Wadi N. Suki

Acute treatment of hypercalcemia with furosemide.

Abstract Eight patients with serum calcium values ranging between 12.3 and 18.4 mg per 100 ml were treated with large doses of furosemide intravenously. Their urinary losses of water, sodium and potassium were measured and carefully replaced. Serum calcium was reduced to normal in three patients and to near normal in another three. In the remaining two patients serum calcium fell from 18.4 to 14.6, and from 18.0 to 14.8 mg per 100 ml. The mean fall in serum calcium was 3.1 mg, with a range of 2.3 to 3.8 mg per 100 ml. The decrease was the consequence of the excretion of 0.7 to 2.7 g of calcium in the period of diuresis. Magnesium losses were considerable and had to be replaced. This method of treatment appears safe in patients with compromised cardiac reserve, and effective even in patients with moderate renal insufficiency. The careful replacement of water and electrolyte losses (sodium, potassium and magnesium), however, is essential if this therapy is to be safe.

Plasma Acid-Base Patterns in Diabetic Ketoacidosis

In a study of the types of plasma acid-base patterns present at 196 admissions for diabetic ketoacidosis we found no relation between the initial level of serum total carbon dioxide and the plasma anion gap; instead, there was a broad spectrum of acid-base patterns, ranging from pure anion-gap acidosis to pure hyperchloremic acidosis. Although the degree of renal dysfunction on admission, which reflected the magnitude of volume depletion, was independent of the severity of metabolic acidosis, it was responsible for the variable retention of plasma ketones: the more severe the volume depletion on admission, the greater the ketone retention and the less prominent the hyperchloremic acidosis. Recovery from acidosis was significantly slower in patients admitted with pure hyperchloremic acidosis. After therapy, hyperchloremia developed in most patients at four to eight hours after admission, because of the retention of chloride in excess of sodium and the excretion of ketones by the kidney.

p38 Kinase Activity Is Essential for Osmotic Induction of mRNAs for HSP70 and Transporter for Organic Solute Betaine in Madin-Darby Canine Kidney Cells

In renal cells, hypertonicity induces genes for heat shock proteins (HSP70, αB-crystallin), as well as enzymes and transporters directly involved in the metabolism and transport of protective organic osmolytes. While heat shock proteins are induced by many stresses including osmotic stress, the induction of the osmolytes genes appears to be specific to osmotic stress. These two adaptive mechanisms allow kidney cells to survive and function in the hypertonic environment that exists on routine basis in kidney medulla. In mammalian cells, hypertonicity induces three mitogen-activated protein kinase pathways: ERK (extracellular regulated kinase), JNK (Jun N-terminal kinase), and p38. ERK activation by osmotic stress is a consistent finding in many cells, but it is not essential for transcriptional regulation of mRNA for transporter of organic osmolyte betaine. While the growth of yeast cells on NaCl-supplemented medium is dependent on HOG1 pathway, it is still unclear which pathway mediates the adaptation to osmotic stress in mammalian cells. Here, we show that inhibition of p38 kinase activity, using the specific inhibitor SB203580 (4-(fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl) imidazole), abolishes the hypertonicity-mediated induction of mRNAs for HSP70 and betaine transporter in Madin-Darby canine kidney cells. The inhibition is dose-dependent and correlates with thein situ activity of native p38 kinase, determined as MAPKAPK-2 activity in cell extracts. As reported previously, the activities of ERK-1 and -2 were not affected by SB203580, but surprisingly, inhibition of native p38 kinase activity correlates with up-regulation of native JNK-1 activity in osmotically stressed cells. p38 mRNA is induced by hypertonic stress and is attenuated with p38 kinase inhibition. We also find that thermal induction of HSP70 mRNA is not affected by p38 kinase inhibition. Such findings suggest that p38 kinase activity is essential for the induction of genes involved in the adaptation of mammalian cells to osmotic stress and that the increased activity of JNK-1 during p38 kinase inhibition is consistent with regulation of JNK-1 by p38 kinase in osmotically stressed cells. In addition, the transduction pathways mediating HSP70 mRNA induction by different stresses appear to be divergent; osmotic induction of HSP70 is p38 kinase-dependent, while thermal induction is not.

The Site of Action of Furosemide and Other Sulfonamide Diuretics in the Dog

The discovery of the countercurrent multiplier system as the mechanism responsible for the concentration and dilution of the urine has provided a framework for the identification of the site of action of diuretic drugs. Agents that act at a single anatomic site in the nephron can be expected to alter the pattern of urine flow in a predictable way. A drug that acts solely in the proximal convoluted tubule, by causing the delivery of increased amounts of filtrate to the loop of Henle and the distal convolution, would augment the clearance of solute-free water (CH2o) during water diuresis and the reabsorption of solute-free water (TCHO) during water restriction. In contrast, drugs that inhibit sodium reabsorption in Henles loop would impair both CHSo and TCHO. Finally, drugs that act only in the distal tubule would reduce CHSo but not TcH2o (1). It is possible, however, that a diuretic drug might inhibit sodium reabsorption at multiple sites. Under such circumstances, localization of the areas of the nephron where the drug acts is far more difficult, since the effects of action in one segment might alter or obscure the effects on another. A new sulfonamide diuretic, furosemide, 4-chloro-N-(2-furylmethyl)-5-sulfonylanthranilic acid (2), offers several advantages in the study of localization of action: a) it is extremely potent, and therefore produces large effects; and b) its duration of action is brief, thereby facilitating multiple studies during a single experiment. A study * of furosemide was, therefore, undertaken to ex plore its effects on water excretion during hy-dration and hydropenia, and on potassium excre-tion during potassium loading. In addition, the diuretic effect of furosemide was compared to three other sulfonamide diuretics: chlorothiazide, chlor-thalidone, and benzhydroflumethiazide. The conventional sulfonamide diuretics resulted in the excretion of about 10% of filtered sodium and inhibited CQ2o without decreasing TCH2O. In contrast, as much as 38% of filtered sodium was excreted during furosemide diuresis, and both CH20 and TCHSo were inhibited. None of the diu-retics had an inhibitory effect on potassium secretion. The effects of the conventional sulfonamide diuretics can be explained by a single site of action distal to the loop of Henle. In contrast, furose-mide clearly has a potent effect in the ascending limb of Henles loop and probably in the proximal convoluted tubule as well. Methods A total of 50 experiments was performed on 40 dogs. All dogs were fasted overnight before each study. Mild pentothal anesthesia was induced …

Localization of diuretic action from the pattern of water and electrolyte excretion.

The response to diuretic agents is principally determined by three factors: the locus in the nephron where the drug exerts its inhibitory effect on sodium reabsorption; the potency of its action; and the nature and magnitude of the internal regulatory influences which augment the renal tubular reabsorption of sodium. The present studies in dogs were undertaken to ascertain the site of action within the nephron of various diuretic agents. The site of action was inferred from the pattern of water and electrolyte excretion during water diuresis and hydropenia. In general, the following criteria were used: An action in the proximal tubule was assumed if the fraction of filtrate delivered out of this portion of the nephron after administration of a diuretic (as estimated from clearance studies) exceeded that normally delivered out of the proximal convolution (as disclosed by micropuncture studies). An action in the ascending limb of Henle’s loop was assumed if free-water clearance was impaired, either alone or together with an impairment of free-water reabsorption. Finally, an action in the distal tubule and collecting duct was assumed if potassium and hydrogen excretion was reduced at any given rate of sodium excretion. Micropuncture studies in dogs, utilizing the inulin tubular fluid to plasma ratio (inulin TF/P) at the end of the proximal convolution as an index of fractional reabsorption of the filtrate, have delineated the magnitude of sodium reabsorption in this portion of the nephron during normal circumstances and during water diuresis, saline diuresis, and contraction of effective blood volume.13 No similar characterization of reabsorption in the thick ascending limb is available, since micropuncture has not been applicable in the dog to this segment of the nephron. It was necessary, therefore, to examine the normal reabsorptive characteristics of the thick ascending limb as a function of delivery of filtrate before the effects of diuretics could be ascertained.

FK506-associated thrombotic microangiopathy: report of two cases and review of the literature.

BACKGROUND FK506 is a recently developed immunosuppressant that has been useful in improving the survival of transplanted organs. Among the numerous adverse side effects of FK506, thrombotic microangiopathy (TMA) stands out as an infrequent but severe complication. METHODS We report two cases of FK506-associated TMA and review the 19 previous reported cases. RESULTS From these 21 cases, the reported incidence of FK506-associated TMA is between 1% and 4.7%. It is more frequent in females, and the mean age at presentation is 47 years. Eighty-one percent of the cases occurred in patients with kidney allografts, and the remaining patients had liver, heart, or bone marrow transplants. Clinically, TMA was diagnosed at an average interval of 9.3 months from the time of transplantation. Patients may be asymptomatic or may present with the full-blown picture of hemolytic uremic syndrome. All patients had an elevated serum creatinine level but did not always show signs of hemolysis. Trough levels of FK506 were not predictive for the development of TMA, but generally a reduction of drug dose correlated with kidney function improvement and disappearance of the hemolytic picture. The renal allograft biopsy provided a conclusive diagnosis in all 17 cases in which this procedure was performed. Treatment, which mainly consisted of reduction or discontinuation of FK506, anticoagulation, and/or plasmapheresis with fresh-frozen plasma exchange, resolved TMA in most patients (57%). However, in one of these patients (5%), the graft was subsequently lost due to causes unrelated to TMA, such as acute or chronic rejection. Despite treatment, one patient (5%) lost the graft due to acute rejection and persistent TMA, and three other patients (14%) who had bone marrow, heart, and liver transplants, died of multiple organ failure, probably unrelated to TMA. In the remaining four patients (19%), response to treatment was not reported. CONCLUSIONS TMA must be considered in organ transplant patients treated with FK506 whenever kidney function deteriorates, even in the absence of microangiopathic hemolytic anemia. Although TMA usually responds to treatment, it may, in rare cases, lead to loss of kidney function or even the patients death.

Determinants of plasma potassium levels in diabetic ketoacidosis.

The classic proposal of intracellular K+ for extracellular H+ exchange as responsible for the hyperkalemia of diabetic ketoacidosis (DKA) has been questioned because experimentally induced organic anion acidosis fails to produce hyperkalemia. It has been suggested, instead, that the elevated serum [K+] of DKA might be the result of the compromised renal function, secondary to volume depletion, that usually accompanies DKA. However, several metabolic derangements other than volume depletion and acidosis, which are known to alter potassium metabolism, also develop in DKA. This study of 142 admissions for DKA examines the possible role of alterations in plasma pH, bicarbonate, glucose (G), osmolality, blood urea nitrogen (BUN) and plasma anion gap (AG) on the levels of [K+]p on admission. Significant (p less than 0.01) correlations of [K+]p with each of these parameters were found that could individually account for 8 to 15 percent of the observed variance in the plasma potassium levels; however, the effects of some or all of these parameters on the [K+]p could be independent and therefore physiologically additive. Since the parameters under study are themselves interrelated, having statistically significant correlations with each other, their possible independent role on [K+]p was evaluated by multiple regression analysis. Only plasma pH, glucose and AG emerged as having a definite independent effect on [K+]p, with no independent role found for bicarbonate, BUN and osmolality. The equation that best describes [K+]p on admission for DKA was: [K+]p = 25.4 - 3.02 pH + 0.001 G + 0.028 AG, (r = 0.515). These results indicate that the endogenous ketoacidemia and hyperglycemia observed in DKA, which result primarily from insulin deficit, are the main determinants of increased [K+]p. Since exogenous ketoacidemia and hyperglycemia in the otherwise normal experimental animal do not increase [K+]p, it is postulated that insulin deficit itself may be the major initiating cause of the hyperkalemia that develops in DKA. Renal dysfunction by enhancing hyperglycemia and reducing potassium excretion also contributes to hyperkalemia.

Renal neoplasm in acquired cystic kidney disease

The development of renal cell neoplasms ranging from adenoma to metastatic carcinoma is the most serious complication of acquired cystic kidney disease (ACKD). A comprehensive review of the pertinent literature shows that there is up to 50-fold increased risk of renal cell carcinoma in ACKD compared to the general population. The ACKD-associated renal cell carcinoma is seen predominantly in males, occurs approximately 20 years earlier than in the general population, and is frequently bilateral (9%) and multicentric (50%). Acquired cystic kidney disease-associated renal cell carcinoma is frequently asymptomatic (86%), but may be associated with bleeding, abrupt changes in hematocrit, fever, and flank pain or rarely with hypoglycemia, hypercalcemia, or metastases at presentation. Computed tomography seems to provide a better diagnostic yield than sonography or magnetic resonance imaging; nevertheless, large (up to 8 cm) tumors not visualized by any imaging techniques have been reported. It is generally agreed that there is a need for regular screening of symptomatic ACKD patients for early detection of renal cell carcinoma; however, whether screening is needed for asymptomatic patients remains controversial. Nephrectomy is indicated for tumors larger than 3 cm. Management for tumors smaller than 3 cm with persistent symptoms, such as back pain or hematuria, remains controversial, but nephrectomy may be recommended since many of these tumors turn out to be unequivocal renal cell carcinoma. Asymptomatic tumors smaller than 3 cm should be serially screened, and tumor enlargement may be an indication for nephrectomy. Acquired cystic kidney disease-associated renal cell carcinoma accounts for approximately 2% of deaths in renal transplant patients. A median length of survival of approximately 14 months and a 5-year survival rate of 35% are comparable to the same data for renal cell carcinoma in the general population. Successful renal transplant probably decreases the risk of renal cell carcinoma in ACKD patients, but this preliminary observation needs confirmation. The development of ACKD-associated renal carcinoma is a continuous process with evolving phenotypic expression, including damaged renal tubule, simple cyst, cyst with atypical lining, adenoma, and, finally, carcinoma. The pathogenesis of this continuous process is not entirely known, but growth factor-induced compensatory growth of tubular epithelium initiated by the changes of end-stage kidney disease, and probably perpetuated by activation of proto-oncogenes, seems to be the most significant factor.

Systemic Calciphylaxis Revisited

A syndrome characterized by rapidly progressive ischemic necrosis involving large areas of the skin and muscle, and by peripheral gangrene associated with extensive vascular calcifications was observed in a patient with end-stage renal failure on chronic hemodialysis. In an effort to control the disease, parathyroidectomy was performed which resulted in rapid improvement of tissue perfusion. However, the patient eventually died from sepsis within 2 months after admission. This case presents the typical features of the syndrome of systemic calciphylaxis. The literature is reviewed searching for similar cases of this poorly recognized, but life-threatening, clinical syndrome. The pathogenesis, clinical manifestations, and therapy of this unusual and rapidly progressive, but potentially reversible, condition are reviewed with emphasis on its prompt recognition and appropriate management.

Calcium transport in the thick ascending limb of Henle. Heterogeneity of function in the medullary and cortical segments.

Calcium transport was studied in medullary and cortical segments of the thick ascending limb of Henle perfused in vitro. 45Ca was added to the perfusate for measuring lumen-to-bath flux (JlbCa), to the bath for measuring bath-to-lumen flux (JblCa), or to both perfusate and bath for measuring net flux (JnetCa). In the medullary segment JlbCa exceeding JblCa and the efflux:influx coefficient ratio was not different from the value predicted from the observed potential difference (PD). In the cortical segments, however, efflux:influx coefficient ratio was greater than the value predicted from the PD, suggesting that calcium transport in this segment may be active, while it is passive in the medullary segment. Furosemide, which reversibly decreases PD in both cortical and medullary segments, inhibited JlbCa only in the medullary segment. Parathyroid hormone (PTH), on the other hand, had no effect on JnetCa in the medullary segment, but it significantly augmented JnetCa in the cortical segment. These results indicate that calcium transport in the thick ascending limb is heterogeneous. In the medullary segment it is passive, inhibited by furosemide and not influenced by PTH. In the cortical segment, however, calcium transport appears to be active, not inhibited by furosemide and stimulated by PTH.