This report was reviewed for medical and scientific accuracy by David A. Laskow, MD, Chief, Kidney/Pancreas Transplant Service, Associate Professor of Surgery, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

The short-term outcome of renal transplantation has improved substantially over the past two decades. The introduction of cyclosporine for the prevention of acute and chronic rejection in the 1980s led to an increased rate of graft survival at 1 year.¹ In recent years, newer immunosuppressive agents such as tacrolimus and mycophenolate mofetil have been associated with further reduction in the incidence of acute rejection episodes.^2,3 With improved control of early rejection and graft loss,⁴ the emphasis in renal transplantation has now shifted towards improving the long-term transplant course. This includes a focus on reducing late graft loss by stabilizing and improving renal function, controlling side effects of immunosuppressive agents, and reducing risk factors for patient survival.

Despite improvements in short-term outcome, the frequency of late graft loss remains excessive: approximately 7% of renal transplants will fail each year, with approximately half due to patient death and the remainder due to loss of function. Retrospective examinations of failures due to loss of function typically focus on outcomes such as graft survival and half-life. However, these approaches are limited because they do not distinguish grafts with poor initial function from grafts with excellent function that subsequently deteriorate. Additionally, the focus is on grafts that have failed completely.

Additional information can be obtained by evaluating renal function outcomes and change in function, thus allowing examination of the entire spectrum of renal transplant recipients versus graft failures. Renal function has been established as a critical determinant of the probability of graft survival,⁵ and its role as a predictor of survival has recently been confirmed.⁶ Hariharan and colleagues demonstrated that 1-year creatinine and change in creatinine values predict long-term renal graft survival, and that the recent improvements in graft half-life are related to conservation of renal function within the first year post-transplanta-tion.⁷ While serum creatinine and creatinine clearance have been proposed as outcomes measures,^7-11 the stability of renal function has been less studied.

Utilizing the United Network for Organ Sharing (UNOS) database, Hunsicker and Bennett demonstrated that the stability of renal function could be calculated post-transplantation from the slope of the calculated Cockcroft-Gault creatinine clearance beyond 6 months.¹² However, this study raised several critical issues. How are the 6-month creatinine clearance and/or rate of change in creatinine clearance changing over time, and how are they affected by factors such as immunosuppressive agents and severity of rejection episodes?

A recent study by Gourishankar and colleagues examined these important issues and found a striking improvement in the course of renal transplants since 1997 attributed to an enhanced stability of renal function correlating with reduced rejection due, at least in part, to the newer immunosuppressive agents.¹³ This Transplantation Express Report™ reviews that study and the latest literature exploring the relationship between renal function and graft survival.

Assessment of Renal Function and Change in Function

Using renal function outcomes and change in function to assess the probability of graft survival, Gourishankar and colleagues explored how the creatinine clearance at 6 months and/or rate of change after 6 months are affected by factors such as immunosuppressive agents, cause of donor death, hypertension, lipid disorders, cytomegalovirus infection and severity of rejection episodes.¹³

A total of 429 patients were included in the study from a renal transplant database (University of Alberta Hospital, Alberta, Canada) that included all cadaver renal allograft recipients between January 2, 1990 and August 30, 2000. Creatinine clearance was determined using the Cockcroft-Gault formula at Month 6, Year 1, Months 13 to 23, Year 2, and every 6 months until Year 10 post-transplantation. The individual slope of the creatinine clearance was also calculated using linear regression and was based on as many creatinine clearance values as were available including and after 6 months post-transplantation (at least 5 values, average 12).

Recipient characteristics examined included age, gender, ethnicity, cause of original renal disease, regraft status, year of transplant, type of initial immunosuppression, use of induction therapy, date of allograft failure (defined as the date of reinitiation of dialysis), and date of death or loss to follow-up. Also examined were hypertension, dyslipidemia, cytomegalovirus infection and donor-recipient cytomegalovirus mismatch status. Furthermore, the association of era of transplantation both as a continuous variable and categorized as 1990 to 1993, 1994 to 1997, and 1998 to 2000 were evaluated.

After transplantation, all 429 patients received the standard immunosuppressive regimen of a calcineurin inhibitor (approximately 80% of subjects received cyclosporine), prednisone and either azathioprine (before 1995 - 53.9%), mycophenolate mofetil (from 1995 - 46.1%), or an investigational drug. Tacrolimus use became widespread for new transplants after 1998. Antilymphocyte globulin or OKT3 was used in 33.6% of recipients with poor early function or at high immunologic risk as a result of previous grafts or anti-human leukocyte antigen (HLA) antibodies.

Assessment of Creatinine Clearance Over Time

The mean 6-month creatinine clearance was 64.6 ±1.1 mL/min and did not change significantly throughout the period of observation (P = .43). The mean rate of change in the creatinine clearance was -1.4 ±0.5 mL/min per year and improved significantly between 1990 and 2000 (Figure 1). Interestingly, the rate of change of function for each transplant era was different from a zero slope. The kidneys that were transplanted before 1997 deteriorated significantly over time. From 1990 to 1993, the mean slope was -0.34 mL/min per month (P<.001) and from 1994 to 1997 the mean slope was -0.20 mL/min per month (P<.001). Conversely, the function in transplants from 1998 to 2000 actually showed a statistically significant improvement with a mean slope of +0.29 mL/min per month (P = .009).

Adjustment for the length of follow-up had no significant effect on the observed improvement in slope in the more recent era (1997 to 2000). Moreover, analysis of data for the first 2 years of follow-up confirmed significant improvements were limited to the more recent era. Therefore, differences in follow-up time did not account for the improved slope observed in the more recent era. Although each era showed improvements in function over time, the proportion of patients in the more recent era was far greater (65.4%) compared to 1990 to 1993 (39.2%) and 1994 to 1997 (37.9%).

Investigators also examined whether the rate of loss of function was elevated in kidneys with low creatinine clearance and found there was no increase in the rate of decline of creatine clearance at low creatinine clearance levels.

Variables associated with a reduced 6-month creatinine clearance included donor factors (age, gender, low creatinine clearance), recipient factors (age, gender, regraft status), and delayed graft function, hypertension and episodes of acute rejection. In multivariate analysis, variables associated with a lower 6-month creatinine clearance were a combination of non-immunologic and immunologic variables that included older donors, female donors, lower donor creatinine clearance, a rejection episode within 6 months, female recipients, and previous failed transplants.

Univariate analysis was used to determine what factors were associated with the stability of creatinine clearance. A more stable creatinine clearance (ie, lower rate of loss of creatinine clearance) was associated with, but not limited to, the use of mycophenolate mofetil versus azathioprine, use of tacrolimus versus cyclosporine, the absence of rejection episodes, and a later (after 1997) transplant year (Table 1). In multivariate analysis, a more rapid rate of loss of creatinine clearance was associated with earlier transplant year, higher diastolic blood pressure at Year 2, female recipient and the presence of any rejection episode.

Importantly, observed rejection rates fell over time, especially comparing the eras before and after 1997 (P<.001), correlating with changes in immunosuppression. Thus, a greater proportion of patients on azathioprine than on mycophenolate mofetil (61.2% vs 36.1%; P≤.001) and on cyclosporine versus tacrolimus (54.2% vs 42.6%; P = .05) had rejection episodes, demonstrating the interaction between rejection and immunosuppression.

In contrast to the 6-month creatinine clearance, the stability of creatinine clearance beyond 6 months was mainly influenced by immune variables and improved throughout the observation period, as rejection rates fell. Because the available choices of immunosuppressive agents changed during the study, it should be noted that the importance of this variable might have been absorbed by the transplant year variable. The improving slopes of creatinine clearance in the more recent transplant era may reflect improvements in the medical management of the renal transplant recipient (eg, hypertension control). In addition, new options for minimizing calcineurin inhibitor toxicity may have also contributed to the improved stability of renal function.

Data from this study demonstrate an enhanced stability of renal function in the recent transplant era and suggests that cadaveric kidney transplants retain a capacity for long-term improvement in function. The effectiveness of new immunosuppressive protocols in controlling rejection presumably permits this improvement to occur, in addition to improvements in medical management. Thus, deterioration of a cadaveric transplant should not be an expected outcome but one that should initiate efforts to identify and reverse the mechanism of injury.¹⁴

Post-transplant Renal Function Predicts Long-term Kidney Transplant Survival

Hariharan and colleagues examined renal function in the first year of transplantation as an independent variable in determining long-term renal graft survival.⁷ A total of 105,742 adult renal transplants (77,582 cadaveric; 28,160 living donor) performed in the United States between 1988 and 1998 were included in the study; patients with multiple organ transplants were excluded. Data was collected from the Organ Procure-ment and Transplantation Network (OPTN)/UNOS. Post-transplant renal function was defined as serum creatinine at 6 months and 1 year and the change in creatinine from 6 months to 1 year. The Kaplan-Meier method was used to estimate graft survival.

The 1-year graft survival rate for living donor transplants in 1988 was 89.7%, improving to 94.3% in 1998. During the same period, graft survival rates for cadaveric transplants improved from 76.0% to 89.3%. The cohorts of patients transplanted in recent years were observed to have better short- and long-term survival rates than patients transplanted in early years.

Post-transplant creatinine >1.5 mg/dL at 6 months and 1 year, and change in creatinine ≥0.3 mg/dL were associated with a decline in long-term graft survival. The mean creatinine values at 6 months and 1 year declined over time. For example, mean creatinine at 1 year decreased for living donor transplants from 1.65 mg/dL (1988) to 1.55 mg/dL in 1998 (P<.001). During the same period, 1-year serum creatinine values for cadaveric transplants steadily improved from 1.82 mg/dL to 1.67 mg/dL (P<.001).

According to 1-year creatinine values, an overall improvement in half-life was observed for cadaveric transplants from 7.9 years in 1988 to 11.2 years in 1997, an increase of 42%. During the same period, improvements in cadaveric transplants with creatinine >1.5 mg/dL was 6.2 to 7.5 years, an increase of 21%, and for 1-year creatinine ≤1.5 mg/dL, was from 10.9 to 19 years, an increase of 74%. Serum creatinine increment of 1.0 mg/dL (at 1 year post-transplant and without a change in creatinine), increased the relative hazard of graft failure to 1.63 (P<.0001). However, when accompanied with a change in creatinine of 0.5 and 1.0 mg/dL, the relative hazard of graft failure increased to 2.26 and 3.13, respectively (P<.0001).

Investigators concluded 1-year creatinine and change in creatinine values are the variables that correlate best with long-term renal graft survival, and that the recent improvements in graft half-life are related to the preservation of renal function within the first year post-transplantation.

Long-term Effect of Immunosuppressive Agents: Impact on Allograft Outcome

Comparison of Tacrolimus and Cyclosporine
Vincenti and colleagues recently published the results of a 5-year follow-up period of a multicenter trial comparing tacrolimus- and cyclosporine-based immunosuppressive therapy.¹⁵ Intent-to-treat analysis revealed similar 5-year patient and graft survival rates with tacrolimus (n = 191) and cyclosporine (n = 185), 79.1% versus 81.4% (P = .472) and 64.3% versus 61.6% (P = .558), respectively. However, when crossover due to treatment failure was accounted for, there was a significant difference in graft survival between tacrolimus and cyclo-sporine (63.8% vs 53.8%; P = .014). Interestingly, significantly more patients switched from cyclosporine to tacrolimus during the study (27.5% vs 9.3%; P<.001) than did from tacrolimus to cyclosporine. Refractory rejection accounted for 68.4% of all crossovers from cyclo-sporine to tacrolimus. Graft failure due to rejection was more common among cyclosporine-treated patients (22.1%) than among tacrolimus-treated patients (17%); however, this difference did not achieve statistical significance (P = .299).

At 60 months, median serum creatinine levels were consistently higher in the cyclosporine-treated patients (1.7 mg/dL vs 1.4 mg/dL; P = .0014) and elevated serum creatinine levels (>1.5 mg/dL) were significantly more common among cyclosporine-treated patients than among tacrolimus-treated patients (62.0% vs 40.4%, respectively; P = .0017).

Investigators concluded that tacrolimus-based immunosuppressive therapy resulted in significantly reduced risk of graft failure as compared to cyclosporine.

Mycophenolate mofetil
Although mycophenolate mofetil has been shown to significantly decrease acute rejection episodes in renal transplant recipients during the first year, the beneficial effect of mycophenolate mofetil on long-term graft survival has been more difficult to demonstrate. Ojo and colleagues conducted a registry analysis (N = 66,774) to assess the impact of mycophenolate mofetil on chronic allograft failure.¹⁶ Mycophenolate mofetil decreased the relative risk for the development of chronic allograft failure by 27% (risk ratio 0.73, P<.001). This effect was independent of its outcome on acute rejection. Siddiqi et al conducted a pooled analysis (N = 1,489) to evaluate the long-term survival benefit (at 3 years) of mycophenolate mofetil given in conjunction with cyclosporine and corticosteroids.¹⁷ The 3-year graft survival rates observed with mycophenolate mofetil (2 gm) were 81.1%, 84.8%, and 81.9%, respectively, compared to 74.7%, 78%, and 80.2%, respectively, for patients receiving azathioprine. The odds of overall graft failure at 3 years was lower with mycophenolate mofetil compared to azathioprine (odds ratio 0.73, 95% Confidence Interval (CI), 0.54-1.00; P = .05). There was no differential survival benefit observed with 3 gm versus 2 gm mycopheno- late mofetil.

Sirolimus
In an attempt to further reduce nephrotoxicity in renal transplant recipients, recent efforts have focused on calcineurin inhibitor minimization- and avoidance-based immunosuppressive regimens. In a study of 525 renal allograft recipients, Oberbauer and colleagues examined early cyclosporine withdrawal from a sirolimus-cyclosporine-corticosteroid regimen.¹⁸ At 24 months, cyclosporine withdrawal resulted in no statistically significant differences in patient survival, graft survival, acute rejection after randomization, or discontinuations. Moreover, patients in whom cyclosporine was withdrawn demonstrated a significantly better serum creatinine level (1.90 vs 1.45 mg/dL, P<.001) as well as systolic blood pressure (141 vs 134 mm Hg, P<.001). Results of a pilot study (N = 29) indicate the use of Campath-1H induction in combination with sirolimus monotherapy may prove to be an effective immunosuppressive regimen for renal transplantation.¹⁹ Eight patients experienced rejection, which was successfully treated in 7 of 8 patients. Biopsies have shown no chronic allograft nephropathy for 3 to 29 months of follow-up. Due to the relatively high incidence of early humoral rejection, investigators plan to modify the immunosuppressive regimen in subsequent pilot studies.

Conclusion

There is considerable evidence demonstrating an association between renal function and long-term renal allograft survival. These data suggest that improvements in immunosuppressive agents, as well as improvements in the medical management of renal transplant recipients, have resulted in preservation of renal function leading to a reduced incidence of rejection. For calcineurin inhibitor-based immunosuppression, these recent publications demonstrate a clear difference in long-term renal function between tacrolimus-treated and cyclosporine-treated patients.

References

1. Merion RM, White DJG, Thiru S, Evans DB, Calne RY. Cyclosporine: five years' experience in cadaveric renal transplantation. N Engl J Med. 1984;310:148-154.
2. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation. 1997;63:977-983.
3. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. Transplantation. 1995;60:225-232.
4. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000;342:605-612.
5. Opelz G, Sasaki N, Terasaki PI. Prediction of long-term kidney transplant survival rates by monitoring early graft function and clinical grades. Transplantation. 1978;25:212-215.
6. Bresnahan BA, Johnson CP, McIntosh MJ, Stablein D, Hariharan S. A comparison between recipients receiving matched kidney and those receiving mismatched kidney from the same cadaver donor. Am J Transplant. 2002;2:366-372.
7. Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson CP. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int. 2002;62:311-318.
8. Seun KY, Soo KM, Suk HD, et al. Evidence that the ratio of donor kidney weight to recipient body weight, donor age, and episodes of acute rejection correlate independently with live-donor graft function. Transplantation. 2002;74:280-283.
9. Kasiske BL, Andany MA, Danielson B. A thirty percent chronic decline in inverse serum creatinine is an excellent predictor of late renal allograft failure. Am J Kidney Dis. 2002;39:762-768.
10. Hunsicker LG, Adler S, Caggiula A, et al. Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study. Kidney Int. 1997;51:1908-1919.
11. Pokorna E, Schuck O, Vitko S, Ekberg H. Estimated and measured donor creatinine clearance are poor predictors of long-term renal graft function and survival. Am J Transplant. 2002;2:373-380.
12. Hunsicker LG, Bennett LE. Acute rejection reduces creatinine clearance (Ccr) at 6 months following renal transplantation but does not affect subsequent slope of Ccr [Abstract]. Transplantation. 1999;67:S83.
13. Gourishankar S, Hunsicker LG, Jhangri GS, Cockfield SM, Halloran PF. The stability of the glomerular filtration rate after renal transplantation is improving. J Am Soc Nephrol. 2003;14:2387-2394.
14. Halloran PF. Call for revolution: a new approach to describing allograft deterioration. Am J Transplant. 2002;2:195-200.
15. Vincenti F, Jensik SC, Filo RS, Miller J, Pirsch J. A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: evidence for improved allograft survival at five years. Transplantation. 2002;73:775-782.
16. Ojo AO, Meier-Kriesche HU, Hanson JA, et al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation. 2000;15:2405-2409.
17. Siddiqi NA, Meurer LN, Hariharan S. Long-term efficacy of mycophenolate mofetil (MMF): a pooled analysis of randomized, double-blind, prospective multicenter trials. Presented at the American Transplant Congress (ATC) 2003, the Fourth Joint American Transplant Meeting, Washington DC, May 30-June 4, 2003. Abstract 259.
18. Oberbauer R, Kreis H, Johnson RW, et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results for the Rapamune Maintenance Regimen Study. Transplantation. 2003;76:364-370.
19. Knechtle SJ, Pirsch JD, Fechner HJ Jr, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant. 2003;3:722-730.

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Disclosure
David A. Laskow, MD
Grant/Research Support-Fujisawa Healthcare, Inc., Roche Speakers Bureau-Roche

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from Fujisawa Healthcare, Inc.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Transplantation Express Report™ does not include discussion of treatment and indications outside of current approved labeling. This Transplantation Express Report™ was made possible through an educational grant from Fujisawa Healthcare, Inc.

© 2004 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education