Micropuncture studies of the recovery phase of myohemoglobinuric acute renal failure in the rat.

Micropuncture studies of the recovery phase of glycerol-induced myohemoglobinuric acute renal failure were performed in rats whose blood urea nitrogen (BUN) had fallen at least 20% below its peak value. The glomerular filtration rate (GFR) of individual nephrons in a single kidney in the recovery period generally either was in the normal range or minimal. Each animal's BUN concentration at the time of the study was inversely related to the proportion of functioning surface nephrons, but did not correlate with individual nephron GFR values. Proximal tubule fractional water absorption was significantly depressed as manifested by both depressed inulin (TF/P) values and supernormal volumes of collections, a finding which, in the absence of a urea-induced osmotic diuresis, suggests impaired sodium transport by the damaged nephron. The mean proximal tubule hydrostatic pressure in recovery was normal and there was little variation in pressure among functioning nephrons. It is concluded that recovery from this model of acute renal failure reflects the progressive recruitment of increasing numbers of functioning nephrons. The recovery of individual nephron glomerular filtration, once begun, was rapid and complete. No evidence could be adduced that the gradual return of renal function towards normal reflects a slow release of tubular obstruction or repair of disrupted tubular epithelium. Rather, recovery appeared to be directly attributable to the return of an adequate effective glomerular filtration pressure. Significant limitation in proximal tubule water absorption persisted after individual nephron GFR had returned to normal or supernormal values in this model of experimental acute renal failure in the rat, a finding which readily accounts for the diuresis associated with the recovery phase of this syndrome.

Factors affecting the frequency infection in renal transplant recipients.

A retrospective review of 149 patients receiving 162 renal transplants showed that 83% of these patients developed one or more infections during a follow-up period averaging one year. In 32 (73%) of 44 deaths, infection was an important contributing cause. In only four (9%) of the deaths were the patients free of infection at the time of death. The Klebsiella-Enterobacter group was the most common agent causing pneumonitis and sepsis. Cryptococcus neoformans caused seven of 11 cases of meningitis. Pseudomonas was the most frequent agent associated with infections documented during postmortem examinations. In a short-term controlled study comparing daily and alternate daily therapy with prednisone, the alternate daily group had significantly (P less than .05) more infections per patient, especially in patients who had no evidence of rejection (P less than .025).

Comparison of the effects of rubidium and potassium on renin secretion from rat kidney slices.

It has been shown previously that both low (less than 2 mM) and high (greater than 45 mM) concentrations of extracellular K inhibit the renin secretory rate of rat kidney slices, and that nonidentical Ca-dependent mechanisms appear to be involved. As Rb can substitute for K in many biological systems, the present experiments were designed to compare the effects of K and Rb on renin secretion of rat kidney slices. Adding either KCl or RbCl to a nominally K-free incubation medium stimulated renin secretory rate in concentration-dependent manners; secretory rate was half-maximally stimulated at approximately 1.5 mM and maximally stimulated at approximately 2-3 mM concentrations of either KCl or RbCl. Ouabain completely abolished the basal secretory rate, in either KCl- or RbCl-containing media. These results suggest that the effects of increasing KCl or RbCl in the range of 0.5-4 mM are attributable to stimulatory effects of Rb and K on Na-K-ATPase activity. Renin secretory rate was greatly inhibited by incubating kidney slices in media containing 60 mM concentrations of either KCl or RbCl. A concentration of methoxy-verapamil which completely blocked the inhibitory effects of 60 mM KCl or of 60 mM RbCl failed to antagonize the inhibitory effects of a nominally K-free medium or of media containing ouabain and either 4 mM KCl or 4 mM RbCl. Taken together with previous results, these observations suggest that Rb can substitute for K in the renin secretory process. Furthermore, they support the hypothesis that inhibitors of Na-K-ATPase, and depolarization inhibit renin secretion by Ca-dependent mechanisms which are not identical.

Evidence that beta 1-adrenoceptor activation mediates isoproterenol-stimulated renin secretion in the rat.

The goal of these experiments was to determine if isoproterenol-stimulated renin secretion in the rat is mediated by activation of beta 1- and/or beta 2-adrenoceptors. The rat renal cortical slice preparation was used. The renin secretory rate was a sigmoid function of the logarithm of the isoproterenol concentration; half-maximal and maximal stimulation occurred at approximately 0.01 and 0.1 microM isoproterenol, respectively. Neither timolol (a nonselective beta-antagonist) nor atenolol (a beta 1-selective antagonist) had a significant effect on basal secretory rate, but both shifted the isoproterenol dose-response curve to the right without changing its slope, suggesting competitive antagonism. Timolol was the more potent, but the response to a maximally effective concentration of isoproterenol could be blocked by timolol (0.9 microM), atenolol (110 microM), or a combination of the two (0.45 microM timolol plus 55 microM atenolol). This latter finding is consistent with action of the two antagonists at one and the same site. If it is assumed that timolol antagonizes both beta 1- and beta 2-adrenoceptors and that atenolol antagonizes only beta 1-adrenoceptors, it follows that isoproterenol-stimulated renin secretion in this preparation is mediated by activation of beta 1-adrenoceptors.

Zinc deficiency: a reversible complication of uremia.

Subnormal plasma zinc levels and decreased zinc concentration in hair and leucocytes as well as increased plasma ammonia and ribonuclease activity in dialyzed and nondialyzed uremic patients indicate that zinc metabolism is abnormal in uremia and is not corrected by dialysis. The effect of oral supplementation with zinc acetate (12 patients) or placebo (12 patients) on the above biochemical parameters in hemodialysis patients was determined as a part of a double-blind study. The zinc-supplemented, but not the placebo, group demonstrated significant increases in mean (+/- SD), plasma zinc (80 +/- 9 to 110 +/- 14, micrograms/dl), leucocyte zinc (56 +/- 13 to 1098 +/- 18, micrograms/10(10) cells), hair zinc (140 +/- 12 to 190 +/- 16 micrograms/g), and decreases in plasma ammonia (76 +/- 10 to 40 +/- 6 micrograms/dl) and plasma ribonuclease activity (1.49 +/- 0.08 to 0.78 +/- 0.10, OD/min/ml). Abnormalities of taste and sexual function improved significantly in patients receiving zinc but not in those on placebo therapy. These improvements in biochemical as well as clinical parameters confirm and extend our earlier observations of improvement in taste and sexual function after zinc supplementation. Together, they suggest that zinc deficiency is a complicating feature of uremia and can be corrected by oral zinc supplementation.

Improvement of uremic hypogeusia by zinc: a double-blind study.

Diminished taste acuity may account for the persistence of protein and caloric malnutrition observed in a majority of hemodialysis patients inspite of liberalization of the prescribed amount of dietary protein. Twenty-two patients undergoing thrice weekly hemodialysis for more than 6 months were tested for taste acuity and plasma zinc concentration, after which a double-blind study was instituted using a zinc supplement (50 mg of elemental zinc as zinc acetate per day) or a placebo. The threshold of taste detection and recognition for salt (NaCl), sweet (sucrose), and bitter (urea) but not for sour (HCl) improved significantly in all patients on zinc supplementation. None of these parameters improved in those taking placebo. During the study period, the mean plasma zinc level increased from 75 +/- 8 to 97 +/- 10 microgram/dl (P less than 0.001) in patients receiving zinc acetate. There was not significant change in plasma zinc level in the placebo group (75 +/- 15 to 80 +/- 15). The results of this study show that uremic hypogeusia improved in association with zinc supplementation and elevation of plasma zinc concentration.

Elevated plasma copper in chronic renal failure.

Hypercupremia has been described in patients undergoing chronic dialysis. To further characterize dialysis-associated hypercupremia, we studied plasma copper (PCu) and ceruloplasmin (Cp) in patients on hemodialysis (n = 20) and peritoneal dialysis (n = 25), in uremic patients (n = 10) not yet on dialysis, and in normal age-matched control subjects (n = 20). PCu was significantly elevated in all three patients groups (mean +/- SD) (20.6 +/- 4.1, 19.8 +/- 4.6, 19.8 +/- 4.9 mumol/L, respectively) vs control subjects (16.5 +/- 2.7 mumol/L). However, Cp levels were not significantly different among the four study groups (330 +/- 60, 320 +/- 70, 370 +/- 100, and 360 +/- 90 mg/L, respectively). Calculated nonceruloplasmin copper was significantly higher in all uremic groups. The measurement of chelatable Cu confirmed the presence of significantly higher extractable Cu in hemodialysis (2.7 +/- 0.6 mumol/L) and peritoneal dialysis patients (2.4 +/- 0.5 mumol/L) than control subjects (1.5 +/- 0.3 mumol/L). Cu is elevated in uremia regardless of dialysis status and this elevation is not accounted for by an increase in plasma ceruloplasmin.

Dynamic changes in serum phosphorus levels in diabetic ketoacidosis.

The dynamic changes in serum phosphorus levels in 69 episodes of ketoacidosis in 48 diabetic patients were retrospectively evaluated. The mean age was 41 +/- 2 years (mean +/- SEM), and the duration of diabetes mellitus was 7 +/- 1 years. The serum phosphorus levels determined within the first six hours of admission were analyzed. Before initiation of therapy, the incidence of hyperphosphatemia was 94.7 percent. At the end of 12 hours, the mean serum phosphorus level fell from 9.2 +/- 0.6 to 2.8 +/- 0.3 mg/dl. Before therapy, the serum phosphorus level correlated positively with the serum glucose level, the effective plasma osmolality, and anion gaps, and correlated negatively with the serum chloride level. It is concluded that hyperphosphatemia is common in diabetic ketoacidosis before therapy. The increase in serum phosphorus is likely to be due to a transcellular shift. Potential factors responsible for the shift are serum glucose, through its osmotic effect, and the organic anions.

Rapidly progressive glomerulonephritis and monoclonal gammopathy.

A case of rapidly progressive glomerulonephritis associated with nephrotic syndrome, hematuria, and edema is reported. Monoclonal IgG-lambda was found in the serum and urine. Renal biopsy revealed diffuse proliferative glomerulonephritis with crescent formation. Immunofluorescent study revealed IgG and lambda in a focal segmental distribution. Subepithelial humps were found on electron microscopic examination. A spectacular feature of the deposits was the presence of organized linear fibrils within the humps. Similar fibrils were found in the mesangium and urinary space. Renal function deteriorated rapidly, necessitating hemodialysis in eight months. In addition to the present case, 24 cases of glomerulonephritis associated with "benign" monoclonal gammopathy reported since 1970 are reviewed, and the potential causal relationship between monoclonal gammopathy and glomerular involvement is stressed.

Effect of renal transplantation on zinc metabolism and taste acuity in uremia. A prospective study.

The effect of successful renal transplantation on zinc metabolism and taste acuity was determined prospectively in 15 adult uremic patients. Before transplantation all patients had subnormal concentrations of zinc in plasma and hair, as well as abnormal taste detection and recognition thresholds for sodium (salty), sucrose (sweet), hydrochloric acid (sour), and urea (bitter). Following renal transplantation, abnormalities of taste acuity and zinc metabolism persisted and were accompanied by increased urinary zinc excretion in all patients. Normalization of zinc concentration in plasma and hair as well as taste acuity did not occur until one year after transplantation and was associated with a concomitant decrease in urinary zinc excretion. The plasma zinc levels and daily urinary zinc excretion were inversely related (r = 0.62, P less than .001) in all patients with normal allograft function. None of the zinc parameters was significantly related to azathioprine or corticosteroid dosage. The results of this study suggest that zinc deficiency and taste abnormalities of uremia persist up to one year posttransplant and may be related to increased urinary zinc losses. The mechanisms underlying post-transplant hyperzincuria as well as clinical significance of zinc deficiency following transplantation remain to be determined.

Leukocyte metabolism and function in uremia.

Leukocyte metabolism was studied in 13 non-diabetic hemodialysis patients, 8 clinically stable, nondiabetic transplant recipients, and 13 control subjects. Metabolic parameters included rates of oxygen consumption (nmoles/min/10(6) cells), glucose uptake, lactate production (nmoles/hr/10(6) cells), and 14C-l-glucose oxidation to 14CO2 (nmoles/hr/10(6) cells). Granulocyte metabolism was stimulated by phagocytosis of opsonized zymosan (Z) and by the membrane perturbing agent phorbol myristate acetate (PMA). Granulocyte motility in response to zymosan-activated plasma (ZAP) was also studied. Granulocytes from hemodialysis patients showed significantly impaired stimulated oxygen consumption (Z = 2.41 +/- 0.30 vs. 3.73 +/- 0.39; PMA = 2.63 +/- 0.33 vs. 3.67 +/- 0.19), resting glucose uptake (17.7 +/- 2.9 vs. 36.5 +/- 3.5), stimulated glucose uptake (Z = 44.2 +/- 7.1 vs. 71.8 +/- 5.3; PMA = 63.7 +/- 5.5 vs. 92.8 +/- 5.6), stimulated lactate production (Z = 68.4 +/- 5.1 vs. 97.5 +/- 9.3; PMA = 70.7 +/- 4.9 vs. 92.7 +/- 5.4), and ZAP-stimulated granulocyte motility (16 +/- 3 vs. 30 +/- 4 mu). Metabolic responses of granulocytes from transplant recipients were frequently intermediate between those of hemodialysis patients and controls, but not significantly different from controls. Abnormalities of glucose and oxygen metabolism in granulocytes from uremic patients may cause or contribute to granulocyte dysfunction and vulnerability to infection in such patients.

Zinc metabolism and taste acuity in renal transplant recipients.

To determine the effect of renal transplantation on taste acuity and zinc metabolism, we tested 43 patients with functioning allografts for 2.5 to 96 months. They were tested for taste by the 3-drop stimulus technique. In 30 of them, we determined zinc levels in plasma, hair, and urine. Subnormal plasma and hair zinc, as well as hyperzincuria, was present in all of the 15 patients less than 12 months posttransplant. In contrast, 10 patients who were more than 12 months posttransplant had plasma zinc levels, hair zinc, and urinary zinc excretions in the normal range. Zinc concentrations in plasma and hair of 5 patients who were more than 12 months posttransplant with renal failure, were subnormal and were similar to those in hemodialysis patients. Similarly, taste detection and recognition thresholds for sodium chloride, sucrose, urea, and hydrochloric acid were normal only in patients more than 12 months posttransplant with normal renal function. Plasma zinc, hair zinc, and urinary zinc were not related to prednisone or azathioprine dosage. These results suggest that abnormalities of zinc and taste persist up to 12 months posttransplant and may be related to increased urinary zinc losses.

Factors underlying abnormal zinc metabolism in uremia.

Zinc balance studies were completed in ten hemodialyzed adult uremic patients and five normal controls to determine the cause of abnormal zinc metabolism in uremia. Subjects were fed standard hospital foods providing nutrients in amounts recommended for adult stable hemodialyzed patients. The amount of zinc in the diet was kept constant at 10 mg per day. After one week of stabilization, blood, urine, used dialysate (in patients on dialysis days) and stool samples were collected daily for the next two weeks. In comparison to controls, patients had lower plasma zinc levels (mean +/- SD, 112 +/- 10 vs. 82 +/- 12 micrograms/dl, P less than 0.01), lower urinary zinc excretion (560 +/- 120 vs. 40 +/- 20 mg/24 hrs, P less than 0.001) and higher fecal zinc losses (8.1 +/- 0.7 vs. 10.2 +/- 0.6 mg/24 hrs, P less than 0.01). Dialytic zinc losses were minimal (26 +/- 4 micrograms/treatment). During the study period, patients were in a negative zinc balance while normal controls maintained a positive zinc balance on 10 mg dietary zinc intake. These results demonstrate that augmented fecal zinc excretion in the presence of hypozincemia contributes to the negative zinc balance in hemodialyzed uremic patients.

Lymphatic complications in renal allografts--a new look.

The pathophysiology of lymphatic complications was evaluated in 10 patients as to the possible source of lymphatic fluid. Both the recipient's peripheral lymphatics and the allograft's lymphatics were found to contribute to lymphatic complications. The prevention of lymphoceles and lymphatic fistulas may be accomplished by careful ligation of both the recipient's and the allograft's lymphatics.

Does decreasing extracellular Na inhibit in vitro renin secretion by affecting Na-Ca exchange?

It has been shown previously that in vitro renin secretion is inhibited by partial replacement of extracellular NaCl with either mannitol or choline chloride; the inhibitory effect is attributed to an increase in intracellular Ca, resulting from a decreased rate of Ca efflux via Na-Ca exchange. In the present experiments, we confirmed that partially replacing NaCl with choline chloride inhibited renin secretion from rat renal cortical slices, but we found that atropine completely blocked the effect, suggesting cholinergic mediation. Partially replacing NaCl with mannitol also inhibited renin secretion, but the effect could not be attributed specifically to a reduction in extracellular Na. Moreover, the stimulatory effect of Ca chelation on renin secretion was antagonized by either mannitol- or choline chloride -containing incubation media. These results do not support the hypothesis that lowering extracellular Na inhibits renin secretion by a mechanism involving decreased Ca efflux via Na-Ca exchange.

Quinacrine antagonizes the effects of Na,K-ATPase inhibitors on renal prostaglandin E2 release but not their effects on renin secretion.

Previous results have demonstrated that two inhibitors of Na-and-K-activated adenosine triphosphatase (ouabain, vanadate) lead to stimulated prostaglandin E2 release and to inhibited renin secretion in the rat renal cortical slice preparation. It was speculated that stimulation of phospholipase A2 activity accounted for the effect on prostaglandin E2 release. We used the same preparation in the present experiments, and showed that another inhibitor of Na-and-K-activated adenosine triphosphatase (K-free incubation medium) stimulates prostaglandin E2 release and inhibits renin secretion. Quinacrine antagonized the stimulatory effects of ouabain, vanadate, and K-free medium on prostaglandin E2 release (consistent with phospholipase A2 involvement), but did not antagonize their inhibitory effects on renin secretion. Collectively, these observations lend further weight to the argument against a mediatory role of prostaglandin synthesis in the renin secretory process.

Cyclosporine A inhibits prostaglandin E2 release, and has no effect on renin secretion, from rat renal cortical slices.

These experiments were designed to test the hypothesis that cyclosporine A (CSA) inhibits renin secretion and stimulates renal prostaglandin E2 (PGE2) release in vitro. In rat renal cortical slices incubated at 37 degrees C in a buffered and oxygenated physiological saline solution containing 4 mM KCl, CSA concentrations ranging from 1 to 30 microM had no significant effect on renin secretion. Furthermore, partial depolarization of the cells, produced by increasing extracellular KCl concentration to 20 mM, failed to reveal any latent inhibitory or stimulatory effects of CSA on renin secretion. On the other hand, PGE2 release was significantly inhibited by CSA over the same range of concentrations. This inhibitory effect might be explained by the previous findings of others, that CSA inhibits phospholipase A2 activity, thereby decreasing arachidonic acid production, the rate-limiting step in PG synthesis. In conclusion, CSA inhibits PGE2 release but fails to affect renin secretion in vitro. These results suggest that the occasional effects of CSA on renin secretion in intact animals must be attributable to indirect and/or chronic effects.

Acute renal failure.

Acute renal failure is divided into its classic parts: prerenal azotemia, postrenal azotemia (obstruction), and renal azotemia (including acute tubular necrosis). The division of acute tubular necrosis into the ischemic and toxic varieties is supplemented by an analysis of toxic varieties into those caused by antibiotics, radiologic contrast agents, chemotherapeutic-immunosuppressive agents, heavy metals, organic solvents, etc. Acute tubular necrosis caused by hemoglobin and myoglobin is described in detail. The importance of urinalysis and the urinary indices in distinguishing prerenal azotemia from acute tubular necrosis is stressed. Finally, current prognosis and treatment are reviewed.

Acute drug-associated rhabdomyolysis: an examination of its diverse renal manifestations and complications.

Thirty patients with drug associated acute nontraumatic rhabdomyolysis were evaluated. Acute renal failure, oliguric (ORF) in ten and nonoliguric (NORF) in another ten patients, was observed. The remaining ten patients did not develop renal failure (NRF). To identify factors that may have contributed to this clinical diversity, these three groups were compared. Data from 51 patients reported in the literature were also included in the analysis. The patients with ORF were slightly younger than patients with NORF. They had higher incidence of muscle swelling and higher serum potassium. ORF was more severe, lasted longer, and required more dialysis than NORF. The group of patients with renal failure had higher incidence of coma and more patients with very high muscle enzyme elevation than NRF patients. Hypercalcemia, a unique complication of rhabdomyolysis, was reported in 22 patients. It was not seen in patients without renal failure. There were no differences in age, incidence of coma, muscle swelling, and muscle enzyme between those who did and those who did not develop hypercalcemia. Sixteen patients with nerve entrapment had higher incidence of coma and muscle swelling than the rest of the patients.