Endothelin antagonists in renal disease

Abstract

and a beta blocker was added to the antihypertensive therapy. Approximately six months after surgery, the serum creatinine was 1.0 mg/dL, and proteinuria was virtually absent (0.12 g/day). The patient did well until one month before admission; the serum creatinine then rose slowly from 1.2 mg/dL to 2.0 mg/dL. On admission to the hospital, her blood pressure was 110/80 mm Hg; the renal graft was neither swollen nor tender. The CsA level was 169 ng/mL and her serum creatinine concentration was 2.1 mg/dL. Renal function, estimated by the plasma clearance of nonradiolabeled iohexol, was 49 mL/min/1.73 m; renal plasma flow, measured by the renal clearance of paraaminohippuric acid, was 208 mL/min/1.73 m. A percutaneous renal biopsy disclosed normal glomeruli and arterioles. Focal isometric vacuolization of proximal tubules was observed. Prominent tubular atrophy and striped interstiCASE PRESENTATION tial fibrosis were present. Mild focal collection of mononuclear A 43-year-old woman was admitted to the Ospedali Riuniti cells in the interstitium also was documented. Intense staining for endothelin-1 (ET-1) mRNA by in situ hybridization was Bergamo for a renal biopsy to evaluate a rising serum creatinine found in tubules but not in glomeruli, which were essentially 14 months after receiving a cadaveric renal allograft at the same negative for the ET-1 mRNA signal. High-intensity signal for institution. The patient initially had developed renal failure ET-1 mRNA was mainly observed in the epithelial cells of due to chronic glomerulonephritis (proliferative extracapillary tubules located in areas of interstitial fibrosis. Staining for glomerulonephritis) and hypertension, which required chronic MCP-1 mRNA also was selectively localized in tubules. In hemodialysis beginning 10 years ago. After receiving a kidney addition, the tubules stained markedly for RANTES mRNA, transplant 7 years ago, she received immunosuppressive treatwhich was also detected minimally in glomeruli. ment with cyclosporine (Sandimmune), azathioprine, and prednisone. The renal allograft functioned well initially; the serum creatiDISCUSSION nine concentration fell to 1.2 mg/dL on day 4 but rose to 2.1 mg/dL on day 22. The blood cyclosporine (CsA) level was 323 Dr. Ariela Benigni (Head, Department of Molecular ng/mL. A clinical diagnosis of acute graft rejection prompted Medicine, Mario Negri Institute for Pharmacological Rethe initiation of methylprednisolone pulse therapy. Her renal search, Bergamo, Italy): In the last 20 years, it has become function gradually recovered; beginning on the 34 postoperaclear that the endothelium participates directly in regutive day, the serum creatinine level stabilized at a baseline of lating vascular tone through the release of a wide variety 1.0 mg/dL to 1.2 mg/dL over the next 13 months. A CsA of vasoactive substances. The discovery of prostacyclin pharmacokinetic profile performed on day 32 documented an area-under-the-blood concentration-time curve (AUC) of 9722 in 1976 [1] was followed in 1980 by evidence that the ng/mL/h, a blood CsA trough level of 357 ng/mL, and a peak endothelium regulates vascular smooth muscle tone by blood CsA concentration of 1897 ng/mL (one hour after doselaborating potent endothelium-dependent vasodilators ing). Along with immunosuppressants given from the immedi[2]. Rubanyi and Vanhoutte reported in 1985 that hypate post-transplant period, a calcium-channel blocker also was oxia induces release of a diffusible vasoconstrictor subadministered to control blood pressure. Two months after stance from endothelial cells independent of prostaglandin transplantation, her blood pressure still was not well controlled, synthesis [3]. But it was not until 1988 that Yanagisawa and coworkers isolated from porcine aortic endothelial The Nephrology Forum is funded in part by grants from Amgen, cells an extremely potent vasoconstrictor that they idenIncorporated; Merck & Co., Incorporated; AstraZeneca LP; Dialysis tified as endothelin-1 (ET-1) [4]. Clinic, Incorporated; and R & D Laboratories.