Role of genetic variants of the renin-angiotensin system in chronic renal allograft injury
1998; Elsevier BV; Volume: 53; Issue: 6 Linguagem: Inglês
10.1046/j.1523-1755.1998.00930.x
ISSN1523-1755
AutoresArya M. Sharma, Joachim Beige, Armin Distler,
Tópico(s)Hormonal Regulation and Hypertension
ResumoRole of genetic variants of the renin-angiotensin system in chronic renal allograft injury. In the vast majority of patients undergoing kidney transplantation, long-term success is markedly limited by a gradual decrease in graft function over time, often termed as “chronic rejection” or “chronic allograft injury.” Although there have been no formal studies examining the role of genetic factors other than those related to histocompatibility for the development or progression of chronic allograft rejection, it is likely that genetic factors affecting blood pressure regulation, mesangial or vascular proliferation, or aspects of inflammatory response including thrombosis, chemotaxis, or fibrosis may play an important role in this complex syndrome. There is currently little hope that the responsible genes can be identified through sib-pair or linkage studies in families. Therefore, the study of candidate genes selected on the basis of our current understanding of the pathophysiological mechanisms involved in the chronic rejection response appears the only feasible approach. Thus far, studies have focused mainly on the role of functional genetic variants of the renin-angiotensin system on renal allograft funding. These studies, however, have not identified these variants as important determinants of renal allograft survival. Clearly, future studies will have to address the role of other variants of this system as well as genes encoding for other systems deemed to be of pathophysiological significance for the development and progression of chronic transplant injury. Role of genetic variants of the renin-angiotensin system in chronic renal allograft injury. In the vast majority of patients undergoing kidney transplantation, long-term success is markedly limited by a gradual decrease in graft function over time, often termed as “chronic rejection” or “chronic allograft injury.” Although there have been no formal studies examining the role of genetic factors other than those related to histocompatibility for the development or progression of chronic allograft rejection, it is likely that genetic factors affecting blood pressure regulation, mesangial or vascular proliferation, or aspects of inflammatory response including thrombosis, chemotaxis, or fibrosis may play an important role in this complex syndrome. There is currently little hope that the responsible genes can be identified through sib-pair or linkage studies in families. Therefore, the study of candidate genes selected on the basis of our current understanding of the pathophysiological mechanisms involved in the chronic rejection response appears the only feasible approach. Thus far, studies have focused mainly on the role of functional genetic variants of the renin-angiotensin system on renal allograft funding. These studies, however, have not identified these variants as important determinants of renal allograft survival. Clearly, future studies will have to address the role of other variants of this system as well as genes encoding for other systems deemed to be of pathophysiological significance for the development and progression of chronic transplant injury. During the last two decades, remarkable improvements in immunosuppression have resulted in dramatic improvements in short-term renal allograft survival. However, in the vast majority of patients undergoing kidney transplantation, long-term success is markedly limited by a gradual decrease in graft function over time. The mechanisms leading to the progressive loss of graft function, often termed “chronic rejection” or “chronic allograft injury,” remain largely unknown and no effective therapy is available[1H OSTETTER T.H. Chronic transplant rejection.Kidney Int. 1994; 46: 266-279Abstract Full Text PDF Scopus (126) Google Scholar]. Thus far, both immunologic and non-immunologic factors have been implicated in the development and progression of chronic allograft injury. While the degree of HLA mismatch has not been unequivocally found to be an important determinant of chronic rejection[2H ELD P.J. K AHAN B.D. H UNSICKER L.G. L ISKA D. W OLFE R.A. P ORT F.K. G AYLIN D.S. G ARCIA J.R. A GODOA L.Y. K RAKAUER H. The impact of HLA mismatches on the survival of first cadaveric kidney transplants.N Engl J Med. 1994; 331: 765-770Crossref Scopus (177) Google Scholar,3M ASSY Z.A. G UIJARRO C. W IEDERKEHR M.R. M A J.Z. K ASISKE B.L. Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors.Kidney Int. 1996; 49: 518-524Abstract Full Text PDF Scopus (303) Google Scholar], the most consistent immunologic factor related to chronic allograft injury has been the occurrence of acute rejection episodes[3M ASSY Z.A. G UIJARRO C. W IEDERKEHR M.R. M A J.Z. K ASISKE B.L. Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors.Kidney Int. 1996; 49: 518-524Abstract Full Text PDF Scopus (303) Google Scholar,4F ERGUSON R. Acute rejection episodes–Best predictor of long-term primary cadaveric renal transplant survival.Clin Transplant. 1994; 8: 328-331Google Scholar]. Nevertheless, although the introduction of more potent immunosuppressive drugs including cyclosporine has resulted in a marked reduction in acute allograft rejection, to date this has not had a discernible effect on long-term allograft survival[1H OSTETTER T.H. Chronic transplant rejection.Kidney Int. 1994; 46: 266-279Abstract Full Text PDF Scopus (126) Google Scholar,3M ASSY Z.A. G UIJARRO C. W IEDERKEHR M.R. M A J.Z. K ASISKE B.L. Chronic renal allograft rejection: Immunologic and nonimmunologic risk factors.Kidney Int. 1996; 49: 518-524Abstract Full Text PDF Scopus (303) Google Scholar]. Non-immunological factors implicated in chronic allograft injury include ischemia time, extremes of age of donor, smoking history, and the presence of hypertension, hyperlipidemia or proteinuria[1H OSTETTER T.H. Chronic transplant rejection.Kidney Int. 1994; 46: 266-279Abstract Full Text PDF Scopus (126) Google Scholar]. Despite these associations found in epidemiological cohort and cross-sectional studies, the protective value of intervention with specific anti-hypertensive, lipid-lowering, or anti-proteinuric drugs in preventing chronic allograft rejection has yet to be demonstrated. Although there have been no formal studies examining the role of genetic factors other than those related to histocompatibility for the development or progression of chronic allograft rejection, it is likely that genetic factors play an important role in this complex syndrome[1H OSTETTER T.H. Chronic transplant rejection.Kidney Int. 1994; 46: 266-279Abstract Full Text PDF Scopus (126) Google Scholar]. Biopsy findings characteristically show vascular sclerosis with mural thickening and occlusion of renal arteries and ischemic glomeruli, interstitial infiltration by macrophages and lymphocytes, and interstitial fibrosis[5S OLEZ K. B ENEDIKTSSON H. C AVALLO T. C ROKER B. D EMETRIS A.J. D RACHENBERG C. E MANCIPATOR S. F URNESS P.N. G ABER L.W. G IBSON I.W. G OUGH J. G UPTA R. H ALLORAN P. H AYRY P. K ASHGARIAN M. M ARCUSSEN N. M ASSY Z.A. M IHATSCH M.J. M OROZUMI K. N ORONHA I. O LSEN S. P APADIMITRIOU J. P AUL L.C. P ICKEN M. R ACUSEN L.C. et al.Report of the Third Banff Conference on Allograft Pathology (July 20–24, 1995) on classification and lesion scoring in renal allograft pathology.Transplant Proc. 1996; 28: 441-444Google Scholar]. It is thus conceivable that genetic factors affecting blood pressure regulation, mesangial or vascular proliferation, or aspects of inflammatory response including thrombosis, chemotaxis, or fibrosis may determine the extent and progression of chronic allograft injury. These genetic factors can be active both in the host or within the transplanted kidney. Given the complexity of the factors apparently involved in chronic rejection, there is no reason to believe that a single gene or genetic variant will act as a strong determinant of the loss of renal function by itself. It is more likely that a variety of genetic factors will play a role in determining the response to environmental factors, development of risk factors like hypertension, dyslipidemia or proteinuria, development of allograft injury, and the rate of progression Figure 1. As a result, a host of candidate genes could be envisioned to play a role at one or more of these steps in the development of chronic rejection. Luckily, development of end-stage renal failure remains a relatively rare event, and therefore studies in families with several members undergoing kidney transplantation are largely limited to anecdotal reports in families with hereditary renal disease. While in some instances genotyping non-affected parents may play a role in demostrating preferential transmission of deleterious alleles to affected offspring, there is currently little hope that genes determining the processes involved in chronic allograft injury can be identified through affected sibling-pair or linkage studies in families. Therefore, the study of candidate genes selected on the basis of our current understanding of the pathophysiological mechanisms involved in the chronic rejection response appears to be the only feasible approach. It is obvious that the study of functional variants of genes implicated in the development of hypertension or inflammatory response should serve as prime candidates for a role in chronic rejection. Based on this line of reasoning, the components of the renin-angiotensin system are clearly candidate genes of considerable interest. Several lines of evidence do indeed suggest a role for this system in the development and progression of chronic allograft injury. Thus, hypertrophy of the juxtaglomerular apparatus is a common histological feature of chronic rejection and presumably indicates increased renin secretion[6C ROCKER B. Pathology of the renal allograft.Renal Pathology. edited by TISHER C, BRENNER B. Lippincott, Philadelphia1989: 1518Google Scholar]. Higher plasma renin activity has been reported in patients with worsening of graft function[7B RESTICKER M. N ELSON J. H UANG C. W OLF J. A NDERSON B. Plasma renin activity in renal transplant patients with hypertension.Am J Hypertens. 1991; 4: 623-626Google Scholar], and has also been implicated as a cause of post-transplant hypertension[8L UKE R.G. Pathophysiology and treatment of posttransplant hypertension.J Am Soc Nephrol. 1991; 2: S37-S44Google Scholar], an important risk factor for allograft injury[1H OSTETTER T.H. 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Effect of perindopril on the immune arterial wall remodeling in the rat model of arterial graft rejection.Am J Med. 1992; 92: 39S-46SAbstract Full Text PDF Scopus (17) Google Scholar] allografts in rats has been previously demonstrated by attenuation of injury by administration of angiotensin converting enzyme (ACE) inhibitors. Also, short-term studies in humans have demonstrated reduced proteinuria with ACE inhibition in hypertensives with renal transplants[12B OCHICCHIO T. S ANDOVAL G. R ON O. P EREZ G ROVAS H. B ORDES J. H ERRERA A COSTA J. Fosinopril prevents hyperfiltration and decreases proteinuria in post-transplant hypertensives.Kidney Int. 1990; 38: 873-879Abstract Full Text PDF Scopus (67) Google Scholar]. Recent studies have identified a variety of genetic variants of the components of the renin-angiotensin system[13J EUNEMAITRE X. S OUBRIER F. K OTELEVTSEV Y.V. L IFTON R.P. W ILLIAMS C.S. C HARRU A. H UNT S.C. H OPKINS P.N. W ILLIAMS R.R. L ALOUEL J.M. C ORVOL P. 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We have also reported that the AGT 235M/T-variant is associated with an early onset of hypertension in German Caucasian populations both in Berlin and Heidelberg[22S CHMIDT S. S HARMA A.M. Z ILCH O. B EIGE J. W ALLA F RIEDEL M. G ANTEN D. D ISTLER A. R ITZ E. Association of M235T variant of the angiotensinogen gene with familial hypertension of early onset.Nephrol Dial Transplant. 1995; 10: 1145-1148Google Scholar]. In a recent meta-analysis we found a 20 to 40% increase in the risk for hypertension associated with the AGT 235T variant in Caucasians[23K UNZ R. K REUTZ R. B EIGE J. D ISTLER A. S HARMA A.M. Association between the angiotensinogen 235T-variant and hypertension in Caucasians: A systematic review and methodological appraisal.Hypertension. 1997; 30: 1331-1337Crossref Scopus (186) Google Scholar]. 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Given that hypertension is an important risk factor for the progression of chronic allograft injury, and as many as 70% of all renal transplant recipients develop hypertension[1H OSTETTER T.H. Chronic transplant rejection.Kidney Int. 1994; 46: 266-279Abstract Full Text PDF Scopus (126) Google Scholar], it is conceivable that a variant of the angiotensinogen gene associated with essential hypertension may also increase the risk for the development of post-transplant hypertension. In rats exogenous angiotensinogen increases blood pressure under a low salt diet, demonstrating that with high renin levels, availability of angiotensinogen determines angiotensin I generation[25M ENARD J. E L A MRANI A.I. S AVOIE F. B OUHNIK J. Angiotensinogen: An attractive and underrated participant in hypertension and inflammation.Hypertension. 1991; 18: 705-707Crossref Scopus (60) Google Scholar]. 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Angiotensinogen-M235T genotype and post-transplant hypertension.Nephrol Dial Transplant. 1995; 11: 1538-1541Crossref Scopus (22) Google Scholar]. Genomic DNA for genetic analysis was prospectively collected from all recipients and donors and the presence of hypertension, and graft survival was analyzed by blinded review of all case records over a follow-up period up to 30 months. Angiotensinogen genotype was determined by a mutagenically-separated allele-specific polymerase-chain-reaction technique. While post-transplant hypertension was present in 78% of all patients, we found no relationship between either donor or recipient genotype and the presence or severity of post-transplant hypertension. Furthermore, there was no relationship between angiotensinogen genotype and graft survival during the course of the study. These findings clearly do not support the hypothesis that the M235T-variant of the angiotensinogen gene is a risk factor for the development of post-transplant hypertension. This finding may indicate that other factors including administration of cyclosporine, salt and fluid retention, or administration of glucocorticoids may have a greater impact on the development of hypertension than the angiotensinogen genotype. However, this study does not rule out that this genetic variant may predispose to the development of post-transplant hypertension or chronic rejection in a subset of patients. In most tissues ACE is the key catalyst of the conversion of angiotensin I to angiotensin II. Serum and tissue levels of ACE are now known to be under genetic control[14T IRET L. R IGAT B. V ISVIKIS S. B REDA C. C ORVOL P. C AMBIEN F. S OUBRIER F. 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Genetic variants of the renin-angiotensin system, diabetic nephropathy and hypertension.Diabetologia. 1997; 40: 193-199Crossref Scopus (80) Google Scholar. In 1995 Gaciong et al also reported a higher prevalence of the ACE-D allele (qD = 0.63) in kidney transplant recipients versus healthy age-matched blood donors (qD = 0.52), and suggested that this may be due to the fact that the ACE-D allele is a risk factor for the progression of renal disease[46G ACIONG Z.A. R ELIGA P. P LACHA G. R ELL K. P ACZEK L. ACE genotype and progression of IgA nephropathy.Lancet. 1995; 346: 570Abstract Full Text PDF Scopus (17) Google Scholar]. In a more recent study, homozygosity for the ACE-D variant has also been described as a risk factor for early development of end-stage renal failure in patients with PKD1 adult polycystic kidney disease[47B ABOOLAL K. R AVINE D. D ANIELS J. W ILLIAMS N. H OLMANS P. C OLES G.A. W ILLIAMS J.D. Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease.Kidney Int. 1997; 52: 607-613Abstract Full Text PDF Scopus (104) Google Scholar]. The implication of this genetic variant in the progression of a variety of renal diseases of considerable etiological heterogeneity suggests that the role of this polymorphism may be rather unspecific, possibly affecting structural or inflammatory processes common to the majority of progressive renal disorders. Based on these findings, we recently examined the hypothesis that the ACE I/D genotype may be related either to the onset or progression of chronic allograft injury. This question was addressed in three distinct settings: a single-center cohort of 269 Caucasian patients undergoing kidney transplantation between 1988 and 1993 in whom we analyzed the appearance of biopsy-confirmed chronic rejection or allograft loss over a follow-up period of 30 months[48B EIGE J. S CHERER S. W EBER A. E NGELI S. O FFERMANN G. O PELZ G. D ISTLER A. S HARMA A.M. Angiotensin-converting enzyme genotype and renal allograft survival.J Am Soc Nephrol. 1996; 8: 1319-1323Google Scholar]; a multi-center case-control study in 328 patients with an allograft survival of less than three years (median survival 11 months) versus 461 patients with an allograft survival of at least three years (median survival 65 months)[48B EIGE J. S CHERER S. W EBER A. E NGELI S. O FFERMANN G. O PELZ G. D ISTLER A. S HARMA A.M. Angiotensin-converting enzyme genotype and renal allograft survival.J Am Soc Nephrol. 1996; 8: 1319-1323Google Scholar]; a group of 86 transplant recipients with a graft survival of at least 10 years (median survival 156 months)[49Beige J, Offermann G, Distler A, Sharma AM: Angiotensin-converting-enzyme insertion/deletion genotype and long-term allograftsurvival. Nephrol Dial Transplant (in press)Google Scholar]. Neither in the cohort nor in the case control was there a significant effect of recipient or donor ACE genotype on transplant survival. Furthermore, the frequency of the ACE-D allele both in donors and recipients was similar to that reported by us and others in healthy Caucasian controls Figure 2. Likewise, in the patients surviving with a renal allograft for at least ten years, the frequency of the ACE-D allele was similar to that found in patients with early graft loss. This lack of relationship between the ACE-I/D genotype is also in line with a recent report on a Dutch cohort[50B OECKOELOFS J. S TEGEMAN C.A. N AVIE G.J. S CHEFFER H. T EGZESS A.M. D E Z EEUW D. D E J ONG P.E. Is donor or recipient ACE-genotype associated with long-term graft survival after renal transplantation?.Kidney Int. 1997; 52: 559Abstract Full Text PDF Google Scholar] of 318 patients with at least one year of graft survival. In that study, the relative risk for graft failure over a five year follow-up period in DD recipients was 1.82 (95% CI 0.66 to 5.01) versus the II genotype. After correction for acute rejection and inclusion of patients dying with a functioning allograft, the five-year allograft failure in DD recipients was higher than in II recipients (RR 1.92; 95% CI 0.91 to 4.02), but this result was not statistically significant. These authors, therefore, likewise concluded that neither donor nor recipient ACE-genotype significantly affected graft survival. Nevertheless, the lack of relationship between renal allograft survival and the ACE I/D genotype does not completely rule out a role for increased ACE activity in the development of chronic allograft rejection. Other variants of the ACE gene[51V ILLARD E. T IRET L. V ISVIKIS S. R AKOTOVAO R. C AMBIEN F. S OUBRIER F. Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis.Am J Hum Genet. 1996; 58: 1268-1278Google Scholar] might yet be associated with either the development of end-stage renal failure or the progression of renal injury including chronic transplant rejection, and the ACE-gene therefore remains an attractive candidate gene. Furthermore, given that the development of chronic transplant rejection is probably the result of a complex interaction between a variety of immunologic, genetic, and environmental factors[1H OSTETTER T.H. Chronic transplant rejection.Kidney Int. 1994; 46: 266-279Abstract Full Text PDF Scopus (126) Google Scholar], these findings do not completely rule out an importance of the ACE genotype in certain subsets of patients or under certain environmental conditions. Since the ACE-D allele has also been associated with increased humoral and tissue activity of this enzyme14T IRET L. R IGAT B. V ISVIKIS S. B REDA C. C ORVOL P. C AMBIEN F. S OUBRIER F. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels.Am J Hum Genet. 1992; 51: 197-205Google Scholar, 29R IGAT B. H UBERT C. A LHENC G ELAS F. C AMBIEN F. C ORVOL P. S OUBRIER F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.J Clin Invest. 1990; 86: 1343-1346Crossref Scopus (3518) Google Scholar, 33C OSTEROUSSE O. A LLEGRINI J. L OPEZ M. A LHENC G ELAS F. Angiotensin I-converting enzyme in human circulating mononuclear cells: Genetic polymorphism of expression in T-lymphocytes.Biochem J. 1993; 290: 33-40Crossref Scopus (501) Google Scholar, it appears worthwhile to pursue the question of whether individuals with the DD genotype profit more from therapeutic blockade of the renin-angiotensin system than other individuals. This suggestion is based on the findings of Yoshida et al[39Y OSHIDA H. M ITARAI T. K AWAMURA T. K ITAJIMA T. M IYAZAKI Y. N AGASAWA R. K AWAGUCHI Y. K UBO H. I CHIKAWA I. S AKAI O. Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy.J Clin Invest. 1995; 96: 2162-2169Crossref Scopus (348) Google Scholar], who demonstrated a significant reduction of proteinuria following ACE inhibition in patients with IgA nephropathy and the DD genotype, but not in patients with the ID or II genotype. Similarly, individuals harboring the D allele were found to have a larger decrease in blood pressure during ACE inhibition than II patients[52H INGORANI A.D. J IA H.Y. S TEVENS P.A. H OPPER R. D ICKERSON J.E.C. B ROWN M.J. Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition.J Hypertens. 1995; 13: 1602-1609Google Scholar], indicating that the ACE genotype may significantly influence the therapeutic response to blockade of the renin-angiotensin system. While the complexity and variability of chronic allograft rejection makes it very likely that genetic factors play a role in the development or progression of this syndrome, current studies focusing on the renin-angiotensin system have thus far not identified genetic variants of this system as important determinants. These negative findings, however, do not rule out a role for this system in the functional, inflammatory, or structural changes found in chronic rejection. Clearly, future studies will have to address the role of genetic variants of genes coding for components of other systems that may play a role in these processes. However, given our current limited understanding of the pathomechanisms involved, the host of potential candidate genes makes this a daunting, if not impossible, task. Hopefully, further experimental and clinical studies will improve our understanding of the pathophysiological mechanisms determining progressive renal allograft injury and will thus facilitate the selection of relevant candidate genes for future investigations.
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