Mortimer Levy

Effects of Acute Volume Expansion and Altered Hemodynamics on Renal Tubular Function in Chronic Caval Dogs

It is well established that dogs with chronic partial constriction of the thoracic inferior vena cava develop sodium retention, ascites, and respond poorly to acute saline loading. A group of such chronic caval dogs, and a group of normal controls were studied during hydropenia, and again after acute saline loading by clearance and recollection micropuncture techniques. After volume expansion, the caval dogs excreted 52 muEq/min per kidney of sodium compared with 370 muEq/min per kidney for the normal controls. During hydropenia and after the saline infusions, single nephron filtration rates, fractional reabsorption of sodium within the proximal tubule, and proximal delivery of filtrate to the distal nephron were comparable in both groups of dogs. Micropuncture of distal tubular segments confirmed that the loop of Henle was the major site for salt and water retention in the expanded caval dogs. Alteration of intrarenal hemodynamics by vasodilating one kidney and elevating systemic arterial blood pressure induced a normal natriuretic response in the saline-loaded caval dogs. Proximal tubular function remained unchanged and the loop of Henle appeared to be the major site responsive to these hemodynamic maneuvers. These same experiments in saline-loaded control dogs had no effect on function of the proximal or distal nephron and did not increase urinary excretion of sodium or water. These experiments provide evidence that the loop of Henle is the major site for sodium retention in volume-expanded chronic caval dogs excreting minimal amounts of sodium.

Dogs with experimental cirrhosis of the liver but without intrahepatic hypertension do not retain sodium or form ascites.

Dogs with portal cirrhosis but without portal hypertension (end-to-side portacaval anastomosis) retain sodium and expand plasma volume before ascites formation. In our study, dogs were subjected to bile duct ligation and simultaneous side-to-side portacaval anastomosis (PCA) in order to create a canine model of hepatic cirrhosis without intrahepatic or portal hypertension. The effect of normalizing intrahepatic pressures in the face of venous outflow block on sodium handling was studied. 13 dogs survived the surgical procedures and were followed. Two dogs developed sodium retention and ascites at 5-6 wk (livers were cirrhotic) when the PCA spontaneously closed. 11 dogs were free of sodium retention and ascites for as long as 12 wks after surgery, while ingesting 35 meq/d of sodium. In this group glomerular filtration rate remained normal throughout the period of observation and there was no expansion of plasma volume. Nine of these dogs were then fed 85 meq/d of sodium; eight remained in sodium balance and one retained sodium and went on to develop ascites. When 10-15 mg i.m. of desoxycorticosterone acetate (DOCA) was given daily, five dogs developed sodium retention and ascites, while four escaped from DOCA. Dogs who developed ascites had either a partially occluded PCA (4/5) or a patent PCA, but with a significant portacaval pressure gradient of 9.5 cm H2O (1/5). In all four dogs who escaped from DOCA, the PCA was widely patent and the mean pressure gradient was only 1.6 cm H2O. Both groups were equally cirrhotic, as judged by histological and biochemical parameters. We conclude that normalizing intrahepatic pressure by providing an outflow tract for the cirrhotic liver will abolish that component of early renal tubular sodium retention not due to portal venous hypertension or ascites sequestration.

Anti–glomerular basement membrane glomerulonephritis after extracorporeal shock wave lithotripsy

Extracorporeal shock wave lithotripsy (ESWL) is a common noninvasive procedure for removal of upper urinary tract stones. We present a case of a man who developed anti-glomerular basement membrane (anti-GBM) disease after ESWL and review the two other cases described in the medical literature. In all cases, the affected individuals expressed the HLA DR2/HLA DR15 major histocompatibility antigen and developed a rapidly progressive anti-GBM-induced glomerulonephritis 3 to 7 months after ESWL. Anti-GBM disease may be a rare complication of ESWL in susceptible individuals and should be considered in patients who develop acute renal failure after lithotripsy.

D-Penicillamine-lnduced Crescentic Glomerulonephritis and Antimyeloperoxidase Antibodies in a Patient with Scleroderma

Therapeutic use of D-penicillamine has been associated with a range of adverse effects. We present a patient with scleroderma, treated with D-penicillamine for 5 years, who developed severe renal failure due to rapidly progressive glomerulonephritis with both crescents and subepithelial immune deposits on renal biopsy. Serological findings included perinuclear antineutrophil cytoplasmic antibodies and antihistone antibodies. She was treated with cyclophosphamide, prednisone, discontinuation of D-penicillamine, and hemodialysis. Therapy resulted in partial recovery of renal function. The clinical course of our patient is in keeping with D-penicillamine-induced chronic membranous nephropathy, followed by rapidly progressive crescentic glomerulonephritis. We discuss the effects of D-penicillamine in our patient, and review the literature on immune-mediated renal disease associated with the use of this drug.

Renal tubular responsiveness to atrial natriuretic peptide in sodium-retaining chronic caval dogs. A possible role for kinins and luminal actions of the peptide.

60% of chronic caval dogs with ascites did not respond to atrial natriuretic peptide (ANP) (75 ng.kg-1.min-1) with a natriuresis (TIVC-NR; delta UNaV = 2 +/- 0.8 mu eq/min) whereas the remaining 40% responded normally (TIVC-R; delta UNaV = 216 +/- 50 mu eq/min). Since proximal tubule neutral endopeptidase 24:11 (NEP) destroys most of intrarenal luminal ANP and kinins, we attempted to convert TIVC-NR into TIVC-R by providing NEP inhibition with SQ 28603 at 30 mg/kg. This potent and specific NEP inhibitor produced a natriuresis when administered alone to nine TIVC-NR dogs (delta UNaV = 67 +/- 2 mu eq/min) and permitted a natriuresis in the presence of ANP (delta UNaV = 97 +/- 18 mu eq/min). A natriuretic response to ANP could also be induced in TIVC-NR dogs by providing renal arterial bradykinin or intravenous captopril, a kininase inhibitor. Urodilatin, a natriuretic peptide not destroyed by intrarenal NEP was without effect in TIVC-NR dogs but increased UNaV when given to TIVC-R and normal dogs. Providing bradykinin to TIVC-NR now permitted an increment in delta UNaV (62 mu eq/min) when urodilatin was reinfused. TIVC-R dogs could be converted into TIVC-NR by pretreating with a specific bradykinin antagonist before infusing ANP. We conclude that TIVC-NR dogs are deficient in intrarenal kinins but are converted to responding dogs after NEP inhibition because of increased kinin delivery to the inner medullary collecting duct.

Acute Renal Effects of Endothelin-A Blockade: Interspecies Differences

The acute renal effects of LU135252 (LU), a selective endothelin-A (ETA) receptor antagonist, were studied in conscious rats after i.p. administration of 1-10 mg/kg LU, and in clearance studies in anesthetized dogs during left intrarenal infusion of 0.01-0.1 mg/kg/min. In the rat (n = 12), LU (10 mg/kg i.p.) decreased diuresis (-36%), excretion of Na (-55%) and Cl (-38%) but not of K and creatinine, as measured in 8-h collections in metabolic cages. Excretion of oral NaCl load (5% of body weight) during 4 h decreased from 68 +/- 2% (vehicle) to 50.5 +/- 5% (LU; n = 12, p < 0.01). Blood pressure was not affected. In contrast, left intrarenal LU infusion at 0.01, 0.03 and 0.1 mg/kg/min in the dog (n = 4) had no effect on renal hemodynamics or excretory function, whereas it mildly decreased blood pressure. In addition, intrarenal LU (0.03 mg/kg/ min; n = 6) had no effect on the renal response to volume expansion (7% bw) by 0.9% NaCl i.v. These markedly different effects of acute ETA blockade were observed at similar systemic plasma levels of LU in the two species. It is concluded that in the rat, but not in the dog, acute blockade of ETA receptors can impair renal excretory function, most likely at the tubule level. This interspecies difference in the role of endogenous ET in the regulation of renal function is probably due to a different ET receptor profile and distribution in rat and dog kidneys.

Effect of a selective octapeptide analogue of somatostatin on renal water excretion in the dog

Somatostatin produces a modest water diuresis in dogs by inhibiting the renal tubular action of ADH. SMS 201-995, an octapeptide analogue of somatostatin, is more potent and longer-acting than the native hormone, and possesses greater specificity in the inhibition of growth hormone secretion. In the present study we tested the ability of the analogue to produce urinary dilution following infusion (0.12 to 0.50 micrograms/min) into the left renal artery. Infusion in this dose range increased urine flow from 0.20 to 0.55 mL/min (P less than 0.05) and caused a 49% to 56% reduction in urine osmolarity. We conclude that SMS 201-995 is effective in causing a water diuresis in dogs and at smaller doses than required for the native hormone.

Renal excretion of urobilinogen in the dog

The renal excretion of urobilinogen was studied in dogs by standard clearance techniques. The use of radiochemically pure tritiated mesobilirubinogen as a representative urobilinogen afforded much greater analytical precision than can be obtained with the usual colorimetric and fluorimetric techniques which are only semiquantitative. With constant plasma levels of urobilinogen, raising urinary pH from 5 to 8 increased urobilinogen excretion from about 30% to up to 200% of the filtered load. When urinary pH was kept constant, changes in blood pH had no effect on urobilinogen excretion. Increases in urinary flow had no effect on urobilinogen excretion when the urine was alkaline but increased excretion markedly during aciduria. Probenecid did not influence urobilinogen excretion by the kidney. It is concluded that urobilinogen is excreted by a three-component system of glomerular filtration, active secretion, and pH-dependent nonionic diffusion in the distal nephron. Urobilinogen is a weak acid, and this mode of excretion is similar to that of other weak, organic acids, such as salicylates. These results indicate that urinary pH and flow must be considered in the clinical interpretation of measurements of urinary urobilinogen.

Salt and Water Balance in Liver Disease

Virtually all patients with cirrhosis of the liver, particularly in the ascitic phase of the disease, eventually develop perturbations of renal excretion of salt and water. The process appears to be initiated by hepatic venous outflow block, which leads to increased portal venous pressure and intrahepatic pressure.

Molecular forms of atrial natriuretic peptides in dog atrium and plasma

The level of immunoreactive ANP (iANP) as determined by radioimmunoassay, exhibits a fairly even distribution throughout the canine atria. However, the maximal concentration was found in the appendages of both the left and right atrium, and the level was significantly higher on the left side in all analyzed localizations. Reverse-phase HPLC of atrial extracts, coupled with RIA, revealed the presence of three iANP fractions. The dominant fraction (65% of iANP) has an estimated molecular weight 16,300, showing that it corresponds to the hormone precursor. By contrast, in the plasma extract, 92% of iANP coelutes with synthetic human ANP99-126, thus confirming the structural identity of dog and human ANP.