Renin system activation and delayed function of the renal transplant

AJH 2001; 14:1270 –1272 Medical Hypothesis Renin System Activation and Delayed Function of the Renal Transplant Jon D. Blumenfeld, Daniel F. Catanzaro, Milan Kinkhabwala, Jhoong Cheigh, Choli Hartono, David Serur, Sandi Kapur, William T. Stubenbord, Rudy Haschemeyer, and Robert Riggio Delayed graft function (DGF), defined as persistent renal failure that requires dialysis within the first week after kidney transplantation, occurs commonly after cadaveric renal transplantation (CRT). This has important implications for long-term outcome because the 1-year allograft survival rate is significantly reduced when DGF occurs. The mechanisms contributing to the development of DGF are not well established. However, several lines of evidence indicate that excess renin system activity, in both D the cadaver kidney donor and recipient, contributes importantly to the pathogenesis of DGF. If this hypothesis can be verified in clinical studies, then pharmacologic agents that interrupt the renin-angiotensin system (eg, type 1 angiotensin II receptor blockade, angiotensin converting enzyme inhibition, and ␤-adrenergic blockade) in the donor and recipient might significantly improve the outcome of cadaveric renal transplants. Am J Hypertens 2001;14: 1270 –1272 © 2001 American Journal of Hypertension, Ltd. elayed graft function (DGF), defined as persistent renal failure that requires dialysis within the first week after transplantation, is a complication that occurs in approximately half of all cadaveric renal transplants (CRT) performed in New York City. At New York Presbyterian Hospital, DGF occurred in 47% of all CRT performed since the routine use of cyclosporine was begun in 1983. After controlling for the occurrence of acute rejection, the 1-year allograft survival after cadaver renal transplantation is significantly reduced in DGF patients, when compared with transplants that function initially (79.9% v 92.1%; P ⫽ .003). It has been proposed that transplant renal injury, whether caused by immunologic or nonimmunologically mediated mechanisms, promotes the progressive deterioration of allograft function, referred to as chronic allograft nephropathy.1 Moreover, the prolonged time on dialysis and increased hospital length of stay in DGF patients substantially increase the morbidity and financial impact of transplantation. Although characteristics associated with an increased risk of DGF are especially prevalent among donors in the New York region, including older age (⬎55 years), hypertension, and prolonged cold preservation, the pathophysiology of DGF has not been well defined and there are few effective strategies for its prevention and treatment.2,3 We propose a role for excess renin-angiotensin system activity in the pathophysiology of DGF that is based on clinical and laboratory observations. The risk of DGF is directly related to the magnitude of donor renin system activation. Koller et al4 reported that 41% of cadaver kidney transplants were complicated by DGF. After controlling for age, HLA matching, and cold ischemia time, they found that kidneys from donors with higher plasma renin and angiotensin II (Ang II) levels measured during procurement (renin, 5.1 v 2.6 ng/mL/h, P ⫽ .02; Ang II 62.8 v 48.5 pg/mL, P ⫽ .01) were significantly more likely to develop DGF. Furthermore, Huland and co-workers5 reported that pretreatment of cadaver kidney donors with the Ang II receptor antagonist saralasin 10 min before clamping of the aorta, decreased the incidence of acute renal failure immediately after transplantation (25% [n ⫽ 24] v 58.3% [n ⫽ 24]; P ⬍ .02). Plasma Ang II levels are reportedly elevated after renal transplantation, peaking within 24 h, and decreasing over several days.6 Various factors may stimulate the renin– Ang II system during the perioperative period. First, brain death of the donor before kidney procurement is often accompanied by hypotension, sympathetic nervous system activation, and by treatment with vasopressors (eg, dopamine, norepinephrine). Second, after procurement, the kidney is perfused with a preservation solution containing vasodilators. For example, prostaglandin E1 (PGE1), a renal vasodilator, reportedly decreases the incidence of DGF.7 However, PGE1 also directly stimulates renin se- Received March 14, 2001. Accepted August 16, 2001. From the Rogosin Institute, Departments of Surgery (JDB, MK, JC, CH, DS, SK, WTS, RH, RR) and Cardiothoracic Surgery (DFC, JB), New York Presbyterian Hospital, Weill Medical College of Cornell University, New York, New York. This work is supported in part by funding from the FII Foundation. Dr. Jon D. Blumenfeld, The Rogosin Institute, 505 East 70 Street, New York, NY 10021; e-mail: 0895-7061/01/$20.00 PIIhttps://academic.oup.com/ajh/article-abstract/14/12/1270/153948 S0895-7061(01)02264-6 Downloaded from © 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc. by guest on 08 May 2018 RENIN AND DELAYED GRAFT FUNCTION 1271 AJH–December 2001–VOL. 14, NO. 12 cretion, which may account for its inconsistent clinical benefit. Third, cooling reduces renin secretion, but rewarming the kidney immediately before transplantation may enhance it.8 Fourth, low blood pressure during transplant surgery directly stimulates renin secretion. This may account for the greater risk of DGF in patients who are hemodialyzed immediately before transplantation, compared to those treated with peritoneal dialysis.9 Finally, loop diuretics, which are routinely administered during renal transplant surgery and in the immediate postoperative period, directly stimulate renin secretion by blocking macula densa sodium chloride reabsorption as well as by causing volume depletion.10 Several mechanisms may contribute to an adverse effect of excess renin system activity on allograft function. Angiotensin II is a potent vasoconstrictor that promotes ischemic acute tubular necrosis in animal models.11,12 In addition, Ang II has other direct cellular effects on the vasculature that may adversely influence the renal allograft. Specifically, Ang II stimulates vascular smooth muscle cell growth and migration, promotes oxidative stress by enhancing superoxide radical formation, activates monocyte/macrophage migration and release of adhesion and inflammatory molecules, and is prothrombotic by stimulation of plasminogen activator inhibitors.13–17 These effects contribute to endothelial dysfunction, which may be reversible during treatment with an angiotensin converting enzyme (ACE) inhibitor.18 In the Fisher-Lewis rat model of chronic allograft nephropathy, treatment with a type 1 Ang II receptor antagonist lowers glomerular pressure, inhibits macrophage chemoattractants and recruitment, and suppresses macrophage-associated cytokines.19 Altogether, these findings implicate a pathophysiologic role for Ang II in delayed graft function and in the progression to chronic allograft nephropathy. Plasma renin and Ang II levels (...truncated)