In this issue of the journal, Choy et al. review the current state of knowledge regarding etiology, prevention, and treatment of diseases that may recur after a kidney transplant (1). Their descriptions are illustrative of how poor our alternatives are: ‘there is no effective therapy for the prevention and treatment of IgAN’[IgA nephropathy]; ‘the pathogenesis of recurrent FSGS [focal segmental glomeruloselerosis] is unclear’; ‘no effective therapy is available for the prevention or treatment of recurrent MPGN’[membranoproliferative glomerulonephritis]. The problem of recurrent disease in transplant outcomes has an odd quality: it tends to be acknowledged but then ignored. In the United States, a multicenter registry was established and did a retrospective report (2,3). And a prospective observational study was begun at 12 US centers in 1998, but, to date, little information has been provided (4). The issue of recurrent disease in transplantation looms larger and larger as immunologic problems are better defined and controlled, yet has little representation in the transplant literature. Our argument is that recurrent disease is our problem and it must be addressed.
The goal of kidney transplant programs is to achieve long-term patient survival, excellent graft function, and no immunosuppression-related morbidity. Transplant research in the 1970s and 1980s focused on reducing acute rejection rates and improving short-term graft outcome. It was hoped that minimizing acute rejection would eliminate late graft dysfunction and late graft loss. The 1990s saw a marked improvement in short-term outcome; 1-year patient and graft survival rates are now greater than 90%, with rates of acute rejection in the first year of <15% at many centers. Yet the expected improvement in long-term outcome has not materialized and there have been only modest improvements in actuarial 20-year graft survival rates. Late graft loss has become one of the leading causes of end-stage renal disease (ESRD).
There are multiple causes of late kidney allograft loss. Each must be addressed if we are to improve outcomes. Most attention is paid to the two commonest causes—death with function and a collection of changes lumped together as ‘chronic allograft nephropathy/chronic rejection’ (CR). A third cause, recurrent disease, now requires attention. Historically, recurrent disease has accounted for about 10% of graft losses (5). This may be an underestimate, as many kidney transplant recipients with slow deterioration of graft function never undergo allograft biopsy and a presumed diagnosis of ‘chronic rejection’ is inappropriately made. Currently, as more grafts are functioning beyond the first year, recurrent disease is becoming more of a concern. Data from the University of Minnesota showed an increased in incidence of biopsy-proven recurrent disease between 1996 and 2005 versus the previous decade (1986–2005) (Sturdevant et al., personal communication).
Recurrent disease is more of a problem for younger recipients. Of graft losses in recipients <20 years of age, 95 reported to the OPTN/UNOS database between 1999 and 2003 (for recipients transplanted between 1991 and 2003), recurrent disease was responsible for 11.6% of living donor (LD) graft losses and 7.2% of deceased donor (DD) graft losses; for recipients 21–45 years, 7.5% of LD losses and 4.6% DD graft losses; for recipients 46–65 years, 2.9% of LD losses and 1.7% of DD graft losses.
Our concern should not be just about graft losses; elevated creatinine levels are associated with increased cardiovascular morbidity and mortality (6). Elevated creatinine levels due to recurrent disease in transplant recipients may contribute to increased morbidity and mortality in that subpopulation.
Given its impact, why is little attention paid to recurrent disease after kidney transplantation? In part, this is because many individual diseases can recur; because only a limited number of cases of any one disease occur at each transplant center; because disease recurrence is unpredictable (although associations or risk factors have been observed, none are 100% predictable); and because pathophysiology and treatment for the primary diseases are poorly understood. Finally, recurrent disease is part of the problem of primary renal diseases, which in many cases are not currently the subject of active research.
Progress will only come in this area if the nephrology and transplant community together make it a priority. Multicenter studies and multidisciplinary efforts are necessary. New technologies such as microarrays, proteomics, and metabolomics can be applied. Patients with renal diseases that may recur posttransplant are referred to a nephrologist at various stages in the disease process; but, for each patient, the transplant is a clearly defined event that can be studied—a significant advantage for the scientist interested in disease pathogenesis and etiology.
Multicenter studies are necessary at the point of disease presentation and at the time of transplantation. Because of small numbers, no single center will be able to do large-scale intervention or prevention trials for either the primary or recurrent disease. National or international trials are necessary. Recurrent disease should be viewed in the same way that the FDA views an ‘orphan drug’. Funding agencies, the government, and the nephrology and transplant community should band together to attack this problem. Only by such large-scale cooperation will we be able to improve the outcome for this cohort of patients. But the advantages of infusing this area with new energy in transplantation may spread beyond transplantation: perhaps the observational and interventional opportunities in recurrent disease in transplantation can re-energize the studies of primary diseases and shed new light on pathogenesis in research areas that have otherwise become stagnant.