Acute renal failure following bone marrow transplantation: a retrospective study of 272 patients.

To assess the incidence, risk factors, and course of acute renal failure (ARF) following bone marrow transplantation (BMT), a retrospective analysis of 272 patients receiving transplants at the Fred Hutchinson Cancer Research Center during 1986 was undertaken. The patients were divided into three groups: group 1, hemodialysis requiring ARF; group 2, mild renal insufficiency (doubling of serum creatinine, Scr, but no dialysis); group 3, relatively normal post-BMT renal function (no doubling of Scr). Fifty-three percent of patients at least doubled their Scr (Groups 1 and 2), and 24% required dialysis. The degree of renal functional impairment had a dramatic impact on patient mortality rates (84%, 37%, and 17% in groups 1, 2, and 3, respectively). Jaundice (bilirubin greater than or equal to 2.0 mg/dL), weight gain (greater than or equal to 2.0 kg), amphotericin B use, and a pretransplant Scr greater than or equal to 0.7 mg/dL were independently associated with the subsequent development of dialysis-requiring ARF (P less than 0.001; relative risks, 3.0 to 7.7). Neither aminoglycoside/vancomycin/cyclosporine A use nor acute graft v host disease correlated with the development of ARF. A mismatched graft was a significant risk factor for ARF by univariate but not by multivariate analysis. Within 48 hours before doubling the Scr, 63% of group 1 patients had positive blood cultures and 39% developed hypotension. Of the 26 group 1 patients who had urine Na concentrations measured, 85% had values less than or equal to 40 mEq/L. Autopsy kidney specimens provided no clear explanation for ARF in the vast majority of patients in group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure.

To evaluate mechanisms in hemoglobinuric acute renal failure (ARF) rats were infused with hemoglobin under aciduric or alkalinuric conditions. Aciduric rats developed azotemia, distal heme casts, and proximal tubular cell (PTC) necrosis, whereas alkalinuric rats developed no renal damage. Aciduria converted hemoglobin to met-hemoglobin, which precipitated, forming distal casts and inducing ARF. Hematin formation was not observed. The importance of met-hemoglobin production was indicated by its greater toxicity than hemoglobin during aciduria and by its ability to induce ARF even under alkalinuric conditions. A link between obstructing casts and PTC necrosis was identified; tubular obstruction induced by various mechanisms (met-hemoglobin casts; ureteral ligation; ischemic ARF) increased PTC hemoglobin uptake, producing lysosomal overload (giant endolysosomes) and PTC necrosis. This worsened ischemic ARF despite an otherwise subtoxic hemoglobin dose being used that had no discernible acute renal vasoconstrictive effect. Iron chelation (deferoxamine)/hydroxyl radical scavenger (Na benzoate) therapy did not mitigate this exacerbation of ischemic injury, suggesting a nonoxidant mechanism. We conclude that H is nephrotoxic, particularly when intratubular obstruction facilitates PTC heme uptake. Thus aciduria-induced met-hemoglobin cast formation and concomitant ischemic renal injury predispose to its nephrotoxic effect.

Evidence against oxidant injury as a critical mediator of postischemic acute renal failure.

The purpose of this study is to confirm previous evidence for reactive oxygen species (ROS) as critical mediators of postischemic renal injury by documenting lipid peroxidation after ischemic-hypoxic insults and by demonstrating that antioxidants confer protection. Renal malondialdehyde (MDA) concentrations, an index of lipid peroxidation, were measured using uncorrected and tissue-chromagen-corrected methods in 1) cortical (C), outer medullary stripe (OMS), inner medullary (IM) whole renal tissues, and C and OMS mitochondria obtained 15 min after in vivo renal artery occlusion (RAO; x 45 min); 2) C, OMS, and IM whole tissues obtained 15 min after completing 45 min of ischemia in an isolated perfused kidney; and 3) isolated proximal tubular cell (PTC) suspensions after 45 min of hypoxia with 15 min of reoxygenation. Despite significant oxygen deprivation-induced injury in each of these systems, no significant rise in MDA concentrations could be documented, with the sole exception of the in vivo IM region (by uncorrected MDA assay only). The latter rise could be attributed to medullary vascular congestion causing a hemoglobin-induced artifact in the MDA assay. Sixty-minute in vivo RAO plus reflow also did not raise MDA. To validate the MDA assay 4.2 mM H2O2 was added to PTC. An abrupt fourfold rise in MDA resulted. Pretreatment of 30- and 45-min RAO rats with two antioxidants (allopurinol or superoxide dismutase) failed to confer functional or morphological protection. We conclude that ROS may not be critical consistent mediators of in vivo postischemic acute renal failure.

Degradation and resynthesis of adenine nucleotides in adult rat heart myocytes.

The degradation and short-term resynthesis of adenine nucleotides have been examined in a preparation of isolated rat heart myocytes. These myocyte preparations are essentially free of vascular and endothelial cells, contain levels of adenine nucleotides quite comparable to those of intact heart tissue, and retain these components remarkably well for up to 2 h of aerobic incubation in the presence of 1 mM Ca2+. When the cells are rapidly and synchronously de-energized by addition of uncoupler, an inhibitor of respiration and iodoacetate, cellular ATP is degraded almost quantitatively to AMP. The AMP is then converted to either intracellular adenosine, which accumulates to high concentrations before release to the cell exterior, or to IMP. The relative contribution of these two pathways depends on the metabolic state of the cells just prior to de-energization, with IMP production favored when respiring cells are de-energized and adenosine formation predominant when glycolyzing myocytes are subjected to this treatment. Cells de-energized by anaerobiosis in the absence of glucose lose ATP and adenine nucleotides with the production of IMP and adenosine. Upon reoxygenation, these cells restore a high adenylate energy charge and about 60% of control levels of GTP. There is a net resynthesis of 5-7 nmol of adenine nucleotides.mg-1 protein with a corresponding decline in IMP. Added [14C]adenosine labels the adenine nucleotide pool, but little net resynthesis of adenine nucleotides via adenosine kinase can be detected. It therefore appears that a rapid regeneration of adenine nucleotides can occur via the enzymes of the purine nucleotide cycle in heart myocytes and is limited by the size of the IMP pool retained.