Rocco C. Venuto

Acute Oliguric Renal Failure Induced by Indomethacin: Possible Mechanism

A patient with compensated congestive heart failure suffered acute deterioration of her renal function and cardiac status, requiring peritoneal dialysis, in association with indomethacin therapy. Discontinuation of this inhibitor of prostaglandin synthesis led to a prompt improvement in both her renal function and cardiac status. The patient was rechallenged with indomethacin and again developed acute reduction of her glomerular filtration rate and severe volume retention, which were again totally reversed when the drug was stopped. Urinary prostaglandin E was measured by radioimmunoassay in this patient and five additional patients with congestive heart failure and prerenal azotemia. All patients were found to have elevated levels of urinary prostaglandin E. The possible role for renal prostaglandin E as a compensatory mechanism to the vasoconstrictive stimuli present in congestive heart failure is discussed. The potential danger of inhibitors of prostaglandin synthesis in patients with congestive heart failure and prerenal azotemia is emphasized.

Preoperative use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers is associated with increased risk for acute kidney injury after cardiovascular surgery.

BACKGROUND AND OBJECTIVES Acute kidney injury (AKI) occurs commonly after cardiac surgery. Most patients who undergo cardiac surgery receive long-term treatment with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB). The aim of this study was to determine whether long-term use of ACEI/ARB is associated with an increased incidence of AKI after cardiac surgery. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a retrospective cohort study of 1358 adult patients who underwent cardiac surgery between January 1, 2001, and December 31, 2005, in two tertiary care hospitals in Buffalo, NY. The incidence of AKI was determined after cardiac surgery. Clinical data were collected using a standardized form that included comorbid condition, use of ACEI/ARB, and intraoperative and postoperative complications. RESULTS Overall, 40.2% of patients developed AKI. Preoperative variables that were significantly associated with development of AKI included increasing age; nonwhite race; combined valve surgery and coronary artery bypass grafting compared with coronary artery bypass grafting alone; American Society of Anesthesiologists (ASA) Risk Score category 4/5 compared with 2 to 3; presence of diabetes, congestive heart failure, or neurologic disease at baseline; use of ACEI/ARB; and emergency surgery. Intra- and postoperative factors that were associated with postoperative AKI were hypotension during surgery, use of vasopressors, and postoperative hypotension. Multiple regression logistic model confirmed an independent and significant association of AKI and preoperative use of ACEI/ARB. This was confirmed using a bivariate-probit and propensity score model that adjusts for confounding by indication of use and selection bias. CONCLUSIONS Preoperative use of ACEI/ARB is associated with a 27.6% higher risk for AKI postoperatively. Stopping ACEI or ARB before cardiac surgery may reduce the incidence of AKI.

Heroin nephropathy: A clinicopathologic and epidemiologic study☆

The existence of a nephropathy secondary to intravenous narcotic use remains a matter of debate. To determine whether heroin use and renal disease are associated, a clinicopathologic and epidemiologic study was undertaken in the Buffalo Standard Metropolitan Statistical Area (Buffalo-SMSA). Over the past 10 years, 23 addicts presented with the nephrotic syndrome and/or renal insufficiency. All patients were black men 18 to 45 years of age. Kidney biopsies performed on 21 patients uniformly showed sclerosing glomerulonephritis. End stage renal disease (ESRD) developd in 15 of these patients. In the epidemiologic evaluation which spanned four and a half years, heroin use was highly correlated with both sclerosing glomerulonephritis and ESRD. A history of intravenous heroin use was found in 26 per cent of the new cases of sclerosing glomerulonephritis and in 13 per cent of the new cases of ESRD in patients aged 18 to 45 years (p less than 0.000001). This investigation confirms the existence of heroin-associated sclerosing glomerulonephritis in black men. Heroin use appears to be a major risk factor for ESRD in the Buffalo-SMSA.

A Comprehensive Review of Hypertension in Pregnancy

Hypertension is the most common medical disorder encountered during pregnancy. Hypertensive disorders are one of the major causes of pregnancy-related maternal deaths in the United States. We will present a comprehensive update of the literature pertinent to hypertension in pregnancy. The paper begins by defining and classifying hypertensive disorders in pregnancy. The normal vascular and renal physiological changes which occur during pregnancy are detailed. We will summarize the intriguing aspects of pathophysiology of preeclampsia, emphasizing on recent advances in this field. The existing diagnostic tools and the tests which have been proposed for screening preeclampsia are comprehensively described. We also highlight the short- and long-term implications of preeclampsia. Finally, we review the current management guidelines, goals of treatment and describe the potential risks and benefits associated with various antihypertensive drug classes. Preeclampsia still remains an enigma, and the present management focuses on monitoring and treatment of its manifestations. We are hopeful that this in depth critique will stimulate the blossoming research in the field and assist practitioners to identify women at risk and more effectively treat affected individuals.

Early and severe hyperparathyroidism associated with hypercalcemia after renal transplant treated with cinacalcet.

Bone disease is a common clinical problem following renal transplantation. In renal transplant recipients, multiple underlying factors determine the extent of bone loss and the subsequent risk of fractures. In addition to the well‐recognized risk to bone disease posed by steroids, calcineurin inhibitors and pre‐existing bone disease, persistent hyperparathyroidism (HPT) contributes to post‐transplant bone loss. HPT is usually treated with vitamin D supplements combined with calcium. Patients whose HPT is associated with hypercalcemia pose a difficult therapeutic dilemma which often requires parathyroidectomy. Cinacalcet, a calcium mimetic agent, offers a unique pharmacologic approach to the treatment of patients with post‐transplant hypercalcemia and HPT. In this paper, we describe the clinical course and biochemical changes in 10 renal transplant recipients with hypercalcemia and severe HPT early after renal transplantation treated with cinacalcet. Cinacalcet therapy corrected hypercalcemia and decreased parathyroid hormone (PTH) levels in all cases. A transient rise in the level of alkaline phosphatase was noted following initiation of cinacalcet therapy. In this patient population, correction of HPT was not permanent as discontinuing cinacalcet therapy led to a rapid rise in PTH level.

Uterine prostaglandin E secretion and uterine blood flow in the pregnant rabbit.

Studies were performed in pregnant rabbits to assess the effect of inhibition of prostaglandin synthesis on uterine blood flow. Cardiac output and uteroplacental blood flow (UPBF) were measured using radiolabeled microspheres. Prostaglandin E (PGE) concentration was measured by radioimmunoassay in the uterine vein and peripheral artery of the pregnant nephrectomized rabbit. Either meclofenamate or indomethacin 2 mg/kg were utilized to inhibit prostaglandin synthesis. Systemic arterial pressure increased from 86 mm Hg to 98 mm Hg (P less than0.0001) after prostaglandin inhibition. Cardiac output was unchanged after the inhibition of prostaglandin synthesis, 326 ml/min to 7.8 ml/min. Uterine vein PGE concentration was extremely high, 172.4 ng/ml, with concomitant peripheral arterial PGE 2.1 NG/ML. Intravenous administration of either meclofenamate or indomethacin reduced uterine vein PGE to 23 ng/ml (P less than 0.01) and arterial PGE to 1.0 ng/ml (P less than 0.05). Male and nonpregnant female rabbits had lower arterial PGE, 0.37 ng/ml (P less 0.05). Studies in non-nephrectomized pregnant animals demonstrated that uteroplacental secretion of PGE was greater than five times renal secretion. These studies demonstrate that the rabbit uteroplacental unit is a rich source of PGE and suggest that production of the vasoactive lipid may have a key role in regulating UPBF during pregnancy.

Increased Peripheral Resistance During Reduced Uterine Perfusion Pressure Hypertension in Pregnant Rabbits

The role of an increase in total peripheral resistance (TPR) and the contribution of angiotensin II (ANG II) to the hypertension induced by reduced uterine perfusion pressure (RUPP) was explored in pregnant rabbits. On the 22nd day of gestation, a catheter and a microthermocouple were placed in the aorta to measure mean arterial pressure (MAP) and cardiac output (CO), respectively. Three days later, RUPP was induced by a clip on the aorta proximal to the ovarian and distal to the renal arteries. Mean arterial pressure distal to the clip (uterine perfusion pressure) was reduced to 56 +/- 8% (mean +/- SD) of the initial level. Twenty-four hours later, MAP rose from 65 +/- 3 to 84 +/- 11 mm Hg; CO index decreased from 207 +/- 18 to 169 +/- 27 ml/min/kg; and TPR index increased from 0.32 +/- 0.03 to 0.51 +/- 0.08 mm Hg kg/ml/min, respectively (n = 7, all p less than 0.01). Sham-operated pregnant rabbits (n = 7) and non-P rabbits (n = 5) with a comparable distal aortic pressure reduction experienced no change in MAP or CO. Infusion of a receptor antagonist of angiotensin II (Sar1,Ile8-Ang II, 1 microgram/kg/min for 20 min) decreased MAP in sham-operated pregnant rabbits from 64 +/- 6 to 54 +/- 6 mm Hg (p less than 0.01) but did not change MAP in RUPP hypertensive rabbits (86 +/- 9 mm Hg before and 87 +/- 8 at the end of infusion, n = 6). These data indicate that RUPP in pregnant rabbits leads to a high resistance form of hypertension in which the formation of Ang II is not increased.

Nephrotoxicity and hyperkalemia in patients with acquired immunodeficiency syndrome treated with pentamidine

INTRODUCTION Recently, the use of pentamidine has risen because of its efficacy in managing patients with acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii infection. We undertook a retrospective analysis of the charts of 22 patients with AIDS given pentamidine when they were hospitalized over a two-year period. PATIENTS AND METHODS Collectively, these 22 patients were admitted 28 times during this period and received a total of 23 courses of pentamidine. During five of these admissions, pentamidine was not given. The duration of therapy ranged from five to 33 days (mean: 13.4 days). Three admissions were excluded because of insufficient laboratory data or concomitant use of therapies that could affect the parameters being studied. RESULTS In 19 of the remaining 20 admissions, the patients treated with pentamidine were observed to have elevations of potassium (5.1 to 8.7 mEq/L), creatinine (1.5 to 11.8 mg/dL), and blood urea nitrogen (27 to 183 mg/dL), and a decrease in serum bicarbonate (14 to 21 mEq/L). Of the 19 patients exhibiting these abnormalities, most required sodium polystyrene sulfonate and two required dialysis. During the admissions when pentamidine was not given, hyperkalemia was not observed. After discontinuation of pentamidine therapy, these metabolic derangements normalized in all patients except for one who died while still in acute renal failure. Four patients received more than one course of therapy and upon reinstitution of pentamidine treatment, the same metabolic abnormalities recurred. CONCLUSION In conclusion, pentamidine is more nephrotoxic in patients with AIDS than previously reported in other subjects and can cause life-threatening hyperkalemia.

Methylprednisolone Pharmacokinetics, Cortisol Response, And Adverse Effects In Black And White Renal Transplant Recipients

It is generally assumed that chronic glucocorticoid therapy is similar pharmacologically when administered to either black or white renal transplant recipients, resulting in adrenal suppression, low circulating plasma cortisol concentrations, and a similar degree of drug exposure and toxicity. To examine this theory and to investigate the relationship of glucocorticoid metabolism to steroid-induced adverse effects among specific ethnic groups of renal transplant recipients, 9 black and 9 white male patients chronically receiving methylprednisolone were enrolled. All patients had stable renal function and were matched for age, weight, and time since transplant. Standard pharmacokinetic parameters for methylprednisolone were determined and cortisol responses were characterized by total cortisol area under the concentration curve (AUC), return cortisol AUC, and cortisol suppression half-life. All patients received their daily oral dose of methylprednisolone (mean daily dose = 11 mg for blacks and 11 mg for whites) as an intravenous infusion with serial plasma samples obtained over 24 h. The patients were assessed for the presence of specific cushingoid manifestations (buffalo hump, moon facies) and steroid-associated diabetes. Methylprednisolone and cortisol were analyzed via HPLC. In the black patients, the mean clearance of methylprednisolone (206 +/- 70 ml/hr/kg) was significantly slower with a smaller volume of distribution (0.95 +/- 0.32 L/kg) when compared with the white group (327 +/- 129 ml/hr/kg, P = 0.03; volume of distribution = 1.33 +/- 0.27 L/kg, P = 0.015). Despite chronic methylprednisolone therapy, a definite 24-hr cortisol response pattern was noted in 15 of the 18 patients with a mean total cortisol AUC of 732 +/- 443 ng.hr/ml in blacks and 539 +/- 361 ng.hr/ml in whites (P = 0.17, black vs. white). The mean cortisol suppression half-life was 4.31 +/- 1.54 hr in black recipients and 4.11 +/- 1.49 hr in whites (P = 0.48). The mean return cortisol AUC for the black patients was 327 +/- 279 ng.hr/ml and 370 +/- 207 ng.hr/ml for white patients (P = 0.28). The serum cortisol nadir for black patients was 12.3 +/- 7.2 ng/ml, which was significantly higher than the cortisol nadir in white patients (6.4 +/- 4.4 ng/ml; P = 0.03). A majority (94%) of patients (9 black, 8 white) had moon facies and 27% of patients (3 black, 1 white) had a buffalo hump. While 5 of 9 black patients had steroid-associated diabetes, no white patients manifested this adverse effect. The black patients with diabetes had higher cortisol AUCs with lower methylprednisolone clearances than the white group.(ABSTRACT TRUNCATED AT 400 WORDS)

CKD in MYH9-related disorders.

MYH9-related disorders are rare causes of chronic kidney disease (CKD) presenting as chronic glomerulonephritis and derive from mutations of the MYH9 gene, which encodes for the nonmuscle myosin heavy chain IIA. These disorders are autosomal dominant and include May-Hegglin anomaly and Sebastian, Fechtner, and Epstein syndromes. Diagnosis of these disorders is made first in early childhood because of the characteristic peripheral-blood smear findings of thrombocytopenia, giant platelets, and variably detected basophilic cytoplasmic inclusion bodies in leukocytes. CKD typically develops later in adulthood and may progress to end-stage renal disease. MYH9-related disorders may be associated with deafness and cataract; hence, Alport syndrome becomes important in the differential diagnosis. However, the autosomal dominance pattern of inheritance and characteristic peripheral-blood smear findings in the former help differentiate the two conditions. New evidence suggests that MYH9 gene alterations also are associated with a greater risk of focal segmental glomerulosclerosis and hypertensive nephrosclerosis in African Americans. The purpose of this review is to focus on the known, but rarely recognized association of MYH9-related disorders with CKD and highlight the recent discoveries related to the MYH9 gene that may explain the reason for a high CKD burden in African Americans.