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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2006  |  Volume : 17  |  Issue : 1  |  Page : 70-76
Immunological Factors and Renal Allograft Survival for More than Fifteen Years: A Single Center Study from Tunisia

1 Department of Immunology, Nephrology, Charles Nicolle Hospital, 1006 Tunis, Tunisia
2 Department of Faculty of Medicine and Laboratory of Immunology, Nephrology, Charles Nicolle Hospital, 1006 Tunis, Tunisia

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Late loss of kidney allograft, caused by immunological and non-immunological factors, remains a major problem in the field of transplantation. The aim of this study was to analyze the risk factors affecting long-term kidney graft survival more than 15 years. In a retro­spective analysis, clinical and laboratory variables and outcome of 330 patients who received a kidney transplant from living or cadaveric ABO-compatible donors at the Charles Nicolle Hospital, Tunis between 1986 and 2005 were recorded. A total of 58 patients who had follow-up data longer than 15 years constituted the subjects of this study. Patients were classified into two groups: Group I (Gp I), those who had kidney graft survival more than 15 years and Group II (Gp II), those who had kidney graft survival less than 15 years. There were 27 patients in Gp I (46.5%) and 31 in Gp II (53.5%). Graft loss in Gp II patients occurred in the first year in 15.1%, at three years in 35.5 %, at five years in 71 % and at 10 years in 83.9 %. The cause of graft loss was chronic graft dysfunction in 24 cases (77.4%), recurrence of the original kidney disease in three and graft versus host disease, urinary fistula, vascular rejection and graft rupture in one case each. There was no statistically significant difference between recipient and donor age or sex, duration on dialysis, number of acute rejections and infections between the two groups. Eleven of 27 patients (40.7 %) in Gp I and eight of 31 patients (25.8 %) in Gp II received total mismatched kidneys while the others received kidneys with varying degrees of match. The HLA DR2 matching was higher in Gp I (44.4 %) than in Gp II (29 %), whereas DR3 matching was higher in Gp II (45.2 %) in comparison with Gp I (11.1 %). Cross-match was negative in all our patients. Thirteen patients (48.1%) in Gp I and 17 (54.8 %) in Gp II.had a history of having episode(s) of acute rejection The number of acute rejection episodes did not contribute significantly to long-term graft survival in our series. Delayed graft function significantly lowered long-term graft survival; it was seen in seven cases in Gp I (25.9 %) versus 23 cases in Gp II (74.2 %) (X2=13.46). In our study, the long-term graft survival was similar to what is reported from developed countries. The main risk factors were HLA DR matching and delayed graft function.

How to cite this article:
Boubaker K, Bouabid B, Bardi R, Abderrahim E, Abdallah T B, Ayed K. Immunological Factors and Renal Allograft Survival for More than Fifteen Years: A Single Center Study from Tunisia. Saudi J Kidney Dis Transpl 2006;17:70-6

How to cite this URL:
Boubaker K, Bouabid B, Bardi R, Abderrahim E, Abdallah T B, Ayed K. Immunological Factors and Renal Allograft Survival for More than Fifteen Years: A Single Center Study from Tunisia. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2020 Jul 5];17:70-6. Available from: http://www.sjkdt.org/text.asp?2006/17/1/70/32450

   Introduction Top

The improvement of patient and graft survival rates as well as the quality of life post­transplant depends on many immunological and non-immunological factors.[1],[2],[3] The main immunological factor is the immune response against a transplant which is directed by the HLA class II antigens.[3] Non­immunological factors include recipient and donor characteristics such as age, sex, body size, recipient's pre-transplant medical status (such as diabetes or hepatitis B and C), drug regimen and the development of acute rejection after kidney transplantation.[1],[2] Other factors such as social status and patients' education also influence graft survival. [4] In cadaveric donor transplants, cause of death in the donor and cold ischemia time are incriminated in long-term survival of kidney graft. [2] In this study, both immuno­logical and non-immunological factors are evaluated. The long-term results of renal allo­transplants performed between 1986 and 2005 at our center in Tunis having a minimal follow-up of 15 years, is presented.

   Subjects and Methods Top

In this retrospective study, we analyzed data on graft survival in 330 transplant recipients who received kidney transplants from living or cadaveric ABO-compatible donors at the Charles Nicolle Hospital, Tunis, Tunisia between 1986 and 2005.

Immunological factors assessed included HLA matching and pre- and post-transplant profile of anti-HLA antibodies. The non­immunological factors included donor and recipient age and gender, acute rejection, chronic rejection, infection, time of initiation of dialysis, interval between dialysis and transplantation, use of anti-T-cell induction therapy and the type and dosage of immuno­suppressive regimen.

Acute graft rejection episodes were diagnosed on the basis of renal dysfunction occurring after transplantation with or without other clinical symptoms (fever, enlargement or tenderness of kidney graft). Renal ultra­sound and doppler were performed on all these patients while allograft biopsy was performed only in some patients.

Chronic graft dysfunction was diagnosed when there was progressive impairment of renal function, which was confirmed by renal biopsy in some patients.

HLA study was performed by micro­lymphotoxicity complement dependent method (for HLA A and B). Molecular biology by PCR-SSP technique was used particularly for determination of HLA class II antigens (DRB1).

Peak panel reactive antibodies were looked for by micro-lymphotoxicity complement dependent method in the pre-transplant period in our patients and in 57 patients in the post­transplant period.

Complement-dependent cytotoxicity cross­match was performed in all patients before renal transplantation.

Fifty-eight patients constituted the subjects of this study. Of them, 52 received graft from living related donors, one from living un­related donor and five from cadaveric donors. The patients were classified into two groups: Group I (Gp I), those who had kidney graft survival more than 15 years and Group II (Gp II), those who had kidney graft survival less than 15 years.

Immunosuppression in all patients was with prednisolone and azathioprine. Cyclosporin A was added to patients who received trans­plants from donors with three mismatches and/or after an acute rejection episode. Mycophenolate mofetil was used in patients with cyclosporin A nephrotoxicity.

   Results Top

There were 27 patients (46.5 %) in Gp I, and 31 (53.5 %) in Gp II. The following factors were assessed for their contribution to long­term graft survival.

Immunological factors

Eleven patients (40.7 %) in Gp I and eight (25.8 %) from Gp II received total mismatched kidneys (X2 =0.294). Sixteen patients (59.2 %) from Gp I received kidneys with varying degrees of match (2 mis-matches, n = 3; 3 mismatches, n = 13) as against 23 patients in Gp II (74.2%) (2 mismatches, n = 2; 3 mismatches n = 20 and 5 mismatches n = 1).

Comparing HLA in Gp I and Gp II, it was found that DR2 was found more frequently, but without statistical significance, in Gp I (12 patients, 44.4%) vs Gp II (9 patients, 29 %) (X2=0.261), whereas DR3 was higher in Gp II, again without statistical significance (11 patients, 45.2 %) vs Gp I (3 patients, 11.1 %) (X2=1.52). Ten patients in Gp I showed pre-transplant anti-HLA antibodies vs 12 patients in Gp II (X2=0.017) while 15 patients in Gp I showed post-transplant anti-HLA antibodies vs 10 patients in Gp II (X2=3.742). Cross-match was negative in all our patients. Thirty patients had a history of having had acute rejection episode(s). Of them, 13 (48.1 %) were in Gp I and 17 patients (54.8 %) in Gp II.

Loss of kidney graft function is shown in [Figure - 1]. Graft loss occurred in 15.1 % of the patients in the first year, in 35.5 % at three years, in 71% at five years and in 83.9 % at 10 years post-transplantation. Graft loss was due mainly to chronic allograft dysfun­ction seen in 24 cases (77.4%). Three grafts showed recurrence of the original kidney disease. One graft each was lost due to graft versus host disease, which occurred five years after transplantation, urinary fistula, vascular rejection and graft rupture. Death of a patient with functioning graft was not considered as graft loss.

Non- immunological factors

There were no statistically significant differences between the two groups in any of the non-immunological factors studied [Table - 1].

Status of patients with functioning grafts 15 years after transplantation

Fifteen years after renal transplantation, 27 patients have functioning grafts. Medical and social rehabilitation is very good in the vast majority although some of these patients have varying degrees of chronic renal dysfunction.

   Discussion Top

Transplantation is the optimal form of renal replacement therapy for patients with end-stage renal disease. [5] Living unrelated renal transplantation, frequently performed in some countries, [5],[6],[7] was rare in our study (only one patient). The vast majority of our patients underwent living related donor renal transplantation (52 patients, 89.6 %).

Late loss of kidney graft caused by immuno­logical and non-immunological factors is an ongoing problem in the field of transplant­tation.[3] Its frequency varies in different studies and depends on the type of donors and the years after transplantation. Kidney graft survival is more crucial in living donors than cadaveric donor transplants since survival rate from living-related and living­unrelated donor kidneys are six and four percentage points higher, respectively, at one year after transplantation compared to the rate for cadaveric donor kidneys.[2],[8],[9],[10] In living donors, the reported kidney graft survival is 97 % at 3 months, 94.6 % at 1 year, 87.4 % at 3 years, 79.2 % at 5 years and 54.4 % at 10 years. The long-term graft survival is slightly higher in related than unrelated donors [1],[11] It was 94 %, 84 % and 78.8 % 3, 5 and 10 years for living-related donor transplants versus 91.9 %, 88.5 % and 74.7 % for living-unrelated donor transplants. The reported graft survival in cadaveric donors is 93.9 % at 3 months, 89 % at 1 year, 84.5 % at 2 years, 77.3 % at 3 years, 66.2 % at 5 years and 36.4 % at 10 years. In our study, the kidney allograft survival at 15 years was 20 % in cadaveric donors and 50 % in living related donors.

The survival of transplanted kidneys largely depends, amongst other factors, on the degree of histocompatibility.[12] Long-term graft survival among ABO-incompatible kidney transplants from HLA-identical sibling donors was better than HLA-non identical sibling donors.[9] Kidney graft survival more than six years was observed in 57.1 % cases in transplanted pairs with three identical antigens. [12] In our study, kidney graft survival more than 15 years was observed in 48.1 % of patients with three-antigen match.

During the early post-transplant period (6 months), HLA-DR mismatches have a stronger influence on graft survival than HLA-A or B mismatches which have a very small influence.[13],[14] However, during the period of six months to five years post­transplantation, all three HLA loci have approximately the same influence.[13] The difference in survival between grafts with 0 or 2 mismatches is 6 % and this frequency increases to 17 % between grafts with 0 or 6 mismatches for HLA-A, B or DR at five years post-transplant.[13] In our study, only HLA-DR had an influence on long-term graft survival with a favorable effect of DR2 and an unfavorable effect of DR3 on recipients.

Peak panel reactive antigen in the pre- or post-transplant period is incriminated in kidney graft survival.[2] Donor-specific anti­HLA antibodies in the post-transplant period is a good marker for graft loss.[15] Monitoring these antibodies by ELISA is a useful tool for tailoring immunosuppression after kidney transplantation.[15] In our study, there was no statistically significant effect of anti-HLA antibodies in pre- and post­transplant period on graft survival.

Acute rejections often occur in the first two weeks following transplantation.[12] Their number increases as the number of blood transfusions per patient decrease, as HLA mis-matching increases and also based on the presence of donor-specific anti-HLA-I antibodies in the post-transplant period.[12],[15],[16] Only patients with HLA class I antibodies lose their graft due to vascular acute rejection.[15] Acute rejection markedly decreases the long-term kidney graft survival in living donors.[11] However, in our study, acute rejection did not affect the long-term kidney graft survival, and it seems that the number of acute rejections, especially if it occurs more than three times, is incri­minated.[11],[17],[18],[19] Therefore, proper manage­ment of acute rejection is essential for long­term graft survival.[11]

Delayed graft function is an important risk factor that influences graft survival.[17],[18],[19] In our study, it was significantly associated with kidney graft loss.

Flow cytometry crossmatch is a newer and more sensitive technique than classical complement-dependent cytotoxicity since it is positive in 7.1 % of patients with negative complement dependent cytotoxicity. [8] The role of this new technique in predicting long-term graft survival of kidney grafts is still unclear.[20] In some studies, survival analysis revealed that kidney graft outcome is better in negative T-flow cytometry cross­match recipients.[20] These results suggest that a positive pre-transplant T-flow cyto­metry crossmatch despite a negative comple­ment-dependent cytotoxicity is associated with an impaired long-term graft survival.[20]

Other variables influence graft-survival like the age and sex of the donor.[10],[17],[18],[19] It is demonstrated that graft survival rate decreases with donor age and in males. [10] Variations in donor age, recipients' pre­transplant medical status such as diabetes, hepatitis B or coronary heart disease and drug regimen tend to influence recipients of living-unrelated donor kidneys more than living related donors.[10],[11] In our study, age and sex of the recipient and donor and duration on dialysis did not affect kidney graft survival. Race also is incriminated since black recipients of living-related, living-unrelated and cadaveric kidneys demonstrate half lives of 17, 11 and 7 years respectively, compared to 17, 16, and 11 years in their white counterparts. [10],[21],[22] Cytomegalovirus infection in recipients from living-donors also results in lower graft survival rates. 10 Other factors such as social status and patient's education also influence graft survival. [4]

   Conclusion Top

In our study, long-term graft survival was similar to what is reported from developed countries. The main risk factors were HLA DR and delayed graft function. HLA DR is associated with long-term kidney graft survival with a favorable effect of DR2 and an unfavorable effect of DR3 on recipients' survival in contrast with literature, which incriminates all three loci (HLA-A, B and DR).

In conclusion, proper attention and care to immunological and non-immunological factors known to promote long-term graft survival essentially HLA-DR compatibility and delayed graft function, detection of donor­specific anti-HLA antibodies in the post­transplant period and use of T-flow cyto­metry crossmatch are important for improving long-term kidney graft survival.

   References Top

1.Kim SI, Huh KH, Kwon KW et al. Kidney transplantation in Yonsei University from 1979-2003. Clin Transpl2003;:183-92.  Back to cited text no. 1    
2.Su X, Zenios SA, Chakkera H, Milford EL, Cherlow GM. Diminishing significance of HLA matching in kidney transplantation. Am J Transplant 2004;4(9):1501-8.  Back to cited text no. 2    
3.Hernandez-Fuentes MP, Lechler RI. Chronic graft loss. Immunological and non-immunological factors. Contrib Nephrol 2005;146:54-64.  Back to cited text no. 3    
4.Lutz J, Stangl M, Heemann U. Kidney transplantation in Germany-2002. Zentra­lbl Chir 2003;128(10):816-20.  Back to cited text no. 4    
5.Ivanovski N, Popov Z, Cakalaroski K, Masin J, Spasovski G, Zafirovska K. Living-unrelated (Paid) renal transplant­tation- Ten years later. Transplant Proc 2005 ;37:563-4.  Back to cited text no. 5    
6.Sever MS, Kazancioglu R, Yildiz A, et al. Ontcome of living unrelated (comme­rcial) renal transplantation. Kidney Int 2001;60:1477-83.  Back to cited text no. 6    
7.Higgins R, West N, Fletcher S, et al. Kidney transplantation in patients travelling from the UK to India or Pakistan. Nephrol Dial Transplant 2003;18:851-2.  Back to cited text no. 7    
8.Wolters HH, Palmes D, Heidenreich S, August C, et al. Long-term follow-up of double kidney transplantation using a score for evaluation of marginal donors. Transpl Int 2005;18(4):453-7.  Back to cited text no. 8    
9.Shimmura H, Tanabe K, Tokumoto T, et al. Impact of HLA-identity on results of ABO-incompatible living kidney transplant­tation. Transplant Proc 2004;36(7):2172-4.  Back to cited text no. 9    
10.10.Gjertson DW. Look-up survival tables for living-donor renal transplants: OPTN /UNOS data 1995-2002. Clin Transpl. 2003;:337-86.  Back to cited text no. 10    
11.11.Park YH, Min SK, Lee JN, et al. Risk factors on graft survival of living donor kidney transplantation. Transplant Proc 2004 ;36(7):2023-5.  Back to cited text no. 11    
12.12.Kolevski P, Popov Z, Hristova-Dimceva A, Petrovski D, Cakalaroski K, Ivanovski N. Living donors : immunologic factors. Ann Urol 2000;34(5):319-22.  Back to cited text no. 12    
13.13.Opelz G. Strength of HLA-A, HLA-B, and HLA-DR mismatches in relation to short-and long-term kidney graft survival. Collaborative Transplant Study Transpl Int 1992;5:S621-4.  Back to cited text no. 13    
14.14. Ross W, Solomon H, Reese J, Fairchild R, Garvin P, Kurtz M. Benefical effects of HLA-DR3 gene expression on renal allograft survival in black recipients. Transplant Proc 1993;25:2408-10.  Back to cited text no. 14    
15.15. Fernandez-Fresnedo G, Pastor JM, Lopez-Hoyos M, et al. Relationship of donor-specific class-I anti-HLA antibodies detected by ELISA after kidney transplan­tation on the development of acute rejection and graft survival. Nephrol Dial Transplant 2003;18 (5):990-5  Back to cited text no. 15    
16.16.Rodriguez DS, Jankowska-Gan E, Haynes LD, et al. Immune regulation and graft survival in kidney transplant recipients are both enhanced by human leucocyte antigen matching. Am J Transplant 2004;4(4):537-43.  Back to cited text no. 16    
17.17.Kerr SR, Gillingham KJ, Johnson EM, Matas AJ.Living donors > 55 years: to use or not to use. Transplantation 1999; 67:999-1004.  Back to cited text no. 17    
18.18.Schreiber M, HMils S, Kuhn R, Neumayer HH. Causes of early graft failue at less then 12 months after renal transplantation. Transplant Proc 1993;25:2614-5.  Back to cited text no. 18    
19.19.Knight RJ, Burrows L, Bodian C. The influence of acute rejection on long term renal allograft survival: a comparison of living and cadaveric donor transplantation. Transplantation 2001;72:69-76.  Back to cited text no. 19    
20.20.Rebibou JM, Bittencourt MC, Saint-Hillier Y, et al. T-cell flow-cytometry crossmatch and long-term renal graft survival. Clin Transplant 2004;18(5):558-63.  Back to cited text no. 20    
21.21.Ngcobo TK, Becker P, Mobida MC. Effect of HLA-DR3 gene expression on cadaveric renal allograft survival in blacks. Clin Transplant 1996;10:60-2.  Back to cited text no. 21    
22.22.OPTN/SRTR Data 2004.  Back to cited text no. 22    

Correspondence Address:
Kh Ayed
Department of Immunology Charles Nicolle Hospital 1006 Tunis
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PMID: 17297543

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