Rhabdomyolysis and acute myoglobinuric renal failure following heroin use.

Four life-threatening dermatoses—Stevens-Johnson syndrome, toxic epidermal necrolysis, Kaposi''s varicelliform eruption and purpura fulminans—are unique in their abrupt onset and rapid progress to death, but prompt diagnosis and proper therapy can often cure the condition or prevent undesirable sequelae. Since two of the four conditions can follow the use of a variety of drugs and all may be secondary to an infectious agent, any physician may encounter them in practice and should be aware of their seriousness.     

Preventive effects of hyperbaric oxygen treatment on glycerol-induced myoglobinuric acute renal failure in rats

Myoglobinuric acute renal failure (ARF) is a uremic syndrome caused by traumatic or non-traumatic skeletal muscle breakdown and intracellular elements that are released into the bloodstream. We hypothesized that hyperbaric oxygen (HBO) therapy could be beneficial in the treatment of myoglobinuric ARF caused by rhabdomyolysis. A total of 32 rats were used in the study. The rats were divided into four groups: control, control+hyperbaric oxygen (control+HBO), ARF, and ARF+hyperbaric oxygen (ARF+HBO). Glycerol (8 ml/kg) was injected into the hind legs of each of the rats in ARF and ARF+HBO groups. 2.5 atmospheric absolute HBO was applied to the rats in the control+HBO and ARF+HBO groups for 90 min on two consecutive days. Plasma urea, creatinine, sodium, potassium, calcium, aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, creatinine kinase and urine creatinine and sodium were examined. Creatinine clearance and fractional sodium excretion could then be calculated. Superoxide dismutase, catalase, glutathione and malondialdehyde (MDA) levels were assessed in renal tissue. Tissue samples were evaluated by Hematoxylin-eosin, PCNA and TUNEL staining histopathologically. MDA levels were found to be significantly decreased whereas SOD and CAT were twofold higher in the ARF+HBO group compared to the ARF group. Renal function tests were ameliorated by HBO therapy. Semiquantitative evaluation of histopathological findings indicated that necrosis and cast formation was decreased by HBO therapy and TUNEL staining showed that apoptosis was inhibited. PCNA staining showed that HBO therapy did not increase regeneration. Ultimately, we conclude that, in accordance with our hypothesis, HBO could be beneficial in the treatment of myoglobinuric ARF.     

Molsidomine, a nitric oxide donor and L-arginine protects against rhabdomyolysis-induced myoglobinuric acute renal failure

Rhabdomyolysis-induced myoglobinuric acute renal failure accounts for about 10-40% of all cases of acute renal failure (ARF). Nitric oxide and reactive oxygen intermediates play a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). This study was designed to investigate the effect of molsidomine and L-arginine in glycerol induced ARF in rats. Six groups of rats were employed in this study, group I served as control, group II was given 50% glycerol (8 ml/kg, intramuscularly), groups III and IV were given glycerol plus molsidomine (5 mg/kg, and 10 mg/kg p.o. route respectively) 60 min prior to the glycerol injection, group V animals were given glycerol plus L-arginine (125 mg/kg, p.o.) 60 min prior to the glycerol injection, and group VI received L-NAME (10 mg/kg, i.p.) along with glycerol 30 min prior to glycerol administration. Renal injury was assessed by measuring plasma creatinine, blood urea nitrogen, creatinine and urea clearance. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, reduced glutathione and superoxide dismutase. Tissue and urine nitrite levels were measured as an index of total nitric oxide levels. Glycerol treatment resulted in a marked decrease in tissue and urine nitric oxide levels, renal oxidative stress and significantly deranged the renal functions along with deterioration of renal morphology. Pre-treatment of animals with molsidomine (10 mg/kg) and L-arginine 60 min prior to glycerol injection markedly attenuated fall in nitric oxide levels, renal dysfunction, morphological alterations, reduced elevated TBARS and restored the depleted renal antioxidant enzymes. The animals treated with L-NAME along with glycerol further worsened the renal damage observed with glycerol. As a result, our results indicate that molsidomine and L-arginine may have beneficial effects in myoglobinuric ARF.     

N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure

This study evaluated the effects of N-acetyl-L-cysteine (NAC), a free radical scavenger, and N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthesis inhibitor, on the changes in renal function, intrarenal blood flow distribution (laser-Doppler flowmetry), and plasma peroxynitrite levels during the acute renal failure (ARF) produced by inferior vena cava occlusion (IVCO; 45 min) in anesthetized rats. Renal blood flow fell on reperfusion (whole kidney by -45.7%; cortex -58.7%, outer medulla -62.8%, and papilla -47.7%); glomerular filtration rate (GRF) also decreased (-68.6%), whereas fractional sodium excretion (FE(Na%)) and peroxynitrite and NO/NO plasma levels increased (189.5, 46.5, and 390%, respectively) after ischemia. Pretreatment with L-NAME (10 microg. kg(-1). min(-1)) aggravated the fall in renal blood flow seen during reperfusion (-60%). Pretreatment with NAC (150 mg/kg bolus + 715 microg. kg(-1). min(-1) iv) partially prevented those changes in renal function (GFR only fell by -29.2%, and FE(Na%) increased 119.4%) and laser-Doppler blood flow, especially in the outer medulla, where blood flow recovered to near control levels during reperfusion. These beneficial effects seen in rats given NAC seem to be dependent on the presence of NO, because they were abolished in rats pretreated with L-NAME. Also, the antioxidant effects of NAC prevented the increase in plasma peroxynitrite after ischemia. In conclusion, NAC ameliorates the renal failure and the outer medullary vasoconstriction induced by ICVO, effects that seem to be dependent on the presence of NO and the scavenging of peroxynitrite.     

Value of renal biopsy in acute intrinsic renal failure.

Eighty-four patients presented with acute renal failure and features suggesting a diagnosis of intrinsic renal disease other than "acute reversible renal failure." Renal biopsy proved valuable in establishing the diagnosis, in indicating the reversibility of the lesion, and in helping to decide on treatment.     

Role of apoptosis of renal tubular cells in acute renal failure: Therapeutic implications

Acute renal failure (ARF) can be defined as a sudden loss of renal function and is a common and serious clinical problem. There are many causes of ARF but the most common cause results from injury to the renal tubular epi-thelial cells (RTECs). RTECs can be injured by schemia or by cytotoxic agents and, once injured, can die by necrosis or apotosis. In general, necrosis occurs in response to any severe injury, which leads to the biochemical collapse of the cell. Milder forms of the same types of injury cause apoptosis. At the cellular level there are fundamental differences between necrosis and apoptosis. Necrosis results from the additive effect of a number of independent biochemical events that are activated by severe depletion of cell energy stores. By contrast, apoptosis occurs via a coordinated, predictable and pre-determined pathway. These biochemical differences between apoptosis and necrosis have important therapeutic implications. Once a cell has been severely injured, necrosis is difficult to prevent. By contrast, the apoptotic pathway can potentially be modulated to maintain cell viability. The components of the apoptotic pathway that are potentially amenable to therapeutic modulation are discussed in detail in this review.     

Aldosterone-induced glycoproteins: further characterization

Aldosterone induces the synthesis of a group of glycoproteins (GP65,70) in toad urinary bladders which are potential effectors of the natriferic action of this hormone. The GP65,70 complex is composed of two molecular weight classes of proteins (Mr 65 and 70 kDa), each class being composed of several discrete proteins of varying isoelectric points (5.8-6.2). These proteins can be partially enriched (approximately 20-fold) using wheat germ agglutinin-sepharose affinity chromatography, are neuraminidase-resistant, and can be N-deglycosylated by endoglycosidase-H and N-glycanase. Treatment with N-glycanase leads to the appearance of a microheterogeneous group of proteins, all having the same Mr (approximately 40 kDa). From these studies it can be concluded that these particular aldosterone-induced proteins: (1) are heavily glycosylated, (2) contain multiple high mannose and hybrid oligosaccharides side chains, and (3) contain similar (if not identical) peptide backbones. Post-translational N-glycosylation accounts, at least in part, for their electrophoretic polymorphism (variation in Mr) but not for their electrophoretic microheterogeneity (variation in pI). The latter may reflect other types of post-translational modification (e.g. O-glycosylation, phosphorylation) or may be due to subtle differences in amino acid composition. The partial purification and biochemical characterization of GP65,70 should ultimately lead to a better understanding of the function of these putative "effectors" of aldosterone-stimulated Na+ transport.     

Enhanced antiplasmin activity in acute renal failure.

Plasmatic slow plasmin-inhibitor activity was assessed in 20 patients with acute renal failure and 12 controls with the fibrin plate method. The area of fibrinolysis was 250-5 +/- 5 mm2 in the patients and 289 +/- 6mm2 in the controls (P less than 0.001) and was negatively correlated with antiplasmin activity. Thirteen patients had areas of lysis equal to or inferior to the minimal lysis observed in the controls. No correlation was found between antiplasmin activity and serum fibrin-fibrinogen related antigen titres, the presence or absence of disseminated intravascular coagulation, or the causative disease.     

Impaired muscle glucose metabolism in acute renal failure

Renal failure is associated with peripheral insulin resistance and consequent carbohydrate intolerance. This report investigates carbohydrate metabolism in vitro in epitrochlearis and hemidiaphragm muscles taken from acutely uraemic and sham-operated rats. Muscles from acutely uraemic rats (compared to those from sham-operated rats ) incubated with 5 mM glucose showed increased rates of basal and insulin-stimulated glycolysis and glycogen turnover, but pyruvate dehydro-genase and tricarboxylic acid - cycle flux was not increased in uraemia. Glycolysis (but not glycogen turnover) in muscles from acutely uraemic rats tended to show decreased responsiveness to stimulation by insulin. It is concluded that acute uraemia is associ-ated with a defect(s) in muscle that produces intrinsic insulin resistance and results in diversion of glucose (both in basal and insulin-stimulated states) from glycogen synthesis into glycolysis.