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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2017  |  Volume : 28  |  Issue : 3  |  Page : 499-506
Outcome of recipients of human leukocyte antigen incompatible kidney transplants who underwent desensitization at King Fahad Specialist Hospital, Dammam, Saudi Arabia


Multi-Organ Transplant Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia

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Date of Web Publication18-May-2017
 

   Abstract 

In patients whom are highly sensitized immunologically, the benefit of kidney transplantation can be extended to this population through the utilization of organs from human leukocyte antigen incompatible (HLAi) donors. This retrospective observational study was designed to identify the incidence and predictors of acute antibody-mediated rejection/acute cellular rejection (AMR/ACR) in our kidney recipients from living kidney donors (sensitized and those with low immunologic risk). This single-center study has been conducted at King Fahad Specialist Hospital, Dammam (KFSH-D), Saudi Arabia; during the period of September 2008- August 2013. All eligible recipients of living donor kidneys during the study period were included (n = 213) in the study. Over 60% of patients in the study were females. Thirty of the 213 kidneys were from HLAi donors. During the follow-up period (median follow-up time = 16 months; 3–27 months), the incidence rate of ACR among HLA compatible (HLAc) and HLAi groups was 22.2% and 16.7%, respectively (P >0.05). The incidence rate of AMR was 2.6% in HLAc group and 16.7%in the HLAi group (P<0.05). The significantly higher incidence of AMR in HLAi group can be explained by the presence of the donor-specific antibodies in weak titers. These results are consistent with studies from similar populations in published literature. However, the relatively small number and short duration of the study are considered, and longer follow-up of this population will be needed for conclusions on the sustainability of our findings.

How to cite this article:
Idris MA, Hossain A, Muntasir MA, Marmi A, Aldajani AA, Aljamaan YM, Akhtar M, Housawi A. Outcome of recipients of human leukocyte antigen incompatible kidney transplants who underwent desensitization at King Fahad Specialist Hospital, Dammam, Saudi Arabia. Saudi J Kidney Dis Transpl 2017;28:499-506

How to cite this URL:
Idris MA, Hossain A, Muntasir MA, Marmi A, Aldajani AA, Aljamaan YM, Akhtar M, Housawi A. Outcome of recipients of human leukocyte antigen incompatible kidney transplants who underwent desensitization at King Fahad Specialist Hospital, Dammam, Saudi Arabia. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 May 22];28:499-506. Available from: http://www.sjkdt.org/text.asp?2017/28/3/499/206447

   Introduction Top


Kidney transplant is the best available treatment of choice for selected patients with end-stage kidney disease. It offers better survival rates and quality of life over any other modality of renal replacement therapy.[1],[2]

For recipients of living donor kidneys, patient survival rate is 91%. For recipients of kidneys from standard criteria deceased donors, survival rate is 84%, and for recipient of kidneys from extended criteria deceased donors, survival rate is 70%.[3]

Patients who are sensitized against their potential donors which reduce their chance of finding can be achieved by overcoming the barrier of human leukocyte antigen incompatible (HLAi) sensitization through a variety of desensitization procedures, for example, plasmapheresis.

The desensitization protocols showed promising outcome although the short-term and long-term antibody-mediated rejection (AMR) occurrences have been high.[4],[5],[6],[7],[8]

Sensitization to non-self-HLA antigen can occur due to certain sensitizing events including pregnancy, blood transfusion, or previous transplantation. This exposure leads to the formation of anti-HLA antibodies. Donor-specific antibodies (DSAs) present at transplantation cause AMR.[9]

Plasmapheresis helps by removing potentially harmful antibodies. Intravenous immuno- globulins (IVIGs) are known to have a broader ability to regulate cellular immunity, including innate and adaptive components, in part, by modulating complement activation.[10]

An alternate option to conventional plasma- pheresis is the use of antigen-specific immuno- adsorption. In some reports, a total number of 45 desensitization attempts in blood group ABO-incompatible (ABOi) kidney transplantation using this technology combined with rituximab have led to 43 transplantations after successful desensitization.[11]

The combination of plasmapheresis and IVIG is more effective in desensitizing patients than high-dose IVIG alone.[12],[13]

It has been reported by several centers that outcomes after transplantation with a kidney from an HLAi live donor were inferior to outcomes after transplantation with a kidney from a HLA compatible (HLAc) donor,[14],[15],[16],[17] and many centers avoid performing transplantations with kidneys from incompatible donors to avoid regulatory scrutiny.[18] Despite these reports, for some patients receiving a compatible kidney is not an option and so their option is to undergo desensitization and receive an incompatible kidney or to remain on the waiting list which is associated with worse outcome and a high mortality rate.[18] It should be kept in mind that it may be in the patient’s best interest to undergo an HLAi kidney transplant with a lower success rate than an HLAc one to avoid the complications of remaining on the waiting list.[18]


   Study Design and Participants Top


The purpose of this retrospective observational study is to identify the incidence of AMR/acute cellular rejection (AMR/ACR) and to assess the predictors of these outcomes in sensitized and low immunologic risk living kidney donor transplant recipients.

We aimed to look at the incidence of acute rejection of both ACR and AMR in HLAi living-related renal transplants and compared them to that of HLAc living-related renal transplants and determined the effects of these results on the short-term graft and patient survival in HLAi transplants.

Other endpoints include graft-patient survival, incidence of cytomegalovirus (CMV) infection, BK virus (BKV) infection, and new- onset diabetes after transplant (NODAT).


   Materials and Methods Top


This study was conducted in a setting of tertiary single-centered, King Fahad Specialist Hospital, Dammam (KFSH-D), which had a kidney transplant program since September 2008. We started the practice of HLAi living kidney transplants in June 2011.

We included all 219 living kidney transplant recipients within the time frame of June 2011- August 2013 to eliminate the potential sources of selection bias. Deceased donor transplants, ABOi transplants, and Kidney-pancreas transplants were all excluded from the study.

Of those 219 living kidney transplants, there were 30 HLA incompatible and 189 HLAc living kidney transplants.

[Table 1] shows the variables and data sources and measurement collected from recipient’s charts and used in this study for analyses.
Table 1: Population demographics.

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The study has been approved by our Institutional Ethics Board of KFSH-D IRB Reference Number: MOT010–99.

All statistical evaluations were performed for all the groups combined as well as performed separately for HLAc and HLAi groups. We excluded any cases with missing data from our analysis. Kolmogorov-Smirnov test was used to check for normality of the dataset. The /?-test for paired data was used to compare for differences among the groups. We used Kaplan-Meier test for survival analysis. With HLAi as the risk factor, we performed multiple logistic regression analysis to identify the predictors for developing ACR, AMR, or any type of acute rejection (ACR/AMR). Continuous data are presented as mean ± standard deviation (except if otherwise mentioned) and discrete variables as frequency (%). In all cases, P <0.05 was considered statistically significant.

We used the Statistical Package for the Social Sciences (SPSS) version 21.0 (IBM SPSS Statistics for Windows, IBM Corp., Armonk, NY, USA) and MS Excel to perform the analyses.

We defined HLAi living-related renal transplants as those who had either a positive flow cytometry crossmatch (FXM) with their donors or a negative FXM with their donors but were positive for DSAs with an intensity of more than 1000 mean fluorescent intense (MFI).

We defined HLAc living-related renal transplants as those who had a negative FXM with their donors and negative DSAs (or DSAs with less than 1000 MFI).

The HLAi group had DSAs with an MFI ranging between 1000 and 9900.

Our center’s desensitization protocol consists of a single dose of 375 mg/m2 of rituximab and plasmapheresis 5–8 sessions, each session followed by a dose of IVIG at a dose of 100 to 400 mg/kg.

All HLAi transplant recipients received anti- thymocyte globulin (ATG) as an induction therapy and were then maintained on prednisone, mycophenolate, and tacrolimus. The induction therapy for HLAc transplant recipients was either ATG or basiliximab, guided by their immunological risk. Those who are considered as a high risk are: those who are HLA or ABO incompatible, those who has a positive HLA antibodies and those who has 3 or more HLA mismatches with their potential donors. The maintenance therapy is the same as in HALi patients.

We defined slow graft function (SGF) as a failure of reduction of serum creatinine to 50% or more of the preoperative baseline by postoperative day 5.

We defined delayed graft function (DGF) as the need for renal replacement therapy (hemodialysis or peritoneal dialysis) in the 1st postoperative week.


   Results Top


[Table 1] shows the patients’ demographics. Mean age, height, weight, and BSA were consistent with average transplant program population stats. In the HLAc population, the mean age was 41 ± 15. In HLAi population, the mean age was 46 ± 11 years. The age and diabetic status were not significantly differentbetween the two groups, whereas there were significantly more females in the HLAi group than in the HLAc group (62.5% vs. 34.4%, respectively).

There were 30 cases of HLAi incompatible transplants from live donors. Median follow-up time for the HLAi group is 16 months (3–27 months). There was no patient or graft lossduring the study follow-up period.

The incidence of ACR is comparable between the two groups [Figure 1]a (22.2% and 16.7%, respectively, P >0.05). However, the incidence of AMR was significantly higher (P <0.05) in the HLAi group (16.7%) than that of the HLAc group (2.6%) [Figure 1].
Figure 1: Incidence of rejection: (a) Acute cellular rejection; the incidence was not significant between the two groups; (b) Antibody-mediated rejection. With a significant increased risk of antibody-mediated rejection in the human leukocyte antigen incompatible group.

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We used multiple logistic regression to determine the association between HLAi and kidney rejection, after adjustment for confounding variables. The results suggest that the HLAi group was more prone to develop rejection (both ACR and AMR) after correction for age, sex, induction agent used, and presence or absence of DGF/SGF.

Patient survival and graft survival (both censored and uncensored) are comparable between compatible and incompatible kidney transplants (P >0.05) ([Table 2] and [Figure 2]).
Table 2: Patient survival, graft (censored) survival and graft (uncensored) survival.

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Figure 2: (a) Patient survival, (b) graft (censored) survival, and (c) graft (uncensored) survival.

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We found that there was a higher incidence of immediate graft function in the HLAi group (95.8%) than that of the HLAc group (87.8%) (P <0.05). SGF was observed in 6.9% in the HLAc group and in none in the HLAi group (P <0.5). DGF was not significantly different between the two groups (5.3% and 4.2%, respectively) (P >0.05) [Figure 3].
Figure 3: Graft function showed significantly more immediate graft function and less slow graft function in HLAi group while the delayed graft function incidence was the same between the two groups (see the text).
HLAi: Human leukocyte antigen incompatible.


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We found significantly higher incidence of interstitial fibrosis and tubular atrophy (IF/TA) on renal biopsy in the HLAi group than in the HLAc group (56.5% and 23.5%, respectively, P <0.05) [Figure 4].
Figure 4: IF/TA is significantly more in HLAi group.
IF/TA: Interstitial fibrosis/tubular atrophy,
HLAi: Human leukocyte antigen incompatible.


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For NODAT, we found no significant differ- rences between the two groups (P <0.05) in the incidence of NODAT (23% and 28.6%, respectively) ([Table 3] and [Figure 5]).
Table 3: Incidence of NODAT, CMV, and BK virus.

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Figure 5. NODAT incidence is not different
between the two groups.
NODAT: New onset diabetes after transplant,
HLAi: Human leukocyte antigen incompatible.


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Five patients developed CMV disease in the HLAc group (2.6%) compared to four patientsin the HLAi group (12.5%) (P <0.05) ([Table 3] and [Figure 6]).
Figure 6: CMV infection incidence is higher in HLAi group.
CMV: Cytomegalovirus, HLAi: Human leukocyte antigen incompatible.


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Incidence rate of BK polyomavirus infection (polymerase chain reaction: Viral load) on post transplant patients was 7% and 4.5% onHLAc and HLAi groups, respectively, with no statistical difference (P >0.05) [Table 3] and [Figure 7].
Figure 7: BK polyoma virus infection is not statistically different between the two groups.
HLAi: Human leukocyte antigen incompatible.


Click here to view



   Discussion Top


Analysis of the HLAi patients showed comparable incidence of ACR during the follow- up. Incidence of AMR was significantly higher in the HLAi group which can be explained by the presence of the DSAs in weak titers.

Graft survivals were comparable between the two groups. In fact, there was no patient or graft loss in the HLAi group during the period of follow-up. We cannot come up with a strong conclusion in terms of survival because it is a short-term follow-up study.

We found that no difference in the immediate postoperative course between the two groups. Regarding the SGF, no clear explanation was found for the higher incidence of SGF in theHLAc group although the incidence in both groups remains generally low as expected in living kidney transplant. There was no difference in the incidence of DGF.

The incidence of IF/TA was higher in the HLAi group although transplant glomerulo- pathy was not higher in this group. The finding of higher incidence of IF/TA with a comparable incidence of transplant glomerulopathy did not result in increased short-term graft loss in the HLAi group but may indicate a possibility of inferior long-term graft survival compared to HLAc group, so a long-term follow- up is needed to see if there are any implications on long-term graft survival.

The HLAi group received more intense immunosuppression posttransplant compared to HLAc group. We hypothesized that there is a possibility that this group of patient was more vulnerable to develop NODAT and infections due to increased exposure to immunosuppressive medications including steroids. In our study, we found the incidence of CMV infection to be significantly higher in the HLAi group, but the incidence of NODAT and BKV infection was comparable.


   Conclusion Top


Overcoming the HLA incompatibility barrier by desensitization protocol seems to be a good strategy in expanding the donor pool and to increase the number of kidney transplantations. Although the short-term graft and patient survival are comparable between the HLAi and HLAc renal transplant groups, and the fact that higher rates of rejection in the HLAi do not seem to be affecting the graft or patient survival in the short-term. Our study is limited by the fact that it is a retrospective study for a short-term follow-up. A long-term follow-up is needed to assess the long-term rejection rates and graft and patient survival.

Conflict of interest: None declared.

 
   References Top

1.
Abecassis M, Bartlett ST, Collins AJ, et al. Kidney transplantation as primary therapy for end-stage renal disease: A National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference. Clin J Am Soc Nephrol 2008;3:471-80.  Back to cited text no. 1
    
2.
Schnuelle P, Lorenz D, Trede M, Van Der Woude FJ. Impact of renal cadaveric transplantation on survival in end-stage renal failure: Evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 1998;9:2135-41.  Back to cited text no. 2
    
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Vacher-Coponat H, Purgus R, Indreies M, et al al. Cold ischemia time in renal transplantation is reduced by a timesheet in a French transplant center. Transplantation 2007;83:561-5.  Back to cited text no. 3
    
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Glotz D, Antoine C, Julia P, et al. Desensiti- zation and subsequent kidney transplantation of patients using intravenous immunoglobulins (IVIG). Am J Transplant 2002;2:758-60.  Back to cited text no. 4
    
5.
Tyan DB, Li VA, Czer A, Trento A, Jordan SC. Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histocompatible organ. Transplantation 1994; 57:553-62.  Back to cited text no. 5
    
6.
Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 2000;70:887-95.  Back to cited text no. 6
    
7.
Issa N, Cosio FG, Gloor JM, et al. Transplant glomerulopathy: Risk and prognosis related to anti-human leukocyte antigen class II antibody levels. Transplantation 2008;86:681-5.  Back to cited text no. 7
    
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Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med 2011; 365:318-26.  Back to cited text no. 8
    
9.
Nankivell BJ, Alexander SI. Rejection of the kidney allograft. N Engl J Med 2010;363: 1451-62.  Back to cited text no. 9
    
10.
Jordan SC, Toyoda M, Kahwaji J, Vo AA. Clinical aspects of intravenous immunoglo- bulin use in solid organ transplant recipients. Am J Transplant 2011;11:196-202.  Back to cited text no. 10
    
11.
Genberg H, Kumlien G, Wennberg L, Tyden G. The efficacy of antigen-specific immuno- adsorption and rebound of anti-A/B antibodies in ABO-incompatible kidney transplantation. Nephrol Dial Transplant 2011;26:2394-400.  Back to cited text no. 11
    
12.
Marfo K, Ling M, Bao Y, et al. Lack of effect in desensitization with intravenous immuno- globulin and rituximab in highly sensitized patients. Transplantation 2012;94:345-51.  Back to cited text no. 12
    
13.
Alachkar N, Lonze BE, Zachary AA, et al. Infusion of high-dose intravenous immuno- globulin fails to lower the strength of human leukocyte antigen antibodies in highly sensitized patients. Transplantation 2012;94:165-71.  Back to cited text no. 13
    
14.
Haririan A, Nogueira J, Kukuruga D, et al. Positive cross-match living donor kidney transplantation: Longer-term outcomes. Am J Transplant 2009;9:536-42.  Back to cited text no. 14
    
15.
Bentall A, Cornell LD, Gloor JM, et al. Five- year outcomes in living donor kidney transplants with a positive crossmatch. Am J Transplant 2013;13:76-85.  Back to cited text no. 15
    
16.
Gloor JM, Winters JL, Cornell LD, et al. Baseline donor-specific antibody levels and outcomes in positive crossmatch kidney transplantation. Am J Transplant 2010;10:582-9.  Back to cited text no. 16
    
17.
Orandi BJ, Garonzik-Wang JM, Massie AB, et al. Quantifying the risk of incompatible kidney transplantation: A multicenter study. Am J Transplant 2014;14:1573-80.  Back to cited text no. 17
    
18.
Orandi BJ, Luo X, Massie AB, et al. Survival benefit with kidney transplants from HLA- incompatible live donors. N Engl J Med 2016; 374:940-50.  Back to cited text no. 18
    

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Correspondence Address:
Abdulrahman Housawi
Multi-Organ Transplant Center, King Fahad Specialist Hospital, Dammam
Saudi Arabia
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DOI: 10.4103/1319-2442.206447

PMID: 28540885

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