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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 4  |  Page : 371-376

Allograft rejection in kidney transplantation – A retrospective study of impact on graft and patient outcome


Department of Nephrology, Nizams Institute of Medical Sciences, Hyderabad, Telangana, India

Date of Submission18-Sep-2021
Date of Acceptance02-Feb-2022
Date of Web Publication30-Dec-2022

Correspondence Address:
Dr. Raja Karthik
Department of Nephrology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_93_21

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  Abstract 


Background: Renal allograft rejection is a major cause of graft dysfunction, and it is a predictor of long-term allograft loss. Advances in immunosuppression have decreased the influence of acute rejection on graft survival. In this study, we assessed clinicopathological profile and immediate and long-term treatment outcomes of different types of allograft rejections in our institute. Materials and Methods: We retrospectively analyzed patients who underwent renal transplantation and had biopsy-proven renal allograft rejections from January 2010 to December 2019 in our institute. Recipient–donor characteristics at the time of transplantation and graft function post transplantation were documented. Patients were followed up till graft loss or patient loss or a minimum 12-month period after rejection episode for all survived patients. Results: Allograft rejection occurred in 88/424 (20.75%) renal transplant recipients during the study period. Active antibody-mediated rejection (ABMR) was the most common type of rejection (40.9%) and was common in early posttransplant period also (54.5%). Graft dysfunction was the dominant presentation in all groups except chronic active ABMR, where heavy proteinuria was common. Chronic active ABMR was common (37.5%) in second episode of rejection. Overall graft survival, death-censored graft survival, and patient survival at the end of the study were 52.27%, 82.95%, and 69.3%, respectively. Conclusion: Renal allograft rejection decreases both graft and patient survival. Hence recommend regular surveillance for early detection and treatment.

Keywords: Allograft rejection, antibody-mediated rejection, graft survival


How to cite this article:
Shamsudheen M P, Kuchay A, Gupta VC, Tiwari I, Karthik R, Das U, Guditi S, Taduri G. Allograft rejection in kidney transplantation – A retrospective study of impact on graft and patient outcome. Indian J Transplant 2022;16:371-6

How to cite this URL:
Shamsudheen M P, Kuchay A, Gupta VC, Tiwari I, Karthik R, Das U, Guditi S, Taduri G. Allograft rejection in kidney transplantation – A retrospective study of impact on graft and patient outcome. Indian J Transplant [serial online] 2022 [cited 2023 Feb 8];16:371-6. Available from: https://www.ijtonline.in/text.asp?2022/16/4/371/364629




  Introduction Top


Chronic kidney disease is an important contributor to morbidity and mortality from noncommunicable diseases, and is an important public health problem. Among different renal replacement therapies, kidney transplantation is currently the best clinical option for patients with end-stage renal disease because of the increased life expectancy and higher quality of life.[1] The most common complication of transplantation is allograft rejection, which in some cases leads to graft loss. Better immunosuppressive drugs and induction agents resulted in lower incidence of early rejections. Here, we have undertaken the analysis of clinicopathological profile and immediate and long-term treatment outcomes of different histological types of renal allograft rejections in our institute.


  Materials and Methods Top


This was a retrospective, observational study of patients who underwent renal transplantation (both live and deceased) and had biopsy-proven renal allograft rejections from January 2010 to December 2019 in our institute. Patients with lost follow-up and patients who underwent surgery and initial follow-up in another hospital were excluded. We also excluded chronic T-cell-mediated rejection (TCMR) as there was major disparity in biopsy reporting during the study period.

Baseline and follow-up data were collected from hospital records and through direct phone calls. Recipient and donor characteristics including age, gender, native kidney disease, dialysis vintage, mode of dialysis, donor relationship, induction agent used, human leukocyte antigens (HLA) mismatch (in live transplant), cold ischemia time, and graft function post transplantation were documented. Renal allograft rejections were classified by Banff criteria (2017) to active antibody-mediated rejection (ABMR), chronic active ABMR, acute TCMR, borderline, and combined rejection. Immediate treatment outcome was described as either complete/partial response or no response. Patients were followed up prospectively to assess long-term outcomes such as stable graft with normal or abnormal function, graft loss, and patient loss. All patients were followed till graft loss or patient loss or a minimum 12-month period after rejection episode for all survived patients.

Patients were categorised into groups like responders (complete and partial) or non-responders, early (<6 months posttransplant) or late (>6 months) rejection and compared each other.

We performed HLA typing for all live transplant recipients and donors. Complement dependent cytotoxicity (CDC) crossmatch was done for all patients, and donor specific antibody (DSA by Flow Cross Match technique, reported in medial channel shift) was done only in live transplantation (from 2018). For patients with antibody-mediated rejection, DSA was done at the time of rejection episode, if financial status permitted. Howeever, DSA by single-antigen bead was not performed in these patients due to financial reasons.

Immunosuppressive regimens

All patients received three consecutive doses of 1 g intravenous methylprednisolone (IVMP) and maintenance triple immunosuppression with tacrolimus (0.1 mg/kg/day and if induction was given at 0.08 mg/kg/day), mycophenolate mofetil (600 mg/m2/dose twice a day), and prednisolone 20 mg a day. Tacrolimus dose was tapered according to serum drug levels which were monitored on a monthly basis for the first 6 months and as and when required subsequently. Dose of steroid was tapered from 20 mg/day to 5 mg/day at the end of 6 months and continued thereafter. Induction therapy was given in spousal and deceased donor transplantation with either basiliximab (20 mg in two doses on day 0 and day 4) or antithymocyte globulin (ATG) (2–3 mg/kg).

Rejection was treated with three doses of 0.5–1 g IVMP and escalation of baseline immunosuppression. Steroid-resistant ABMR was treated with five sessions of plasmapheresis, high-dose intravenous immunoglobulin (IVIG) (1–2 g/kg), and/or rituximab (375 mg/m2). In steroid-resistant cellular rejection, ATG for 3–5 days at 1 mg/kg/day was given.

Definition of terms used

  • Complete response – Return of posttreatment serum creatinine or proteinuria to <25% of baseline value within 2 weeks of therapy
  • Partial response – If creatinine or proteinuria was >25% to <75% of baseline within 2-week therapy
  • No response – If creatinine or proteinuria was >75% of baseline or worsening post rejection therapy
  • Stable graft with normal function – Maintains stable baseline serum creatinine or proteinuria
  • Stable graft with some dysfunction – Maintains stable graft function but with some loss of function
  • Graft loss – Irreversible graft dysfunction which leads to initiation of maintenance renal replacement therapy.


Graft survival was calculated from the date of transplantation to the date of graft loss and patient survival was calculated from the date of transplantation to the date of death. Death-censored graft survival illustrates the rate of success in terms of graft survival, and it assumes that all deaths are associated primarily with causes other than the transplantation.

Statistical analysis

All quantitative variables were expressed as mean ± standard deviation and all categorical variables were summarized as percentages. For comparison of clinical and pathological features of patients, Student's t-test, ANOVA, and Chi-square test were used. Kaplan–Meier curves were used to analyze the graft and patient survival. Statistical significance was considered if P < 0.05.

Declaration of patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

The study was carried out in accordance with the Declaration of Helsinki and international Council for harmonization-Good Clinical practice. The study was approved by the NIMS institutional ethics committee (NIEC, EC/NIMS/2545/2020, 31/08/2020).


  Results Top


Over the study period, 88/424 (20.75%) transplant recipients had biopsy-proven rejection and hence included in the analysis [Figure 1]. The mean age of recipients at the time of transplantation was 30.43 ± 9.03 years, and majority (87.5%, n = 77) of patients were <40 years. Majority (77.3%, n = 68) were males and were on hemodialysis (93.2%). Although there are hypotheses that higher the dialysis exposure prior to transplantation, more the rate of acute rejection due to modulation of immune system, 62.5% (n = 55) of our patients were with dialysis vintage of <1 year.
Figure 1: Flow diagram of the study

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The mean donor age was 40.8 ± 11.1 years. Among live donors, 69.4% (n = 43/62) were in >40 years' age group (only 3 donors in >60 years), whereas among deceased donors, 69.2% (n = 18/26) were in 20–40 years' age group and 26.9% (n = 7/26) were in >40 years' age group. Majority of kidney donors were females (77.4%) in live donors, and males (80.8%) in deceased donors. Among the live donors, 48.4% (n = 30) were mothers and 25.8% (n = 16) wives. All deceased kidney donors (n = 26, 29.5%) met standard criteria of donation. HLA matching in live transplantation revealed haplomatch in 58.1% (n = 36) and nil match in 17.7% (n = 11). The mean donor estimated glomerular filtration rate was 90.72 ± 23.18 ml/min.

Despite high mean cold ischemia time (439 ± 198.04 min versus 61 ± 2.5 min) and mean dialysis vintage (39.3 ± 14.06 months versus 6.5 ± 6.8 months) in deceased donation compared to live donation, respectively, graft rejection incidence was comparable (21.8%, n = 26/119 versus 20.3%, n = 62/305). Among the recipients where used induction therapy, 97.7% (n = 43) received basiliximab and only 2.3% (n = 1) received ATG. Only 28.4% (n = 25) of patients with rejection had either delayed or slow graft function (DGF or SGF). Noncompliance to treatment was observed only in 6.8% of cases, but reduction or modification of immunosuppression was done in 34.1% of cases just prior to rejection. One patient had his second transplant and 45.5% (n = 40) of recipients received blood transfusion prior to transplantation.

Prior to rejection episodes, 13 (14.8%) had drug toxicity. CNI toxicities observed in 9.1% patients were graft dysfunction (biopsy proven) and tremor. Common mycophenolate mofetil-induced side effects (in 5.7% patients) included cytopenias and diarrhea. Urinary tract infection (14.8%) and pneumonia (13.6%) were common infections seen in our patients prior to rejection episode.

In our study, 62.5% (n = 55/88) of patients had first episode of rejection within 1 year post renal transplantation. The mean time of first rejection episode was 14.2 ± 20.5 months.

Active ABMR and acute TCMR were more common as early rejection as compared to other types with significant P < 0.001. In early posttransplant period, predominant type of rejection was active ABMR (54.5%, n = 24/44). Majority of chronic active ABMRs presented after 1 year compared to other groups (P < 0.001). There was a significant difference in mean hemoglobin between different types of rejection. We observed that active ABMR had the lowest mean hemoglobin compared to other groups (P = 0.007). Graft dysfunction was the most common presentation in all groups except chronic active ABMR, where proteinuria was common (P < 0.001). Among 17 patients where DSA was performed at the time of rejection, 5/6 patients with chronic active ABMR were positive against either HLA 1 or II (3 positive for both, 1 for each), compared to other rejection groups where all were negative for DSA [Table 1].
Table 1: Profile of different histological types of rejection (first episode)

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Analysis of second episode of rejection

Twenty-four out of 88 (27.3%) patients included in analysis had second episode of rejection during the study period. The most common type of rejection in second episode was chronic active ABMR (37.5%, n = 9). The mean time duration for developing second episode of rejection after first episode was 20.5 ± 25.8 months (in deceased transplant recipients, second episode developed earlier compared to live recipients; 7.3 ± 5.4 months versus 25.9 ± 28.9 months).

Analysis of treatment outcomes in allograft rejection

Compared to other rejection types, 61.1% of patients with active ABMR and 38.9% of acute TCMR achieved complete remission immediate to rejection therapy (P = 0.004). However, in terms of long-term outcome, no significance difference noticed between rejection types at the end of study [Table 2]. No patients attained complete remission after treatment of second episode of rejection; 14/24 (58.3%) patients achieved partial remission and 10/24 (41.7%) not responded to any therapy.
Table 2: Immediate and long-term outcome in different types of rejection

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Majority of patients (61.4%, n = 27) with early rejection attained complete response after antirejection therapy compared to late rejection (P ≤ 0.001), though there were no significant difference in long-term outcome at the end of study period. The comparison between responders/nonresponders is depicted in [Table 3].
Table 3: Comparison of responders and nonresponders to immediate rejection therapy

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The mean duration for graft loss after rejection episode was 8.5 ± 12.3 months and for patient loss was 6.3 ± 7.2 months. Sepsis was the common cause of death, and 8/27 (29.6%) patients expired with functioning graft.

Estimated graft survival time was more in borderline rejection (89.1 ± 16.8 months), whereas estimated patient survival time was more in antibody-mediated rejection (96.95 ± 8.3 months) [Table 4] and [Figure 2] and [Figure 3].
Table 4: Survival analysis

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Figure 2: Graph showing graft survival among different types of rejection

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Figure 3: Graph showing patient survival among different types of rejection

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  Discussion Top


Renal allograft rejection is an expected complication in transplantation, and it significantly affect long-term graft and patient survival.[2] After introduction of modern immunosuppressive agents, 1-year kidney graft survival has improved dramatically, but the longevity of the graft has not changed much.[3] Hence, standards of care protocols recommend regular surveillance by checking creatinine, urine proteinuria, and/or by routine biopsy at regular posttransplant intervals.[4]

In a study reported by K L Gupta et al. on renal transplant outcomes over 8 months, observed 26.2% had graft rejection and among that 14.8% were with antibody mediated rejection, 4.1% with T-cell-mediated rejection and 7.4% with combined rejection, which is higher than the incidences in our centre.[5] As per the Organ Procurement and Transplantation Network data, the incidence of one episode of acute rejection over 5 years (between 2005 and 2009) was approximately 17% for living donor kidneys and 20% for deceased donor kidneys, whereas in our study (over 10 years), it was 20.3% and 21.8%, respectively.[6]

Donor age >45 years, recipient age <40 years, number of acute rejection episodes, and re-transplantation are potential risk factors of chronic rejection and also observed use of old donors (>45 years), as a response to organ shortage is detrimental for long-term renal function.[3] In our study, 87.5% of recipients were <40 years and 56.8% of donors were >40 years of age.

A disproportionately greater number of female donors have been observed in live donor programs in most countries.[7] The reason is unclear although differences in medical and psychosocial factors may be contributing.[8],[9] Female donors are associated with a greater risk of rejection and poorer posttransplant graft function,[10] which may be attributed to “inadequate” nephron mass with subsequent hyperfiltration injury.[11] In our cohort with rejection patients, donors were mainly females and recipients were males.

Long dialysis vintage period leads to an increase in T-cell alloimmunity, which may contribute to the inferior outcomes in this population with a longer dialysis vintage. But here 62.3% of our patients were with dialysis vintage of <1 year.

Cold ischemia triggers a cascade of noxious effects, which are amplified by restoration of blood supply. This generates inflammatory and immune response that may result in delayed graft function and enhanced alloimmune reactivity. The mean cold ischemia time in our study was comparable to other Indian studies where CIT was around 6–8 h. In a systematic review published by Juan C Scornik et al., suggested avoiding blood transfusions whenever possible could prevent detrimental effects due to allosensitization like increased rejection and graft loss.[12]

In a retrospective analysis by Luis M Pallardó Mateu et al., patients with delayed graft function and induction therapy with antilymphocyte globulin were associated with lower incidence of acute rejection.[13] In our data, basiliximab was used as an induction agent in 97.7% of cases.

Patients with chronic rejection may have more episodes of infections prior to rejection, especially UTI as compared to those without rejection.[14] Patients who develop rejection are subjected to increased dosage of immunosuppression which may predispose to increased risk of developing infections.[15]

Clayton et al. analysed Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data between 1997 and 2017, they observed cellular rejection (without vascular component) was more common (55%).[16] In our study, active ABMR was most common type of rejection in early posttransplant period.

Chronic active ABMR, commonly accompanied by transplant glomerulopathy, is often characterized by heavy proteinuria. In Nishika et al. study, the mean 24-h proteinuria at the time of biopsy was 3.4 ± 0.9 g.[17] In our study also, chronic active ABMR patients have heavy proteinuria than graft dysfunction. Treatment options are limited, and a single-center study observed minimal benefit in response to therapies that included plasmapheresis, IVIG, rituximab, and bortezomib.[18]

In a retrospective study, where they analysed outcomes of humoral rejection, concluded that when diagnosed early and treated aggressively with plasma exchange and IVIG, carries a 'better' short term prognosis that is similar to acute cellular rejection.[19] In our analysis also, both active ABMR and TCMR have better immediate outcome to rejection therapy. Late acute rejection had a negative impact on long-term renal allograft survival, and it is a risk factor for chronic graft dysfunction.[20] There was no significant difference in long-term outcome between early and late rejections in our study, though there was a better immediate outcome in early rejection. Koo et al. had similar observation, regardless of its timing acute rejection significantly worsened graft survival.[21]

Clayton et al. observed 14.7% graft losses and 17.1% deaths. Overall patient survival was lower in those with acute rejection, largely attributable to an excess of deaths from cardiovascular disease or cancer.[16]

Limitation

It is single center study. Multicentric studies from other centres may help validate the results.


  Conclusion Top


Active ABMR was the most common histological type of rejection and was common in early posttransplant period also. Early rejection showed better immediate response, though there was no significant difference in long-term outcomes. Single episode of rejection reduced both allograft and patient survival. Hence, regular surveillance is required for early detection and immediate treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Rambod M, Shabani M, Shokrpour N, Rafii F, Mohammadalliha J. Quality of life of hemodialysis and renal transplantation patients. Health Care Manager 2011;30:23-8.  Back to cited text no. 1
    
2.
Wu J, Chen J, Wang Y, Zhang J, Zhu Z, Shou Z, et al. Impact of acute rejection episodes on long-term renal allograft survival. Chin Med J (Engl) 2003;116:1741-5.  Back to cited text no. 2
    
3.
Delmas S, Picot MC, Vergnes C, Cristol JP, Mourad G. Facteurs de risque de rejet chronique en transplantation rénale, résultats d'une étude monocentrique. Nephrologie 1999;20:153-8.  Back to cited text no. 3
    
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National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-266.  Back to cited text no. 4
    
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Gupta KL, Pattanashetti N, Ramachandran R, Nada R, Aggarwal R, Sharma A. Renal transplant and its outcomes: Single-center experience from India. Exp Clin Transplant 2019;17:78-82.  Back to cited text no. 5
    
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Available from: http://srtr.transplant.hrsa.gov/annual_reports/2011/default.aspx. [Last accessed on 2013 May 17].  Back to cited text no. 6
    
7.
Kayler LK, Meier-Kriesche HU, Punch JD, Campbell DA Jr., Leichtman AB, Magee JC, et al. Gender imbalance in living donor renal transplantation. Transplantation 2002;73:248-52.  Back to cited text no. 7
    
8.
Bloembergen WE, Port FK, Mauger EA, Briggs JP, Leichtman AB. Gender discrepancies in living related renal transplant donors and recipients. J Am Soc Nephrol 1996;7:1139-44.  Back to cited text no. 8
    
9.
Schaubel DE, Stewart DE, Morrison HI, Zimmerman DL, Cameron JI, Jeffery JJ, et al. Sex inequality in kidney transplantation rates. Arch Intern Med 2000;160:2349-54.  Back to cited text no. 9
    
10.
Øien CM, Reisaeter AV, Leivestad T, Pfeffer P, Fauchald P, Os I. Gender imbalance among donors in living kidney transplantation: The Norwegian experience. Nephrol Dial Transplant 2005;20:783-9.  Back to cited text no. 10
    
11.
Brenner BM, Cohen RA, Milford EL. In renal transplantation, one size may not fit all. J Am Soc Nephrol 1992;3:162-9.  Back to cited text no. 11
    
12.
Scornik JC, Bromberg JS, Norman DJ, Bhanderi M, Gitlin M, Petersen J. An update on the impact of pre-transplant transfusions and allosensitization on time to renal transplant and on allograft survival. BMC Nephrol 2013;14:217.  Back to cited text no. 12
    
13.
Pallardó Mateu LM, Sancho Calabuig A, Capdevila Plaza L, Franco Esteve A. Acute rejection and late renal transplant failure: Risk factors and prognosis. Nephrol Dial Transplant 2004;19 Suppl 3:i38-42.  Back to cited text no. 13
    
14.
Moradi M, Abbasi M, Moradi A, Boskabadi A, Jalali A. Effect of antibiotic therapy on asymptomatic bacteriuria in kidney transplant recipients. Urol J 2005;2:32-5.  Back to cited text no. 14
    
15.
Mohan MV, Neeraja M, Sudhaharan S, Raju SB, Gangadhar T, Lakshmi V. Risk factors for urinary tract infections in renal allograft recipients: Experience of a tertiary care center in Hyderabad, South India. Indian J Nephrol 2017;27:372-6.  Back to cited text no. 15
[PUBMED]  [Full text]  
16.
Clayton PA, McDonald SP, Russ GR, Chadban SJ. Long-term outcomes after acute rejection in kidney transplant recipients: An ANZDATA analysis. J Am Soc Nephrol 2019;30:1697-707.  Back to cited text no. 16
    
17.
Madireddy N, Uppin M, Guditi S, Taduri G, Raju S. Chronic antibody rejection in renal allograft: An underestimated cause of renal allograft dysfunction. Indian J Transplant 2019;13:9.  Back to cited text no. 17
  [Full text]  
18.
Gupta G, Abu Jawdeh BG, Racusen LC, Bhasin B, Arend LJ, Trollinger B, et al. Late antibody-mediated rejection in renal allografts: Outcome after conventional and novel therapies. Transplantation 2014;97:1240-6.  Back to cited text no. 18
    
19.
Rocha PN, Butterly DW, Greenberg A, Reddan DN, Tuttle-Newhall J, Collins BH, et al. Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. Transplantation 2003;75:1490-5.  Back to cited text no. 19
    
20.
Jalalzadeh M, Mousavinasab N, Peyrovi S, Ghadiani MH. The impact of acute rejection in kidney transplantation on long-term allograft and patient outcome. Nephrourol Mon 2015;7:e24439.  Back to cited text no. 20
    
21.
Koo EH, Jang HR, Lee JE, Park JB, Kim SJ, Kim DJ, et al. The impact of early and late acute rejection on graft survival in renal transplantation. Kidney Res Clin Pract 2015;34:160-4.  Back to cited text no. 21
    


    Figures

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