Objectives: To study the characteristics of, and predictors for, survival in renal transplant recipients with an allograft functioning for more than 20 years.

Materials and Methods: Of 144 renal transplants done between 1976 and 1985, 31 allografts were still functioning for more than 20 years (range, 21-28.5 years). The characteristics of the patients and determinants of the outcomes were obtained by reviewing the patients’ medical records. 

Results: Fourteen patients were treated with cyclosporine, while 17 patients had primary immunosuppression with azathioprine-based regimens. Episodes of acute rejection occurred in 17 patients (58%), 7 of these experienced 2 or more episodes. At most-recent follow-up, the mean serum creatinine level was 132 ± 44 µmol/L . Four patients were assessed by graft biopsy 15 or more years after the transplant, revealing 2 cases of mild glomerulosclerosis and 2 cases of moderate chronic allograft nephropathy. The most common complication was hypertension (54%). The independent determinants of long-term graft survival were donor age and source, hypertension both before and after renal transplant, and histopathological findings of chronic allograft nephropathy.

Conclusions: Renal transplant offers a near-normal life to patients with end-stage renal disease soon after transplant and for upwards of 20 years and more. We found no significant benefit to cyclosporine-based immunosuppression on long-term graft survival.

Key words : Renal allograft, Long-term, Survival

Introduction

Kidney transplant and restoring continuous renal functioning represents the best physiological replacement therapy for patients with chronic end-stage renal disease. The goal of renal transplant is to relieve patients of the burden of dialysis and to allow a return to a productive life. Compared with patients on dialysis, recipients of a successful transplant enjoy a better quality of life, which for obvious reasons is directly linked to continued function of the graft (1). Since the 1980s, significant progress has made in graft and patient survival rates after renal transplant (2). Although numerous studies on 5- and 10-year survival rates for kidney grafts and their recipients have been published, data at 20 years or more are scarce. The factors influencing long-term survival of the graft are debated, and the only factor fully agreed upon is that grafts from living donors last longer than do grafts from deceased donors (2-6).

This study sought to determine the nature of complications and study the characteristics and predictors of survival observed in our live-donor renal transplant recipients at a single institution who have an allograft that has functioned for 20 years or more. 

Patients and Methods

Between March 1976 and December 1985, 144 consecutive live-donor renal transplants were performed at our center. Renal transplant recipients with grafts that have functioned for more than 20 years (range, 21-28.5 years) were included in this retrospective study. A review of the records revealed 31 such patients (21.5%). Thirty patients (96.8%) had received an allograft from a related donor. The clinical and laboratory data and the various medical and surgical complications found were documented chronologically on the patients’ flow sheets. Graft function was monitored using the serum creatinine level and the calculated glomerular filtration rate (cGFR) using the Cockroft-Gault formula. All posttransplant comorbidities were recorded; hypertension was defined as a systolic blood pressure higher than 140 mm Hg and/or a diastolic blood pressure higher than 90 mm Hg; hypertension was graded according to the number of antihypertensive medications the patient took. Diabetes mellitus was diagnosed if the fasting blood glucose level was greater than 7.0 mmol/L. Any bacterial, viral, or fungal infections were diagnosed by specific investigations and cultures as appropriate. Other complications including cardiovascular morbidities and history of malignancy were recorded. 

Patients who had received a transplant before 1983 (17 patients) were treated with combination therapy consisting of oral prednisolone (7.5 to 15 mg) and azathioprine (3 mg/kg). From 1983, 14 patients were treated with a triple regimen comprising daily prednisolone (5-10 mg/days), azathioprine (1 mg/kg), and cyclosporine (10 mg/kg), adjusted to keep cyclosporine whole-blood trough levels between 300 and 400 ng mL during the first 2 months and then between 100 and 150 ng /mL thereafter. No induction therapy was used at that time. All acute rejection episodes were documented by biopsy and treated by giving 5-day pulses of 500 mg methylprednisolone. Steroid-resistant episodes were treated with antibody therapy, antithymocyte globulin, or OKT3. We compared patients who had functioning grafts for more than 20 years with patients who had grafts that failed before 20 years, using univariate and multivariate analyses for different variables that can affect the graft survival.

Statistical analyses 
For univariate analyses, the t test was used for continuous data, while noncontinuous data were compared using the Mann-Whitney U test. The chi-square test was used to compare categorical variables. A multivariate analysis of graft survival was performed using Cox proportional hazards regression models to adjust for potentially confounding variables that could influence outcomes. The SPSS statistics package (Statistical Product and Services Solutions, version 11.0, SPSS Inc, Chicago, IL, USA) was used for these analyses. Values for P less than .05 were considered statistically significant.

Results

The demographic and clinical characteristics of long-term allograft survivors show that most of the recipients were middle-aged men (age range, 28.8 ± 5.9 years) at the time of transplant. Most of the donors also were middle-aged men. The patients were followed-up for a mean of 23.1 years (range, 21-28.5 years) (Table 1). 

The immunologic variables demonstrated that more than 96% of the transplant recipients received grafts from related donors. A kidney from an unrelated donor was used in 1 case of a patient with a polycystic kidney. Most recipients were 2-haplotype HLA-A, -B matching (21 cases) and 1-haplotype -DR matching (30 cases) (Table 1).

Renal function
At the last follow-up, the mean serum creatinine concentration was 132 ± 44 µmol/L (range, 70-270 µmol/L), with a mean proteinuria level of 0.47 g/day (only 5 patients had proteinuria levels of 2 g/d or more). 

Acute rejection episodes occurred in 18 patients (58.1%). Most of the episodes were within the first year after transplant. The first acute rejection episode occurred at a median time of 9 days after transplant. All episodes responded promptly to high-dose steroid therapy, except 3 (9.6%) in whom graft function did not recover completely and progressed to biopsy-proven chronic rejection.

Chronic graft dysfunction and pathologic findings 
Histopathological diagnosis of chronic allograft nephropathy was made in 5 patients who presented with clinical evidence of chronic graft dysfunction. Four patients with normal graft function and without a history of acute rejection were assessed by graft biopsy more than 15 years after transplant, which revealed 2 cases of mild glomerulosclerosis and 2 cases of moderate chronic interstitial fibrosis and tubular atrophy. Table 2 shows the most frequently developed complications.

Posttransplant hypertension
Average systolic and diastolic blood pressures were 145 ± 16 and 85 ± 9 mm Hg, respectively. More than one-third of patients received either 1 (36.8%) or 2 drugs (34.5%). Hypertension was found more frequently in patients with serum creatinine levels greater than 141 µmol/L and with posttransplant proteinuria.

Posttransplant cardiovascular risks and disease
Coronary artery disease was documented in 3 patients (9.6%), whereas 6.4% of kidney recipients had a history of arrhythmia. Hypercholesterolemia was present in more than one-third of patients (38.3%). A total of 12 patients received treatment with statins.

Posttransplant infections
Eleven patients (35.5%) developed at least 1 attack of infection during the posttransplant course. The majority of these were urinary tract infections, upper respiratory tract infections, or herpes zoster. More-serious infections occurred in 4 patients: pneumococcal pneumonia in 3 and urinary tuberculosis in 1.

Comorbid conditions 
Posttransplant diabetes mellitus was diagnosed in 9 patients (29%). In 3 patients, insulin therapy was required, and in 6 patients, diet regimen and oral antidiabetic agents could control the diabetic mellitus. A history of malignancy was reported in 1 patient (3.2%). He developed cutaneous Kaposi's sarcoma after 15 years and was treated by a reduction in the dosage of immunosuppression and intralesional injections of bleomycin with a favorable response.

Assessing the quality of life of the patients showed that 80% could perform their normal daily activities without difficulty. 

We compared patients (n=31) who had functioning grafts for more than 20 years with patients who had lost their grafts before this time (n=113) using univariate and multivariate analyses. The multivariate analyses restricted the significance to donor relationship (risk ratio, 0.16; P < .0001), time of late acute rejection episodes (risk ratio, 0.24; P < .0007), serum creatinine levels at 3 months (risk ratio, 0.29; P < .0014) and 12 months (risk ratio, 0.46; P < .017), chronic allograft nephropathy (risk ratio, 0.22; P < .013), and pretransplant hypertension (risk ratio, 0.26; P < .011) and posttransplant hypertension (risk ratio, 0.18; P < .007).

Table 3 shows the characteristics of the long-term renal allograft survivors (n=31) according to the primary immunosuppression: either azathioprine treated (n=17) or cyclosporine treated (n=14). In the azathioprine and cyclosporine groups, serum creatinine level was statistically significantly different at 3 and 12 months after transplant; however, there was no notable difference between the groups at the last follow-up (115 ± 35 and 141 ± 44 µmol/L, respectively; P = .2). The mean numbers of acute rejection episodes per patient was 1.5 and 1.4, respectively (P = .4). There were no significant differences between both groups with regard to posttransplant hypertension, diabetes mellitus, and chronic allograft nephropathy.

Discussion

Since the 1980s, significant progress has made in graft and patient survival rates after renal transplant (2). Among nearly 100 000 renal transplants performed between 1982 and 1996 in the United States, the half-life for deceased-donor and living-related allografts has improved to 13.8 and 21.6 years, respectively (7). In our center, the first renal graft was implanted in March 1976, and since then, more than 1900 live-donor kidney transplants have been done. Because the true success of organ grafting can only be judged by its long-term benefit to patients, we have analyzed the characteristics of patients who received successful kidney grafts that functioned for more than 20 years and tried to identify the predictors of long-term allograft survival. 

Our results show that the survival rate for grafts functioning more than 20 years is 21.5%. Tojimbara and associates (6) found that graft survival in kidney transplant recipients from deceased donors was 44% after 10 years and 23% after 15 years, while Kyllonen and associates (8) reported 107 of 824 kidney transplants (15%) who had a functioning graft lasting longer than 20 years. 

The incidence of various long-term complications seen in our series is similar to that reported previously in patients with graft survivals of 10 years or more (9, 10). Hypertension was the most common complication, occurring in 54% of patients. The overall prevalence of hypertension among kidney transplant recipients in most series ranges between 70% and 80% (11). In our series, we observed that posttransplant hypertension was more prevalent in cyclosporine-treated patients who also had rising serum creatinine levels and proteinuria. We performed univariate and multivariate analyses and showed that posttransplant hypertension has a deleterious effect on renal allograft survival. Several reports have described the role of pretransplant hypertension in the development of hypertension after transplant (12). It seems most probable that the need for antihypertension medications before transplant serves as a marker for posttransplant hypertension that may, in many cases, be marginally or poorly controlled. 

Although several studies implicate acute rejection as being the major risk factor for chronic allograft failure (8, 13, 14), not all other studies agree (15, 16, 17, 18). Notably, we found that long-term allograft success occurred in our series despite early acute rejection. A similar observation has been reported previously by Braun and associates (13). Verghese (16) found a well-documented relation between severity, frequency, late rejection, and long-term chronic allograft dysfunction. In our series, late acute rejections occurring after 1 year posttransplant significantly affected graft survival. One could speculate that acute rejection episodes occurring several years after transplant are due to pathophysiologic processes different from those involved in early rejections; thus, the efficacy of the traditional immunosuppressive regimens would be compromised. Alternatively, those rejections could just be a marker for otherwise undetectable non­compliance with immunosuppressive medications. Our biopsy features in this study showed that the rate of moderate and severe acute rejection was not high, even in the lost-allograft group (6 biopsies/18 patients in the survival group, 40 biopsies/72 patients in the lost-allograft group); however, using Banff 1997 classifications, we found a statistically significant difference between the lost-allograft group and the survival group. Therefore, we conclude that the histopathological grade of acute rejection can be predictive of late graft loss in patients with graft survival longer than 20 years. 

Although poorer rates of graft survival from deceased-donor transplants are well known (19), survival rates for older kidney donors remain controversial (3, 8, 14). Living-related kidney transplant has the benefit of minimal cold ischemia time, which is a significant risk factor for graft survival when marginal kidneys from older donors are used. In our series, we used univariate and multivariate analyses to confirm that donor age was a significant predictor of graft survival. It is known that declining nephron mass in an aged kidney may limit the functional life of the graft. 

Analyses of graft survival according to living-donor source (ie, parent, sibling, other related and unrelated donors) show that there is a trend toward superior graft survival for transplants from related donors (20). A correlation has been noted between use of related donor grafts and risk of long-term graft failure. 

The clinicopathological findings of long-surviving grafts have not been well studied (21). We performed 20-year protocol renal graft biopsies in 4 patients with grafts lasting longer than 20 years with stable renal function. There are reports that clarify the relation between the protocol biopsy and the prognosis of the graft (22). However, the timing of the protocol biopsy is usually 3 months to 2 years; that is, it is a relatively short time after transplant. From this perspective, our results from a 20-year protocol biopsy are rare, and the relation between the 20-year protocol biopsy and graft prognosis is similar to that of short-term grafts. 

The initial immunosuppressive protocols, regardless of protocol changes that were made later, were analyzed in the graft-surviving group (intension to treat). Patients taking cyclosporine-based immunosuppressive regimens showed no significant benefit regarding long-term quality of graft function compared with patients taking azathioprine-based regimens and steroids (P = .06). Moreover, we found that posttransplant hypertension and diabetes mellitus were, although not statistically significant, more prevalent in cyclosporine-treated patients (P = . 2), and the mean serum creatinine level at the current follow-up was not significantly higher in the cyclosporine group. Our data agree with those of other studies (22), making it clear that cyclosporine has contributed to a dramatic improvement in 1-year graft outcomes; however, its impact on long-term graft survival is questionable

In conclusion, renal transplant, even soon after transplant, and despite numerous complications, enhances quality of life and can provide 20 or more years of near-normal life to patients with end-stage renal disease who otherwise would be dialysis dependent. Interestingly, predictors of good long-term graft outcome include young related donors, less hypertension before and after transplant, and severe and late acute rejections together with 1-year graft function. 

References:

1. Flechner SM, Novick AC, Braun WE, Popowniak KL, Steinmuller D. Functional capacity and rehabilitation of recipients with a functioning renal allograft for ten years or more. Transplantation. 1983;35(6):572-576.
2. Terasaki PI, McClelland ID, Yuge J, et al. Advances in kidney transplantation 1985-1995. In: Cecka JM, Terasaki PI, eds. Clinical Transplants Los Angeles, CA: UCLA Tissue Typing Laboratory; 1996:487-501.
3. Tanaka T, Takahara S, Hatori M, et al. The differences between late graft loss group and long-term graft survival group in renal transplantation. Clin Transplant. 2001;15(suppl 5):16-21.
4. El-Agroudy AE, Bakr MA, Hassan NA, et al. Characteristics of long-term live-donor renal allograft survivors. Am J Nephrol. 2003;23(3):165-171.
5. Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant. 2004;4(8):1289-1295. 
6. Tojimbara T, Fuchinoue S, Iwadoh K, et al. Improved outcomes of renal transplantation from cardiac death donors: a 30-year single center experience. Am J Transplant. 2007;7(3):609-617.
7. 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(9):605-612.
8. Kyllönen L, Koskimies S, Salmela K. Renal transplant recipients with graft survival longer than 20 years: report on 107 cases. Transplant Proc. 2001 Jun;33(4):2444-2445.
9. Gueco IP, Evans BD, Calne RY. Prolonged survival after renal transplantation. A study of 54 patients who lived ten or more years after operation with functioning allografts. Transplant Proc. 1985;17(1):108-109.
10. Silkensen JR. Long-term complications in renal transplantation. J Am Soc Nephrol. 2000;11(3):582-588.
11. Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int. 1998 Jan;53(1):217-222.
12. Mange KC, Cizman B, Joffe M, Feldman HI. Arterial hypertension and renal allograft survival. JAMA. 2000;283(5):633-638.
13. Braun WE, Popowniak KL, Nakamoto S, Gifford RW Jr, Straffon RA. The fate of renal allografts functioning for a minimum of 20 years (level 5A)--indefinite success or beginning of the end? A proposed classification of long-term allograft survivals. Transplantation. 1995;60(8):784-790.
14. Prommool S, Jhangri GS, Cockfield SM, Halloran PF. Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol. 2000;11(3):565-573.
15. Ashraf S, Parrott NR, Dyer P, Roberts I, Johnson RW. Clinical response and temporal patterns of acute cellular rejection: relationship to chronic transplant nephropathy. Transpl Int. 1998;11(suppl 1):S5-S9.
16. Varghese Z. Immunologic and nonimmunologic correlates of chronic renal allograft dysfunction. Transplant Proc. 1999;31(8):3356-3338.
17. Joseph JT, Kingsmore DB, Junor BJ, et al. The impact of late acute rejection after cadaveric kidney transplantation. Clin Transplant. 2001;15(4):221-227.
18. Troppmann C, Gillingham KJ, Benedetti E, et al. Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. The multivariate analysis. Transplantation. 1995;59(7):962-968.
19. Kouli F, Morrell CH, Ratner LE, Kraus ES. Impact of donor/recipient traits independent of rejection on long-term renal function. Am J Kidney Dis. 2001;37(2):356-365.
20. Opelz G. HLA compatibility and kidney grafts from unrelated live donors. Collaborative Transplant Study. Transplant Proc. 1998;30(3):704-705.
21. Okamoto M, Nobori S, Higuchi A, et al. Clinicopathological evaluation of renal allografts of four patients by 20-year protocol biopsies. Clin Transplant. 2003;17(suppl 10):20-24. 
22. Halloran PF. Immunosuppression in the postadaptation period. Transplantation. 2000;70(1):3-5.