Correspondence
C3 Polymorphisms and Outcomes of Renal Allografts
N Engl J Med 2009; 360:2477-2479June 4, 2009
- Article
To the Editor:
Varagunam et al. (Feb. 26 issue)1 do not confirm the previously reported association between the complement component 3 (C3) SS genotype and worsened outcomes of renal transplantation.2 However, the disparity in the results of these two studies may be due to differences in the proportion of recipients with specific risks of chronic allograft dysfunction. Moreover, the C3 SS genotype can be either a protective factor1 or an exacerbating factor in the progression of endogenous kidney disease, and it varies according to the disorder. For example, the SS genotype is associated with accelerated progression of membranous nephropathy3 and autosomal dominant polycystic kidney disease. We examined a cohort of 23 patients with autosomal dominant polycystic kidney disease before the development of end-stage renal disease and found that the SS genotype correlated with a younger mean (±SD) age in patients with chronic kidney disease (stage 3 or 4) (37±5 years in patients with the SS genotype vs. 45±7 years in patients with the SF genotype, P=0.046). Furthermore, in a cohort of 13 patients with autosomal dominant polycystic kidney disease and end-stage renal disease, the SS genotype, as compared with other genotypes, was associated with an earlier onset of end-stage renal disease (51±4 years vs. 63±7 years, P<0.002). Thus, C3 genotype associations may be affected by native renal disease, and results should be interpreted in this context relative to outcomes in recipients after kidney transplantation.
3 ReferencesMichal Mrug, M.D.
Juling Zhou, M.D.
Roslyn B. Mannon, M.D.
University of Alabama at Birmingham, Birmingham, AL 35294
mmrug@uab.edu 1
Varagunam M ,Yaqoob MM ,Dohler B ,Opelz G . C3 polymorphisms and allograft outcome in renal transplantation. N Engl J Med 2009;360:874-880
Full Text | Web of Science | Medline2
Brown KM ,Kondeatis E ,Vaughan RW , et al. Influence of donor C3 allotype on late renal-transplantation outcome. N Engl J Med 2006;354:2014-2023
Full Text | Web of Science | Medline3
Papiha SS ,Rodger RS . C3 and Bf complement types in chronic renal failure. Hum Genet 1986;72:260-261
CrossRef | Web of Science | Medline
To the Editor:
Varagunam et al. do not confirm the previously suggested importance of C3 gene polymorphisms in the donor for renal allograft survival.1 One should be careful in the interpretation of the finding that these polymorphisms do not affect renal allograft survival. The absence of an effect of the C3 polymorphism does not imply that other aspects of C3, such as expression, function, or local production, are irrelevant in the outcome of renal transplantation. In animals, locally expressed complement C3 in renal tissue was shown to be important with respect to the risk of acute rejection and ischemia–reperfusion injury.2,3 In humans, we recently showed that the up-regulation of C1, C2, C3, C4, and C6 and expression of complement factor B in kidneys at the time of transplantation of kidneys from deceased donors, as compared with kidneys from living donors, had a significant correlation with renal allograft function.4 Taken together with studies in animals showing beneficial effects of complement inhibition on the risks of ischemia–reperfusion injury, rejection, and tubulointerstitial injury, complement inhibition remains an attractive target for long-term maintenance of renal allograft function and survival.
4 ReferencesMaarten Naesens, M.D., Ph.D.
Atul J. Butte, M.D., Ph.D.
Minnie M. Sarwal, M.D., Ph.D.
Stanford University School of Medicine, Stanford, CA 943051
Brown KM ,Kondeatis E ,Vaughan RW , et al. Influence of donor C3 allotype on late renal-transplantation outcome. N Engl J Med 2006;354:2014-2023
Full Text | Web of Science | Medline2
Pratt JR ,Basheer SA ,Sacks SH . Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002;8:582-587
CrossRef | Web of Science | Medline3
Farrar CA ,Zhou W ,Lin T ,Sacks SH . Local extravascular pool of C3 is a determinant of postischemic acute renal failure. FASEB J 2006;20:217-226
CrossRef | Web of Science | Medline4
Naesens M, Li L, Ying L, et al. Expression of complement components differs between kidney allografts from living and deceased donors. J Am Soc Nephrol (in press).
Author/Editor Response
Mrug et al. suggest that the results of our study, which did not show an association between C3 polymorphisms and graft survival, might be due to an imbalance in the numbers of patients with different causes of renal failure in our study sample. Our statistical analysis took this imbalance into consideration; we adjusted for primary disease in our statistical model. Although the study by Mrug et al. on the association between the SS allele and autosomal dominant polycystic kidney disease is interesting, the results should be interpreted with caution. The study may have been underpowered because of the low number of participants; this could have led to an incorrect statistical inference and hence an incorrect conclusion.
We agree with Naesens et al. Our results should not be interpreted in a way that diminishes the importance of complement in the outcome of transplantation. Indeed, complement inhibition remains an attractive target for the prevention of ischemia–reperfusion injury and humoral rejection; this inhibition may translate into better long-term renal-allograft outcomes. The aim of our study was to repeat the results of Brown et al.,1 which suggested that matching at the C3 loci would be beneficial in the outcome of transplantation. Confirmation of their findings would have been clinically important, leading the way toward the improvement of long-term outcomes in renal transplantation. Our study in a larger study sample did not find any such association, thus highlighting the multifactorial nature of graft failure. It is unlikely that any one gene plays an overwhelming role in the pathways that lead to graft failure.
1 ReferencesMira Varagunum, Ph.D.
Barts and the London School of Medicine and Dentistry, London E1 1BB, United KingdomGerhard Opelz, M.D.
University of Heidelberg, D-69120 Heidelberg, GermanyMuhammad M. Yaqoob, M.D.
Barts and the London School of Medicine and Dentistry, London E1 1BB, United Kingdom
m.m. yaqoob@qmul. ac. uk 1
Brown KM ,Kondeatis E ,Vaughan RW , et al. Influence of donor C3 allotype on late renal-transplantation outcome. N Engl J Med 2006;354:2014-2023
Full Text | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Evy De Witte, Marijn M. Speeckaert, Lot Van De Moortel, Elke Lecocq, Joris R. Delanghe. (2012) Human complement factor 3 polymorphism determination by capillary electrophoresis of serum. ELECTROPHORESISn/a-n/a
CrossRef2
J. Damman, M. R. Daha, H. G. Leuvenink, H. van Goor, J. L. Hillebrands, M. C. van Dijk, B. G. Hepkema, H. Snieder, J. van den Born, M. H. de Borst, S. J. Bakker, G. J. Navis, R. J. Ploeg, M. A. Seelen. (2011) Association of Complement C3 Gene Variants with Renal Transplant Outcome of Deceased Cardiac Dead Donor Kidneys. American Journal of Transplantationno-no
CrossRef
