Aging phenotype(s) in kidneys of diabetic mice are p66ShcA dependent.

The p66ShcA protein controls cellular responses to oxidative stress, senescence, and apoptosis. Here, we test the hypothesis that aging phenotype(s) commonly associated with the broad category of chronic kidney disease are accelerated in diabetic kidneys and linked to the p66ShcA locus. At the organ level, tissue stem cells antagonize senescent phenotypes by replacing old dysfunctional cells. Using established methods, we isolated a highly purified population of stem cell antigen-1-positive mesenchymal stem cells (Sca-1+ MSCs) from kidneys of wild-type (WT) and p66 knockout (p66 KO) mice. Cells were plated in culture medium containing normal glucose (NG) or high glucose (HG). Reactive oxygen species (ROS) metabolism was substantially increased in WT MSCs in HG medium in association with increased cell death by apoptosis and acquisition of the senescent phenotype. DNA microarray analysis detected striking differences in the expression profiles of WT and p66 KO-MSCs in HG medium. Unexpectedly, the analysis for p66 KO-MSCs revealed upregulation of Wnt genes implicated in self-renewal and differentiation. To test the in vivo consequences of constitutive p66 expression in diabetic kidneys, we crossed the Akita diabetic mouse with the p66KO mouse. Homozygous mutation at the p66 locus delays or prevents aging phenotype(s) in the kidney that may be precursors to diabetic nephropathy.

DC-specific ICAM-3-grabbing nonintegrin mediates internalization of HIV-1 into human podocytes.

Human immunodeficiency virus (HIV)-1 has been demonstrated to contribute to the pathogenesis of HIV-associated nephropathy. In renal biopsy studies, podocytes have been reported to be infected by HIV-1. However, the mechanism involved in HIV-1 internalization into podocytes is not clear. In the present study, we evaluated the occurrence of HIV-1 internalization into conditionally immortalized human podocytes and the mechanism involved. Human podocytes rapidly internalized R5 and X4 HIV-1 primary strains via an endocytosis-dependent pathway, without establishing a productive infection. The HIV-1 internalization was dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) receptor mediated. The role of DC-SIGN was confirmed by using specific blocking antibodies and transfection with small interfering (si) RNA/DC-SIGN. Since podocyte HIV-1 trafficking was not altered by pH-modulating agents, it appeared that HIV-1 routing occurred through nonacid vesicular compartments. Interestingly, transfection of podocytes with neither siRNA/caveolin-1 nor siRNA/clathrin heavy chain inhibited podocyte viral accumulation. Thus it appears that clathrin-coated vesicles and caveosomes may not be contributing to HIV-1-associated membrane traffic.

Effects of nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells.

Cross-linking of cell matrix components by nonenzymatic glycosylation may contribute to diabetic glomerulopathy. We examined the effects of modification of matrix by nonenzymatic glycosylation on mesangial cell function. Matrix was generated by growing mesangial cells in tissue culture for 2 wk and removing the cells with a detergent cell-lysis solution. By indirect immunofluorescence and Northern-blot analysis, the remaining matrix contained laminin, fibronectin, and collagens type I and IV. The matrix was modified by incubation for 24 h with 50 mM glycolaldehyde, a highly reactive cross-linking nonenzymatic glycosylation product, or for 2 wk with 200 mM glucose-6-phosphate (G6P). Modification was carried out with or without equimolar aminoguanidine, an inhibitor of cross-link formation. Nonenzymatic glycosylation of the matrix by glycolaldehyde or G6P was confirmed by fluorometry and [14C]G6P incorporation and was prevented by aminoguanidine. [3H]thymidine incorporation for 24 h by mesangial cells plated onto unmodified or modified matrix was then performed. Modification of matrix had no effect on attachment of mesangial cells, determined 4 h after plating. Nonenzymatic glycosylation of matrix by glycolaldehyde or G6P significantly inhibited thymidine incorporation by mesangial cells. This effect was partially reversible by aminoguanidine. Aminoguanidine-modified matrix had no effect on thymidine incorporation. Thymidine-incorporation results were confirmed by direct cell counting. We conclude that modification of matrix by nonenzymatic glycosylation influences growth of mesangial cells, which could contribute to the mesangial abnormalities of diabetic glomerulopathy.

Morphine promotes apoptosis in Jurkat cells.

Patients with intravenous heroin addiction are prone to recurrent infections and at times these infections are fatal. We evaluated the effect of morphine on the apoptosis of Jurkat cells and freshly isolated human T lymphocytes. Morphine promoted apoptosis of both the Jurkat cells and the freshly isolated T lymphocytes in a dose-dependent manner. DAGO, a specific mu receptor agonist, also promoted Jurkat cell apoptosis. DNA isolated from morphine-treated Jurkat cells and T lymphocytes also showed integer multiples of 200 base pairs. Superoxide dismutase (SOD) enhanced lymphocyte apoptosis; whereas catalase attenuated the morphine-induced apoptosis of Jurkat cells as well as of T lymphocytes. Morphine-treated Jurkat cells also showed a decreased expression of bcl-2 and an enhanced expression of bax. In addition, morphine-treated Jurkat cells showed activation of caspase-3. These results indicate that morphine-induced T lymphocyte apoptosis may be mediated through the generation of reactive oxygen species. The change in ratio of bax and bcl-2 seems to tilt the balance toward apoptosis, leading to the activation of caspase-3. This study provides further support for the hypothesis that morphine may be directly compromising immune function by enhancing apoptosis of T lymphocytes in patients with heroin addiction.

Ethanol-induced neutrophil apoptosis is mediated through nitric oxide.

Clinical reports indicate that acute ethanol intoxication in chronic ethanol abusers is associated with neutropenia. We hypothesize that ethanol accelerates the apoptosis of neutrophils thus decreasing the peripheral blood count of neutrophils. We studied the effect of ethanol on neutrophil apoptosis in vivo as well as in vitro. Human neutrophils harvested from healthy subjects after an alcohol drinking binge showed enhanced apoptosis (before, 0.5+/-0.25 vs. after, 26.1+/-2.6% apoptotic neutrophils/field). Peritoneal neutrophils isolated from ethanol-treated rats also showed increased (P < 0.0001) apoptosis when compared with neutrophils isolated from control rats (control, 0.8+/-0.2% vs. ethanol, 11.8+/-0.7% apoptotic neutrophils/field). In in vitro studies, ethanol in concentrations of 50 mM and higher accelerated the apoptosis of human and rat neutrophils. This effect of ethanol on human neutrophils was time dependent. DNA isolated from ethanol-treated human neutrophils displayed integer multiples of 180 base pairs (ladder pattern), further confirming the effect of ethanol on neutrophil apoptosis. N(G)-monomethyl-L-arginine monoacetate and N(G)-nitro-L-arginine methyl ester, inhibitors of nitric oxide (NO) synthase, attenuated the ethanol-induced neutrophil apoptosis. Sodium nitroprusside, a NO donor, also promoted neutrophil apoptosis. Moreover, ethanol enhanced neutrophil expression of inducible NO synthase. In addition, ethanol stimulated neutrophil NO generation. These results suggest that ethanol accelerates neutrophil apoptosis. This effect of ethanol on neutrophil apoptosis seems to be mediated through the generation of NO.

Prevalence and determinants of acute renal failure following cardiopulmonary resuscitation.

BACKGROUND: The purpose of this study was to determine the prevalence and determinants of acute renal failure in patients following cardiac arrest. METHODS: This was a cross-sectional study of 420 consecutive admissions with a diagnosis of cardiac arrest admitted to the Long Island Jewish Medical Center, New Hyde Park, NY, the Long Island Campus for the Albert Einstein College of Medicine, Bronx, NY, over a 2-year period. Fifty-six patients who initially survived cardiopulmonary resuscitation following cardiac arrest and had serial biochemical and renal function data available were studied. The events during cardiopulmonary resuscitation and clinical and biochemical data were compared and contrasted among patients who developed acute renal failure following cardiopulmonary resuscitation (group 1, n = 16) and those who did not (group 2, n = 40). RESULTS: Patients who developed acute renal failure following cardiopulmonary resuscitation (group 1) had longer duration of resuscitation (12.0 +/- 2.1 minutes vs 6.7 +/- 0.9 minutes for group 2) and received larger dosages of epinephrine during cardiopulmonary resuscitation (1.81 +/- 0.36 mg vs 0.90 +/- 0.18 mg for group 2). Patients in group 1 had a significantly higher frequency of congestive heart failure (43.8% vs 12.5% for group 2), coronary artery disease (87.5% vs 37.5% for group 2), and preexisting compromised renal function (50% vs 12.5% for group 2). Patients in group 1 had significantly worsened long-term survival compared with group 2 patients (6.3% vs 47.5% for group 2). CONCLUSIONS: We conclude that acute renal failure occurs commonly in the postcardiac arrest period. Administration of the vasoconstrictor epinephrine, congestive heart failure, coronary artery disease, and preexisting renal insufficiency may be significant risk factors for the development of postcardiac arrest acute renal failure. The development of acute renal failure following cardiopulmonary resuscitation predicts a lesser likelihood of survival to discharge from the hospital.

Outcome of stroke in patients undergoing hemodialysis.

BACKGROUND: While elevated levels of serum creatinine have been shown to be a risk factor for diminished survival after stroke, it is unknown how renal replacement therapy may affect the outcome. METHODS: Strokes occurring in 26 consecutive patients undergoing hemodialysis at our institution were reviewed and clinical and laboratory variables and outcome were compared with those of patients who had a stroke but had normal renal function. RESULTS: Twenty-four strokes in the patients undergoing hemodialysis were ischemic while only 2 were hemorrhagic. Virtually all the patients had hypertension, half had diabetes mellitus, and most had some prior evidence of cardiovascular disease at the time of their stroke. Fifty percent of the patients undergoing hemodialysis had a good outcome (defined as being discharged home) while the remainder had a poor outcome (defined as dying or being discharged to a nursing facility). The combined presence of hypertension and coronary artery disease had a sensitivity of 91.2% for identifying patients with a poor outcome, while male sex, the presence of coronary artery disease, and the combined presence of hypertension, coronary artery disease, and/or congestive heart failure had sensitivities greater than 80% but low specificity. The outcome of patients undergoing hemodialysis was comparable with that of a control group of patients who had a stroke but had normal renal function, although the length of hospital stay was greater (mean [+/-SEM] 29.8+/-6.4 days vs 12.7+/-1.1 days, respectively; P<.01). CONCLUSIONS: Hospitalized patients undergoing hemodialysis in whom stroke occurs appear to have as good an outcome as that of patients with normal renal function, although they are hospitalized longer. In addition, certain clinical variables seem to be associated with a worse outcome. Aggressive measures to prevent and treat stroke seem as warranted for patients undergoing hemodialysis as for patients with normal renal function, although interventions to reduce the length of hospital stay are needed.

Metal-catalyzed oxidation of immunoglobulin G impairs Fc receptor-mediated binding to macrophages.

Enhanced oxidative stress is a feature of inflammatory and infectious conditions. Proteins may be important targets of oxidation and this may alter their function. We evaluated whether metal-catalyzed oxidation of IgG could alter its ability to bind to Fc receptors on macrophages. Human IgG incubated with an FeCl3/EDTA/ascorbate metal-catalyzed oxidation system resulted in a significant increase in carbonyl content, a measure of protein oxidation, compared to IgG treated with EDTA alone (control). Western blot analysis using an antibody to oxidized protein revealed an increase in antibody binding to both the heavy (Fc portion-containing) and light chains of IgG treated with the oxidizing system. Western blot analysis of papain-digested IgG confirmed oxidative modification of the Fc portion. Binding studies carried out with J774.16 macrophages demonstrated significantly diminished ability of the oxidized IgG to bind to macrophage Fc receptors compared to control IgG. These data demonstrate that IgG is susceptible to metal-catalyzed oxidation and that this impairs its ability to bind to macrophage Fc receptors. Oxidation of IgG might play a role in modulating immune function in infection and disorders associated with immune complex formation by diminishing IgG binding to phagocytic cells.

Myoglobinuria and renal failure after status epilepticus.

Acute renal failure developed in a 28-year-old man after status epilepticus. Myoglobinuria was contributed to by convulsions, trauma and coma during status epilepticus, the three mechanisms responsible for this condition.

Rhabdomyolysis in the hyperosmolal state.

PURPOSE: We undertook this study to determine the occurrence of rhabdomyolysis in the hyperosmolal state. PATIENTS AND METHODS: We reviewed 130 hospital admissions due to diabetic ketoacidosis or hyperosmolal coma, or both. Thirty-one patients (12 men and 19 women) were found to be in the hyperosmolal state. Sixteen of 31 patients showed biochemical evidence of rhabdomyolysis. The clinical and biochemical features of the patients with rhabdomyolysis (Group I) and the patients without rhabdomyolysis (Group II) were compared. RESULTS: Patients in Group I showed a 100-fold increase (7,156 +/- 2,820 IU/L) in serum creatine phosphokinase (CPK) when compared to the patients in Group II (61 +/- 11 IU/L). The mean serum osmolality was much higher (p less than 0.001) in patients with rhabdomyolysis (381 +/- 12 mOsm/kg) than in those without rhabdomyolysis (324 +/- 4 mOsm/kg). The serum sodium level was elevated (p less than 0.001) in Group I patients (151 +/- 4 mEq/L) but not in Group II patients (133 +/- 2 mEq/L). There was a linear association between serum CPK versus serum sodium (r = 0.62, p less than 0.05) and serum CPK versus serum osmolality (r = 0.05, p less than 0.05). The mean serum potassium level was lower (p less than 0.01) in Group I than in Group II. Only two patients (12%) in Group I and almost half the patients (seven of 15) in Group II were hyperkalemic. The mean serum phosphorus level was lower in Group II than in Group I. Four patients in Group I and one patient in Group II developed acute renal failure. CONCLUSION: Subclinical rhabdomyolysis is a common finding in the hyperosmolal state. Absence of hyperkalemia in the presence of muscle injury, hyperosmolality, hyperglycemia, and acidosis suggested pre-existing total-body potassium deficiency in many of these patients. In addition to hypokalemia, the hyperosmolal state predisposes to the development of rhabdomyolysis.

Prevalence and predictors of rhabdomyolysis in patients with hypophosphatemia.

PURPOSE: We undertook this study to determine the prevalence and predictors of rhabdomyolysis in the hypophosphatemic state. PATIENTS AND METHODS: To identify patients with hypophosphatemia, we reviewed medical admissions for the period of January through December 1989. The hypophosphatemic state was considered whenever the serum phosphate was less than or equal to 2.0 mg/dL. Rhabdomyolysis secondary to hypophosphatemia was defined when serum creatine kinase levels were greater than or equal to 224 IU/L; it occurred within 72 hours of the hypophosphatemic episode; and it subsequently normalized. Patients who had any other independent etiology for rhabdomyolysis were excluded. Clinical and biochemical characteristics of patients with rhabdomyolysis (Group I) and patients without rhabdomyolysis (Group II) were compared. Variables that predicted rhabdomyolysis in hypophosphatemia were identified by stepwise logistic regression using a backward elimination procedure. RESULTS: One hundred twenty-nine patients were found to have hypophosphatemia. Forty-six (Group I) of 129 patients (36%) showed biochemical evidence of rhabdomyolysis. There was no difference in serum phosphate and potassium concentrations between Group I and Group II patients. Patients in Group I showed higher values for serum osmolality (p less than 0.05), serum glutamic oxaloacetic transaminase (p less than 0.001), chloride (p less than 0.01), and blood urea nitrogen (less than 0.05) when compared with Group II patients. When biochemical profiles of patients with rhabdomyolysis were evaluated on the day of their peak creatine kinase level, only 16 patients were hypophosphatemic, and the majority of patients showed a transient increase in serum phosphate levels because of ongoing muscle cell injury. Of 17 potential predictors, six variables emerged including sodium, chloride, glucose, blood urea nitrogen, uric acid, and osmolality. These variables provided high sensitivity (0.88) as well as moderate specificity (0.79) for predicting the occurrence of rhabdomyolysis in hypophosphatemia. CONCLUSION: We conclude that rhabdomyolysis commonly occurs in the hypophosphatemic state and that at times severe hypophosphatemia as an etiology may be masked because of ongoing rhabdomyolysis. Serum sodium, chloride, glucose, blood urea nitrogen, uric acid, and osmolality have a predictive role for the occurrence of rhabdomyolysis in the hypophosphatemic state that shows a high specificity and a moderate sensitivity.

Determinants of elevated creatine kinase activity and creatine kinase MB-fraction following cardiopulmonary resuscitation.

OBJECTIVE: We undertook this study to determine the occurrence and the determinants of elevation of serum creatine kinase (CK) levels and CK MB-fraction following cardiopulmonary resuscitation (CPR). DESIGN: Four hundred twenty consecutive adult admissions to the Long Island Jewish Medical Center from January 1989 through December 1990 with a diagnosis of cardiac arrest were reviewed. SETTING: The Long Island Jewish Medical Center, New Hyde Park, NY, the Long Island Campus for the Albert Einstein College of Medicine, Bronx, NY. PATIENTS: Sixty-three patients survived for at least 12 h following cardiac arrest for evaluation of post-CPR CK levels and were included into the study. MEASUREMENTS: Clinical features, biochemical profiles, and administered drug profiles were studied in these patients. The clinical and biochemical features of the patients with (CK greater than 224 IU/L [3.7 mu kat/L]) and without rhabdomyolysis were also compared. MAIN RESULTS: Two major determinants responsible for elevated CK levels emerged, including physical injury (number of chest compressions during CPR) and electrical injury (cumulative number of joules administered during defibrillation). Post-CPR CK levels showed positive correlations with both the number of chest compressions given (p less than 0.001) and the number of joules administered during defibrillation (p less than 0.001). Post-CPR CK-MB levels also showed a positive correlation with the number of joules administered (p less than 0.005) and the number of chest compressions (p less than 0.02). Forty-three (68.3 percent) of the 63 patients developed rhabdomyolysis. Serum CK levels were higher (p less than 0.005) in the patients who received electrical countershock therapy as well as chest compressions when compared with patients who received chest compressions alone. There were no significant differences in electrolyte levels between patients with and without rhabdomyolysis. Thirty patients had a history of coronary artery disease (CAD) and 18 (60.0 percent) of these had a positive MB-fraction post-CPR while only ten of the 33 patients without known CAD had a positive MB-fraction post-CPR (30.3 percent, p less than 0.05). Patients with no known CAD but positive CK-MB fraction had significantly higher total CK levels, physical injury, and electrical injury compared with patients with negative CK-MB fraction. Twenty patients survived CPR and were discharged from the hospital without significant neurologic sequelae. The remaining 43 either died or suffered severe neurologic injury. The patients who survived CPR had a significantly shorter duration of CPR (p less than 0.01) compared with those who did not. Patients who did not have long-term survival following CPR were more likely to have elevated serum potassium, phosphate, and creatinine values. CONCLUSIONS: CK elevation is a common finding following successful CPR after cardiac arrest and this elevation of post-CPR CK levels is related to both physical as well as electrical injury sustained during CPR. Elevation of post-CPR CK-MB fraction seems to be only a crude indicator of preexisting CAD; however, a positive CK-MB fraction in patients without CAD is related to severity of physical injury and electrical injury during CPR. Patients who survive CPR without neurologic impairment appear to be those with a shorter duration of CPR. Elevated serum potassium, phosphate, and creatinine values may be related to an adverse effect on long-term survival.

Rhabdomyolysis and renal failure following status asthmaticus.

Acute renal failure developed in a 25-year-old man following status asthmaticus. He was found to have myoglobinuria. Vigorous contraction of the respiratory muscles and hypoxia were considered to be responsible for the development of myoglobinuria. Associated dehydration, in the presence of myoglobinuria, also contributed to the development of acute renal failure.

Laboratory abnormalities in patients with bacterial pneumonia.

STUDY OBJECTIVES: This study was undertaken to evaluate the laboratory abnormalities observed in patients with bacterial pneumonia as predictors of the severity of illness. DESIGN: Retrospective analysis. SETTING: Tertiary care hospital. PATIENTS AND PARTICIPANTS: We studied 302 consecutive patients who were admitted to the Long Island Jewish Medical Center from January through December 1993 and treated for bacterial pneumonia. The patients were subdivided into two groups based on their serum phosphorus level either on hospital admission or 4 days before the onset of pneumonia, if this was acquired in-hospital. Hypophosphatemia (group 1) was defined as serum phosphorus level of < or = 2.4 mg/dL and normophosphatemia > 2.4 mg/dL (group 2). Three hundred randomly selected hospitalized patients treated for conditions other than pneumonia comprised the control group (group 3). MEASUREMENTS: Groups 1 and 2 were compared with respect to laboratory data, mortality rate, and duration of hospitalization. The laboratory data of patients in group 3 were compared with those treated for bacterial pneumonia (groups 1 and 2). Stepwise multivariate logistic regression analysis was employed to identify the variables that best predicted the onset of pneumonia. RESULTS: In groups 1 and 2, a greater (p < 0.0001) number of patients (135 of 302 patients with pneumonia, 44.7%) developed hypophosphatemia compared with patients in group 3 (31 of 300 control subjects, 10.3%). Patients with pneumonia (groups 1 and 2) had higher levels (p < 0.01) of bicarbonate compared with control subjects. Moreover, patients with pneumonia demonstrated lower levels (p < 0.01) of calcium, phosphorus, albumin, cholesterol, and alanine aminotransferase compared with control patients (group 3). Among patients with pneumonia, those with hypophosphatemia (group 1) had significantly lower levels (p < 0.05) of potassium, calcium, and albumin compared to those subjects with normophosphatemia (group 2). Furthermore, hypophosphatemic subjects manifested higher levels of glucose (p < 0.01) and creatine phosphokinase (p < 0.05) compared to their normophosphatemic counterparts. In addition, hypophosphatemic patients experienced a longer duration of hospital stay (hypophosphatemia, 24.6 +/- 2.0 days, vs normophosphatemia, 14.1 +/- 1.0, p < 0.001) and higher (p < 0.001) mortality compared to normophosphatemic subjects. The incidence of nosocomial pneumonia was higher (p < 0.0001) in hypophosphatemic patients compared to those with normophosphatemia. CONCLUSION: We conclude that hypophosphatemia, hypocalcemia, hypokalemia, and hypoalbuminemia may be predictors of the severity of illness in patients admitted to the hospital with bacterial pneumonia.

Applied pressure modulates mesangial cell proliferation and matrix synthesis.

Substantial in vivo evidence suggests a significant role for glomerular capillary pressure in the pathogenesis of progressive glomerulosclerosis. One presently available in vitro system allows one to study cells while undergoing stretch. However, no comparable system is available to allow one to study in an in vitro system how direct application of pressure to glomerular mesangial cells might result in the development of glomerulosclerosis. We constructed a pressure chamber in which mesangial cells could be subjected to an applied pressure by means of a roller pump and adjustable outlet valve. Mesangial cells were grown either under control conditions or under an applied pressure of 40 to 50 mm Hg corresponding to physiologic intraglomerular pressure. Application of pressure significantly decreased mesangial cell number in prolonged culture though no discernable effect on cell proliferation could be detected after only short-term exposure. Long-term exposure to increased pressure significantly enhanced mesangial cell [3H] proline incorporation, a marker for synthesis of the matrix component collagen, an event considered to be a precursor to the development of glomerulosclerosis. Mesangial cell matrix synthesis was significantly greater for cells subjected to 50 to 60 mm Hg pressure compared to 40 to 50 mm Hg pressure. Secretory products from macrophages subjected to 40 to 50 mm Hg of applied pressure were found to significantly enhance mesangial cell proliferation compared to secretory products from macrophages grown under normal pressure. The enhancement of mesangial cell matrix synthesis by pressure could not be attributed to any change in partial pressure of oxygen in the media nor pH. These data suggest that the direct application of pressure to mesangial cells may result in the development of glomerulosclerosis by increasing mesangial cell matrix synthesis. These in vitro data support a role for glomerular capillary pressure in the pathogenesis of progressive glomerulosclerosis.

Pressure modulates monocyte migration.

Migration of monocytes into the subendothelial space of the aorta has been considered to be an important event in the development of atherosclerosis. Because hypertension is commonly associated with atherosclerosis, we studied the effect of applied pressure on the migration of monocytes. Direct applied pressure increased the migration (P < .001) of monocytes across a filter when compared with normal atmospheric pressure. The migration of monocytes was found to be directly related to the amount of the applied pressure. Amlodipine, a calcium channel blocker, attenuated the migration of monocytes under normal as well as increased pressure conditions in a dose-dependent manner. These studies provide a basis to speculate on the role of direct pressure in the migration of monocytes into the subendothelial space and the possibility that vasoactive agents may modulate the migration of monocytes independent of their pressure-lowering effect.

Acute renal failure of obstetric origin.

Acute renal failure of obstetric origin is common among North Indian patients and comprised 72 (22.1%) of 325 patients undergoing dialysis over an 11-year period. Of these, 46 gravidas had developed renal failure following abortion, and 29 cases were due to complications of late pregnancy. The most striking feature of this study was a high incidence of irreversible renal lesions of bilateral diffuse cortical necrosis in early (18.6%) as well as late pregnancy (37.8%). Overall incidence of diffuse cortical necrosis was 25%. In the remainder, acute tubular necrosis was seen in 52 (72.2%), patchy cortical necrosis in 1 (1.4%), and tubular necrosis along with glomerular involvement in 1 patient (1.4%). Pathogenetic factors which contributed to the development of renal failure, either singly or in combination, were loss of blood failure, either singly or in combination, were loss of blood (79.1%), septicemia (31.9%), hypotension due th hemorrhagic and septicemic shock (51.4%), eclamptic toxemia (11.1%), and disseminated intravascular coagulation in 12.5% patients. Infrequent occurrence of disseminated intravascular coagulation in the septic anc eclamptic patients who developed diffuse cortical necrosis was an interesting finding, as was the fact that coagulopathy was more frequently observed in acute tubular necrosis. Late referral, frequent sepsis, and high incidence of bilateral diffuse cortical necrosis contributed significantly to a high mortality (55.3%).

Fatal complication of intravesical formalin during control of intractable hemorrhage from radiation cystitis.

Fatal acute tubular necrosis occurred in 1 patient in whom intravesical formalin was used to control massive persistent hemorrhage from radiation cystitis. A suggestion is made to monitor blood formic acid levels and institute prompt dialysis whenever these exceed 80 mg. per 100 ml. to avert such a catastrophe. Intravenous sodium bicarbonate appears to be indicated prophylactically in combating the associated metabolic acidosis due to absorbed formic acid.

Determination of erythrocyte superoxide dismutase, catalase, glucose-6-phosphate dehydrogenase, reduced glutathione and malonyldialdehyde in uremia.

Erythrocyte superoxide dismutase (SOD: EC 1.15.1.1), catalase (EC 1.15.1.6), glucose-6-phosphate dehydrogenase (G-6-PD: EC 1.1.1.49), reduced glutathione (GSH) and malonyldialdehyde (MDA) were studied in 27 patients with chronic and 11 patients with acute renal failure. A comparison with 15 age- and sex-matched healthy subjects showed that patients with both acute and chronic renal failure had significantly low G-6-PD (p less than 0.05) values whereas SOD, catalase and MDA showed significantly elevated levels (p less than 0.05). After adequate dialysis or renal transplantation the SOD, G-6-PD, catalase and MDA values returned to normal. The findings suggest that the erythrocyte SOD, catalase, and G-6-PD can undergo an adaptive alteration which however appears reversible.

Acetazolamide toxicity and pharmacokinetics in patients receiving hemodialysis.

Acetazolamide-induced central nervous system toxicity occurred in two patients undergoing hemodialysis. Symptoms of toxicity included fatigue, lethargy, and confusion, which resolved several days after discontinuing acetazolamide. Pharmacokinetic studies showed markedly elevated serum concentrations of the drug during the period of toxicity, which decreased at a slower rate compared with that reported in patients with normal renal function. The effect of hemodialysis on acetazolamide clearance was quantified. The agent should be avoided in patients receiving dialysis unless the dosage is reduced and serum concentration monitoring can be performed in a timely manner. These patients should be monitored closely for central nervous system toxicity if acetazolamide is given.