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Background

Complement activation plays a role in the development of chronic allograft nephropathy, a common cause of late allograft loss. The role of two complement component 3 (C3) allotypes, called C3F (fast) and C3S (slow) on the basis of their electrophoretic motility, in the long-term outcome of renal allografts remains controversial.

Methods

We selected a random sample of 1147 donor and recipient pairs from the Collaborative Transplant Study DNA bank, and their DNA specimens were genotyped for the C3F and C3S alleles.

The genotyping results were analyzed according to allograft outcome.

Transplants were divided into four groups, according to the recipient and donor genotypes: SS recipient and FS or FF donor (the standard for comparison, since this combination has been reported to have the best outcome), SS recipient and donor, FS or FF recipient and SS donor, and FS or FF recipient and donor.

Results

Baseline characteristics of the four transplant groups were similar. The hazard ratios for allograft survival in the SS recipient and FS or FF donor group as compared with the other three groups (SS recipient and donor, FS or FF recipient and SS donor, and FS or FF recipient and donor) were not significant: 0.90 (95% confidence interval [CI], 0.7 to 1.14; P=0.33), 0.87 (95% CI, 0.65 to 1.16; P=0.33), and 0.89 (95% CI, 0.65 to 1.23; P=0.48), respectively.

The four groups had similar patient-survival rates and similar cumulative rates of acute rejection and allograft dysfunction, as assessed by means of serum creatinine levels.

Conclusions

Our results suggest that transplantation of FS or FF kidneys to SS recipients is not advantageous, possibly because chronic allograft nephropathy is a multifaceted disease involving the interplay of many biologic pathways.

Kidney transplantation improves the quality of life of patients with end-stage kidney failure, increasing their longevity and freeing them from the restrictions and complications of dialysis.

Despite continued improvements in immunosuppressive drugs and medical care, the 10-year allograft survival rate remains disappointingly low, mainly because of chronic allograft nephropathy.¹

Activation of the complement cascade is inevitable in kidney transplantation, because of both the specific and nonspecific immunologic responses of the recipient.

Complement component 3 (C3) is central to all three complement activation pathways.² Local production of C3 in the donor kidney is up-regulated in tubules, and the C3 is deposited on the tubule surface adjacent to the T-cell infiltrate in kidneys during allograft rejection.³

A single base substitution in C3 defines two allelic variants: S (slow) and F (fast), based on the differential mobility on gel electrophoresis of the resulting proteins in serum.⁴

The relative ease of use of polymerase-chain-reaction (PCR) technology and the central role of complement in many diseases have resulted in studies that have examined associations between C3F and C3S polymorphisms and disease states.

Generally, the presence of the F allele has a detrimental effect, as has been reported in IgA nephropathy,⁵ age-related macular degeneration,⁶ and systemic vasculitis.⁷

Such reports imply a functional variation in the phenotype associated with the genotype.

The allelic frequency of C3F varies markedly among races: 20% among whites, 5% among blacks, and 1% among Asians.⁸ The presence of the C3F allele in either the donor or the recipient has been associated with allograft dysfunction.⁹

However, a recent study showed an improved long-term outcome with donor kidneys carrying the F allele transplanted into S recipients.¹⁰

If confirmed, this observation would mean that it would be important for transplantation laboratories to perform routine genotyping at the C3 locus.

Given this finding, we genotyped DNA from 1147 pairs of donors and recipients to examine the importance of this gene in transplantation and its influence on long-term survival of allografts.

VER FULLTEXT

NEJM: Volume 360:874-880 February 26, 2009 Number 9

Mira Varagunam, Ph.D., Muhammad M. Yaqoob, M.D., Bernd Döhler, Ph.D., and Gerhard Opelz, M.D.

http://content.nejm.org/cgi/content/full/360/9/874