that altered Na+ and H2O reabsorption were due to ischemia-induced loss of surface membrane polarity was investigated. Following 15 min of renal ischemia and 2 hr of reperfusion, proximal tubule cellular ultrastructure was normal. However, abnormal redistribution of NaK-ATPase to the apical membrane domain was observed and large alterations in apical membrane lipid composition consistent with loss of surface membrane polarity were noted. These changes were associated with large decreases in Na+ (37.4 vs. 23.0%, P less than 0.01) and H2O (48.6 vs. 36.9%, P less than 0.01) reabsorption at a time when cellular morphology, apical Na+ permeability, Na+-coupled cotransport, intracellular pH and single nephron filtration rates were normal. We propose that the abnormal redistribution of NaK-ATPase to the apical membrane domain is in part responsible for reduced Na+ and H2O reabsorption following ischemic injury. [ABSTRACT FROM AUTHOR]

The present studies measured vessel diameter, before and after addition of hemolysate, in isolated afferent arterioles (AA) and efferent arterioles (EA) obtained from the rat kidney. Human red blood cells (RBC) were hemolyzed in distilled water and membranes were discarded after centrifugation. Hemolysate added to the bath solution caused vigorous AA and EA contraction and, after washout, hypersensitized the AA and EA to doses of angiotensin II (AII) which would normally only elicit 50% contraction (EC50). Neither the contraction nor the hypersensitization were mimicked by pure human hemoglobin. The vasoconstrictive responses in the AA and EA were accompanied by increased cytosolic-free calcium concentration. Further purification (desalting) of the hemolysate to remove substance of < or = 1000 Da (which include ATP) did not eliminate the vasoconstrictive component from the hemolysate. Finally, cultured rat aortic vascular smooth muscle cells also demonstrated a rapid increase in (Ca2+i) when exposed to hemolysate. This increase in (Ca2+i) was, in part, dependent on Ca2+ influx since it could be attenuated with diltiazem (10(-5) M). In conclusion, hemolysate contains a factor which induces contractions of the isolated rat kidney AA and EA and rapid elevations in (Ca2+i). This factor, from hemolyzed RBC, is not hemoglobin itself.

Background: Atrial natriuretic peptide, a hormone synthesized by the cardiac atria, increases the glomerular filtration rate by dilating afferent arterioles while constricting efferent arterioles. It has been shown to improve glomerular filtration, urinary output, and renal histopathology in laboratory animals with acute renal dysfunction. Anaritide is a 25-amino-acid synthetic form of atrial natriuretic peptide., Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial of anaritide in 504 critically ill patients with acute tubular necrosis. The patients received a 24-hour intravenous infusion of either anaritide (0.2 microgram per kilogram of body weight per minute) or placebo. The primary end point was dialysis-free survival for 21 days after treatment. Other end points included the need for dialysis, changes in the serum creatinine concentration, and mortality., Results: The rate of dialysis-free survival was 47 percent in the placebo group and 43 percent in the anaritide group (P = 0.35). In the prospectively defined subgroup of 120 patients with oliguria (urinary output, < 400 ml per day), dialysis-free survival was 8 percent in the placebo group (5 of 60 patients) and 27 percent in the anaritide group (16 of 60 patients, P = 0.008). Anaritide-treated patients with oliguria who no longer had oliguria after treatment benefited the most. Conversely, among the 378 patients without oliguria, dialysis-free survival was 59 percent in the placebo group (116 of 195 patients) and 48 percent in the anaritide group (88 of 183 patients, P = 0.03)., Conclusions: The administration of anaritide did not improve the overall rate of dialysis-free survival in critically ill patients with acute tubular necrosis. However, anaritide may improve dialysis-free survival in patients with oliguria and may worsen it in patients without oliguria who have acute tubular necrosis.

A variety of therapeutic approaches have been used both to prevent acute ischemic and nephrotoxic renal injury and to improve renal function and reduce mortality once acute renal failure (ARF) has developed. Unfortunately, there have been few rigorous assessments of the efficacy of these treatment interventions. The reasons for the lack of abundant critical data regarding treatment effects in ARF are several. First, ARF is a functional disorder. It has a spectrum of etiologies, occurs in a variety of clinical settings and varies in severity. Second, selected endpoints of treatment success vary and co-morbid factors frequently determine outcome. Third, it had been difficult to carry out prospective controlled studies in a disorder in which the mortality rate approaches 50%. In this review, an effort was made to analyze the available literature with a primary focus on controlled studies to determine significant prophylactic and treatment effects of various interventions in ARF. Three endpoints of therapy (change in renal function, change in course of azotemia, and change in mortality) were examined for pharmacologic agents. Changes in course of azotemia and mortality were assessed in evaluating different dialysis modes. Effect on nitrogen balance, change in course of azotemia, and change in mortality were used as endpoints to determine treatment effects of different nutritional regimens. When weight was given to prospective controlled studies, some insights emerged as to treatment interventions that are most likely to have beneficial effects in specific settings of ARF. Among pharmacologic agents, mannitol appears to have a positive prophylactic effect in kidney transplantation. There are no other significant beneficial effects of diuretics for prophylaxis or as treatment in early or established ARF. Of vasoactive agents, there is a relatively small amount of data suggesting that diltiazem may have a positive prophylactic effect in kidney transplantation, and dopamine possibly is beneficial early in the evolutionary phase of ARF. Atrial natriuretic peptide and calcium channel blockers may have beneficial effects in established disease. No other pharmacologic interventions are supported by substantial data. At best, the results are equivocal regarding the use of early and vigorous dialysis in ARF. However, there are recent impressive data indicating that the use of biocompatible membranes is efficacious in recovery and survival. There is no clear evidence that one form of nutritional therapy has advantages over others, but some level of amino acid supplementation in addition to basic energy replacement is supported by the overall data.

Ischemia-reperfusion injury as a general rule is accompanied by dramatic changes in basal and reactive vascular function in most organs. There are similarities in altered organ vascular function, particularly in the first 24 to 48 hours, with decreased basal organ blood flow, hypersensitivity to vasoconstrictor stimuli, attenuated responses to vasodilators, and increased vascular permeability. The reduced responsiveness to endothelium-dependent vasodilators may be due to reduced endothelial NOS activity or to spontaneous maximal activation of NOS/NO activity, which cannot be stimulated further by endothelium-dependent agents. There are also notable quantitative and qualitative differences in ischemia-reperfusion injury vasoreactive response in organs such as kidney, heart, and brain, the basis of which is unexplored, but may reflect regional differences in endothelium and/or organ parenchyma. Further examination of both the mechanisms and consequences of ischemia-reperfusion injury to the vasculature, as well as the clinical implications, should be a rewarding pursuit in organ pathophysiology.

A patient with oliguric acute renal failure (ARF) following mitral valve surgery is presented. The patient was treated with parenteral nutrition and hemodialysis. While the patient survived, there were several complications of nutrition therapy. In this review, the benefits, risks, and uncertainties regarding parenteral nutrition in ARF are considered. First, the differences in metabolism in complicated and uncomplicated acute uremia are discussed. The important roles of alterations in intermediary metabolism and of proteases in the catabolism of ARF are emphasized. The historical basis of parenteral nutrition treatment in ARF is reviewed. The results are divided regarding the relationship among nutritional support, improvement in renal function, and enhanced patient survival. A critical analysis of nitrogen metabolism results reported in the literature does not convincingly support the effectiveness of parenteral nutrition formulae in generating positive nitrogen balance. The complications of parenteral nutrition therapy are outlined. In light of the uncertain efficacy and recognized risks of prolonged parenteral nutrition, a rationale for approaching therapy is presented that is based on the estimated metabolic stress and protein-energy requirements of the individual ARF patient.

Evidence suggests that acute and chronic cyclosporine (CsA) nephropathy may be related to its renal vasoconstrictor effects. While the mechanism of CsA-induced renal vasoconstriction is uncertain, several studies indicate that endogenous constrictor agonists including endothelins (ET), platelet activating factor (PAF), and thromboxane A2 (TXA2) play a mediating role. In this study, two possible mechanisms explaining the participation of multiple constrictor agonists in CsA vasoconstriction were investigated: sequential activation of agonists initiated by CsA and site-specific mediation of CsA constriction by different agonists. The acute constrictor effects of CsA were examined in isolated rat renal afferent (AA) and efferent arterioles (EA) without and with specific receptor antagonists of ETA (BQ123, 10(-7) M), PAF (L-659,989, 10(-7) M), and TXA2/PGH2 (SQ29,548, 10(-7) M) in the bathing media. Both BQ123 and L-659,989 completely inhibited CsA, constriction in AA, but had no significant inhibiting effect in EA. Constriction to ET-1 was also blocked by the PAF antagonist L-659,989 in AA, but not EA. There was no effect of SQ29,548 on CsA constriction in AA--however, there was partial attenuation of CsA constriction in EA. Based on these results in isolated rat renal arterioles, it is suggested that CsA-induced constriction in AA is likely mediated by sequential activation of ET and PAF. However, CsA constriction of EA involves a different mechanism or mediator that, in part, may involve TXA2/PGH2 stimulation.

Through the release of a variety of relaxing and contracting factors, including nitric oxide and endothelin-1, the endothelium exerts a complex paracrine influence on vascular smooth muscle cells. Dysfunction of these mechanisms for regulating tone may have relevance to various clinical entities, including hypertension, atherosclerosis, renal failure, and diabetes.

Renal blood flow (RBF) autoregulation has been found to be impaired in both norepinephrine (NE) and renal artery clamp (RAC) rat ischemic acute renal failure models. However, the decline in RBF at the normal lower limit of autoregulation is greater in NE-ARF. The present study was designed to determine if this difference in autoregulatory profiles has potential functional and morphologic significance. After demonstrating a fall in RBF to renal perfusion pressure reduction to 90 mm Hg that was twofold more in one week NE- than RAC-ARF (p < 0.001), separate rats of both ischemic ARF types with nearly identical levels of azotemia and glomerular filtration rate reduction and sham-ARF rats were subjected to four-hour controlled reduction in mean arterial pressure to 90 by transient phlebotomy at one week. On day 9, two days after mean arterial pressure reduction, blood urea nitrogen (BUN), serum creatinine (SCr) and creatinine clearance (CCr) showed continued improvement in RAC-ARF, but there were significant increases in BUN (46 +/- 22 to 72 +/- 10 mg/dl) and SCr (1.2 +/- 0.2 to 1.5 +/- 0.2 mg/dl) and a decline in CCr (0.434 +/- 0.127 to 0.334 +/- 0.079 ml/min) in the NE-ARF group (all P < 0.02). The mean sum of scores of morphologic indices of ARF was higher in NE- than RAC-ARF kidneys of rats sacrificed on day 9 but interstitial edema was the only individual index that was worse in NE-ARF.(ABSTRACT TRUNCATED AT 250 WORDS)

Distinguishing between oliguric and nonoliguric acute renal failure (ARF) has clinical relevance. However, there is a paucity of data regarding the pathophysiologic basis for variations in urine flow rates in ARF. This study was designed to determine whether differences in residual levels of glomerular filtration rate (GFR) or differences in tubular reabsorption of filtered solutes and H2O accounted for the variations in urine flow rates among ARF patients. Twenty-five patients with ARF of 3 to 6 days duration having ischemic and nephrotoxic etiologies, increasing serum creatinines of more than 0.7 mg/dL/d, urine sodium concentrations and fractional excretions of sodium (FENa) of more than 20 mEq/L and more than 1%, respectively, 12 hours after stopping diuretics and urine sediments consistent with acute tubular necrosis were studied. Urine and serum collections were made over an 8-hour period to determine creatinine clearance (Ccr), filtered osmolar load, urine to serum creatinine ratio (U/Scr), urine to serum creatinine osmolality (U/Sosm), and FENa. These were compared with urine flow rates. Creatinine clearance was validated as an estimate of GFR in ARF with simultaneous inulin clearances x 12 measurements (r = 0.935, P < 0.001). Residual Ccr was strongly correlated with urine flow rate (r = 0.857, P < 0.001), as was filtered osmolar load (r = 0.810, P < 0.001). However, the latter relationship was totally dependent on Ccr. There was no correlation between U/Scr, U/Sosm, or FENa and urine flow rates. It is concluded that the residual level of GFR is the primary determinant of variations in urine flow rate in patients with ARF.

Fifty-three consenting patients meeting clinical and urine composition criteria for established intrinsic ARF were assigned to two treatment groups. Group I patients were treated with human atrial natriuretic peptide (ANP) with or without diuretics. Groups II patients were treated with or without diuretics and with no ANP. Age, sex, etiology of ARF, entry serum creatinines (SCr) (Group I, 5.3 +/- 1.8; Group II, 5.1 +/- 2.1 mg/dl) and creatinine clearances (CCr) (Group I, 9.9 +/- 2.1; Group II, 9.2 +/- 2.1 ml/min) were similar. Thirty patients received ANP [0.20 micrograms/kg/min i.v. x 24 hr (N = 20) or 0.08 micrograms/kg/min i.a. x 8 hr (N = 10)] and furosemide, 0.5 mg/kg/hr x 24 hr or mannitol, 12.5 g every six hours x 4, or no diuretic; 23 Group II patients received diuretics as above or no diuretic in a similar distribution to Group I. CCr (verified with simultaneous inulin clearances x 12, r = 0.93, P < 0.001) increased significantly by eight hours of ANP treatment to 17.1 +/- 3.2 ml/min and by 24 hours after discontinuing ANP to 21.0 +/- 4.4 ml/min (both P < 0.05). There was no corresponding increase in CCr in Group II. Dialysis was required in 23% of Group I and in 52% of Group II patients (different at P < 0.05). Mortality rates of 17% for Group I and 35% for Group II were not significantly different (P = 0.11). It is concluded that parenteral ANP increases CCr and reduces need for dialysis in patients with established intrinsic ARF.

Naturally occurring serum antibodies specific for the A and B blood group isoantigens are of great importance in medicine. By using A-type terminal trisaccharide (ATS) or B-type terminal trisaccharide (BTS) coupled to albumin as coating antigens, an enzyme-linked immunosorbent assay capable of detecting all ATS/BTS-binding antibodies was performed. The combination of this enzyme-linked immunosorbent assay with limiting-dilution methodology, using a polyclonal B-lymphocyte activator, permitted a monoclonal analysis of the human antibody repertoire that is specific for ATS and BTS in persons of different blood types. Most (78%) positive supernatants from type O cultures were monospecific for either ATS or BTS, and these were present at roughly equivalent frequencies. Nine supernatants with reactivity toward both ATS and BTS were tested by red cell adsorption; six had properties expected for true dually reactive monoclonal antibodies: adsorption with either A1 or B red cells eliminated both anti-ATS and anti-BTS activity. This finding accords with a monoclonal origin for anti-A,B. The analysis of cultures of peripheral blood lymphocytes from type A and B donors unexpectedly showed significant numbers of clones with apparent autospecificity. However, none of the anti-ATS-positive supernatants from type A cultures or anti-BTS-positive supernatants from type B cultures were adsorbable with A1 or B red cells, respectively. Consideration of only true (adsorbable) positives indicates that the type A and B anti-trisaccharide repertoires differ significantly from the type O repertoire, probably as a result of the action of normal self-tolerance mechanisms.

A high proportion of the antibodies in the preimmune repertoire bind to several unrelated antigens and are considered to be multireactive. This property is reportedly associated with the antibodies produced by CD5+ B lymphocytes. Because many antibodies specific for bromelain-treated mouse red blood cells (BrMRBC) derive from CD5+ B cells, we tested monoclonal antibodies of this specificity for multireactivity. Two variable region combinations, VH11/V kappa 9 and VH12/V kappa 4, account for greater than 80% of this repertoire, but none of these antibodies exhibited a multireactive phenotype. In contrast, three anti-BrMRBC binding antibodies belonging to the J558 family (BrM1, BrM8, and CH12) showed varying degrees of multireactivity, and bound both highly negatively and positively charged antigens. The amino acid sequences of the VH regions of these antibodies are highly homologous (greater than 85% identical) and they possess large VH-D-J junctions with extensive N-region insertions. The kappa chains of two of these antibodies utilize an identical V kappa gene segment, while the third uses a very different V kappa with only 50% homology. The entire H chain V regions of these antibodies are unusually basic, with isoelectric points of 9.5-10, a feature which might be important in promoting interactions with acidic epitopes. The multireactive antibodies also contain regions with a high concentration of hydroxylside chain amino acids, especially in their VH-D-J junctions. This region also contains acidic amino acid residues, which may be important in binding of positively charged epitopes. We propose that an open, accessible binding site and a charge polarity may be features which facilitate the binding of charged epitopes, providing a structural basis for multireactivity of at least some antibodies.

Functionally similar ischemic acute renal failure (ARF), as estimated by glomerular filtration rates (GFR), was induced by renal artery clamping (RAC) or intrarenal norepinephrine (NE) in rats and renovascular reactivity was examined at 1 week. With RAC-ARF induction there was total renal ischemia followed by abrupt return of renal blood flow (RBF). With NE-ARF induction there was subtotal ischemia (10-15% of basal RBF) with RBF recovery over several hours. Renovascular resistance (RVR) did not change to renal perfusion pressure (RPP) reduction in the autoregulatory range in RAC-ARF but paradoxically increased in NE-ARF. There was an exaggerated response to renal nerve stimulation in NE-ARF but no response in RAC-ARF. There was a vasoconstrictor response to intrarenal norepinephrine in the former but a negligible response in the latter. There was no vasodilation to acetylcholine in either group, but there was a normal response to prostacyclin in NE-ARF. Smooth muscle necrosis was found in 46% of resistance arterial vessels in RAC- but in only 8% of NE-ARF (p less than .001). When mean arterial pressure was reduced to 90 mm Hg for 4 h at 1 week, recurrent azotemia and fresh ischemic injury were noted in NE- but not RAC-ARF. It is concluded that different models of ischemic ARF induction result in different patterns of abnormal postischemic vascular reactivity. Differences in vascular smooth muscle and endothelial injury are due to differences in initial ischemia or rates of postischemic reperfusion.

Recent studies have shown that atrial natriuretic peptide (ANP) alone or combined with dopamine (D) markedly improved renal function when given immediately after an ischemic insult. However, the potential beneficial effect of ANP or ANP-D in the established phase of acute renal failure (ARF) and the duration of this effect have not been examined. In the present study atriopeptin III (APIII) and D, sufficient to maintain mean arterial pressure between 100 and 110 mm Hg, or normal saline were given i.v. for four hours to awake Munich-Wistar rats (N = 6 each group) two days after ARF induction with intrarenal norepinephrine (NE). Renal function and morphology were then examined two days after treatment (Day 4). Serum creatinine (SCr) was similarly increased in both groups at the time of APIII-D or saline infusion (Day 2). By Day 4 SCr had decreased to the pre-ARF induction level in APIII-D-treated rats (P less than 0.005), but continued to rise in saline-treated animals (P less than 0.025). Day 4 renal blood flow and glomerular filtration rate (GFR) were higher in APIII-D-compared to the saline-treated group (9.13 +/- 1.14 vs. 4.41 +/- 2.25 ml/min and 0.787 +/- 0.066 vs. 0.370 +/- 0.185 ml/min, respectively, both P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the mechanism of observed differences in vasoreactivity in norepinephrine-induced (NE) and renal artery clamp (RAC) models of ischemic acute renal failure (ARF), induction renal blood flow (RBF) was measured and vascular reactivity examined one week thereafter in NE- and RAC-ARF rat kidneys that had identical levels of renal dysfunction. Morphology also was compared at 48 hours and one week. In NE-ARF, RBF was 14% during 90 minutes of induction and by 60 minutes post-NE infusion was only 18% of baseline. In contrast, in RAC-ARF RBF was effectively 0 for 75 minutes but returned to 95% of baseline by 60 minutes after clamp release. At one week there was a paradoxical increase in renovascular resistance (RVR) to renal perfusion pressure (RPP) reduction in the autoregulatory range and an augmented vasoconstriction to renal nerve stimulation (RNS) in NE-ARF, but no change in RVR and minimal reduction in RBF to these same respective stimuli in RAC-ARF (both different at P less than 0.001). NE-ARF were more sensitive to intrarenal norepinephrine than RAC-ARF kidneys (P less than 0.001). Neither NE- nor RAC-ARF kidneys responded to endothelium-dependent acetylcholine (ACh). Vasodilation to endothelium-independent prostacyclin (PGI2) in NE- was similar to sham-ARF, but there was an attenuated response in RAC-ARF kidneys (P less than 0.001). Morphology at 48 hours showed smooth muscle necrosis in half of the resistance vessels in RAC- but in less than 10% of those in NE-ARF. Except for a slightly greater frequency of tubular casts at 48 hours in RAC-ARF, tubular injury was indistinguishable. It is concluded that NE-ARF has evidence of a predominant functional endothelial vascular injury while RAC-ARF has both morphologic and functional evidence of a predominant smooth muscle injury. Differences in vascular injury between the two models, at least in part, may be the consequence of differences in severity of initial ischemia and/or the rates of recovery of RBF; however, an additional or separate toxic effect of infused NE cannot be excluded.

Serial measurements were performed in Munich-Wistar rats with five-sixths nephrectomy that had undergone prior selective thyroidectomy (Tx group) or thyroidectomy with thyroxine replacement (TxT4 group) to determine the effects of Tx on glomerular and tubular dynamics in relation to Tx attenuation of renal failure progression. At 1 week, inulin clearance rates (Cin) in TxT4 and Tx rats were 0.367 +/- 0.171 and 0.120 +/- 0.036 mL/min, respectively, different at P less than 0.01. Corresponding single-nephron filtration rate (SNGFR), glomerular plasma flow (QA), glomerular transcapillary hydraulic pressure (delta P), and proximal tubular reabsorption (Jv) were all reduced in Tx compared with TxT4 rats (P less than 0.01). Protein excretion (UPROT) was 151 +/- 40 in TxT4 rats, and 9 +/- 5 mg/d in Tx animals. Glomerular mesangial matrix expansion and focal tubulointerstitial changes were more frequent in TxT4 than Tx rats. By 4 weeks, Cin, SNGFR, QA, glomerular ultrafiltration coefficient (Kf) and Jv were similar in Tx and TxT4. Only glomerular capillary pressure (PGC) remained lower in Tx rats (35 +/- 3 v 50 +/- 3 mm Hg in TxT4, P less than 0.001). UPROT was 161 +/- 24 in TxT4 and 17 +/- 12 mg/d in Tx rats. While 7% +/- 4% of glomeruli showed focal sclerosis in TxT4 rats, there was none in the Tx group. Maximal glomerular planar area increased between 1 and 4 weeks in the TxT4 group, but not in the Tx group. However, this measurement was not significantly different between TxT4 and Tx glomeruli at 1 or 4 weeks. Minimal focal tubulointerstitial changes were found in TxT4, but there were not progressive from those observed at 1 week. The reduced PGC at 1 week was the result of a disproportionately greater increase in afferent (RA) than efferent arteriolar resistance (RE) in Tx rats (P less than 0.025); however, at 4 weeks, both RA and RE had decreased to values identical to those in TxT4 animals and the lower PGC in Tx rats was the result of a reduced mean arterial pressure. In conclusion, a reduced PGC was the sole functional correlate of decreased proteinuria and glomerulosclerosis afforded by Tx in this partial nephrectomy model. Suppression of either nephrectomy-related hypertrophy or tubulointerstitial injury by Tx could not be excluded as at least partially protective factors.

In order to ascertain the protective role of a potent calcium entry blocking agent in human acute renal failure, 10 patients were randomised to treatment with either intrarenal gallopamil plus intravenous furosemide (frusemide) 0.5 mg/kg/h for 24 hours, or furosemide alone. Gallopamil was infused into each kidney at the rate of 40 to 80 micrograms/min for 4 hours. During 7 days of post-treatment follow-up, the gallopamil treatment group exhibited a significantly higher urine output [257 ml/h vs 81 ml/h (p less than 0.001) after 2 days, and 199 ml/h vs 120 ml/h (p less than 0.005) after 7 days] and creatinine clearance [20 vs 4 ml/min (p less than 0.005) after 2 days, and 38 vs 14 ml/min (p less than 0.001) after 7 days] than the furosemide-only control group. Furthermore, gallopamil treatment accelerated the decline of serum creatinine after renal failure and reduced the requirement for dialysis. Although patient numbers were small, these results indicate that the addition of intrarenal gallopamil to intravenous furosemide treatment enhances the recovery of renal function after acute renal failure.

Uric acid, as the end-product of purine metabolism in humans, presents a clinical problem because of its relative insolubility, particularly in the acid environment of the distal nephron of the kidney. As a result, states of enhanced purine catabolism increase the urate load on the kidney, leading to intrarenal precipitation. Major causes of increased purine metabolism are malignancies with rapid cell turnover, such as leukemias and lymphomas, and the added acceleration of cell lysis that occurs with chemotherapy and radiation. Serum urate levels rise rapidly, and acute renal failure occurs as a consequence of tubular deposition of urate and uric acid. The keys to the diagnosis of acute uric acid nephropathy are the appropriate clinical setting of increased cell lysis, oliguria, marked hyperuricemia, and hyperuricosuria. A urinary uric acid-to-creatinine ratio greater than 1 helps to distinguish acute uric acid nephropathy from other catabolic forms of acute renal failure in which serum urate is elevated. Preventive treatment involves pharmacologic xanthine oxidase inhibition with allopurinol and alkaline diuresis. Occasionally, acute renal failure occurs despite allopurinol because of the tubular precipitation of the precursor metabolites, such as xanthine, which accumulate with xanthine oxidase inhibition. Dialysis therapy may be required both to correct azotemia and to reduce the body burden of urate. Hemodialysis is preferred because it can achieve greater clearance than other dialysis modes.

Selective thyroidectomy (Tx) has been shown to attenuate proteinuria and disease progression in models of chronic renal failure (CRF). In this investigation, four groups of Munich-Wistar rats were studied to determine if glomerular dynamics or another renal metabolic consequence of Tx was responsible for the protective effect as measured by 24-hour protein excretion (UPROT). The groups were TxT4, thyroxine-replaced Tx rats with five-sixths nephrectomy; Tx, Tx rats not receiving replacement thyroxine with five-sixths nephrectomy; TxI, Tx rats not receiving replacement thyroxine with five-sixths nephrectomy that were given continuous intraperitoneal isoproterenol to restore systemic and renal hemodynamics; and TxT4(C), two-kidney Tx rats receiving replacement thyroxine that served as normal controls. Five-sixths nephrectomy was carried out 2 weeks after Tx, and experiments were carried out 1 week later. Serum T4 was profoundly reduced and there was failure to gain weight in Tx and TxI rats, despite similar protein intakes in all groups. Cardiac output was reduced in Tx, but was similar in TxI to levels in TxT4 rats. Whole-kidney glomerular filtration rate was lower in Tx, at 0.145 +/- 0.052 mL/min (P less than 0.05), but similar in TxI (0.305 +/- 0.147 mL/min) to that in TxT4 rats (0.317 +/- 0.135 mL/min). Twenty-four-hour urinary protein, which was 129 +/- 57 mg in TxT4, was reduced in Tx to 9 +/- 3 mg (P less than 0.01) but restored in TxI to 89 +/- 30 mg, a level similar to that in TxT4.(ABSTRACT TRUNCATED AT 250 WORDS)

Proteinuria is the clinical hallmark of diabetic nephropathy and the harbinger of progressive renal disease. Therefore, the present study was designed to examine the effect of phosphate restriction on the proteinuria of streptozotocin-induced diabetes mellitus in the rat. Uninephrectomy was performed in experimental and control groups to worsen the degree of diabetic nephropathy. Proteinuria was prevented in Sprague-Dawley rats treated with the intestinal phosphate binder, dihydroxyaluminum aminoacetate (DHAAA) (24.75 +/- 20.35 mg/d at 3 months v control, 77.45 +/- 44.72 mg/d, P less than 0.001); an effect that was independent of protein and caloric intake, plasma albumin and lipids, severity of diabetes, mean arterial pressures, cardiac output, and renal calcium accumulation. The effect of DHAAA on protein excretion and glomerular hemodynamics was examined in similarly prepared Munich-Wistar rats; these rats did not tolerate long-term studies. Three weeks of DHAAA again caused a consistent fall in proteinuria (5.98 +/- 7.28 v 34.94 +/- 24.28 mg/d) and in transmembrane hydraulic pressure difference (41.1 +/- 1.2 v 46.4 +/- 2.8 mm Hg, P less than 0.005). In conclusion, phosphate restriction significantly decreases the proteinuria of Sprague-Dawley and Munich-Wistar uninephrectomized rats with streptozotocin-induced diabetes mellitus. Micropuncture of Munich-Wistar rats suggests that a reduction of intraglomerular pressure may be at least partially responsible for such an effect.