Renal Data from the Arab World

Saudi J Kidney Dis Transpl 2011;22(4):818-824 2011 Saudi Center for Organ Transplantation Saudi Journal of Kidney Diseases and Transplantation Renal Data from the Arab World Why does Kidney Allograft Fail? A Long-term Single-center Experience Sameer Alarrayed, Amgad El-Agroudy, Ahmed Al-Arrayed, Sumaya Ghareeb, Eman Farid, Taysir Garadah, Sadiq Abdulla Nephrology and Kidney Transplantation Department, Salmaniya Medical Complex, MOH, College of Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain ABSTRACT. We studied the characteristics and the predictors of survival in Bahraini renal transplant recipients with an allograft that functioned for more than 10 years. Seventy-eight patients underwent renal transplantation between 1982 and 1999. Among them, 56 patients maintained functioning allografts for more than 10 years (range 10-30 years). Characteristics of the surviving patients, data on graft survival, and determinants of outcome were obtained by reviewing all medical records. The mean age at time of renal transplantation was 33.6 ± 15.3 years. The source of the graft in 42 (75%) recipients was from living related donors with a mean age of 31.4 ± 7.7 years, and it was the first graft in 48 recipients. The primary immunosuppression regimen consisted of cyclosporine (CsA) and prednisolone. Azathioprine (AZA) was given to 52 (92.9%) recipients, while four patients received steroids and AZA only. Induction therapy was administered to 30 patients in the CsA group. Acute rejection episodes occurred in eight (14.3%) patients, of whom two experienced two episodes. During the last follow-up in January 2010, the mean serum creatinine was 118.3 ± 46.5 µmol/l. A history of cancer was noted in one patient, whereas hypertension was encountered in 54% and diabetes mellitus in 20.5%. We compared the graft functioning group with the graft failure group and found that the independent determinants of long-term graft survival included time of late acute rejection episodes and histopathologic findings of chronic allograft damage, posttransplant hypertension and serum creatinine at one year. We conclude that renal transplantation even in its earliest years and despite the associated numerous complications has provided a ten-year or more of near-normal life to patients with end-stage renal disease. Correspondence to: Dr. Sameer Alarrayed, Consultant, Head of Nephrology and Kidney Transplantation Department, Salmaniya Medical Complex, Ministry of Health, Manama, Kingdom of Bahrain E-mail: salarrayed@yahoo.com Introduction Kidney transplantation restoring continuous renal functions represents the most physiological replacement therapy for chronic end-stage renal disease (ESRD). Recipients of successful transplants enjoy a higher quality of life, which for obvious reasons is directly linked to the continued normal graft function. 1

Long-term renal allograft survival in Bahrain 819 During the last two decades, a significant progress has been achieved in the graft and patient survival rates after renal transplantation. 2 Although numerous reports on 1- and 5-year survival of kidney grafts and their recipients have been published, data on 10-year survival or more are scarce. The factors influencing longterm survival of the graft are still being debated and the only one fully accepted is kidney origin, i.e. those from living donors survive longer than those from the deceased. 2-6 Predictors of long-term graft survival in patients who receive live-donor grafts are of special interest because they depend less on donor factors in comparison with the patients receiving grafts from deceased donors. 7 The aim of this study is to determine the nature of complications and study the characteristics and define the predictors of survival observed in live-donor renal transplant recipients in our center with an allograft that functioned for more than ten years. This is the first report of long-term follow-up of renal transplantation recipients from our country. Patients and Methods We reviewed 82 consecutive live-donor renal transplantations performed at our center (Al- Moayyed Nephrology and Transplant Center, Salmaniya Medical Complex, Manama, Bahrain) between March 1982 and December 1999. Four recipients were excluded because of graft failure that occurred during the first year posttransplantation and or due to technical reasons. We included in this study 56 (71.8%) renal transplant recipients who maintained functioning grafts for more than ten years (range 10-18 years). Forty-two (75%) patients received allografts from related donors. The patients data included clinical parameters, laboratory tests, and various medical and surgical complications, and they were documented chronologically on their flow sheets. The graft function was monitored by serum creatinine and calculated creatinine clearance (ccrcl) using the Cockroft-Gault formula. Hypertension was defined as systolic blood pressure (SBP) >140 mmhg and/or diastolic blood pressure (DBP) >90 mmhg and graded according to the number of anti-hypertensive medications. Diabetes mellitus was defined as fasting blood glucose of >120 mg/dl. Any bacterial, viral, or fungal infection was diagnosed by specific investigations and cultures as appropriate. Other complications including cardiovascular morbidities and history of malignancy were also recorded. There were four patients transplanted before 1983 and received daily oral combined therapy of prednisolone 7.5-15 mg and azathioprine (AZA) 3 mg/kg. From 1983 onward, there were 52 patients who received renal allograft and were maintained on oral triple immunosuppressive regimen comprising daily prednisolone (5-10 mg/day), cyclosporine (CsA) at a dose of 10 mg/kg, adjusted to keep CsA whole-blood trough level between 200 and 250 ng/ml in the first two months and then between 100 and 150 ng/ml thereafter, and either AZA 1 mg/kg (45 patients) or mycophenolate mofetil (MMF) (seven patients). Induction therapy was used in 30 patients in the form of intravenous baziliximab 20 mg on days zero and four post-transplantation. All acute rejection episodes were documented by biopsy and treated by administering intravenous methylprednisolone 500 mg daily for five days. Steroid-resistant episodes were treated with antibody therapy: antithymocyte globulin (ATG), or orthoclone (OKT3). In order to characterize parameters associated with poor graft survival, we compared two groups of patients using univariate and multivariate analyses for different variables that may affect the graft survival: patients who had functioning grafts for more than ten years (graft surviving group) and those who had failed grafts before this period (graft non-surviving group). Statistical Analysis For univariate analysis, t -test was used in numeric data, which were homogenously distributed, while nonparametric Mann-Whitney test was used for non-homogenously distributed numeric data. A multivariate analysis of graft survival was performed using Cox proportional ha-

820 Alarrayed S, El-Agroudy A, Al-Arrayed A, et al Table 1. Characteristics of the study subgroups. Graft surviving group Failed graft group P (n = 56) (n = 22) Recipient age at transplant, years (Mean ± SD) 3.6 ± 15.3 36.9 ± 12.2 0.8 Recipient sex (M/F) 38/18 14/8 0.7 Donor age, years (Mean ± SD) 31.4 ± 7.7 33.8 ± 10.3 0.3 Donor sex (M/F) 40/16 12/10 0.3 Donor source (related/unrelated) 42/14 17/5 0.6 Causes of end-stage kidney diseases (%) 0.06 Interstitial nephritis 6 (10.7) 2 (9.1) Glomerulonephritis 5 (8.9 3 (13.7) Others 16 (28.6) 8 (12.3) Inapplicable 29 (51.8) 9 (40.9) HLA mismatches 3 (%) 25 (44.6) 9 (40.9) 0.2 Pre-emptive transplant (%) 10 (17.9) 2 (13.6) 0.2 Retransplantation (%) 8 (14.3) 2 (1.8) 0.5 Pre-transplant hypertension (%) 23 (41.1) 13 (59.1) 0.02 Primary immunosuppression (%) 0.5 AZA-prednisolone 4 (7.1) 1 (4.6) CsA-AZA-prednisolone 43 (76.8) 18 (81.8) CsA-MMF-prednisolone 8 (16.1) 3 (13.6) zards regression models to adjust for the potentially confounding variables that could influence outcomes. The SPSS statistics package (SPSS V17.0, SPSS Inc., Chicago, IL, USA) was used for these analyses. P value <0.05 was considered statistically significant. Results The demographic and clinical characteristics of the long-term allograft survivors showed that most of the recipients were males and in the middle age (33.6 ± 15.3 years) at the time of transplantation. Most of the donors were also males of middle age. The patients were followed up for a mean period of 171 ± 48.1 months (range 120-320 months) (Table 1). The immunological variables demonstrated that more than 75% received grafts from related donors. There were 14 recipients of renal allograft from unrelated living donors, who were transplanted outside our center. Most of the recipients had less than three human leukocyte antigen (HLA) mismatches (41 cases). Determination of the data on panel reactive antibody (PRA) levels was possible in 13 patients and all were less than 10%. The mean of the serum creatinine levels at the last follow-up was 118 ± 46.5 µmol/l (range 58-260 µmol/l), with a mean proteinuria level of 0.47 g/day. There were only three patients with proteinuria equal to or just slightly greater than 2 g/day. The complications in our study patients are shown in Table 2. Acute rejection episodes occurred in eight patients (14.2%); most of them were within the first year post-transplantation. The first acute rejection episode occurred at a median time of 15 days post-transplantation. All these episodes responded promptly to high-dose steroid therapy except in two (3.6%) patients whose graft function did not recover completely and progressed to biopsy-proven chronic rejection. Chronic graft dysfunction (CAD) was histologically diagnosed in the allograft biopsies of 12 patients presenting clinically with this complication. There were four biopsies that showed moderate chronic interstitial fibrosis and tubular atrophy (25-50%) as described by Banff classification 8 and the others showed mild findings. Staining for c4d was possible in only four cases and all were negative. The mean of the SBP and DBP measurements was 145 ± 18 and 85 ± 8 mmhg, respectively. Also, 40.1% of the patients received one anti-hypertensive drug and 59.9% received two drugs. Hypertension was

Long-term renal allograft survival in Bahrain 821 Table 2. Post-transplant clinical events in the study subgroups. Graft surviving Failed graft P group group (n = 56) (n = 22) ATN (%) - 1 (4.5) 0.3 Acute rejection episodes Frequency (1/ 2) 6/2 5/2 0.07 Severity (mild, grade I/grade II, III) 7/3 7/2 0.06 Resistant to steroids (%) 2 (3.6) 2 (9.1) 0.05 Date of first episode, days (Mean ± SD) 18.0 ± 10.1 17.1 ± 11.3 0.4 Date of last episode, days (Mean ± SD) 956 ± 283 1525 ± 1060 0.001 Chronic allograft nephropathy (%) 12 (21.4) 17 (77.2) 0.0001 Graft function Serum creatinine at 3 months, µmol/l (Mean ± SD) 79.1 ± 15.6 99.4 ± 33.1 0.05 Serum creatinine at 12 months, µmol/l (Mean ± SD) 98.1 ± 23.1 129.1 ± 13.1 0.0002 Proteinuria (>2 g/l) at 12 months (%) 3 (5.4) 4 (18.2) 0.04 Cyclosporine doses at 3 months, mg/day (Mean ± SD) 196 ± 26 186 ± 29 0.09 Post-transplant complications (%) Hypertension 17 (54.2) 85 (75.2) 0.001 Diabetes mellitus 6 (10.7) 3 (13.6) 0.06 Infection 11 (19.6) 5 (4.5) 0.3 Malignancy 3 (5.4) 1 (9.7) 0.08 Hepatic dysfunction 5 (8.9) 6 (13.2) 0.5 Cardiovascular 7 (12.5) 4 (18.8) 0.06 was detected more frequently in patients with serum creatinine levels >161 ± 26.1 µmol/l and associated with post-transplant proteinuria. Coronary artery disease was documented in seven (12.5%) patients, and three (5.4%) had history of arrhythmia. Hypercholesterolemia was present in 43.1% patients; 21 patients received one of the cholesterol reducing agents. Post-transplant diabetes mellitus (PTDM) was diagnosed in six (10.7%) patients and its control was maintained with insulin therapy in two, while diet regimen and oral hypoglycemic agents were prescribed in the rest. All PTDM patients had family history of diabetes mellitus and five of them were obese [body mass index (BMI) > 30%]. Post-transplant infection developed at least once in 11 (19.6%) patients. The majority of these were urinary tract infections (eight patients), upper respiratory tract infections (six patients) and herpes zoster (three patients). Serious infections that required hospitalization included pneumococcal pneumonia, which was treated with intravenous broad-spectrum antibiotics in four patients, and cytomegalovirus (CMV) infection in two, which was treated with intravenous gancyclovir therapy. Development of malignancy occurred in three patients (5.4%). One female patient developed thyroid cancer after ten years and was treated by reduction of immunosuppression and by radiotherapy, with a favorable response. The other two male patients developed prostate cancer after 12 and 13 years post-transplant. They responded well to gradual reduction of their immunosuppression and removal of the prostate gland. Assessment of quality of life showed that 70% of the study patients had normal activity without any difficulties. More than 50% of the patients returned back to their previous jobs. We compared patients who had functioning grafts for more than ten years with those who had lost them before. The significant predictors for long-term graft survival included pre-transplant hypertension, CsA dose at one year, severity and frequency of acute rejection episodes, time of late acute rejection episodes, presence of CAD and serum creatinine 12 months after transplantation, significant post-transplant proteinuria (more than 2 g/24 hours), and post-trans-

822 Alarrayed S, El-Agroudy A, Al-Arrayed A, et al The half-life for cadaver and living related allografts had improved to 13.8 and 21.6 years, respectively. 9 Our results show that graft survival rate is 71.8% after more than ten years of follow-up. El-Agroudy and his group 4 found that 62 renal transplant recipients out of 144 patients (43%) had a functioning graft for more than 15 years (range 15-24 years). Tojimbara et al 7 found that graft survival in kidney transplant recipients from deceased donor was 44% and 23% after 20 and 15 years, respectively, while Kyllonen and his group 10 reported that 107 patients out of 824 kidney transplants (15%) had functioning grafts longer than 20 years. The incidence of various long-term complications found in our study is similar to those reported previously in patients with graft survival equal to or greater than ten years. Hypertension was the most common complication that occurred in 54.2% of patients. The overall prevalence of hypertension among kidney transplant recipients ranges, in most series, between 70% and 80%. 13-15 In our series, we observed that post-transplant hypertension was more pre- Table 3. Characteristics of long-term renal allograft survivors according to the primary immunosuppression. AZA-Pred. CsA-AZA- CsA-MMF- P group Pred. group Pred. group (n = 4) (n = 43) (n = 9) Acute rejection episodes Frequency (1/ 2) 1/- 5/2 1/- 0.08 Severity (mild, grade I/grade II, III) 1/1 4/2 1/1 0.3 Resistant to steroids 1 1-0.6 Date of first episode, days (Mean ± SD) 14.8 ± 12.5 24.9 ± 14.6 27.9 ± 16.6 0.07 Chronic allograft nephropathy (%) 1 (25) 9 (20.9) 2 (22.2) 0.1 Post-transplant hypertension (%) 1 (25) 22 (46.5) 2 (22.2) 0.04 Post-transplant infections (%) 1 (25) 8 (18.6) 2 (22.2) 0.3 Post-transplant diabetes mellitus (%) - 4 (9.3) 1 (11.1) 0.06 Post-transplant cardiovascular morbidity (%) - 8 (18.6) 2 (22.2) 0.03 Serum creatinine, µmol/l (Mean ± SD) At 3 months 69.1 ± 13.1 96.1± 31.3 97.3 ± 29.3 0.04 At 12 months 75.3 ± 15.1 102 ± 35.2 109 ± 42.1 0.03 At last follow-up 102 ± 34.7 113 ± 89.3 105 ± 29.6 0.09 ccrcl at last follow-up (ml/min) (Mean ± SD) 88 ± 20 79 ± 19 83 ± 19 0.3 Clinical grading (last follow-up visit) (%) 0.06 Excellent (Cr. 150 µmol/l) 3 (75) 27 (62.8) 7 (77.8) Good (Cr. 150-250 µmol/l) 1 (25) 13 (30.2) 1 (11.1) Moderate (Cr. 250 µmol/l) - 3 (7) 1 (11.1) plant hypertension. The multivariate analysis shortlisted these predictors to the time of late acute rejection episodes [relative risk (RR) 0.29, P < 0.0007], serum creatinine at one year (RR 0.18, P < 0.001), presence of severe CAD (RR 0.23, P < 0.0013), and post-transplant hypertension (RR 0.16, P < 0.009). The characteristics of long-term renal allograft survivors (n = 56) according to the primary immunosuppression, AZA and prednisolone treated patients (n = 4), CsA, prednisolone and AZA treated patients (n = 43) and CsA, prednisolone and MMF treated patients (n = 9), are shown in Table 3. In all the groups, the difference in serum creatinine at 3 and 12 months after transplantation was statistically significant, but not at the last follow-up (P = 0.09). The numbers and the severity of acute rejection episodes together with response to treatment were not significantly different. There was no significant difference between all the groups with regard to post-transplant CAD, diabetes mellitus and infection. However, there were more patients complicated with hypertension and cardiovascular events in both CsA treated groups (P = 0.04 and 0.03, respectively). Discussion

Long-term renal allograft survival in Bahrain 823 valent in the CsA-treated patients, in parallel with rising serum creatinine and in the presence of proteinuria. Long-term allograft and patient survival may be negatively influenced by posttransplant hypertension. In a large study of 29,751 renal transplant recipients, the presence of hypertension was significantly associated with allograft loss. 15 The RR of graft failure with the use of anti-hypertensive medications was 1.42 for live donor grafts and 1.58 for deceased donor grafts, indicating an approximately 40-50% excess risk of graft failure for patients who required these medications. Our data demonstrate that post-transplant hypertension had a deleterious effect on renal allograft survival. Several reports described the role of pre-transplantation hypertension in the development of hypertension after transplantation 16 and it is considered both as a consequence of reduced renal function and a risk for graft failure. Although several studies implicated acute rejection as a major risk factor for chronic allograft failure, 10,17,18 in contrast to others, 19,20 notably, we found a long-term allograft survival despite early acute rejection. The timing of the occurrence of acute rejection has been described to affect graft survival. 21 In our series, any acute rejection occurring later than one year post-transplantation significantly impacted graft survival. One could speculate that acute rejection episodes occurring late post-transplantation are due to pathophysiological processes different from the ones 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 non-compliance with immunosuppressive medications. The biopsy features in our study patients revealed that the rate of moderate and severe acute rejection was not high in either the shortor long-term surviving grafts. The correlation between the elevated serum creatinine levels at 12 months and graft survival has been documented in multi-center studies. 22 This correlation was also present in our study population and can be explained by the degree of graft dysfunction due to nephron loss from nonimmunological causes or the undetected lowgrade chronic immunologic injury. Regardless of the etiology, the variance in creatinine levels observed during the first year, as described in our population, could function as a sensitive early marker of such processes. Although diabetes mellitus developed in six (10.7%) of our patients during the post-transplantation course, it had no significant impact on graft survival. Other medical complications such as coronary heart disease (9.4%) and malignancy (3.2%) were relatively uncommon, which may be attributed to the policy of selection of young patients in our transplantation program. Post-transplant infection was not uncommon among our long-term allograft survivors (35.5%); urinary tract and upper respiratory tract infection were the most common without significant morbidity. Our patients on CsA-based immunosuppression clearly did not show any significant benefit on long-term quality of graft function than the patients on AZA and steroids. Moreover, we found that post-transplant hypertension and cardiovascular morbidity were more statistically significantly prevalent in the CsA-treated patients, and the mean serum creatinine early in the first year post-transplant was also significantly higher in this group; however, this was not the case at the last follow-up visit. Our data are not in agreement with many other studies, 23,24 and early replacement of CsA by another immunosuppressive agent to prevent the long-term toxicity should be considered. In conclusion, renal transplantation even in its earliest years and despite the numerous complications has provided ten or more years of nearnormal life to patients with ESRD, who otherwise would remain dialysis dependent. Interestingly, absence of post-transplantation hypertension and severe and late acute rejections together with good graft function at one year could predict good long-term graft outcome. References 1. Fletcher SM, Novick AC, Braun WE, Popowaniak KL, Steinmuller D. Functional capacity and reha-

824 Alarrayed S, El-Agroudy A, Al-Arrayed A, et al bilitation of recipients with a functioning renal allograft for ten year or more. Transplantation 1983;35:572-7. 2. Terasaki PI, McClelland ID, Yuge J, et al. Advances in kidney transplantation 1985-1995, in Cecka JM, Terasaki PI (eds.): Clinical transplants. 1995, 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 longterm graft survival group in renal transplantation. Clin Transplant 2000;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;23:165-71. 5. Meier-Kriesche H, Schold JD, Kaplan B. Longterm renal allograft survival: Have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 2004;4:1289-95. 6. de Mattos AM, Bennett WM, Barry JM, Norman DJ. HLA-identical sibling renal transplantation: A 21-yr single-center experience. Clin Transplant 1999;13:158-67. 7. Tojimbara T, Fuchinouea S, Iwadoha K, et al. Improved outcomes of renal transplantation from cardiac death donors: A 30-year single center experience. Am J Transplant 2007;7:1-9. 8. Soleza K, Colvinb RB, Racusenc LC, et al. Banff 07 classification of renal allograft pathology: Updates and future directions. Am J Transplant 2008;8:753-60. 9. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ Stablein D. Improved graft survival and renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000;342 (9):605-12. 10. Kyllonen L, Koshimies S, Salmela K. Renal transplant recipients with graft survival longer than 20 years: Report on 107 cases. Transplant Proc 2001;33(4):2444-5. 11. 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):108-9. 12. Mahony JF. Long-term results and complications of transplantation: The kidney. Transplant Proc 1989;21(1):1433-4. 13. Silkensen JR. Long-term complications in renal transplantation. J Am Soc Nephrol 2000;11(3): 582-9. 14. Golbabaic M, Kayedi M, Nojafi I, et al. Chronic renal allograft dysfunction: Immunologic and nonimmunologic risk factors. Transplant Proc 2001;33(5):2641-2. 15. Opelz G, Wujciak T, Ritz E. the Collaborative Transplant Study. Association of chronic kidney graft failure with recipient blood pressure. Kidney Int 1998;53:217-23. 16. Manage KC, Cizman B, Jaffe M, Feldman HI. Arterial hypertension and renal allograft survival. JAMA 2000;283(5):633-7. 17. Bruan WE, Popowniak KL, Nakamoto S, Gifford RW, Straffon RA. The fate of renal allografts functioning for a minimum of 20 yr- indefinite success or beginning of the end? A proposed classification of long-term allograft survivals. Transplantation 1995;60:784-90. 18. Prommool S, Jhangri GS, Cockfield SM, Halloran PF. Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 2000;11 (3):565-9. 19. Ashraf S, Parrott N, Dyer P. Clinical response and temporal patterns of acute cellular rejection: relationship to chronic transplant nephropathy. Transplant Int 1998;11(1):5-10. 20. Varghese Z. Immunologic and nonimmunologic correlates of chronic renal allograft dysfunction. Transplant Proc 1999;31(8):3356-8. 21. Joseph JT, Kingsmore DB, Junor BJ, et al. The impact of late acute rejection after cadaveric kidney transplantation. Clin Transplant 2001; 15:221-7. 22. Troppmann C, Gillingham KJ, Benedetti E, et al. Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. Transplantation 1995;59(7):962-9. 23. Opelz G. HLA compatibility and kidney grafts from unrelated live donors, Collaborative Transplant Study. Transplant Proc 1998;30(3):704-5. 24. Halloran PF. Immunosuppression in the postadaptation period. Transplantation 2000;70:3-5.