Richard B. Wait

Renal failure complicating obstructive jaundice

Postoperative acute renal failure in patients with obstructive jaundice remains a clinically significant complication. Acute renal failure occurs in approximately 9 percent of patients requiring surgery for relief of obstructive jaundice, and contributes to eventual mortality in 76 percent of those who develop it. The overall mortality rate for patients undergoing surgery for obstructive jaundice is 16 percent. Despite advances in perioperative care, these figures have changed very little over the past 25 years. This article describes the clinical association between jaundice and renal failure and reviews the studies that have contributed to the delineation of the possible underlying pathophysiologic mechanisms, as well as possible preventive measures which have been developed as a result of these investigations. With increased awareness of the potential risk of developing postoperative acute renal failure, the institution of prophylactic measures may result in an improvement in the mortality rate seen after surgery for obstructive jaundice.

Verapamil attenuates stress-induced gastric ulceration

Since many of the proposed etiologic factors leading to gastric stress ulceration involve stimulation of calcium influx, the effect of verapamil, a potent calcium channel blocker, on the gastric mucosa in cold-restrained inbred rats was assessed. Twenty-nine rats received intraperitoneal normal saline (2 ml) while the experimental group (N = 29) received 1 mg/kg verapamil in an equal volume of normal saline intraperitoneally. All animals were then stressed at 4 degrees C for 4 hr and sacrificed. Gastrin and fatty acid levels were measured and blinded ulcer scoring of the gastric mucosa was carried out. Verapamil-treated animals had decreased frequency and severity of gastric stress ulceration as assessed by ulcer index, ulcer grade, and number of ulcers/animal. In addition, the plasma gastrin levels tended to be lower in the verapamil group. Fatty acid levels were similarly depressed following cold restraint in both groups. Pretreatment with verapamil significantly decreased gastric ulcerative response to cold-restraint stress in the rat. This effect of verapamil pretreatment may be secondary to cytoprotection of the gastric mucosa, preservation of gastric mucosal blood flow, or blockade of calcium-mediated ulcerogenic stimuli.

THE RELATIONSHIP OF URINARY THROMBOXANE EXCRETION TO CYCLOSPORINE NEPHROTOXICITY

Alterations in renal prostaglandin production have recently been postulated to modulate the decrease in renal blood flow associated with cyclosporine nephrotoxicity. In particular, increases in renal production of the potent vasoconstrictor thromboxane A2 have been implicated in the pathogenesis of this disorder. The present study was undertaken to explore the relationship between alterations in urinary thromboxane B2 excretion (UTxB2V) and CsA nephrotoxicity in two rat models. Male Sprague-Dawley (SD) rats were treated for 14 days with CsA 50 mg/kg/day (n = 8) or olive oil (C) (n = 9) by gavage. Creatinine clearance (Ccr), urine flow (V), and urinary excretion rates of sodium, N-acetyl-beta-D-glucosaminidase (NAG), glucose, and TxB2 were determined before and after treatment. A similar study was conducted using Fischer rats (CsA: n = 10, C: n = 13). In Fischer rats, CsA caused a 35% decrease in Ccr (P = 0.01), a 33% decrease in sodium excretion (P = 0.02), and a greater than 2-fold increase in NAG excretion (P = 0.03), while V, glucose excretion, and UTxB2V did not change. Although similar changes in sodium and NAG excretion were seen after CsA administration in SD rats, Ccr was not affected. Additional findings in SD rats included a 3-fold increase in V (P less than 0.01), a 24-fold increase in glucose excretion (P = 0.03), and a 5-fold increase in UTxB2V (P = 0.04). Thus, Fischer rats developed CsA nephrotoxicity in the absence of increased UTxB2V. In contrast, SD rats failed to develop nephrotoxicity despite a marked increase in UTxB2V. We conclude that changes in renal TxA2 production are unrelated to the development of CsA nephrotoxicity.

EFFECTS OF CHRONIC CYCLOSPORINE ADMINISTRATION ON RENAL BLOOD FLOW AND INTRARENAL FLOW DISTRIBUTION

Cyclosporine-induced decreases in renal blood flow (RBF) and glomerular function are well documented. Glomerular filtration and tubular function may be affected by changes in both total renal blood flow and cortical blood flow distribution (CBFD). The effect of CsA on RBF, CBFD, glomerular filtration rate, and tubular function was studied in conscious ewes receiving a mean CsA dose of 30 mg/kg/day for 28 days with mean CsA trough levels of 344 +/- 45 ng/ml. RBF and CBFD were determined by the injection of 15 microns radioactive microspheres before and after one month of treatment with CsA or its vehicle, olive oil. RBF decreased by 24% from 7.65 +/- 0.87 to 5.79 +/- 0.42 ml/min/g of kidney in CsA-treated ewes (P = 0.014), while no decrease was noted in the control group (7.92 +/- 1.10 vs. 7.62 +/- 0.71). Intracortical blood flow decreased in proportion to the fall in total renal blood flow--thus CsA treatment did not change the cortical distribution of flow. There was a 25% decrease in GFR, as determined by inulin clearance, in the CsA-treated group (80 +/- 6 vs. 62 +/- 3 ml/min; P = 0.027) while there was a nonsignificant increase in control animals (62 +/- 11 vs. 92 +/- 7 ml/min). There was no evidence of tubular dysfunction in either group. There were also no changes in urinary excretion rates of prostaglandins PGE2, 6-keto-PGF1 alpha or thromboxane B2, nor were there changes in plasma renin activity. CsA induced decreases in RBF occur red without redistribution of cortical blood flow, indicating that altered cortical distribution of blood flow is not responsible for the changes in GFR or tubular function that have been reported. The changes in renal blood flow and glomerular filtration rate are independent of changes in renal prostaglandin production, and are likely not associated with altered plasma renin activity.

Role of renal sympathetic nerve activity in renal failure associated with obstructive jaundice in the rat

The propensity for renal failure associated with obstructive jaundice and liver disease may be related to enhanced vasoconstriction of the renal vascular bed with resultant decreases in renal blood flow. Renal sympathetic nervous activity may be a mediator of this effect. The increased renal production of prostaglandins which has been observed in previous models of bile duct ligation may serve to counterbalance the effects of such vasoconstricting influences. This study was undertaken to assess the effect of bile duct ligation on renal function and prostaglandin production in the rat. Furthermore, this study was designed to determine if renal sympathetic nerve activity contributes to the development of renal failure after bile duct ligation. Sprague-Dawley rats underwent either sham operation (n = 8), bilateral renal denervation (n = 10), bile duct ligation alone (n = 11), or bile duct ligation and bilateral renal denervation (n = 10). Renal function was assessed before and 4 days after operation. Bile duct ligation resulted in a 46% decrease in creatinine clearance (p less than 0.01), a 33% decrease in urinary sodium excretion (p less than 0.01), a twofold increase in urine flow (p less than 0.01), and twofold increases in urinary excretion of PGE2, 6-keto-PGF1 alpha, and thromboxane B2 (p less than 0.01). Renal denervation did not prevent the decreases in creatinine clearance and sodium excretion seen after bile duct ligation and had no effect on the changes in urine flow and prostaglandin excretion. These findings demonstrate that bile duct ligation in the rat results in impaired renal function, accompanied by increases in renal prostaglandin production. In addition, this study indicates that the perturbations in renal function and renal prostaglandin production induced by bile duct ligation are not mediated by renal sympathetic nerve activity.