Long-Term Graft Survival In Kidney Transplant Recipients

Jerry McCauley, MD, MPH

Disclosures

May 19, 2004

For patients receiving a renal transplant in the mid- to late 1980s (1985-1989), graft survival at 5 years was only a little better than 50%. Allograft half-life, an estimate of long-term graft survival, is longer for patients who received kidneys in the recent period compared with patients who received kidneys during earlier intervals. The data reveal that almost two thirds of kidneys that were transplanted from 1995 to 1999 were still functioning 5 years later.[1] Although renal allograft survival rates have improved over the years, approximately one third of renal allografts transplanted in the present era will fail within 5 years.

Hariharan and colleagues[2] analyzed data collected from 93,934 patients who received renal transplants in the United States between 1988 and 1996. Between 1988 and 1995, allograft half-life more than doubled for patients who did not experience an episode of acute rejection within the first year. Among patients who received a transplant in 1988, the projected allograft half-life was 8.8 years, compared with a half-life of 17.9 years for patients who received an allograft in 1995. This represents a 103% increase in projected allograft half-life for 1995 vs 1988. During the same period, the half-life of renal transplants for patients who had at least 1 acute rejection remained relatively steady. These data suggest that acute rejection within the first year posttransplantation is a negative predictor of long-term renal allograft survival.

Acute rejection and delayed graft failure (DGF), both seen more frequently in black than in white renal transplant recipients, are associated with decreased allograft survival rates. The data depict the significantly lower rate of allograft survival in black recipients without acute rejection compared with white recipients without acute rejection (P < .01).[3] Among recipients with acute rejection, the 5-year survival rate was 50% for blacks and 76% for whites (P < .01). The disparity between these 2 groups suggests that acute rejection more negatively affects allograft outcomes in black recipients. Immunosuppressant therapy and other treatments that minimize the incidence of acute rejection may improve long-term renal allograft survival, and this study suggests the impact may be even greater for black recipients.

In a phase 3 clinical trial, Pirsch and colleagues[4,5] randomized 412 renal transplant recipients to treatment with either tacrolimus (TAC) or cyclosporine (CsA). Data were evaluated after 1 year and again after 5 years of study. The study protocol allowed for crossover to the alternative primary immunosuppressive agent (TAC or CsA) under very specific conditions. The crossover rate was > 25% for patients randomized to receive CsA and < 10% for patients randomized to receive TAC (27.5% vs 9.3%; P < .001). Most crossovers (60.5%) occurred within the first year posttransplantation. Immunosuppression with TAC was associated with a significantly lower rate of acute rejection compared with CsA-based immunosuppression (30.7% vs 46.4%, respectively, P < .001).

This study was designed to investigate different combinations of immunosuppressive agents for renal transplantation. Two hundred twenty-three (223) patients who received a first cadaveric kidney transplant were randomized into 1 of 3 treatment groups: (1) TAC + azathioprine (AZA), n = 76; (2) TAC + mycophenolate mofetil (MMF), n = 72; and (3) CsA (Neoral) + MMF, n = 75. The acute rejection rate at 1 year was similar for the 3 groups, ranging from 15.3% for treatment with TAC + MMF to 20% for treatment with CsA + MMF.[6] Allograft survival at 3 years was similar for all 3 treatment groups, ranging from 80.6% for TAC + MMF to 73.3% for CsA + MMF.[7] Survival was high for all 3 groups.

Kahan and colleagues[8] evaluated the impact of adding sirolimus (SRL) vs AZA to CsA (Neoral)-based immunosuppressive therapy in renal transplant recipients. A total of 719 patients were randomized to receive 1 of 3 regimens: (1) SRL 2 mg/day + CsA, n = 284, (2) SRL 5 mg/day + CsA, n = 274, or (3) AZA 2-3 mg/kg/day + CsA, n = 161. The addition of SRL to CsA-based immunosuppression significantly decreased the incidence of acute rejection (in an apparently dose-dependent fashion) at 6 months compared with immunosuppression with AZA + CsA.

This study compared MMF and SRL in combination with either TAC or CsA.[9] A total of 150 renal transplant recipients were randomized to 1 of the following treatment groups: (1) TAC + SRL, n = 50; (2) TAC + MMF, n = 50; or (3) CsA (Neoral) + SRL, n = 50. This is an ongoing study in which patients will be studied for up to 3 years posttransplantation. This slide presents the 12-month interim results. The incidence of acute rejection at 12 months was similar for the 2 TAC-treated groups (4% each) and significantly lower than the incidence observed in the CsA + SRL treatment group (21%) (P < .05).

Ojo and colleagues[10] analyzed data on 66,774 renal transplant recipients and supplemented their analysis with end-stage renal disease data from the United States Renal Data System (USRDS). All patients in this analysis received a kidney transplant in the United States between October 1, 1988 and June 30, 1997; 48,436 patients received CsA + AZA (with or without corticosteroids) and 8435 received MMF in place of AZA in CsA-based therapy. The incidence of acute rejection during the first 6 months after transplantation was significantly higher in the AZA-treated group compared with the MMF-treated group (P < .001). Four-year death-censored graft survival and 4-year patient survival were both significantly better in MMF-treated than in AZA-treated patients started on MMF vs AZA: graft survival in MMF- vs AZA-treated patients was 85.6% vs 81.9%, P < .0001; and patient survival in MMF- vs AZA-treated patients was 91.4% vs 89.8%, P < .002.

Even in a subanalysis of patients who never had acute rejection, the risk of chronic allograft failure was 20% lower in the MMF-treated group (P < .001), demonstrating that MMF is associated with improvements in both short-term and long-term results, possibly by different mechanisms.

Data were obtained from 19,246 patients who received primary cadaveric kidney transplants in the United States between 1988 and 1996.[11] Three-year renal allograft survival rates are reported for patients without any report of DGF or early acute rejection (n = 14,276) and for those who had reports of both DGF and early acute rejection (n = 702).

For patients without DGF or early acute rejection, the adjusted allograft survival rates at 36 months were 90.5% for treatment with CsA + AZA, 91.4% for treatment with CsA + MMF, 92.1% for treatment with TAC + AZA, and 92.4% for treatment with TAC + MMF. For patients with both DGF and early acute rejection, the adjusted allograft survival at 3 years was 80.2% for treatment with CsA + AZA, 82.1% for treatment with CsA + MMF, 83.5% for treatment with TAC + AZA, and 83.9% for treatment with TAC + MMF. These data show that TAC in combination with either MMF or AZA, or CsA in combination with MMF, improves long-term renal allograft survival compared with a treatment regimen consisting of CsA + AZA. This is true for patients who do and for those who do not experience early problems posttransplantation (ie, DGF and early acute rejection).

Ciancio and colleagues[9] found no marked overall differences in the mean serum creatinine (SCr) levels from 1 month to 12 months posttransplantation for the TAC + SRL, TAC + MMF and Neoral + SRL treatment groups. It was noted that the change from month 1 to month 12 in both the TAC + SRL and Neoral + SRL treatment groups was +7%, whereas the change in the TAC + MMF group from month 1 to month 12 was -3%. Further follow-up was recommended.

Recent evidence suggests that the SCr level in the first year posttransplantation may be an important prognostic indicator of long-term renal allograft survival. The data in Figure 13 suggest that patients with stable SCr levels during the first year posttransplantation are expected to achieve optimal graft survival.[12] Therefore, immunosuppressive regimens or other treatments that are associated with good renal function during the first year posttransplantation may be expected to help optimize or improve long-term renal allograft survival.

The 1-year,[6] 2-year,[13] and 3-year[7] results from a 3-arm trial comparing TAC + AZA, TAC + MMF, and Neoral + MMF in cadaveric renal transplant recipients are shown in Figure 14. At 1 year, median SCr levels were significantly lower in patients treated with TAC + MMF and TAC + AZA than in patients treated with CsA + MMF. Median SCr levels at 2 years were significantly lower in patients treated with TAC + MMF and TAC + AZA than in patients treated with CsA + MMF. At 3 years, there were no significant differences between the 3 groups for the median SCr level. The authors of all 3 reports came to the conclusion that while all 3 regimens were impressive, the overall results were better in the 2 TAC treatment arms, with the best results achieved with the regimen of TAC + MMF.

This study, conducted by Klein and colleagues,[14] measured the effects of calcineurin inhibitors on renal function in healthy subjects. Treatment with TAC was associated with significantly lower plasma creatinine levels than treatment with CsA (97 vs 105 micromol/L, respectively, P < .05). Treatment with TAC was also associated with a significantly higher glomerular filtration rate (GFR) than treatment with CsA (93 vs 85 mL/min/1.73 m2, respectively, P < .05) and a significantly lower mean arterial pressure than treatment with CsA (96 vs 108 mm Hg, respectively, P < .05). These results suggest that TAC-based immunosuppression is associated with better renal function (lower plasma creatinine and higher GFR) and lower (normal) blood pressure than CsA-based immunosuppression.

Klein and colleagues[14] investigated the effects of calcineurin inhibitors on renal dynamics in healthy subjects. Renal hemodynamics were significantly compromised by exposure to CsA. Conversely, TAC exposure did not change renal hemodynamics. Measures of renal hemodynamics tests include the clearance of insulin and para-aminohippuric acid. Renal hemodynamic compromise is indicated by decreasing effective renal blood flow values and increasing renal vascular flow values.

This slide summarizes the results from renal transplantation studies in which SRL was combined with a calcineurin inhibitor, either CsA (Neoral) or TAC. Kahan and colleagues[8] found that SRL + Neoral was associated with significantly lower rates of acute rejection (21.8% for SRL 2 mg and 14.6% for SRL 5 mg) vs Neoral + AZA (31.1%). The addition of SRL was associated with significantly worse renal function (elevated SCr level) compared with AZA. Six-month data from Gonwa and colleagues[7] showed that the regimen of TAC + SRL + prednisone was associated with worse renal function (elevated SCr level) than the regimen of TAC + MMF + prednisone. These authors suggested that SRL may exhibit drug-drug interactions with CsA. Together with the results from Gonwa and colleagues, these findings indicate that the combination of TAC + MMF appears to offer advantages over the combination of TAC + SRL.

A 2-fold increase in the incidence of acute rejection occurred in low-risk patients when CsA was withdrawn at 3 months: the incidence was 9.8% in the withdrawal arm vs 4.2% in the SRL + CsA arm (P = .035).[15] At 2 years, the difference in post-randomization acute rejection (between CsA withdrawal and SRL + CsA arms) lost statistical significance.[16] However, doubling of the incidence of acute rejection remained clinically significant.

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