ACE genotype and long-term graft survival after renal transplantation

Sir,

Slowinski et al. [1] report that the angiotensin-converting enzyme (ACE) (I/D) recipient genotype has no impact on the occurrence of renal graft dysfunction in 405 Caucasian kidney graft recipients.

In their discussion they refer to the Lancet review by Colhoun et al. [2] on the problems of reporting genetic association studies in disorders with complex outcomes and underline the importance of the publication of negative results in order to avoid publication bias.

Surprisingly, however, they do not cite my group's paper on 435 kidney recipients that showed the D allele of the recipient ACE genotype to be associated with an increased risk for graft loss in high-risk patients, i.e. a 2.5-fold increased risk in subjects with a creatinine clearance of <50 ml/min at 1 year after transplantation and a 3-fold increased risk in subjects with proteinuria of >0.5 g/24 h. Donor genotype had no effect on the risk for graft loss [3].

Renal function loss is doubtless a complex trait. To unravel the role of possible genetic factors involved, proper understanding of the multifactorial nature of renal function loss is required. Our paper illustrates that it would be naïve to study genetic risk factors as isolated entities and that integration of genetic data with the available knowledge on pathophysiology and on phenotypic risk factors would be more likely to generate relevant insights into the role of genetic factors in renal damage. The authors are apparently aware of this, as they mention the possible importance of epigenetic interaction with factors determining RAAS activity, without, however, identifying such interactions in their study. Studies from my group have consistently identified sodium intake—a main determinant of RAAS activity—as a factor that modifies the impact of the D allele on the renal phenotype in different settings, namely proteinuric patients [4], healthy volunteers [5] and uncomplicated diabetics [6]. Unfortunately, data on sodium status are lacking in almost any clinical study on ACE genotype. For proper interpretation of data from association studies, every effort should be made to obtain data on the factors that can interact with the candidate gene and to take into account their effect. Proper consideration of such interacting factors, in particular if these are modifiable factors such as sodium intake, not only will allow more insights to be obtained from the study, but may also lead the way to intervention in genetically conferred renal risk.

Conflict of interest statement. None declared.

Gerjan Navis

Groningen University, Medicine Groningen, the Netherlands Email: g.j.navis{at}int.azg.nl

References

  1. Slowinski T, Diehr P, Kleemann P, Fritsche L, Renders L, Budde K, Hauser I A, Neumayer H H, and Hocher B. No association between renin–angiotensin system gene polymorphisms and early and long-term allograft dysfunction in kidney transplant recipients Nephrol Dial Transplant 2004; 19: 2846–2851[Abstract/Free Full Text]
  2. Colhoun HM, McKeigue PM, Davey Smith G. Problems of reporting genetic associations with complex outcomes. Lancet 2003; 361: 865–872[CrossRef][ISI][Medline]
  3. Broekroelofs J, Stegeman CA, Navis GJ, Tegzess AM, de Zeeuw D, de Jong PE. Is donor or recipient ACE genotype associated with long-term graft survival after renal transplantation? J Am Soc Nephrol 1998; 9: 2075–2081[Abstract]
  4. van der Kleij FGH, Schmidt A, Navis GJ et al. ACE I/D polymorphism and short term response to ACE inhibition: role of sodium status. Kidney Int 1997; 52 [Suppl 63]: S23–S26
  5. van der Kleij FGH, de Jong PE, Henning RH, de Zeeuw D, Navis GJ. Enhanced responses of blood pressure, renal function and aldosterone to angiotensin I in DD genotype are blunted by low sodium intake. J Am Soc Nephrol 2002; 13: 1025–1033[Abstract/Free Full Text]
  6. Luik PT, Hoogenberg KH, van der Kleij FGH et al. The influence of ACE (I/D) polymorphism on systemic and renal vascular responses to angiotensins in normotensive normoalbuminuric type I diabetes mellitus. Diabetologia 2003; 46: 1131–1139[CrossRef][ISI][Medline]




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