MOLECULAR MECHANISMS OF CHRONIC KIDNEY GRAFT INJURY

K. Ivens, M. Siekierka-harreis, C. Bantis, C. Schwandt, N. Kuhr, L. Rump
Department Of Nephrology, Heinrich-Heine University, Düsseldorf/GERMANY

Body: Introduction: An up regulated renin-angiotensin-aldosterone system is considered to contribute to the development chronic allograft nephropathy and graft loss in renal transplantation. In the present study we evaluated the impact of the four major polymorphisms of the renin-angiotensin-system on long-term outcome after renal transplantation. Patients and methods: We studied n=205 consecutive patients, who underwent renal transplantation in our center from 1998 to 2001 (cadaveric: n=161, living related: n=44), followed up for 5.0 ± 2.0 years. One hundred healthy volunteers were analyzed as controls. Aldosterone synthase gene C-344T, angiotensinogen gene M235T, angiotensin converting enzyme gene I/D and angiotensin II-type 1 receptor gene A1166C polymorphisms were determined by PCR amplification. Results: The genotype distribution of the investigated polymorphisms was similar in patients and control subjects (ns). Age of donor and recipient, number of HLA-mismatches, cold ischemia time did not differ between patients with different genotypes (ns). During follow up n=103 (50.2%) patients had at least one episode of acute rejection and n=28 (13.7%) experienced graft failure. No association between the polymorphisms and the incidence of acute rejection was detected (ns). Patients carrying the aldosterone synthase CT/TT genotypes experienced graft failure more frequently (16.1%) compared to the CC genotype (4.5%, x²: 4.0, OR: 1.22, 95%CI: 1.07-1.39, p<0.05). An increased frequency of graft loss was also observed among the patients carrying the angiotensinogen TT genotype (27,8% vs. 10,7% in the MM/TT genotypes, x²: 7.4, OR: 2.43, 95%CI: 1.32-4.48, p=0.007). Combined analysis of the polymorphisms allowed a more precise identification of patients predisposed to graft loss: patients with the genotype combination of aldosterone synthase CT/TT and angiotensinogen TT had an almost three times higher risk for graft loss (31.3% vs. 10.4% in the other genotype constellations, x²=10.0, OR=2.87, 95% CI: 1.53-5.41, p=0.002). The Kaplan Meier analysis confirmed the impact of aldosterone synthase gene C-344T (p<0.05) and angiotensinogen gene M235T (p=0.005) polymorphisms as well as their combined analysis (p<0.001) on graft survival. This effect was prominent after the first two years after renal transplantation. No association between angiotensin converting enzyme gene I/D and angiotensin II-type 1 receptor gene A1166C polymorphisms and any of the parameters studied was observed. Conclusion: Our results suggest that aldosterone synthase gene C-344T and angiotensinogen gene M235T polymorphisms influence the long-term graft survival in renal transplantation, possibly through up regulating the renin-angiotensin-aldosterone system and contributing to the development of chronic allograft nephropathy.

Disclosure: All authors have declared no conflicts of interest.