Acute renal failure associated with the administration of parenteral etidronate.

Etidronate-induced toxicity has not been well documented in humans. This is a detailed account of a case of acute renal failure believed to be due to etidronate. The patient inadvertently received an overdose of etidronate by the intravenous route and subsequently developed acute renal failure as evidenced by a rapid and sustained rise in serum creatinine. The temporal relationship was strongly suggestive of etidronate-induced nephrotoxicity. Other possible causes, such as postrenal obstruction, acute tubular necrosis due to hypotension or sepsis, and other nephrotoxic drugs were excluded through diagnostic and laboratory tests.

The serum osmole gap.

Estimation and measurement of serum osmolality can be of value in the clinical management of certain forms of critical illness. Osmolality is a measure of the concentration of osmotically active particles, or solutes, in a solution. Only low-formula weight ions and uncharged molecules that are present in relatively high concentrations contribute significantly to serum osmolality. Serum osmolality can be easily estimated from the three major osmotic constituents of normal serum (sodium, urea, and glucose) by a simple formula. An understanding of serum osmolality, its laboratory measurement, its bedside estimation, and the concept of the osmole gap, is crucial in making a preliminary diagnosis of methanol and ethylene glycol intoxication, as well as a few other related compounds. There are important caveats to this use of the osmole gap, because under certain circumstances both false-positive and false-negative interpretations may occur. The osmole gap may also be helpful for confirming pseudohyponatremia, as a gauge for dosing mannitol and glycerol when used to treat intracranial hypertension, and as a prognostic indicator in circulatory shock.

Roles of adenosine and theophylline on the recovery of adenine nucleotides in postischemic cultured renal tubular cells.

The effect of adenosine (ADO) on the recovery of cellular adenine nucleotides (AN) was evaluated in the cultured cells deprived of oxygen and substrates (ischemia) and in nonischemic cells (control). The primary cultured cells were obtained from microdissected rabbit proximal straight tubules. Ten-day-old cultured cells were made ischemic for 6 hr, and allowed to recover for 24 hr. At the end of ischemia, cells were incubated with ADO, theophylline (T), dipyridamole (D), coformycin (C) or combined agents for 3 hr. Total AN (TAN) were determined after 3 and 24 hr of recovery. The results, after 3 hr of incubation, suggest that in both control and ischemic cells, ADO is taken up by cultured cells and is preferentially converted to nucleotides. This effect is blocked by D, which inhibits ADO uptake, uninfluenced by C, which inhibits ADO deaminase and potentiated by T, which inhibits 5'-nucleotidase. After 24 hr of recovery, the beneficial effects of ADO alone or combined D, C, or T, on TAN were not seen in control cells. In contrast, in the ischemic cells, after 24 hr of recovery, ADO + T normalized ATP, ADP and TAN to the preischemic levels. T alone significantly increased ATP after 24 hr of recovery. To demonstrate further that the beneficial effect of T is due to inhibition of 5'-nucleotidase, cells were treated with adenosine alpha, beta-methylene diphosphate in the same manner as T. Combined ADO + adenosine alpha, beta-methylene diphosphate normalized ATP, ADP and TAN after 24 hr of recovery. This finding suggests that inhibition of 5'-nucleotidase improves postischemic AN.(ABSTRACT TRUNCATED AT 250 WORDS)

Mannitol-induced acute renal failure.

Mannitol is widely used to reduce intracranial pressure and is protective against ischemic and nephrotoxic acute renal failure. However, the capacity of this seemingly innocuous agent to produce acute renal failure is not well recognized. We report herein the clinical course of 8 cases of mannitol-induced acute renal failure. In addition, we reviewed all previously reported cases of mannitol-induced renal failure. In the present series, acute oliguric renal failure developed within 3.5 +/- 1.1 (mean +/- SD) days after receiving daily and total mannitol doses of 189 +/- 64 g and 626 +/- 270 g, respectively, over 3.5 +/- 1.5 days. The peak serum creatinine was 5.7 +/- 2.7 mg/dl and peak osmolal gap was 74 +/- 39 mOsm/kg water. Renal tubular epithelial cells containing vacuoles were seen in the urinary sediments of 6 patients. Renal function improved rapidly upon discontinuation of mannitol and/or removal of mannitol by hemodialysis. In those previously reported cases in which the baseline renal function was normal, acute renal failure developed after receiving total mannitol doses of 1171 +/- 376 g. The peak osmolal gap was 107 +/- 17. In contrast, in those with underlying renal compromise, renal function worsened after a total mannitol dose of 295 +/- 143 g. The pathogenesis of mannitol-induced renal failure is not yet established but may be associated with renal vasoconstriction produced by high concentrations of mannitol. This may be averted in clinical practice by monitoring the osmolal gap, rather than serum osmolality alone, when using mannitol infusions for the treatment of intracranial hypertension.

Role of adrenoceptors in diphenylhydantoin-stimulated renin release.

We have previously shown that diphenylhydantoin (DPH)-stimulated renin release is mediated by, or requires the presence of, the renal nerves. In the present study, we examined the effects of adrenergic blockers in DPH-stimulated renin release in five groups of anesthetized dogs. In vehicle-treated dogs, DPH at a dose of 0.18 mg/kg-min increased renin secretion rate (RSR) from 56 +/- 14 to 269 +/- 60 and returned to 84 +/- 30 ng of angiotensin (ANG) l/hr-min (P less than 0.01, analysis of variance). In metoprolol-treated dogs, DPH produced no significant changes in RSR (90 +/- 28 to 144 +/- 67 to 100 +/- 51 ng of ANG l/hr-min). Likewise, in atenolol-treated dogs, RSR was 34 +/- 10 before, 59 +/- 15 during, and 23 +/- 8 ng of ANG l/hr-min after the infusion of DPH. In contrast, after pretreatment with ICI 118,551 (a beta 2 adrenoceptor antagonist), RSR was 37 +/- 9 before, 151 +/- 57 during, and 47 +/- 12 ng of ANG l/hr-min after the infusion of DPH (P less than 0.01). In phentolamine-treated dogs, RSR was 69 +/- 20 before, 295 +/- 53 during, and 95 +/- 17 ng of ANG l/hr-min after the infusion of DPH (P less than 0.01). Changes in renal blood flow, renal vascular resistance, and UNa V were in the same directions in all groups. These data suggest that DPH-stimulated renin release is mediated by beta 1 adrenoceptors since both beta 2 and alpha adrenoceptor antagonists have no effects on DPH-stimulated renin release.

Recurrence of monoclonal gammopathy-related glomerulonephritis in renal allograft.

A patient developed hematuria and nephrotic syndrome. A monoclonal IgG-lambda was detected in his serum, urine and glomeruli. Kidney biopsy revealed crescentic glomerulonephritis with characteristic "fibrils" or tactoids in the mesangial and subendothelial areas. Nine months after the diagnosis, he was placed on hemodialysis. Two years later, he received a cadaveric kidney transplantation. Eighteen months later, proteinuria recurred. Renal biopsy revealed crescentic glomerulonephritis, positive immunofluorescence for IgG-lambda and characteristic "fibrils" in the mesangium and subendothelium of the glomeruli. These findings were the same as those found in his native kidney. This finding demonstrates that glomerulonephritis associated with monoclonal gammopathy can recur in the allograft.

Disordered water metabolism: hyponatremia.

Normal osmoregulation is maintained by the proper function and interplay of factors influencing thirst, renal water metabolism, and vasopressin secretion. In pathophysiologic states, body water homeostasis is disrupted and hyponatremia ensures. Hyponatremia associated with cardiac failure, hepatic failure, respiratory failure, diabetes mellitus, the postoperative state, and other disorders is commonly found in the critical care setting. The pathophysiology, diagnosis, and treatment of hyponatremia are discussed.

Disordered sodium metabolism: sodium retention states.

Sodium retention frequently occurs in the critically ill patient. Sodium retention states include cardiac failure, liver failure, nephrotic syndrome, and hypoalbuminemic states. A clear understanding of the pathophysiology and the mechanism of sodium retention are essential for the proper care of these patients.

Role of intracellular calcium in renal nerve-mediated renin release.

We evaluated the role of intracellular calcium in renal nerve-mediated renin release in four groups of anesthetized dogs. Each dog received renal nerve stimulation (RNS)(0.5 Hz) twice as follow: control, RNS, recovery; control, RNS, recovery. Group 1 served as time control. Group 2 received Ca ionophore A23187 (Io) and Groups 3 and 4 received verapamil at 2.5 and 5 micrograms/kg X min respectively during the second RNS. In Group 1, renin secretion rate (RSR) increased from 95 +/- 22 to 223 +/- 73 (P less than 0.05) and from 13 +/- 5 to 108 +/- 20 ngANG I/hr X min (P less than 0.005) during the first and second RNS, respectively. In Group 2, RSR increased from 210 +/- 85 to 402 +/- 118 (P less than 0.02) and from 88 +/- 11 to 157 +/- 39 ngANG I/hr X min (NS) during the first and second RNS, respectively. In both groups, systemic and renal hemodynamics and UNaV did not change. In Group 3, verapamil alone did not increase RSR. During RNS, RSR also did not increase. In Group 4, verapamil alone increased RSR from 42 +/- 12 to 273 +/- 71 ngANG I/hr X min (P less than 0.03) despite a similar reduction in systemic blood pressure as in Group 3. RNS did not increase RSR further during verapamil infusion. The present study suggests that increased intracellular Ca by Io inhibits renal nerve-mediated renin release. A low dose of verapamil has no effect on renin release and does not augment renal nerve-mediated renin release. A high dose of verapamil increases renin release but does not enhance RNS-mediated renin release. We conclude that intracellular calcium plays an important role in renin release and may be the final messenger in renal nerve-mediated renin release.

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.

Mechanism of effect of dibutyryl cyclic adenosine 3',5'-monophosphate on canine renal renin release.

We evaluated the effect of intrarenal arterial infusion of dibutyryl cyclic AMP on renal renin release. Dibutyryl cyclic AMP (300 micrograms/kg X min) produced significant and reversible increases in renin secretion rate, renal blood flow and urinary Na+ excretion. In the non-filtering kidneys, dibutyryl cyclic AMP increased renin secretion rate and renal blood flow. In indomethacin-treated dogs, dibutyryl cyclic AMP also produced significant and reversible increases in renin secretion rate and renal blood flow but had no effect on Na+ excretion. During infusion of dibutyryl cyclic AMP, infusion of the Ca ionophore A23187 failed to inhibit renin release. These findings suggest that the effect of dibutyryl cyclic AMP on renin release is not mediated by prostaglandins or intracellular Ca and does not involve the macula densa. We conclude that dibutyryl cyclic AMP has a direct effect on the juxtaglomerular cells.

Mechanism of effect of diphenylhydantoin on renal renin release.

This study was undertaken to delineate the mechanism of the effect of diphenylhydantoin (DPH) on renal renin release. DPH at a dose of 0.18 mg X kg-1 X min-1 was infused for 30 min into the renal artery of anesthetized dogs with acute unilateral renal denervation. In the innervated kidney, DPH infusion increased renin secretion rate (RSR) from 189 +/- 54 to 939 +/- 279 ng ANG I X h-1 X min-1. In the contralateral denervated kidneys, RSR did not change. An identical study was done in a second group of dogs in which unilateral renal denervation was done 24 h prior to DPH infusion. In this group, DPH infusion increased RSR from 63 +/- 57 to 643 +/- 180 ng ANG I X h-1 X min-1 in the innervated kidneys. In the contralateral denervated kidneys, RSR did not change. In a separate group of indomethacin-treated nondenervated dogs, intrarenal infusion of DPH increased RSR from 131 +/- 32 to 452 +/- 88 ng ANG I X h-1 X min-1. The percent increase in RSR in the indomethacin-treated dogs was not significantly different from the non-indomethacin-treated dogs. These data suggest that the stimulatory effect of DPH on renin release is mediated by or requires the presence of renal nerves. The step(s) after the renal nerves is (are) not mediated by prostaglandins.

Effect of imidazole on the recovery from bilateral ureteral obstruction in dogs.

The effects of indomethacin (INDO) and imidazole (IMID) on postobstructed kidney functions were evaluated in dogs after 24 h of bilateral ureteral obstruction (BUO). In vehicle-treated dogs 1 h after release of BUO, clearances of inulin and PAH (Cin and Cpah) were 37 and 26%, respectively, of the preobstruction values. Fractional sodium excretion (FEna) increased from 0.5 +/- 0.1 to 2.9 +/- 0.6. Urine osmolality (Uosmol) increased by 55 +/- 9 mosmol/kg H2O in response to 50 mU of aqueous vasopressin. In INDO-treated dogs, Cin and Cpah were 39 and 21%, respectively, of the preobstruction values. FEna increased from 0.7 +/- 0.2 to 4.0 +/- 0.9. Uosmol increased by 91 +/- 19 mosmol/kg H2O in response to vasopressin. This lack of beneficial effects of INDO may reflect its cancelling effect on prostaglandins' and thromboxanes' (TX) effects on the renal hemodynamics of the postobstructed kidney. To further assess the roles of TX in the postobstructed kidney, IMID, and inhibitor of TX synthesis, was given before the release of obstruction. In this group of dogs, the Cin of the postobstructed kidney did not differ from the preobstruction value. CC pah was 45% of the preobstruction value, a level significantly higher than in either vehicle- or INDO-treated dogs. FEna wa 1.5 +/- 0.2 before and 3.5 +/- 2.3 after obstruction. Uosmol increased by 187 +/- 51 mosmol/kg H2O after vasopressin, a level significantly higher than in vehicle-treated dogs. The present study suggests that IMID improves Cin, Cpah, FEna, and concentrating ability of the postobstructed kidney. TX may be responsible for the persistent reductions of Cin and Cpah in the postobstructed kidney.

Prescribing medication in long-term dialysis units.

Little information is available regarding the current patterns of medication use in long-term dialysis centers. Therefore, we surveyed the medication records of 1,023 patients undergoing long-term dialysis therapy in 27 dialysis centers. The mean number of medications prescribed per patient was 7.7 +/- 0.54, increasing patient age, increasing duration of dialysis, in-center dialysis, and the presence of underlying diabetic and hypertensive nephropathy were associated with increased frequency of medication use. The use of multiple pharmacologic agents was associated with a high frequency of drug duplication (12%), potential dosage error (9%), potential significant drug interaction (15%), and use of contraindicated drugs (2.5%). A lack of individualization of the use of several pharmacologic agents was apparent. An extreme degree of center variability in drug use was also apparent. Periodic review of medication use should be undertaken in the long-term dialysis setting.

Ethylene glycol poisoning: diagnosis based on high osmolal and anion gaps and crystalluria.

We report a case of ethylene glycol poisoning in a 54-year-old man found comatose on the street. No history was available. The diagnosis was based on the findings of a high anion gap metabolic acidosis, a high osmolal gap, and the presence of oxalate and hippurate crystals in the urine. The diagnosis was confirmed later by an ethylene glycol level of 775 mg/dl. This case illustrates how these parameters can be used in the emergency department for rapid diagnosis and management.

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.

Prostaglandin-mediated hyperemia and renin-mediated hypertension during acute ureteral obstruction.

Acute elevation of ureteral pressure to 100 mm Hg in anesthetized dogs (n=7) resulted in an increase (P less than 0.005) in systemic blood pressure form 151 +/- 7 to 163 +/- 7 mm Hg, a transient (approximately 15 min) increase (P less than 0.05) in renal blood flow from 413 +/- 27 to 465 +/- 27 ml/min and a rise (P less than 0.05) in plasma renin activity from 6.0 +/- 1.6 to 10.3 +/- 2.1 ng/ml/hr. Pretreatment with a competitive inhibitor of angiotensin II, i.e. sar1gly8AII, abolished the hypertensive response to acute ureteral obstruction, and pretreatment with 2 mg/kg of either indomethacin (n=6) or meclofenamate (n=3), 15 min before obstruction, prevented the hyperemic response. These results suggest that acute ureteral obstruction leads to hypertension via activation of the renin-angiotensin system and hyperemia via a prostaglandin-initiated mechanism.

Mechanism of dopamine-induced diuresis in the dog.

This study was undertaken to evaluate the effect of dopamine (D) on renal water excretion. Intravenous (i.v.) infusion of D (7.5 microgram/kg per min) was associated with a significant, reversible increase in free water excretion (CH2O) and a decrease in urinary osmolality (Uosmol). These changes, however, were associated with significant increases in renal blood flow (RBF), glomerular filtration rate (GFR), and urinary sodium excretion (UNaV). These increases could have been responsible for the diuretic response to D. To examine whether D has a direct effect on vasopressin (ADH) release, D was infused into one common carotid artery at a dose equal to one-fourth the i.v. dose. No effects on CH2O and Uosmol were observed. To examine whether D might have an antagonistic effect on ADH a single bolus of ADH (100 mU) was given to the same hypophysectomized dogs with and without D infusion. The antidiuretic response to ADH was the same, whether or not D was given concomitantly. The net changes in Uosmol and CH2O in response to ADH were not significantly different. Taken together, the present results provide no evidence for a direct effect of D on ADH release nor do they indicate an interference with the peripheral action of ADH. The dopamine-induced diuresis is probably the result of increased solute excretion. This, in turn, is the result of the combined effects of dopamine on increasing renal blood flow, GFR, and sodium excretion.