Can ACE inhibitors prevent chronic allograft failure?

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Can ACE Inhibitors Prevent Chronic Allograft Failure? Discussion: Gabriel M. Danovitch, MD

NGIOTENSIN II is a worthy target for the attention of clinicians concerned with the progression of chronic renal failure. Since the 1980s, a convincing body of evidence has supported the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers in diabetic and proteinuric nephropathies, and these drugs have become part of routine clinical management. 1 The article under discussion by Szabo et al2 adds to the growing body of experimental and clinical data that support the use of these drugs in chronic allograft nephropathy (CAN). Is the mechanism of the beneficial effect of ACE inhibition in chronic renal failure relevant to the counterpart lesion in the renal allograft? Endothelial activation is common to various forms of renal injury and may be the link between immune and nonimmune injury. The resulting up-regulation of a series of adhesion molecules, cytokines, and growth factors helps generate the ubiquitous inflammatory infiltration and fibrosis that is common to many chronic renal lesions, a-5 Hyperfiltration in undamaged nephrons, activation of the renin-angiotensin system, proteinuria, and hypertension promote ongoing injury.6,7Transforming growth factor 13(TGF13), a multifunctional cytokine with fibrogenic properties, has been implicated in the pathogenesis of a variety of chronic disease in animal models and native kidneys; the development of interstitial fibrosis in allografts; and the development of acute and chronic lesions associated with administration of the calcineurin inhibitors (cyclosporine and tacrolimus). 5 In experimental From the Division of Nephrology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA. Received and accepted as submitted October 18, 2000. Address reprint requests to Gabriel M. Danovitch, MD, Division of Nephrology, Department of Medicine, UCLA School of Medicine, 10833 Le Conte Ave, Los Angeles, CA 90024-1689. © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3704-0024535.00/0 doi:l O.1053/ajkd.2001.22861 866

models of renal fibrosis, blockade of angiotensin II has been shown to reduce the pathologic change related to up-regulation of TGF-13.8 The rate of decline in renal function in transplant recipients with biopsy-proven chronic fibrosis has been shown to correlate with the degree of expression of intragraft TGF-13,9 and hyperexpression of this growth factor may account for the increased prevalence of renal dysfunction in blacks. I° Angiotensin II, in addition to its familiar role as a vasoconstrictor, is a growth factor that facilitates adhesion and chemotaxis, tissue fibrosis, and infiltration of injured organs by lymphocytes, n It may induce collagen synthesis directly, an effect mediated in part by TGF-13. In a murine model of glomerulonephritis, angiotensin II was shown to play a pathogenic role in mediating immune renal injury, 11 and in a previous Journal Club discussion, Morrissey13 focused on an article by Nataraj et all4 that lent support to the concept that angiotensin II was an immune costimulator by virtue of its capacity to regulate the immune response through the same calcineurin-dependent pathway that is the target of cyclosporine and tacrolimus. The clinical counterpart of these findings is the observation that in chronic renal failure in native kidneys and in transplants, the capacity of ACE inhibitors to reduce proteinuria appears independent of their capacity to reduce blood pressure. 15 In the present study, the authors used a standard experimental model of chronic renal allograft rejection by transplanting kidneys between discordant rat strains. In this model, acute rejec-

American Joumal of Kidney Diseases, Vo137, No 4 (April), 2001: pp 866-870

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fion can be prevented by administration of cyclosporine, and after 20 weeks proteinuria develops with histologic changes that are reminiscent of those found in so-called chronic rejection. In the control group after 20 weeks, extensive tubular atrophy, interstitial fibrosis, intimal thickening, and glomerulosclerosis developed together with heavy proteinuria. The histologic sections in the accompanying illustrations could be confused easily with those seen inhuman CAN. In parallel with these changes, the mRNA levels of several crucial growth factors, cytokines, chemoattractants, and adhesion molecules rose (these included TGF-/3, platelet-derived growth factor A and B chain [PDGF-/3 A and B], insulin-like growth factor-1 [IGF-1], interleukin-1 [IL-1], mon0cyte chemoattractant protein-1 [MCP-1], intercellular adhesion molecule-1 [ICAM- 1], and vascular cell adhesion molecule-1 [VCAM-1]). The experimental group received the same immunosuppressive protocol, but 10 days after transplantation enalapril was added to their drinking water. The effect of enalapril appeared remarkable and Occurred without measurable reduction in blood pressure. Proteinuria was reduced to the level measured in sham-operated control animals; the percentage of sclerosed glomeruli was reduced from 26 to 19 (compared with 5 in the sham-operated animals); the authors reported a significant reduction in the severity of intersti: tial fibrosis and a trend toward the reduction in the degree of tubtllar atrophy and intimal proliferation. The overall impression from the representive histologic specimens provided in the article was of chronic rejection, but of a much less severe degree. Immunohistologic analysis showed that al±ough there was a mononuclear cell infiltration in the control and enalapril-treated group, the number of,macrophages and lymphocytes was reduced in the enalapril group. The presence of 1eukocytes was associated with a strong immuno; reactive Signal of adhesion molecules, and this signal was reduced in the enalapril-treated group, as reflected by reduced extracellular matrix depo t sition of the adhesion molecules ICAM-1 and VCAM, t. PDGF-o~: nnRNA and TGF-/3 mRNA levels were 4-fold higher and 1.6-fold higher in the controls than in ~ e enalapril-treated animalsi There also were significant reductions in mRNA

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levels of the potent chemotactic factor MCP-1, the profibrotic and chemoattractant factor [GF-1, and the monocyte/macrophage product IL-1/3 mRNA, which has been implicated in the development of sclerosis and fibrosis. The authors did not provide growth factor and cytokine mRNA levels in the sham-operated group so that their residual activity in the enalaprit-treated group could not be assessed. Angiotensin mRNA levels in the enalapril group were significantly higher than controls, reflecting the effectiveness of ACE inhibition. Is the experimental model of chronic rejection in rats used by the investigators relevant to the development of CAN in clinical renal transplantation, and why the change in name? The mere change in terminology from the familiar chronic rejection to the more appropriate CAN reflects a rethinking of the mechanism of this troublesome and largely treatment-resistant lesion. CANT. traditionaily thought to be an immunologic lesion (hence the term chronic rejection), is now thought to be due to immune or alloantigen-dependent factors (eg, HLA discrepancies, acute transplant rejection, inadequate immunosuppression~ and a series of nonimmune or atloantigen-independent factors (eg, brain death injury., harvesting and preservation injury, drug toxicity, lipid disorders. hypertension, and aging). This separation between alloantigen-dependent and alloantigenindependent factors is convenient but may be simplistic in that nonimmune injury and stress generate inflammatory signals that may mimic and accelerate the more familiar immune injury. Halloran et ai16 suggested that the common pathway of such a process is caused by senescence of key cell types manifest by progressive epithelial atrophy, endothelial deterioration, and secondary fibrosis. It is tempting to take the impressive results of Szabo et ai2 and presume their relevance to human transplantation. Animal models do not always predict clinical experience, and there are features of the rat model that are different from the human counterpart. The rat model exposes the ~ansplanted kidney to cyclosporine nephrotoxicity and to immunologic injury that may mimic the alloantigen-dependent factors in the human lesion, but there is no counterpart to the alloantigen-independent factors, donor age, and

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delayed graft function that appear to play a pathogenic role in C A N . A C E inhibition was introduced early in the post-transplant course o f this animal model and appeared to have an impressive beneficial effect. It would have been interesting to assess its impact on the histologic lesion and g r o w t h factor m R N A response with introduction at different stages o f the posttransplant course and on the established lesion. Trials o f the protective effect o f A C E inhibition on h u m a n diabetic 17 and proteinuric nephropathies 18 were predicted b y animal models, and the available clinical data on A C E inhibition in kidney transplantation are encouraging. 19,2° Retrospective 21 and nonrandomized, prospective clinical studies 22 have supported the hypothesis that A C E inhibition is beneficial in C A N , and initial reluctance by clinicians to use A C E inhibitors and angiotensin receptor blockers in the single transplanted kidney with impaired function is being replaced by a growing confidence that these drugs are safe and effective39,2° A C E inhibitors m a y have nonrenal benefits, such as decreasing left ventricular hypertrophy in hypertensive transplant patients, as This favorable clinical impression, supported by animal data Such as provided b y Szabo e t a!,2 needs to be supported by controlled clinicalltrials on the prevention o f C A N similar to the landmark studies performed in diabetic nephropathy. 17 S o m e degree o f C A N is an almost inevitable consequence o f renal transplantation, and it is reasonable to ask whether it might be beneficial to add A C E inhibitors routinely to the post-transplant regimen regardless of the presence Of hypertension. The problem o f C A N is likely to remain until donorspecific i m m u n e tolerance b e c o m e s a reality, and a n o n h u m a n source o f pristine kidneys can be found. REFERENCES

1. Flack JM: Minimizing the progression of kidney disease. Am J Kidney Dis 36:1-3, 2000 (suppl) 2. Szabo A, Lutz J, Schleimer K, Balazs B, Hamar R Philipp T, Heeman U: Effect of angiotensin-converting enzyme inhibition on growth factor mRNA in chronic renal allograft rejection in the rat. Kidney Int 57:982-991, 2000 3. Hancock WH, Whitley WD, Tullins SG, Heeman UW, Wasowska B, Baldwin WM, Tilney NL: Cytokines, adhesion molecules, and the pathogenesis of chronic rejection of rat renal allografts. Transplantation 56:643-650, 1993

4. Halloran PF, Melk A, Barth C: Rethinking chronic allograft nephropathy: The concept of accelerated senescence. J Am Soc Nephrol 10:167-181t, 1999 5. Jain S, Furness PN, NichOlsonML: The role of transforming growth factor betain chronic renal allograft nephropathy. Transplantation 69:1759-1766, 2000 6. Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM: Hyperfiltration in remaining nephrons: A potentially adverse response to renal:ablation. Am J Physiol 241:F85-F93;, 1981 7. Heeman UW, Azuma H, Tullius SG, Mackenzie H, Brenner BM, Tilney N: The contribution of reduced functioning mass to chronic kidney allograft dysfunction in rats. Transplantation 58:1317-1322, 1994 8. Itoh H, Mukoyama M, Pratt RE, Gibbons G, Dzan VJ: Multiple autocrine growth factors modulate vascular smooth muscle growth response to angiotensin II. J Clin Invest 91:2268-2274, 1993 9. Cuhaci B, Kumar MS, Bloom RD, Pratt B, Haussman G, Laskow DA, Aldoost M, Grotkowski C, Cahill K, Butani L, Sturgill BC, Pankewycz OG: Transforming growth factor-/3 levels in human allograft chronic fibrosis correlate with rate of decline in renal function. Transplantation 68:785790, 1999 10. Suthanthirarn M, Khauna A, Cukran D, Adhikarla R, Sharma VK, Singh T, August P: Transforming growth factor-131hyperexpression in African American end-stage renal disease patients. Kidney Int 53:639-644, 1998 11. Wolf G, Neilson EG: Angiotensin II as a renal growth factor. JAm Soc Nephrol 3:1521-1540, 1993 12. Hisada Y, Sugaya T, Yamanouchi M, Uchida H, Fujimura H, Sakurai H, Fukamizu A, Murakami K: Angiotensin I plays a pathogenic role in immune-mediated renal injury in mice. J Clin Invest 103:627-635, 1999 13. Morrissey JJ: Angiotensin II: An immune costimulamr? Am J Kidney Dis 36:434-440, 2000 14. Nataraj C, Oliverio MI, Mannon RB, Mannon PJ, Audoly LP, Amuchastegui CS, Ruiz P, Smithies O, Coffman TM: Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J Clin Invest 104:1693-1701, 1999 15. Muller GA, Schettler V, Muller CA, Strutz F: Prevention of progression of renal fibrosis: How far are we? Kidney Int 49:75-82, 1996 (suppl 54) 16. Halloran PF, Melk A, Barth C: Rethinking chronic allograft nephropathy: The concept of accelerated senescence. JAm Soc Nephrol 10:167-181, 1999 17. Lewis EJ, Hunsicker LG, Bain RP, Rhode RD, for the Collaborative Study Group: The effect of angiotensinconverting enzyme-inhibition on diabetic nephropathy. N Engl J Med 329:1456-1462, 1993 18. GISEN Group: Randomized placebo controlled trial of effect of ramipril on decline of glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 349:1857-1863, 1999 19. Stigant CE, Cohen J, Vivera M, Qualtzman J: ACE inhibitors and angiotensin II antagonists in renal transplantation: An analysis of safety and efficacy. Am J Kidney Dis 35:58-63, 2000 20. Wilkinson AW: Use of angiotensin-converting enzyme inhibitors and angiotensin II antagonists in renal

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transplantation: Delaying the progression of allograft nephropathy? Transpl Rev 14:1-7, 2000 21. Breyer Lewis J, Helderman JH: Is it time for ACE inhibitors in chronic allograft nephropathy? Am J Kidney Dis 35:154-156, 2000 22. Lufft V, Ktiem V, Hamkens A, Bleck JS, Eisenberger U, Petersen R, Ehlerding G, Maschek H, Pichlmayr R, Brunkhorst R: Antiproteinuric efficacy of fosinopril after

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renal transplantation is determined by the extent of vascular and tubulointerstitial damage. Clin Transplant 12:409-415, 1998 23. Hernandez D, Lacalzada J, Salido E, Lh-laresJ, Barragan A, Lorenzo V, Higueras L, Martin B, Rodriguez A, Laynez I, Gonzalez-Posada J, Torres A: Regression of left ventficular hypertrophy by fisinoprit after renal transplantation: R01e of ACE gene polymorphism. Kidney Int 58:889-897, 2000

Authors' Reply: Uwe Heemann, MD, and Thomas Philipp, MD NGIOTENSIN II is responsible for many malevolent influences on the progression of chronic renal failure. The role of angiotensin II has been elucidated primarily in animal experiments and in vitro, emphasizing, apart from its well-known hemodynamic effects, its important contributions to the up-regulation of adhesion molecules, cytokines, growth factors, and other factors influencing chronic renal loss.~,z The interaction between angiotensin II and transforming growth factor/3 (TGF-/3) is worth special emphasis. In various models, angiotensin II inhibition has ameliorated the pathologi c changes associated with the upregulation of TGF/3.3 Although increased TGF-/3 expression can induce Collagen synthesis by itself and may mediate tissue scaning directly, whether or not angiotensin II acts as an immune costimulator in the regulation of the immune response remains a matter Of debate. Last but not least, human trials on diabetes and proteinuric nephropathy demon; strate the effectiveness of angiotensin-convert~ ing enzyme (ACE) inhibition. 3,4 All these fin& ings were predicted by animal models. 5 The data obtained by us fit this pattern and indicate a beneficial effect of ACE inhibition on the progression of chronic allografi nephropa; thy, a term that should be preferred with respec~ to the older term chronic allograft rejection.! Should we treat every patient with ACE inhibiFrom Department of Nephrology, University Hospital Essen, Essen, Germany. Received and accepted as submitted December 12, 2000. Address reprint requests to Uwe Heemann, MD, Department of Nephrology, University Hospital Essen, D-45122 Essen, Germany. E-maib [email protected] © 2001 by the National Kidney Foundation, Inc. 02 72-6386/01/3704-0025535.00/0 doi: l O.1053/ajkd.2001.22862

tors based on experimental data obtained in rats? Although the pathomorphologic pattern in our model cannot be distinguished easily from that observed in human chronic allograft nephropathy, this nephropathy is a multifactorial process with differences between rats and humans. In humans, the mechanisms of chronic allograft nephropathy remain poorly defined. Only a few authors identified lesions specific for chronic allograft nephropathy2 The term chronic' rejection is less appropriate than the more descriptive chronic allograft nephropathy. Similarly, we should not speak of immunologic and nonimmunologic processes. The damage induced by diabetes and hypertension appears to have immunological components. Instead. we should refer to alloantigen-dependent and non-alloantigendependent events. In the rat model under investigation, most findings are consistent with nonalloantigen-dependent events. In this rat model. alloantigen-dependent processes occur primarily immediately after transplantation and not over the long-term. The difference between our model and the situation in humans is that a maintenance immunosuppressive therapy is not only useful, but also mandatory in almost all human transplantation situations, whereas it is not in our rat model. The beneficial effects of ACE inNbition on the progression of proteinuric nephropathy and diabetes develop over a long time a time that is longer than in transplantation. Although some studies support a benefit of ACE inhibition in renal transplantation, data are not suf~cient to support a general use of this class of drugs. As long as the mechanisms of this process are not well defined, standard biopsies are not routinely performed, and prospective studies are unavail-