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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 3  |  Page : 370-374
Acute rejection episodes after kidney transplantation


1 Department of Nephrology, Charles Nicolle Hospital, Tunis, Tunisia
2 Laboratory of Immunology: LITRI LR 03SP01, Tunisia
3 Laboratory of Renal Pathology: LR 00SP01, Tunisia

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   Abstract 

Acute rejection episodes (AREs) are a major determinant of renal allograft survival. The incorporation of new immunosuppressive agents explains, at least partially, the improvement seen in the results of transplantation in recent years. The objectives of this study are to analyze the incidence and severity of AREs, their risk factors and their influence on graft and patient survival. We retrospectively studied 280 kidney transplants performed in adults at the Charles Nicolle Hospital, Tunis, between 1986 and 2004. The diagnosis of ARE was based on clinical data and response to treatment. Allograft biopsies were performed in ten cases. The treatment of AREs consisted of pulse methylprednisolone and anti­thymocyte globulin. There were 186 males (66.4%) and 94 females (33.6%), and their mean age was 31 ± 8.9 years. Overall, the 280 study patients experienced a total of 113 AREs. Of them, 85 had only one ARE, 28 had two to three and none had more than three AREs. A total of 68 AREs were completely re­versible, 42 were partially reversible while three could not be reversed with treatment. The mean inci­dence of AREs was 40.4%. The incidence was > 45% between 1986 and 1997, decreased to 20.5% between 1998 and 2000 and to 9% between 2001 and 2004. Graft survival rates in patients with and without AREs were respectively 91% and 93% at three years, 82% and 90% at five years and 73% and 83% at 10 years. We found a decrease in the incidence of AREs in recent years in our study patients, and this was related to the introduction of sensitized cross-match and the newer immunosuppressive agents, particularly MMF. Additionally, AREs had a deleterious impact on late graft survival in our study population.

Keywords: Acute rejection, Kidney transplantation, Risk factors, Survival

How to cite this article:
Hamida FB, Barbouch S, Bardi R, Helal I, Kaaroud H, Fatma LB, Hedri H, Abderrahim E, Abdallah TB, Ayed K, Maiz HB, Kheder A. Acute rejection episodes after kidney transplantation. Saudi J Kidney Dis Transpl 2009;20:370-4

How to cite this URL:
Hamida FB, Barbouch S, Bardi R, Helal I, Kaaroud H, Fatma LB, Hedri H, Abderrahim E, Abdallah TB, Ayed K, Maiz HB, Kheder A. Acute rejection episodes after kidney transplantation. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2019 Oct 24];20:370-4. Available from: http://www.sjkdt.org/text.asp?2009/20/3/370/50758

   Introduction Top


Many risk factors are known to influence graft survival such as age of the recipient, race, pre­sence of diabetes, delayed graft function and hu­man leukocyte antigen (HLA) mismatch. [1],[2] Additionally, acute rejection episodes (AREs) have consistently been reported to be the most im­portant risk factor leading to chronic allograft failure. [3],[4],[5]

The introduction of new immunosuppressive a­gents such as cyclosporine, tacrolimus, sirolimus and mycophenolate mofetil (MMF) explains, at least partially, the improvement seen in the re­sults of transplantation in recent years. [6],[7] However, in spite of the progressive decrease in the inci­dence of AREs, chronic allograft nephropathy re­mains the most common cause of graft loss after kidney transplantation. [3],[8],[9]

The objectives of this study are to analyze the incidence and severity of AREs, the associated risk factors and their influence on graft and patient survival.


   Patients and Methods Top


We retrospectively analyzed data of 280 kidney transplants performed in adults between 1986 and 2004. The recipients included 186 males (66.4%) and 94 females (33.6%) with a mean age of 31 ± 8.9 years (16 to 61 years). There were 136 pa­tients (48.6%) in the age-group 16 to 29 years, 133 (47.5%) in the age-group 30 to 49 years and 11 patients (3.9%) >_ 50 years of age. The donor source was cadaveric in 46 cases (16.4%), living related in 231 cases (82.53%) and living unrelated in three (1.7%). The mean age of the donors was 35.8 ± 12.9 years (16 to 65 years). Sensitized cross-match was introduced in our center in 1997. The immunosuppressive therapy comprised of corticosteroids in all cases, azathioprine in 199 patients (71%), MMF in 114 patients (59.3%) (First introduced in our center in 1999), cylos­porine in 182 cases (65%), tacrolimus in 24 cases (8.6%) and anti-thymocyte globulin (ATG) in 170 cases (60.7%). ATG was not used in HLA iden­tical living related recipients.

The diagnosis of ARE was based on clinical and analytical data as well as response to treatment. Allograft biopsies were performed in 10 cases. The treatment of AREs consisted of pulse me­thylprednisolone and/or ATG.

The data are presented as mean ± SD. Compara­tive analysis was performed using T-test for con­tinuous variables and Chi square test for quanti­tative variables. Cumulative survival rates were calculated according to the actuarial method and comparison was performed using Log rank test. The level of statistical significance was set at P= 0.05%.


   Results Top


Overall, the 280 study patients experienced a total of 113 AREs. Of them, 85 had only one ARE, 28 had two to three and none had more than three ARE. Of the 113 AREs, 68 were completely reversible, 42 were partially reversible while three could not be reversed with treatment. The mean incidence of AREs in our study patients was 40.4%. The incidence was more than 45% bet­ween 1986 and 1997, decreased to 20.5% bet­ween 1998 and 2000 and to 9% between 2001 and 2004. The incidence of AREs was not sig­nificantly related to: (a) type of donors: 30.4% in cadaveric donor transplants and 42.3% in living donor transplants: (b) mode of renal replacement therapy before transplantation: 35.7% in perito­neal dialysis and 41.2% in hemodialysis and (c) number of HLA mismatches (MM): 29.7% in zero MM, 43.4% in one or two MM and 43.6% if there was > two MM.

The proportion of patients experiencing an epi­sode of ARE was significantly lower when sen­sitized cross-match was performed (15.2% vs 57.2%, P< 0.0001) and in MMF-treated patients (22.8% vs 52.4%, P< 0.0001). Since sensitized cross-match and MMF were not introduced si­multaneously in our center, we compared the occurrence of ARE during three periods: first, before the introduction of sensitized cross-match and MMF, second, after the introduction of sen­sitized cross-match but not MMF and third, after the introduction of both sensitized cross-match and MMF. The frequency of occurrence of AREs was respectively 57.1%, 31.4% and 7.8% (P< 0.0001) in the three groups of patients. The occurrence of infectious episodes during the first three months and need for hospitalizations du­ring the first year following transplantation, were not significantly different between patients who had AREs and those who did not. The occurrence of post-transplantation diabetes mellitus was also not significantly different between patients with or without AREs (22.1% vs 19.5%).

The serum creatinine level was significantly higher in patients who had AREs when compared with those who did not have an episode of ARE, both at discharge from the hospital (117 µmol/L vs 107.7 µmol/L, P< 0.03), and at 12 months following transplantation (132.7 µmol/L vs 115.5 µmol/L, P< 0.007) [Table 1].

The actuarial patient survival in patients with AREs was lower than those without AREs, but this difference was not significant 96% vs 97% at one year, 90% vs 94% at three years, 85% vs 91% at five years and 75% vs 79% at ten years. Similarly, the actuarial graft survival in patients with AREs was lower than those without AREs, but this difference was not significant: 98% vs 98% at one year, 91% vs 93% at three years, 82% vs 90% at five years and 73% vs 83% at ten years (P= 0.07) [Figure 1]. However, the difference became significant when we studied late graft survival, censoring graft loss before one year [Figure 2]: 91% vs 95% at three years, 83% vs 93% at five years and 73% vs 88% at ten years in patients with and without AREs, res­pectively (P< 0.02).


   Discussion Top


Renal allograft survival is greatly dependent on the incidence and frequency of rejection episo­des. Histological evidence is considered the gold standard for diagnosis of rejection. However, this invasive technique is not without hazards, and many of our renal transplant patients refuse to undergo graft biopsy and/or have a contraindi­cation for this procedure.

This study has shown that the proportion of renal-allograft recipients with AREs was reduced significantly when sensitized cross-match was performed. Addition of MMF to the immunosu­ppressive regimen along with cyclosporine, has reportedly reduced both the incidence and severity of AREs. [10] Although this reduction has not been associated with a better graft survival in the short­term, longer duration of follow-up has shown that MMF improves allograft survival. [11],[12] This was also observed in our study, as a reduction noted in the incidence of AREs in 1998, coincided with the introduction of MMF in the immunosupp­ressive protocol in our country that year.

Contrary to one large analysis, [13] we observed no influence of the number of HLA-mismatches on the incidence of AREs. In our study, we did not find a significant difference between patients with or without AREs, regarding the occurrence of in­fection during the first three months, the number of hospitalizations during the first year as well as the onset of post-transplantation diabetes mellitus.

Patients with AREs showed higher serum crea­tinine levels at discharge from the hospital and at 12 months after transplantation. Leggat et al, [14] in a review of 31,600 first cadaveric transplants from the US Renal Data System, showed a sig­nificantly lower four year graft survival of 54% in patients with AREs in contrast to 78% graft survival in those who had no rejection. In our study, the lower graft survival in patients with AREs was not statistically significant. However, this difference became significant when late graft loss was analyzed, confirming the findings of other investigators. [10],[15],[16],[17]


   Conclusion Top


We found a decrease in the incidence of AREs in the last decade in adult renal transplants. This is probably related to the introduction of sensi­tized cross-match and newer immunosuppressive agents, particularly MMF. As well documented, ARE had a deleterious impact in late graft sur­vival in our population. These findings stress the importance of effectively preventing acute rejec­tion, which still remains a major determinant in the development of chronic allograft nephropathy. Although our study throws good insight into the incidence and after effects of AREs, one major drawback is that we performed only ten allograft biopsies to confirm the diagnosis of ARE. Thus, a similar study with histological evidence of ARE will throw more light on this entity.

 
   References Top

1.Shoskes DA, Cecka JM. Deterious effects of delayed graft function in cadaveric renal trans­plant recipients independent of acute rejection. Transplantation 1998;66:1697-701.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.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: 605-12.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Almond PS, Matas A, Gillingham K, et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993;55:752-6.  Back to cited text no. 3  [PUBMED]  
4.Paul LC. Chronic allograft nephropathy: An update. Kidney Int 1999;56:783-93.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Humar A, Hassoun A, Kandaswamy R, Payne WD, Sutherland DE, Matas AJ. Immunologic factors: The major risk for decreased long-term renal allograft survival. Transplantation 1999;68: 1842-6.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. US Renal Transplant Mycophenolate Mofetil Study Group.Transplantation 1995;60:225-32.  Back to cited text no. 6    
7.Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of Tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation 1997; 63:977-83.  Back to cited text no. 7    
8.Kasiske BL. Immune and nonimmune clinical correlates of chronic renal allograft rejection. Transplant Proc 1997;29:2557.  Back to cited text no. 8    
9.Ishikawa A, Flechner SM, Goldfarb DA, et al. Quantitative assessment of the first acute rejec­tion as a predictor of renal transplant outcome. Transplantation 1999;68:1318-24.  Back to cited text no. 9    
10.Pallardo Mateu LM, Calabuig AS, Plaza LC, Esteve AF. Acute rejection and late renal trans­plant failure: Risk factors and prognosis. Nephrol Dial Transplant 2004;19(suppl3):38-42.  Back to cited text no. 10    
11.Mathew TH. A blinded, long-term randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: Results at three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1998;65:1450-4.  Back to cited text no. 11    
12.Knoll GA, Macdonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduction and risk of acute rejection after kidney transplan­tation. J Am Soc Nephrol 2003;14:2381-6.  Back to cited text no. 12    
13.Zhou YC, Cecka JM. Effect of HLA matching on renal transplant survival. Clin Transpl 1993: 499-510.  Back to cited text no. 13    
14.Leggat JE, Ojo AO, Leichtman AB. Long term renal allograft survival-prognostic: Implication of timing of acute rejection. Transplantation 1997;63:1268.  Back to cited text no. 14    
15.Shishido S, Asanuma H, Nakai H, et al. The impact of repeated sub clinical acute rejection on the progression of chronic allograft nephro­pathy. J Am Soc Nephrol 2003;14:1046-52.  Back to cited text no. 15    
16.McLaren AJ, Jassem W, Gray DW, Fuggle SV, Welsh KI, Morris PJ. Delayed graft function: Risk factors and the relative effects of early function and acute rejection on long-term survival in cadaveric renal transplantation. Clin Transplantation 1999;13:266-72.  Back to cited text no. 16    
17.Nett PC, Heisey DM, Shames BD, Fernandez LA, Pirsch JD, Sollinger HW. Influence of kidney function to the impact of acute rejection on long-term kidney transplant survival. Transplant Int 2005;18:385-9.  Back to cited text no. 17    

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Correspondence Address:
Fethi Ben Hamida
Department of Nephrology, Charles Nicolle Hospital, Tunis
Tunisia
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PMID: 19414936

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