Bartter's syndrome and the atrial natriuretic factor gene.

We investigated whether the gene for atrial natriuretic factor, a recently discovered peptide hormone with potent natriuretic, diuretic, and vasorelaxant properties, was pathogenetically linked to an uncommon but well-defined fluid and electrolyte disorder, Bartter's syndrome. Restriction fragment length polymorphisms in the atrial natriuretic factor gene were sought in a large kindred with six of 23 family members being affected. A Bgl II polymorphism, identified in two of 40 (5%) apparently normal subjects, was found in one of two first-generation family members. This polymorphism was also present in five of seven unaffected second-generation siblings but in only three of six affected siblings. The failure of the absence or the presence of the polymorphism to cosegregate with the disease clearly indicates that in this kindred, the gene for atrial natriuretic factor is not linked to Bartter's syndrome.

Efficacy of OKT3 monoclonal antibody therapy in steroid-resistant, predominantly vascular acute rejection. A report of three cases with morphologic and immunophenotypic evaluation.

We describe three patients who became oliguric and uremic in the early posttransplantation period. Following treatment with pulse methylprednisolone, all had biopsy evidence of severe residual rejection that was predominantly vascular. T cells formed the bulk of the infiltrates. Subsequent treatment with the monoclonal antibody OKT3 was associated with an immediate diuresis and improvement in serum creatinine. Repeat renal biopsy, obtained in clinical remission, in two of the three patients, showed marked improvement in the vascular lesions. All three patients maintain normal renal function 9, 13, and 18 months later. We conclude that OKT3 was effective in reversing steroid-resistant rejection despite a predominantly vascular pattern of cellular infiltration not usually considered amenable to any antirejection therapy.

Malacoplakia of the prostate in a renal transplant recipient. A complicated course.

Extrarenal malacoplakia in renal transplant recipients is generally associated with a good prognosis. We report the first case of malacoplakia of the prostate in a renal transplant recipient that was associated with a complicated course despite prophylactic antibiotic therapy and reduction of immunosuppression. Malacoplakia in a renal transplant recipient is not always benign.

Deep vein thrombosis in end-stage renal disease.

Patients who have end-stage renal disease have an acquired platelet dysfunction that leads to prolonged bleeding time and that may put them at risk for bleeding. This platelet dysfunction is manifest in reduced platelet adhesion and impaired platelet aggregation. As a result, a bleeding tendency exists in end-stage renal disease, and understandably deep vein thrombosis is vanishingly rare in patients with this condition. We present three end-stage renal disease patients undergoing maintenance hemodialysis who developed deep vein thrombosis. These cases illustrate that in some patients with end-stage renal disease, the pro thrombotic forces may be so profound that they overwhelm the bleeding tendency.

Indomethacin-induced renal insufficiency: recurrence on rechallenge.

We have reported a case of acute oliguric renal failure with hyperkalemia in a patient with cirrhosis, ascites, and cor pulmonale after indomethacin therapy. Prompt restoration of renal function followed drug withdrawal, while re-exposure to a single dose of indomethacin caused recurrence of acute reversible oliguria. Our case supports the hypothesis that endogenous renal prostaglandins play a role in the maintenance of renal blood flow when circulating plasma volume is diminished. Since nonsteroidal anti-inflammatory agents interfere with this compensatory mechanism and may cause acute renal failure, they should be used with caution in such patients.

A filtration method for the separation of cell sap from the large-particle fraction of rat liver suspensions, enabling the rapid measurement of nucleotide distributions.

A simple method is described that allows a rapid separation of a cell-sap fraction from the large-particle fraction of rat liver suspensions. The method is based on the filtration under suction of liver suspensions through Millipore filters that retain nuclei, mitochondria and some of the endoplasmic-reticulum fraction, but allow quantitative passage of cell sap into a collecting tube. The cell sap may be separated in this manner within 2min of the death of the rat. The method was applied to study the intracellular distribution of ATP and of the nicotinamide-adenine dinucleotides and the results obtained were compared with those obtained after separating the cell sap by a rapid centrifuging procedure. The percentage of total liver ATP in the cell sap was found to be 46% by the filtration method and more than 70% by the centrifuging procedure. Corresponding figures found for the distribution of NADP(+)+NADPH were 40 and 49% respectively.

Liver adenosine triphosphate content and bile flow rate in the rat.

The effects of a number of hepatotoxic and other agents on the ATP content of rat liver are described. Changes in the distribution of ATP between the cell sap and the large-particle fraction were determined at intervals after rats had been dosed with various substances. Ethionine produced a rapid decrease in total liver ATP but no alteration in its intracellular distribution. Carbon tetrachloride, sodium salicylate, dimethylnitrosamine, 2,4-dinitrophenol, icterogenin, sodium succinate, sodium malonate and sodium taurocholate did not significantly alter the total ATP content of liver in the periods studied but changes in intracellular distribution were found. Carbon tetrachloride, malonate and taurocholate decreased, and salicylate treatment increased, the proportion of ATP in the cell sap. Treatment with sodium phenobarbitone increased the total liver ATP and the total amount of ATP in the cell sap. The changes in ATP concentration and in the intracellular distribution of ATP are correlated with changes previously reported in bile flow (Delaney & Slater, 1969). No general correlation was found between changes in total ATP and changes in bile flow rate, but there was a relationship between changes in bile flow and in ATP content in the case of ethionine. With the exception of taurocholate and icterogenin, which possibly act on a membrane site, an approximate correlation was found between changes in bile flow and changes in the amount of ATP in the cell sap. The findings are discussed in terms of possible mechanisms for biliary secretion.

Naproxen-induced nephropathy in systemic lupus erythematosus.

A 34-year-old female with an 8-month history of systemic lupus erythematosus and intermittent naproxen use presented with acute oliguric renal failure, hypoalbuminemia, 4+ proteinuria, and an active urinary sediment. The clinical picture suggested a rapidly progressive lupus glomerulonephritis. Renal biopsy, however, demonstrated chronic, active interstitial nephritis without evidence of immune deposits by immunofluorescence or electron microscopy. Nonsclerotic glomeruli revealed diffuse foot process fusion without cellular proliferation. These findings were consistent with nonsteroidal anti-inflammatory drug induced nephropathy. Discontinuation of naproxen and institution of corticosteroid therapy was followed by improvement in renal function and remission of nephrotic syndrome. This case represents the first report of nonsteroidal antiinflammatory drug nephropathy associated with systemic lupus erythematosus.

Gitelman's syndrome (Bartter's variant) maps to the thiazide-sensitive cotransporter gene locus on chromosome 16q13 in a large kindred.

A defect in distal renal tubular sodium chloride handling is thought to be responsible for the clinical phenotype of Gitelman's syndrome, a variant of Bartter's syndrome. To study the possible involvement of the renal thiazide-sensitive NaCl cotransporter gene in the syndrome, a linkage analysis study in the largest reported kindred with the syndrome was performed. A human homolog of rat thiazide-sensitive cotransporter was cloned and mapped to chromosome 16q13 by fluorescent in situ hybridization. All 17 family members in two generations were genotyped at loci in this region. There were no recombinants observed between the Gitelman's syndrome phenotype and inheritance of D16S408 alleles, yielding a lod score of 3.88 at Q = 0. By contrast, recombinants were observed between Gitelman's syndrome and the flanking markers D16S419 and D16S400, localizing the responsible gene in this family to a 15 centimorgan region on chromosome 16q. These genetic data, together with current understanding of the molecular physiology of the thiazide-sensitive cotransporter, are strong evidence that the latter is defective in this kindred with Gitelman's syndrome.

Plasmapheresis as sole therapy in a patient with essential mixed cryoglobulinemia.

An 82-year-old woman with essential mixed cryoglobulinemia type II (IgM K IgG) presented with moderate renal failure and nephritic syndrome. Mesangiocapillary glomerulonephritis with mesangial and subendothelial granular deposits containing IgG, IgM, and C3 in conjunction with small-vessel vasculitis was seen on renal biopsy. Renal symptomatology preceded by a period of 10 months the development of leg ulcers and purpura. The onset of the skin lesions was accompanied by an acute decline of renal function and an increase in liver alkaline phosphatase. Plasmapheresis with a 50% plasma exchange each week over 12 weeks led to improvement in renal function, healing of leg ulcerations, disappearance of purpura, and a return to the baseline of alkaline phosphatase in association with the disappearance of circulating cryoglobulins.

Bartter's syndrome: physiological and pharmacological studies.

Six siblings with Bartter's syndrome were studied. Increased urinary immunoreactive prostaglandin E (iPgE) was corrected by administration of the prostaglandin synthetase inhibitors, indomethacin, ibuprofen and meclofenamate. In addition, plasma potassium rose, plasma renin activity and angiotensin resistance decreased, and the exaggerated natriuresis following saline loading was abolished. Increased urinary iPgE also became normal following the phospholipase inhibitor, mepacrine, but the other abnormalities remained unaltered. The kallikrein inhibitor, aprotinin, did not alter urinary iPgE, plasma potassium or electrolyte balance. During hypotonic saline infusion, proximal tubular potassium or electrolyte balance. During hypotonic saline infusion, proximal tubular sodium reabsorption was normal or increased. Free water clearance and the percentage of distally delivered sodium which was reabsorbed were, however, significantly decreased. The results suggest that neither the increased renal PgE production nor the hyperbradykininemia seen in Bartter's syndrome play a major role in its pathogenesis, or manifestations, and that the effects of the prostaglandin synthetase inhibitors on the syndrome are non-specific. The results and relevant literature are analysed in an attempt to identify the initial defect in the interrelated sequence of events. The data are compatible with an intrarenal defect in sodium transport, leading to increased sodium delivery to the distal tubule, with secondary hyperreninemia, hypokalemia and elevated iPgE excretion.

Autosomal dominant polycystic kidney disease: presentation, complications, and prognosis.

Fifty-three symptomatic adults with autosomal dominant polycystic kidney disease were studied retrospectively for a mean follow-up of 12 years (range 10 months to 33 years). Diagnosis was confirmed by either x-ray, ultrasound, laparotomy, or autopsy. Commonest presenting clinical findings were flank pain (30%), hypertension (21%), symptomatic urinary tract infection (UTI) (19%), gross hematuria (19%), and palpable masses (15%). A total of nine patients (17%) progressed to end-stage renal disease. Change in renal function measured using the reciprocal of plasma creatinine plotted against time was linear for each individual patient with a maximum functional decline of 0.7 mg/dL/yr (slope = -0.07). Past the age of sixty renal failure was uncommon. Easily controlled hypertension developed in 64% attended by mild retinopathy. UTIs were common (53%), often recurrent (61%), precipitated by instrumentation in 6 of 14 patients (43%), leading to death in two (33%). Renal calculi were extremely common (34%) and had no defined metabolic cause. The presence of hematuria (64%), gross or microscopic, bore no relationship to the decline in renal function. Pregnancy was normal in these patients with no increase in fetal or maternal morbidity or mortality. We conclude the following: Renal functional deterioration is linear, less than previously reported, and bears no relationship to hematuria. Hypertension is common, easily treated, and causes minor end-organ damage. Renal calculi are frequent. Urinary tract instrumentation often induces infection with considerable morbidity and mortality and must be avoided. Pregnancy is not contraindicated if renal function is normal. The prognosis for survival in this disease is better than previously reported.

Clinical comparison of I-131 orthoiodohippurate and the kit formulation of Tc-99m mercaptoacetyltriglycine.

Previous studies in animals and humans have shown that technetium-99m mercaptoacetyltriglycine (MAG3) purified by high-performance liquid chromatography is a renal tubular agent with characteristics similar to those of iodine-131 orthoiodohippurate (OIH). A kit formulation for Tc-99m MAG3 has been developed and compared with I-131 OIH in 17 patients with suspected renal dysfunction and three potential kidney donors. There were no adverse reactions. Tc-99m MAG3 images were of good quality and consistently better than I-131 OIH images. There was no significant difference in the relative renal uptake of Tc-99m MAG3 and I-131 OIH. The 30-minute urinary excretion of Tc-99m MAG3 was 36.4%, versus 40.4% for I-131 OIH. The average plasma clearance of Tc-99m MAG3 (138 mL/min +/- 117) was less than that of I-131 OIH (272 mL/min +/- 205) (P less than .001); however, there was good correlation between the Tc-99m MAG3 and I-131 OIH clearances (r = .87). The volume of distribution of Tc-99m MAG3 (5.96 L +/- 1.94) was less than that of I-131 OIH (9.41 L +/- 3.73) (P less than .001). These characteristics and the advantages of a simple kit formulation should lead to widespread clinical use.

Renal allograft rejection: evaluation by Doppler US and MR imaging.

A prospective study compared the efficacy of Doppler ultrasonography (US) and magnetic resonance (MR) imaging in evaluating 38 renal allografts, with specific attention to transplant rejection. Forty-three Doppler US and 42 MR examinations were performed and interpreted. Histologic correlation was obtained from 22 biopsy or nephrectomy specimens. Clinical correlation or a response to instituted therapy was used as confirmation in the remaining allografts. Accuracy in identifying cyclosporine toxicity or acute tubular necrosis could not be evaluated because there were few such cases, with concomitant rejection in most. The ability to predict and identify presence or absence of rejection was not affected by different serum creatinine values. Doppler US was significantly superior to MR imaging in identifying allograft rejection, demonstrating a higher sensitivity (95% vs. 70%), specificity (95% vs. 73%), and accuracy (95% vs. 71%). Because of its low cost and accessibility, Doppler US should become the primary modality for renal transplant screening.