A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure

Muscle injury (rhabdomyolysis) and subsequent deposition of myoglobin in the kidney causes renal vasoconstriction and renal failure. We tested the hypothesis that myoglobin induces oxidant injury to the kidney and the formation of F2-isoprostanes, potent renal vasoconstrictors formed during lipid peroxidation. In low density lipoprotein (LDL), myoglobin induced a 30-fold increase in the formation of F2-isoprostanes by a mechanism involving redox cycling between ferric and ferryl forms of myoglobin. In an animal model of rhabdomyolysis, urinary excretion of F2-isoprostanes increased by 7.3-fold compared with controls. Administration of alkali, a treatment for rhabdomyolysis, improved renal function and significantly reduced the urinary excretion of F2-isoprostanes by approximately 80%. EPR and UV spectroscopy demonstrated that myoglobin was deposited in the kidneys as the redox competent ferric myoglobin and that it's concentration was not decreased by alkalinization. Kinetic studies demonstrated that the reactivity of ferryl myoglobin, which is responsible for inducing lipid peroxidation, is markedly attenuated at alkaline pH. This was further supported by demonstrating that myoglobin-induced oxidation of LDL was inhibited at alkaline pH. These data strongly support a causative role for oxidative injury in the renal failure of rhabdomyolysis and suggest that the protective effect of alkalinization may be attributed to inhibition of myoglobin-induced lipid peroxidation.     

Diagnostic and prognostic significance of an increase in fractional protein clearance ratio before and during rejection of renal transplant

We measured prospectively changes in fractional protein clearance ratio (CPr/CCr) in 21 live-related (LR) and 41 cadaver donor (CD) renal transplants before and during onset of first rejections. Fifty-three recipients manifested a rejection within the first post-transplant month. Fractional protein clearance increased in all patients during rejection. An increase in CPr/CCr prior to other evidence of impending rejection, and therefore clinically useful, required at least a 10-day rejection-free interval dated from onset of diuresis (whether diuresis was immediate or delayed by acute tubular necrosis (ATN)). Twenty-three of 25 nonantilymphocyte globulin (ALG)-treated CD transplants manifested clinical and laboratory signs of the first rejection episode prior to the 10th day of diuresis compared with 5 of 21 LR and none of 16 ALG-treated CD transplants. Persistence of elevated CPr/CCr despite treatment forecast graft loss (11 of 13), whereas a decrease in this ratio was associated with ultimate reversal of the rejection process.     

Hydrogen peroxide induces 21-aminosteroid-inhibitable F2-isoprostane production and cytolysis in renal tubular epithelial cells

F2-isoprostanes are the newly identified reactive oxygen species-catalyzed peroxidation products of arachidonate. The infusion of these prostaglandin F2-like prostanaoids into the rat kidney induces profound parallel reductions in RBF and GFR, suggesting that these metabolites may be partly responsible for the hemodynamic alterations seen in free radical-linked acute renal injury models. The present study examined directly in renal proximal tubular (LLC-PK1) cells whether hydrogen peroxide, a reactive oxygen species implicated in many models of acute renal injury, induces F2-isoprostane production and whether its production can be inhibited by the recently synthesized lipid peroxidation inhibitor 21-aminosteroid (lazaroid U-74389G). The incubation of LLC-PK1 cell layers with hydrogen peroxide for 3 h resulted in a dose-related six-fold increase in F2-isoprostane production, measured by the gas chromatographic-mass spectroscopic method. The preincubation of cells with 21-aminosteroid prevented hydrogen peroxide-induced F2-isoprostane production, a finding also demonstrable with other lipid peroxidation inhibitors, e.g., 2-methyl aminochroman (U-83836E) and diphenyl-p-phenylenediamine. Besides inhibiting isoprostane production, 21-aminosteroid reduced hydrogen peroxide-induced lipid degradation and peroxidation, and protected the cells against hydrogen peroxide-induced cytolysis. The novel finding that hydrogen peroxide induces 21-aminosteroid-inhibitable F2-isoprostane production in renal epithelial cells supports the in vivo report that its levels are elevated in reactive oxygen species-linked renal injury models such as ischemia-reperfusion. Besides direct cell injury, lipid peroxidation by generating F2-isoprostanes may further contribute to renal dysfunction through a vasoconstrictive mechanism. Thus, the inhibition of excess F2-isoprostane production may be one of the additional mechanisms, besides cytoprotection, by which antioxidants ameliorate renal dysfunction in experimental models of acute renal injury.     

Caveolae: from a morphological point of view

The protective effect of quercetin against oxidant-induced cell injury (hypoxanthine/xanthine oxidase system) was studied in the renal tubular epithelial cell line LLC-PK1. Pretreatment with quercetin provided protection from structural and functional cell damage in a concentration-dependent manner (10-100 microM). Comparison with structural variants revealed that the protective property of quercetin depends on the number of hydroxyl substituents in the B-ring, the presence of an extended C-ring chromophore, 3-D-planarity and lipophilicity, indicating that membrane affinity is essential for protection. The hypothesis that quercetin exerts its protective effects via inhibition of lipid peroxidation was further examined. Protection by quercetin was found when lipid peroxidation, assessed by the release of malondialdehyde, was initiated by H2O2 or by the combination of 1-chloro-2,4-dinitrobenzene and aminotriazole. In contrast, the bioflavonoid was not protective when oxidative cell damage was induced by menadione and occurred in the absence of lipid peroxidation. These data suggest that cytoprotective effects of quercetin are related to membrane affinity and may be explained by interruption of membrane lipid peroxidation rather than by intracellular scavenging of oxygen free radicals.     

Distal renal tubular acidosis presenting with rhabdomyolysis

Severe hypokalemia is an uncommon cause of rhabdomyolysis. We describe a patient, 28-year-old woman, with distal renal tubular acidosis (DRTA) who developed severe hypokalemia and rhabdomyolysis. Muscle biopsy shows focal muscular necrosis mainly in type II muscle fibers and mild macrophagic reaction. After correcting the acidosis with oral administration of alkalinizing salts, clinical and laboratory improvement was seen. This clearly establish a causal relationship between the positive acid balance, hypokalemia and the muscular manifestation in DRTA.     

A non-aversive approach to reducing hospital absconding in a head-injured adolescent boy

Human envenomation caused by bee or wasp stings has been reported to cause acute renal failure (ARF), usually due to acute tubular necrosis (ATN), as a frequent complication. The pathogenetic mechanisms of ATN occurring in these accidents are still unclear. In the present study, female Wistar rats weighing 150-200 g were injected intravenously with Africanized bee venom at a dose of 0.4 microl/100 g body weight and used in functional and light microscopy studies. The animals were divided into two groups: the early group was studied 3-8 h after inoculation, and the late group was studied 24-30 h thereafter. The animals showed ARF characterized by reduction of glomerular filtration rate with increasing levels of plasma creatinine. They also showed increased fractional sodium and potassium excretions, suggesting changes in the proximal portion of the nephron. The water transport through collecting tubules was reduced, with consequent diuresis, indicating functional changes in the distal portion of the nephron. These functional changes were more marked in the early group, with recovery tending to occur after 24 h. Albuminuria was also observed in this group. Light microscopy showed ATN mainly in cortex and outer medulla, with isolated necrosis in cells or small groups of cells and cast formation in the distal and collecting tubules. After 24 h frequent mitotic figures were found in the tubular epithelium. The observed ARF was due to ATN which in turn was probably caused by multiple effects, mainly hemodynamic changes secondary to cardiotoxicity and systemic vasodilation caused by the venom, myohemoglobinuria, and the direct action of the venom on tubular cells.     

Myoglobin inhibits proliferation of cultured human proximal tubular (HK-2) cells

Following nephrotoxic injury, renal repair is dependent on tubular regeneration. In the case of myoglobinuric acute renal failure (ARF), persistence of myoglobin within tubular cells, or sublethal injury sustained at the height of exposure to it, might retard this process. To test this hypothesis, a human proximal tubular cell line (HK-2) was cultured for 24 hours in the absence or presence of clinically relevant myoglobin concentrations (0.5, 1, 2, 4 mg/ml). Immediately following myoglobin removal, lethal cell injury (vital dye uptake), lipid peroxidation, and DNA damage (alkaline unwinding assay) were assessed. The extent of cell proliferation was estimated over the next four days by a tetrazolium based (MTT) assay and by determining total intracellular LDH. Myoglobin's effects on protein and DNA synthesis were also assessed (35S-methionine and bromodeoxyuridine incorporation, respectively). Myoglobin induced dose-dependent lipid peroxidation (malondialdehyde generation) and cell death (up to 80% vital dye uptake with the 4 mg/ml challenge). Although 1 mg/ml myoglobin caused no cell death, it induced nearly complete growth arrest. This lasted for approximately three days following myoglobin removal from the media. Neither of two control proteins (albumin; lysozyme) nor a second nephrotoxin (gentamicin; 1 mg/ml) reproduced this effect. The 1 mg/ml myoglobin challenge caused an 80 to 90% depression in protein and DNA synthesis. It also induced significant DNA damage, as assessed by the alkaline unwinding assay (P < 0.01). Iron chelation therapy (deferoxamine) mitigated myoglobin-induced cell killing. However, its addition following myoglobin loading worsened HK-2 outgrowth by exerting a direct anti-proliferative effect. These results indicate that: (1) sublethal myoglobin toxicity can induce transient proximal tubular cell growth arrest, potentially slowing recovery from ARF; (2) this effect correlates with, and could result from, heme-induced DNA damage and a blockade in DNA/protein synthesis; and (3) deferoxamine can inhibit proximal tubular cell proliferation. This possibility needs to be considered in designing clinical trials with DFO for myohemoglobinuric ARF.     

Heterogeneous expression of neurofilament proteins in forebrain and cerebellum during development: clinical implications for spinocerebellar ataxia

Previously it was shown that methylenedioxybenzenes (MDBs), particularly isosafrole, were highly effective at preventing CCl4-induced liver necrosis in vivo (Z.S. Zhao, P.J. O'Brien, The prevention of CCl4-induced liver necrosis in mice by naturally occurring methylenedioxybenzenes, Toxicol. Appl. Pharmacol., 140 (1996) 411-421), probably as a result of forming metabolic intermediate complexes with cytochrome P450. In the following it was shown that pretreatment of mice with isosafrole also completely prevented ferric nitrilotriacetate (FeNTA)-induced renal necrosis and lipid peroxidation, even though metabolic activation by cytochrome P450 is not involved. The naturally occurring or synthetic MDBs that prevented CCl4 hepatotoxicity also prevented hepatocyte lipid peroxidation. induced by FeNTA, but other cytochrome P450 inhibitors were ineffective. These compounds, in decreasing order of antioxidant effectiveness, were sesamol, 4-t-butyl-methylenedioxybenzene, isosafrole, piperonyl butoxide and 4-bromo-methylenedioxybenzene and safrole, whereas, benzodioxole, 3,4-(methylenedioxy)-toluene and 1,2-(methylenedioxy)-4-nitrobenzene were ineffective. Pre-incubating the hepatocytes with P450 inhibitors decreased the protective effects of isosafrole, suggesting that the catecholic metabolites of MDBs were responsible for the antioxidant activity. A greater inhibition of FeNTA-induced lipid peroxidation by catecholic metabolites was observed. Since cytochrome P450 did not participate in FeNTA-induced hepatocyte or microsomal lipid peroxidation, it is likely that the antioxidant properties of MDBs or their catecholic metabolites also contribute to their in vivo protection against CCl4 or FeNTA-induced hepato- or nephrotoxicity.     

Protection from renal ischemia-reperfusion injury by the 2-methylaminochroman U83836E

BACKGROUND: In a prior study the 21-aminosteroid (lazaroid) U74389F provided in vivo protection from oxidative stress when used as a preventive therapy in ischemia-reperfusion injury in the kidney. As the cell membrane is the principal site for lipoperoxidation, in the current study the very lipophilic 2-methylaminochroman U83836E, a recently developed lazaroid, was administered to rats at 3 mg/kg before renal ischemia-reperfusion. In addition to the biochemical parameters, the renal function and the histological appearance were carefully evaluated. METHODS: Glutathione, adenine nucleotides and lipid peroxidation products were determined in kidneys reperfused for 2 and 24 hours after 90 minutes of ischemia. Renal function was assessed by plasma creatinine, and renal injury by histological examination. RESULTS: Reperfusion-induced glutathione oxidation, expressed as an oxidized-to-total glutathione ratio, was significantly attenuated both after 2 and 24 hours of reperfusion by treatment with U83836E. Adenosine triphosphate (ATP) was still significantly depleted after 24 hours in the control group, while at the same time treated animals had already recovered to baseline values. Lipid peroxidation products were significantly lower in lazaroid-groups both after 2 and 24 hours of reperfusion. Renal function after 24 hours of reperfusion was notably better in the treated rats. Histological examination confirmed the protective action of the drug. After 24 hours the control group showed large areas of parenchymal hemorrhage and necrosis with dilated tubules and blood vessel thrombosis, while treated animals showed small necrotic areas with a background of mild interstitial inflammatory cells. CONCLUSIONS: Our results suggest that there is a protective effect of U83836E in ischemia-reperfusion injury, in that tissue damage due to oxidative stress is reduced, thus ameliorating renal function impairment.     

In pursuit of the persistent plasmodium

The case is presented of a 34-year-old woman with rhabdomyolysis due to massive intake of nimetazepam, a benzodiazepine hypnotic. On admission, the patient had numerous blisters all over the body. One of the blisters in the gluteal region developed into a deep ulcer accompanied by muscle necrosis although it was not at a pressure point. The ulcer needed surgical intervention. Rhabdomyolysis is caused by the lysis and necrosis of muscle due to direct or indirect injury, high fever, ischaemia, hypoxia or enzyme defects. Release of myocyte components into the circulation then may induce major problems, especially acute renal failure associated with hypermyoglobinaemia. However, there have been few reports of cutaneous ulcer formation in non-traumatic rhabdomyolysis.     

The CT nephrogram: implications for evaluation of urinary tract disease

The urographic nephrogram is an important indicator of underlying functional and structural renal disease. With expansions in use of cross-sectional imaging, the computed tomographic (CT) nephrogram (ie, contrast material enhancement within the renal parenchyma) has assumed a greater role in the evaluation of urinary tract disorders. Both quantitative and qualitative nephrographic abnormalities are well demonstrated by CT, including global or segmental absence or persistence of the nephrogram, slowed temporal progression, striated pattern, and rim pattern. Global absence is nearly always unilateral and is most often seen with blunt abdominal trauma with renal pedicle injury. Segmental absence is attributable to focal renal infarction, most likely due to arterial emboli. Global persistence, which is much more common than segmental persistence, may be unilateral (caused by renal artery stenosis, renal vein thrombosis, or urinary tract obstruction) or bilateral (due to systemic hypotension, intratubular obstruction, or abnormalities in tubular function). Striated nephrograms may be unilateral or bilateral and are caused by ureteric obstruction, acute pyelonephritis, contusion, renal vein thrombosis, tubular obstruction, hypotension, and autosomal recessive polycystic kidney disease. The rim pattern is most often associated with renal infarction and occasionally with acute tubular necrosis and renal vein thrombosis. Careful evaluation of the CT nephrogram is an integral part of the abdominal CT examination.     

Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome

Recent studies have shown that tetrafluoroethylene is a renal and hepatic carcinogen in the rat. In this study, we have examined the ability of a single i.p. dose of 1,1,2,2-tetrafluoroethyl-L-cysteine (TFEC), a major metabolite of tetrafluoroethylene, to produce hepatic and renal injury in male and female rats. We have also examined the effect of blocking the renal organic anion transport system with probenecid and of inhibiting the activity of cysteine conjugate beta-lyase with aminooxyacetic acid on the extent of renal injury produced by TFEC. Doses of > or = 12.5 mg/kg TFEC produced renal tubular necrosis to the pars recta of the proximal tubules within 24 h in both male and female rats. This was associated with an increased kidney to body weight ratio and plasma urea at doses of > or = 25 mg/kg. No consistent evidence of liver injury was seen at doses up to 50 mg/kg TFEC in rats of either sex, although occasional vacuolation of hepatocytes and a small dose-related increase in liver to body weight ratio was observed. Prior treatment of female rats with probenecid completely prevented the renal injury produced by either 25 or 50 mg/kg TFEC as judged by plasma urea and histopathology. However, prior treatment of female rats with aminooxyacetic acid afforded no protection against the nephrotoxicity produced by either TFEC or the cysteine conjugate of hexachloro-1,3-butadiene. Thus no major sex difference in nephrotoxicity in the rat was seen with TFEC, while accumulation of TFEC, or its N-acetyl derived metabolite, into renal proximal tubular cells via a probenecid sensitive transport system appears to be a key event in the mechanism of nephrotoxicity. The lack of protection observed with the cysteine conjugate beta-lyase inhibitor, aminooxyacetic acid, may reflect the inability to completely inhibit the mitochondrial form of this enzyme and thereby prevent the formation of the reactive metabolite. Our acute studies provide no insight concerning the liver carcinogenicity of tetrafluoroethylene.     

Three-dimensional triple-quantum-filtered 23Na imaging of the dog head in vivo

Uninephrectomized rats with diet-induced hypercholesterolemia develop interstitial inflammation and fibrosis after 8 to 12 weeks. Fibrosis has been associated with the accumulation of lipid peroxidation products within the tubulointerstitium, along with increased renal mRNA levels for transforming growth factor beta-1 (TCF-beta 1), some matrix proteins, and the tissue inhibitor of metalloproteinases (TIMP-1). However, mRNA levels for urokinase-type plasminogen activator (uPA) have been found to be decreased. The purpose of the present study was to determine whether antioxidant therapy could attenuate interstitial fibrosis in hypercholesterolemic rats and to determine changes in the pattern of renal gene expression induced by antioxidant therapy. Three groups of uninephrectomized rats were studied after 12 weeks of feeding standard rat chow, an atherogenic diet (standard chow plus 4% cholesterol/1% cholic acid), or an atherogenic diet supplemented with high doses of the antioxidants probucol and vitamin E. Rats fed the atherogenic diet developed hypercholesterolemia and a 56% increase in total kidney collagen compared with rats fed standard chow. In comparison, the hypercholesterolemic rats treated with antioxidants had normal levels of renal lipid peroxidation products and a normal kidney collagen content. In contrast, there were no significant differences in urinary albumin excretion rates or the number of interstitial macrophages between the two hypercholesterolemic groups. Compared with the untreated hypercholesterolemic group, antioxidant therapy induced significant reductions in renal mRNA levels for procollagen III (to 60% of untreated levels), collagen IV (60%), and TIMP-1 (20%), while uPA levels were significantly increased (to 210%). Paradoxically, antioxidant therapy was associated with a significant increase in renal TGF-beta 1 mRNA levels (to 150%), although TGF-beta 1 protein expression shifted from interstitial to tubular epithelial cells in predominance. The results of the present study demonstrate the efficiency of antioxidant therapy in preventing renal interstitial fibrosis in hypercholesterolemic rats with a single kidney. Based on changes in renal gene expression at the mRNA level, impaired matrix protein synthesis and increased intrarenal activity of the metalloproteinases and uPA/plasmin may play a role in the attenuation of fibrosis.     

A study of various complications in arterial infusion chemotherapy

Complications of arterial infusion chemotherapy were analyzed in 261 cases from December 1983 to December 1993 in our department. Their complications involved nausea and vomiting (40.6%), bone marrow suppression (33.3%), liver dysfunction (20.3%), gastric and duodenal ulcer (9.6%) and so on. Complications involving an implantable device were hepatic arterial obstruction (29.1%), reservoir obstruction (5.7%), dislocation of catheter (4.6%), infection of catheter (3.8%), and obstruction of catheter (1.9%). In another cases with hepatic arterial obstruction, we performed arterial infusion in another artery as a bypass or stopped the infusion. In cases with obstruction of catheter not able to be reopened, we reinserted the catheter. An obstructed and/or infected reservoir was removed or replaced. Nausea and vomiting were found in 46.3% of FAM arterial infusion method (FAM) cases, in 53.3% of 5-FU persistent arterial method (5-FU) + FAM cases, and in 40.5% of intermittently persistent arterial method (IP) cases. Gastric and duodenal ulcer were noted in 9.8% of FAM, 13.3% of 5-FU + FAM, and 8.1% of IP cases. There were no significantly statistical differences between the methods. Hepatic arterial obstruction predominantly occurred in 32.4% of IP and 26.7% of 5-FU + FAM and bone marrow suppression was predominant in cases in which ADM was used. The duration of obstruction after administration was 154.0 +/- 117.4 days on average (21-455 days). Complications of hepatic arterial infusion chemotherapy are based on various causes which can be managed for prevention. We intend to enhance safety and assure the greater effectiveness of hepatic arterial chemotherapy.     

Trimetazidine prevents renal injury in the isolated perfused pig kidney exposed to prolonged cold ischemia

BACKGROUND: Ischemia caused by cold storage (CS) and reperfusion of the kidney is often responsible for delayed graft function after transplantation. Significant attention has been focused on the cascade of events involved in ischemia-reperfusion injury, with the objective of identifying drugs to ameliorate the functional damage that occurs. METHODS: The purpose of this study was to evaluate the renal function of isolated perfused pig kidneys after 48 hr of CS with Euro-Collins (EC) solution plus trimetazidine (EC+TMZ), standard EC solution, or University of Wisconsin (UW) solution. Normothermic isolated perfused pig kidneys were randomized into five experimental groups: (A) control group (cold flush with cold heparinized saline and immediately reperfused; n=6); (B) cold flush with cold heparinized saline with TMZ (10(-6) M), n=6; (C) 48 hr of CS with EC and reperfusion (n=8); (D) 48 hr of CS with EC+TMZ alone and reperfusion (n=8); (E) 48 hr of CS with UW and reperfusion (n=8). Proton nuclear magnetic resonance spectroscopy and biochemical studies were performed for the functional evaluation during reperfusion. Lipid peroxidation was also determined. Histological examination (optical and electron microscopy) was performed after CS and reperfusion. RESULTS: Using TMZ, the renal perfusate flow rate as well as the glomerular filtration rate and proximal tubular function were significantly improved. This improvement of renal function during reperfusion was correlated with a less significant cellular and interstitial edema. In addition, tubular injury markers were significantly lower in the group preserved with EC+TMZ, and TMZ reduced lipid peroxidation dramatically during reperfusion. CONCLUSIONS: The addition of TMZ to the EC solution increased the preservation quality and renal tubular function, and gave protection from reperfusion injury better than EC alone or UW. These results strongly suggest that TMZ has a cytoprotective effect and may therefore be useful for kidney preservation.     

Obstruction of proximal tubules initiates cytoresistance against hypoxic damage

Following acute tubular necrosis (ATN), cytoresistance to further renal injury results. However, the initiating events and the subcellular determinants of this phenomenon have not been defined. Since tubular obstruction is a consequence of ATN, this study evaluated whether it alters tubular susceptibility to hypoxic damage. Extrarenal obstruction (ureteral ligation in rats) was used for this purpose to dissociate obstructive effects from those of ATN. Twenty-four hours following ureteral ligation or sham surgery, cortical proximal tubular segments (PTS) were isolated and subjected to hypoxic (15 or 30 min)/reoxygenation injury. Since oxidant stress, cell Ca2+ overload, and PLA2 attack are purported mediators of hypoxic/reoxygenation injury, degrees of FeS04, Ca2+ ionophore, and phospholipase A2-induced PTS damage also were assessed. The cell injury (% LDH release) which resulted from each of the above was consistently less in PTS obtained from obstructed kidneys. This cytoresistance: (a) did not require prior uremia to develop (seen with unilateral obstruction); (b) it did not appear to correlate with a tubular proliferative response (assessed by proliferating cell nuclear antigen expression); (c) it was uninfluenced by early tubular repair (unchanged by 24 hrs of obstruction release); and (d) it occurred without increased heat shock protein (HSP-70) or antioxidant enzyme (superoxide dismutase, catalase) expression. Total adenylate pools were higher in obstructed versus control PTS during injury; however, this appeared to be a correlate of the protection, rather than a mediator of it. In contrast, obstructed tubules manifested a primary increase in plasma membrane resistance to PLA2 attack (approximately 3-fold less lysophosphatidylcholine and free fatty acid generation in obstructed vs. control PTS during incubation with exogenous PLA2). In sum, these results indicate that: (1) tubular obstruction protects PTS from injury, suggesting that its development during ATN may initiate cytoresistance; and (2) this cytoresistance appears to be mediated, at least in part, by a direct increase in plasma membrane resistance to PLA2 and potentially other forms (such as, oxidant stress, cytosolic Ca2+ loading) of attack.     

Cardiorespiratory and renal responses to arterial chemoreceptor stimulation by hypoxia or almitrine in men

1. The cardiorespiratory and renal responses to 3 h of normobaric whole-body hypoxic hypoxia (FiO2 = 0.12) as well as to arterial chemoreceptor stimulation by the oral administration of 100 mg almitrine bismesylate during normoxia were measured in 12 normotensive young men undergoing water diuresis. A third series of responses obtained under comparable conditions in the same subjects served as time controls. 2. No significant changes could be detected over time in the parameters measured in control experiments. The subjects reacted to both whole-body hypoxic hypoxia and to pharmacological chemoreceptor stimulation with significant increases in heart rate, tidal volume, minute ventilation and filtration-fraction. Overall renal vascular resistance rose significantly in hypoxia; increases in renal vascular resistance in almitrine experiments were not significant. 3. Renal fractional lithium excretion decreased significantly in response to whole-body hypoxic hypoxia and increased slightly in response to almitrine. Fractional urine and sodium excretion showed negligible changes. 4. The data indicate that, in humans, both almitrine and whole-body hypoxic hypoxia affect not only alveolar ventilation but also renal haemodynamics. 5. The renal electrolyte excretion pattern suggests that under certain circumstances (e.g. dilated renal vascular bed) acute, but well-tolerated, whole-body hypoxic hypoxia can simultaneously stimulate renal proximal tubular sodium reabsorption and inhibit distal tubular sodium reabsorption. The renal tubular responses also indicate that almitrine may influence renal tubular lithium reabsorption by, thus far, unknown mechanisms.     

Hemostatic evaluation of a patient with haloperidol-induced neuroleptic malignant syndrome associated with disseminated intravascular coagulation

A 94-year-old man who had been admitted to our hospital for the treatment of senile dementia and restless behavior exhibited consciousness disturbances, acute respiratory failure, high fever, and thrombocytopenia the day after receiving haloperidol as prescribed by a psychiatrist. On the fourth day following administration of haloperidol, acute renal failure with rhabdomyolysis and disseminated intravascular coagulation (DIC) developed in the patient, who was accordingly given a diagnosis of haloperidol-induced neuroleptic malignant syndrome (NMS) associated with DIC. He was then given heparin and antithrombin III, and his DIC symptoms improved soon thereafter. Elevated plasma levels of tissue factor and tumor necrosis factor-alpha (TNF-alpha) were sustained during this therapy course. Other cytokines, including interleukin IL-1 beta, IL-2 and IL-6, were not elevated. There are activation of extrinsic coagulation and an elevated level of TNF-alpha during acute renal failure and rhabdomyolysis associated with NMS, which is thought to trigger the onset of DIC.     

Renal cortical blood flow distribution in obstructive nephropathy in rats

To examine the role of intrarenal hemodynamics in in obstructive nephropathy, we determined cortical blood flow distribution (CBFD) in rats with bilateral ureteral occlusion (BUO) and unilateral ureteral occlusion (UUO) during and after release of obstruction. Prior to release of obstruction of 24 hours' duration, we found that outer cortical perfusion decreased by 20+/-5% in both BUO and UUO rats. Furthermore, one hour after release of BUO, there was rapid normalization of CBFD associated with a modest return of glomerular filtration rate (GFR), an almost complete return of renal blood flow (RBF), and a marked postobstructive diuresis. In contrast, after release of UUO, we observed that outer cortical perfusion remained decreased by 21+/-31%, both GFR and RBF remained markedly depressed, and no diuresis occurred. These data demonstrate (1) marked ischemia of the outer cortex in both BUO and UUO during obstruction, (2) a rapid return of CBFD to a normal pattern after release of BUO, but (3) persistent outer cortical ischemia following release of UUO.