Objectives: Kidney transplant is the treatment of choice for patients with end-stage renal disease. Antibody-mediated rejection is associated with higher rates of graft loss in kidney transplant recipients. Determining the risk factors of antibody-mediated rejection is vital for its prevention, early diagnosis, and appropriate treatment, as these factors may be important in maintaining long-term graft survival in transplant recipients. In our study, we analyzed the risk factors of antibody-mediated rejection in kidney transplant recipients and the negative impact of antibody-mediated rejection on graft function.
Materials and Methods: We analyzed demographic and clinical data of 124 kidney transplant recipients (37 female [30%] and 87 male [70%] patients) who were diagnosed with antibody-mediated rejection at transplant biopsy. We compared graft outcomes of this patient cohort versus 75 kidney transplant recipients (24 female [32%] and 51 male [68%] patients) who were not diagnosed with antibody-mediated rejection.
Results: Mean ages of patients with and without antibody-mediated rejection were 38.2 ± 13.6 and 34.4 ± 13.0 years, respectively. Mean ages of donors for patients with antibody-mediated rejection was significantly higher (48.0 ± 13.2 y) than for donors of patients without antibody-mediated rejection (47.1 ± 11.4 y; P < .05). Rate of graft loss was 15.3% in patients with antibody-mediated rejection; patients without antibody-mediated rejection had no graft loss (P < .05). Positive panel reactive antibody levels and blood transfusion before transplant were found to be risk factors of antibody-mediated rejection in kidney transplant recipients. However, recipients who received tacrolimus had less antibody-mediated rejection episodes than recipients who received sirolimus or cyclophosphamide.
Conclusions: Antibody-mediated rejection is associated with high rates of graft loss in kidney transplant recipients. Avoiding blood transfusion, lowering panel reactive antibody levels, choosing younger donors, and using tacrolimus in high-risk kidney transplant recipients may reduce antibody-mediated rejection rates and provide better graft survival.
Key words : Early diagnosis, Graft survival, Prevention, Renal transplant
Kidney transplant (KT) is considered to be the best treatment option for patients with end-stage renal disease as it can lead to better quality of life and higher rate of survival.1,2 However, allograft rejection remains a major barrier for the longevity of renal graft survival.3 Antibody-mediated rejection (AMR) is a complex and a multifactorial process that involves the activation of anti-HLA/anti non-HLA antibodies that result in complement-dependent cytotoxicity.4-6 Banff classification describes AMR according to the histologic evidence of acute tissue injury, current/recent antibody interactions with vascular endothelium, and detection of donor-specific antibodies (DSAs).7 Antibody-mediated rejection has been well-differentiated from acute cellular rejection (ACR); graft survival rates for AMR are significantly inferior compared with rates for ACR.8,9 In our study, we aimed to determine the risk factors of AMR for prevention, early diagnosis, and appropriate treatment of AMR; determining these factors is vital to maintenance of long-term graft survival.
Materials and Methods
Our study included 124 KT recipients (37 female [29.8%] and 87 male [70.2%]) who underwent KT between 2006 and 2018. Recipients who were diagnosed with AMR on kidney allograft biopsy (AMR group) were evaluated demographically and clinically. Patients in the AMR group who had concomitant acute cellular rejection (AMR + ACR patients; n = 51) were also evaluated. We also compared graft outcomes of 124 AMR patients versus 75 KT recipients (24 female [32%] and 51 male [68%]) who had no diagnosis of AMR on transplant biopsy (non-AMR group).
The standard immunosuppressive treatment in our center consisted of a calcineurin inhibitor or a mammalian target of rapamycin inhibitor, prednisolone, and mycophenolate mofetil.
Continuous variables are expressed as mean ± standard deviation. To evaluate differences between mean values, we used t tests. Chi-square test was used for categorical variables, and P ≤ .05 was accepted as significant. The major statistics were calculated on a computer using SPSS version 20.0 software (Statistical Package for the Social Sciences, Inc., Chicago, IL, USA).
Mean age in the AMR group was 38.2 ± 13.6 years, and mean age in the non-AMR group was 34.4 ± 13.0 years. The mean age of donors for the AMR group (48.0 ± 13.2 y) was significantly higher than mean age of donors (47.1 ± 11.4 y) for the non-AMR group (P < .05). Sex distribution in the AMR group was 87 men (70%) and 47 women (30%), with distribution in the non-AMR group of 51 men and 24 women (68% and 32%, respectively). The mean duration after KT was 47 months in the AMR group and 65 months in the non-AMR group. Importantly, the AMR group had significantly higher rates of blood product transfusion before KT than the non-AMR group (67.4% vs 32.6%, respectively; P < .05). The demographic findings of patients are summarized in Table 1.
When we compared KT recipients according to the immunosuppressive regimens, patients who received tacrolimus had lower AMR episodes than KT recipients who received sirolimus or cyclophosphamide. The prior KT rates of the 2 groups were not significantly different (8% vs 7.3%, respectively). However, KT recipients who were panel reactive antibody (PRA) positive (5%) had an AMR episode and were included in the AMR group. Some patients in the AMR group had a concomitant diagnosis of ACR on transplant biopsy. When we compared the histologic findings of patients with AMR only versus the AMR + ACR group, focal, diffuse, and circular C4d staining results on biopsies were not significantly different. However, significantly higher fibrosis index rates were shown in patients in the AMR + ACR group versus the AMR-only group (39.2% vs 15.2%, respectively; P < .05). Fibrosis index and percentage of C4d staining were not independent risk factors for graft loss in the AMR group. In addition, diffuse staining of C4d was associated with graft loss rate of 47.2% compared with graft loss rate of 21.1% with focal staining and graft loss rate of 31.6% with circular staining (P < .05). Creatinine levels of patients at the time of graft kidney biopsy were significantly higher (3.7 ± 1.7 mg/dL) in patients who experienced a graft loss compared with patients without graft loss (2.2 ± 0.9 mg/dL; P < .05).
Patients in the AMR group experienced 15.3% rate of graft loss, whereas there was no graft loss in the non-AMR group (P < .05). Positive PRA levels and blood transfusion before KT were found to be risk factors of AMR in KT recipients.
Antibody-mediated rejection is a primary factor for graft loss in KT recipients. De novo DSAs also contribute to chronic AMR. Despite intensive conventional immunosuppressive therapies, rates of graft loss because of AMR remain at 15% to 50%.5-7,10 According to Banff classification, AMR is a morphologic, immunologic, and serologic diagnosis that results from an antibody-induced inflammation. Detection of DSAs and C4d staining are pathognomonic findings of AMR.7
In our study, we found no differences in men versus women with regard to AMR diagnosis; however, some studies have found female sex to be an independent risk factor for AMR.11,12 One reason for our different finding could be the unequal distribution of men versus women in our KT population.
Donor biologic sex was not found to be an important factor in development of AMR in our study; however, higher donor age was an independent risk factor for AMR. The older allograft kidneys may be more prone to antibody exposure with higher tendency of inflammatory processes such as atherosclerosis. Aging of the kidney may be a contributing factor for AMR that should be further investigated.
Patients in the AMR group had significantly higher rates of blood product transfusion before KT than patients in the non-AMR group (67.4% vs 32.6%, respectively; P < .05), which is similar to recent literature findings. Even 2 to 3 mL of leukocytes may trigger sensitization in KT recipients.13 Blood product transfusion should be avoided in KT candidates unless necessary.
Our findings showed that KT recipients who are on tacrolimus therapy had lower rates of AMR. This is also comparable to findings in the literature showing lowered DSA levels with tacrolimus therapy combined with mycophenolate.14-16 Tacrolimus doses should be cautiously lowered in the follow-up period after KT.
In our study, fibrosis index rates were significantly higher in patients in the AMR + ACR group compared with patients with AMR only (39.2% vs 15.2%, respectively; P < .05). Fibrosis index is a major sign of chronicity in all tissues and in allografts, and higher fibrosis index was shown to be associated with inferior graft survival in our patient group, which is similar to previous findings.14-17
Creatinine levels in patients at the time of graft kidney biopsy were significantly higher (3.7 ± 1.7 mg/dL) in those who experienced graft loss than in those who did not have graft loss (2.2 ± 0.9 mg/dL; P < .05). This may be because of a late referral of a patient to the transplant unit for allograft biopsy and may also be a feature of the destructive process of AMR with concomitant loss of kidney function.5-8 The monitoring of patients at the outpatient clinic is a vital part of KT, as it may provide early diagnosis and effective management of AMR in especially high-risk KT recipients.
Antibody-mediated rejection is associated with high rates of graft loss in KT recipients. Avoiding blood product transfusions, lowering PRA levels, the use of younger donors, and using tacrolimus in high-risk KT recipients may reduce AMR rates and provide better graft survival.
Volume : 18
Issue : 1
Pages : 29 - 31
DOI : 10.6002/ect.TOND-TDTD2019.O1
From the 1Department of Internal Medicine, 2Department of Nephrology, and the
3Department of General Surgery, Baskent University Faculty of Medicine, Ankara,
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Burak Sayin, Fevzi Cakmak, Mah. 5. Sokak, No:48,06490, Bahcelievler/Cankaya/Ankara, Turkey
Phone: +90 312 2036868(5226)
Table 1. Demographics