There is general consensus that the optimal treatment for most patients with end-stage renal disease (ESRD) is renal transplantation. Benefits have been classically described in terms of improved quality of life (1, 2, 3, 4) and reduced medical expense (2,5). According to the 2001 United Network for Organ Sharing (UNOS) report (6), current 1- and 5-year patient survival rates for recipients of cadaveric kidney transplants are 95% and 81%, respectively, and 98% and 91%, respectively, for living donor transplant patients. Improvements in patient survival after cadaveric transplantation have been demonstrated in several studies (7, 8, 9, 10). However, randomized trials comparing survival during dialysis treatment and after transplantation are neither feasible nor ethical. Moreover, transplant recipients are derived from a highly selected subgroup of patients on dialysis who are on average younger and healthier and of higher socioeconomic status than those dialysis patients not selected for transplantation. Wolfe et al (11) avoided this selection bias by merging data from the U.S. Renal Data System (USRDS) with information about the renal transplantation waiting list from the Scientific Renal Transplant Registry (SRTR) operated by UNOS and found large long-term benefits for cadaveric transplantation versus maintenance dialysis, despite the increased short-term risk of death after transplantation (Fig. 1.1). The relative survival benefits of transplantation were similar for men and women, and although more profound in diabetics, were extended to subgroups of patients with other causes of ESRD. When the results were analyzed according to race, transplantation reduced the long-term relative risk (RR) of death more among Asians and whites than among Native Americans and blacks. However, in all four racial groups, transplantation significantly reduced the long-term risk of death. Likewise, although the greatest difference in long-term survival was found among patients who were 20 to 39 years old at the time of placement on the waiting list, improvements were still noted in patients who were 70 to 74 years old. The findings by Wolfe et al provided a convincing answer to the most basic question about therapy for patients with ESRD and refocused attention on kidney transplantation as a life-prolonging rather than merely a life-enhancing procedure.

The era of clinical organ transplantation began in 1962 with the discovery that azathioprine was clinically useful as an immunosuppressive drug. One-year cadaveric renal allograft survival, previously zero, was increased by the combination of prednisone and azathioprine to 45% to 50%. By the 1970s, it was clear that transplantation of kidneys from living related donors resulted in better initial and long-term graft survival rates than those of kidneys from cadaveric donors. After cyclosporine (12,13) and muromonab-CD3 (OKT3 monoclonal antibody) (14,15) were introduced into clinical practice in the early 1980s, 1-year survival rates for renal allografts improved from approximately 60% to between 80% and 90%. From 1988 to 1996, 1-year graft survival increased from 89% to 94% for recipients of living donors and from 77% to 88% for cadaveric donor recipients (16). In the 1990s, the introduction of new immunosuppressive agents led to a marked decrease in the incidence of acute rejection (17). The 2001 UNOS report (6) shows that the improvements in 1-year graft survival have increased further to 89% and 95% for cadaveric and living donor transplants, respectively.

Using the SRTR, Hariharan et al (16) reported that the projected half-life of grafts has improved progressively from 7.9 to 13.8 years for a cadaveric donor and 12.7 to 21.6 years for a living donor for the period from 1988 to 1995 (Table 1.1). This improvement was not wholly attributable to any of the newer immunosuppressive drugs, as it took place in the era of treatment with cyclosporine, azathioprine, and prednisone. Given these findings, more attention is being paid not only to immunologic but also to nonimmunologic strategies that may improve long-term outcomes through prevention of late allograft loss (18). This chapter will focus on pre- and posttransplant donor and recipient risk factors important to graft and patient survival as well as the effects of pharmacologic advances on these outcome measures.

Data have now emerged to highlight the importance of death with a functioning allograft as a major contributor to late allograft loss (19, 20, 21, 22, 23), particularly as more elderly patients are being transplanted. Depending on the age and comorbidities of the patient population, the transplant era, and the posttransplant interval being studied, death with a functioning allograft ranks as first or second among the leading causes of graft loss (19, 20, 21,24). Death with graft function is usually due to comorbidities, such as heart disease, infection, and
cancer. Many of these conditions can be modified by the immunosuppressive medications utilized in transplant patients and by the level of renal function maintained by the graft. Analysis of graft loss independent of these deaths (death-censored graft loss) allows one to approximate risks for injury to the graft itself, but also may lead to bias by not taking into account factors that may influence both endpoints. Although large interventional trials designed to minimize patient death in the transplant population are not available to establish proof of efficacy, as in the general population, the usual measures aimed at modifying risk factors for patient death, particularly cardiovascular death, are generally applied (19). These measures include weight loss, smoking cessation, strict glycemic control, lipid-lowering therapy, aspirin, and correction of anemia. Most centers aggressively monitor and treat infection in transplant patients and attempt to minimize immunosuppression in those patients at high risk for infections, particularly the elderly. General guidelines for cancer screening are usually followed.

CAN is a poorly defined clinical-pathological entity manifested clinically by a gradual decrease in renal function over months to years after transplantation, coupled with hypertension (HTN) and variable degrees of proteinuria (25). Histopathologic findings include widespread obliterative vasculopathy, glomerulosclerosis and interstitial fibrosis with tubular atrophy (Fig. 1.3). Rarely, transplant glomerulopathy, with splitting of the glomerular basement membrane, is seen. However, these changes overlap those of human aging and age-related diseases in native kidneys. Thus, CAN is better considered a final common pathway of a variety of stresses to renal tissue (20). Both immunologic and nonimmunologic factors have been shown to contribute to CAN (26), although these factors should not be considered mutually exclusive.

Of the immunologic factors, AR (particularly severe, recurrent, and late) remains one of the highest risk factors for the development of CAN. Further evidence for immunologic mechanisms stems from observations that the half-life of cadaveric renal allografts is longer when donated from human leukocyte antigen (HLA)-matched versus HLA-mismatched donors (27). Moreover, in a study by Legendre et al (28), 2-year protocol biopsies on HLA-identical but not HLA-mismatched kidneys from patients that did not have episodes of AR or acute renal failure (ARF) showed no histopathologic findings of CAN. Both cellular (29, 30, 31, 32) and humoral (33,34) mechanisms likely play a role in the pathogenesis of CAN, although the relative contribution of each is still the subject of intense debate. Nonimmunologic factors include brain death in the donor, ischemia-reperfusion injury, inadequate donor kidney nephron mass, calcineurin inhibitor toxicity, hypertension, hyperlipidemia, cytomegalovirus (CMV) infection, and polyoma virus nephropathy.

To date, there have been no convincing studies to demonstrate that secondary intervention is effective in reducing the rate of graft loss due to CAN. The ultimate goal in transplantation is to achieve a state of tolerance (35), which would ideally eliminate the immunologic factors, but which may also serve to attenuate the effects of the nonimmunologic factors (36). It is clear that any successful strategy will need to be broad-based to account for the immunologic, physiologic, infectious, and metabolic aspects of this difficult problem.

Glomerulonephritis (GN) is a major cause of ESRD and is the primary disease in roughly 30% to 50% of patients undergoing renal transplantation (24,37). Accurate estimates
of the incidence of recurrent GN and its associated impact on graft survival are hampered by the paucity of cases seen within any single transplant center. Results from small studies should be interpreted with caution, and although reports from data registries give good estimates of rates of graft loss, they often lack information on recurrence rates and clinical outcomes. Recurrence has been reported in 6.0% to 19.4% of renal allograft recipients, and the prevalence increases with the duration of follow-up (24,38, 39, 40, 41). Those patients with recurrence have a higher rate of graft loss, with recurrence reported as the cause of loss in 1.1% to 8.4% of transplant recipients (24,38, 39, 40, 41, 42).

When interpreting rates of recurrence, several issues require consideration. First, an accurate histologic diagnosis is essential both pre- and posttransplantation. Unfortunately, many patients reach ESRD without a definitive renal biopsy, and most renal transplant centers do not routinely perform diagnostic biopsies on patients with proteinuria and/or chronic allograft dysfunction. These scenarios lead to underdiagnosis and therefore an underreporting of the true recurrence rate. Second, the lack of specificity in the pathologic features of some conditions often leads to errors in diagnosis. Compounding this problem is the frequent occurrence of coexisting glomerular pathologies. Third, recurrence rates can be complicated by the existence of de novo glomerular disease. Finally, the duration of follow-up of a particular study is important, since the impact of recurrence on graft survival will increase with longer periods of follow-up.

Using data compiled by the Australian and New Zealand Dialysis and Transplant Registry, Briganti et al (24) studied the incidence, timing, and relative importance of allograft loss due to the recurrence of GN in 1,505 renal transplant recipients with biopsy-proved GN as the cause of ESRD. At 10-years posttransplantation, the incidence of allograft loss due to recurrent GN was 8.4%, as compared with 4.1% for loss due to acute rejection, 15.0% for loss due to death with a functioning allograft, and 20.3% for loss due to CAN, making recurrent GN the third most common cause of allograft loss in this patient population. Allograft loss due to recurrent GN occurred in patients with focal segmental glomerulosclerosis (FSGS), mesangiocapillary glomerulonephritis type I (MCGN-I), MCGN type III, IgA nephropathy, Henoch-Schoenlein purpura, membranous nephropathy, and pauci-immune crescentic GN. The greatest incidence of allograft loss occurred among patients with FSGS and MCGN-I, and allograft loss tended to occur earlier in these patients. The 10-year incidence of allograft loss from any cause was similar among recipients with biopsy-proved GN and among those with renal failure from other causes. Since the incidence of allograft loss due to GN increases over time, recurrent GN will likely become an increasingly important cause of allograft
loss as overall long-term graft survival rates continue to improve.