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Year : 2018  |  Volume : 12  |  Issue : 1  |  Page : 48-52

Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center

1 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Nephrology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

Date of Web Publication29-Mar-2018

Correspondence Address:
Dr. Megha S Uppin
Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_65_17

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Introduction: Late acute rejection (LAR) is different from early acute rejection with respect to risk factors, management, and prognosis. The long-term graft survival has been shown to be adverse after LAR. Materials and Methods: This was a prospective study including 15 biopsies reported as LAR in 12 patients. The clinical details, transplant duration, risk factors, biopsy findings, antirejection treatment, and outcome are studied. Results: The risk factors for developing LAR in our study included delayed graft function, associated infections, and noncompliance. Majority were combined cellular and antibody mediated. Antibody-mediated rejection (ABMR) component was identified in 13 biopsies. Plasma cell-rich form was seen in four biopsies. Most of the patients had persistent graft dysfunction with five of them going into graft loss. Conclusion: It is important to identify LAR, especially late ABMRs. They are different from chronic rejections. The graft outcome was found to be poor.

Keywords: Allograft biopsy, C4d, graft loss, late acute rejection

How to cite this article:
Kunchala R, Gudipati A, Guditi S, Taduri G, Raju SB, Uppin MS. Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center. Indian J Transplant 2018;12:48-52

How to cite this URL:
Kunchala R, Gudipati A, Guditi S, Taduri G, Raju SB, Uppin MS. Late acute rejection in renal allografts: Clinical, pathologic, and follow-up data from a single tertiary care center. Indian J Transplant [serial online] 2018 [cited 2019 Jul 21];12:48-52. Available from: http://www.ijtonline.in/text.asp?2018/12/1/48/228931

  Introduction Top

Acute rejection of the transplanted kidney is a serious problem which is responsible for immediate graft dysfunction. Rejection is classified as T-cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) based on the underlying immunologic mechanism and as acute or chronic based on the rapidity of progression of the rejection process.[1] Acute rejection usually manifests early while chronic rejection manifests later. However, an acute rejection episode need not necessarily be an early episode posttransplant as it usually happens. An acute rejection process that manifests later in the posttransplant period is termed as late acute rejection (LAR). There is no uniform consensus regarding the point of time to divide rejection episodes into early versus late. Different authors have used different reference times for this purpose.[2],[3],[4],[5],[6] Nevertheless, it is important to recognize LAR since not only the clinical management but also the prognosis is different for acute and chronic rejections.

LAR in most of the cases is antibody mediated. Pure TCMR accounts for only a minority of LAR cases.[7],[8]De novo appearing donor-specific antibodies (DSAs) are believed to be responsible for the former.[9] The risk factors for their development include infections, noncompliance to therapy, de-escalation of immunosuppression and earlier rejection episodes.[10],[11],[12],[13] Irrespective of the underlying cause, Class 1 major histocompatibility complex (MHC) molecules are presented on the surface of the graft by the indirect pathway which induce antibody production in the host. On the other hand, early acute rejection (EAR) is believed to be caused by preformed DSA, and the rejection is mediated by Class 2 MHC (direct pathway).[5],[14],[15] This difference in underlying pathophysiology is responsible for the different response of EAR and LAR to therapy.[16] LAR has also been reported to have an adverse effect on the long-term graft survival.[17],[18],[19],[20],[21],[22] Since either the timing or the clinical or biochemical parameters cannot sufficiently determine the exact nature of rejection, allograft biopsy examination is mandatory to establish the diagnosis. The Banff system has formulated a schema for nomenclature and classification of renal allograft pathology to enable uniformity in reporting.[23] In the present study, we tried to review the renal biopsies reported as LAR and analyze these with respect to the presenting features, risk factors, morphologic features, and outcome.

  Materials and Methods Top

This was a prospective study of 9 months (September 2016–June 2017) wherein we analyzed the allograft biopsies which were typed according to the Banff classification schema 2013. The study was approved by the institutional ethics committee. Total allograft biopsies analyzed during this period were 137 of which 25 were classified as acute rejections. Of these, 10 were EAR and 15 were LAR.

Inclusion criteria

Biopsy-proven cases of acute rejection presenting later than 6-month posttransplant were included in the study.

Exclusion criteria

EARs or any other type of allograft pathology was excluded from the study.

All the biopsies were examined by light microscopy (LM), immunofluorescence (IF), and immunohistochemistry with C4d (cat no. AR 572-5R, Biogenex) was done in all. The LM analysis was performed with the help of hematoxylin and eosin, periodic acid–Schiff, Masson trichrome, and silver methenamine. The biopsies were classified by Banff classification criteria 2013.[23] Activity scores and tubulointerstitial chronicity were given for all the biopsies.[23]

DSAs are evaluated by luminescence assay. Medical records were verified for clinical information with respect to the native kidney disease, type of graft, duration of transplant, type of immunosuppression used, predisposing factors, and baseline biochemical parameters. Serum creatinine levels were noted at the time of biopsy as well as at follow-up. The follow-up was obtained for all the patients.

Institutional protocol for immunosuppression and posttransplant follow-up

The patients receive triple immunosuppression including steroids (20 mg/day tapered to 10 mg/day after 6 months), tacrolimus (0.08 mg–0.1 mg/kg), and mycophenolate mofetil (MMF) (600 mg/m 2). The tacrolimus levels are periodically monitored and maintained between 10 and 12 for first 2 months, 8–10 for next 3 months, and 6–8 for subsequent 6 months. Spousal and cadaver transplants receive an additional induction with interleukin-2 receptor blocker (basiliximab) 20 mg on day 0 and day 4.

The follow-up schedule of patients is alternate day for first 2 months, twice a week for next 2 months, and once a week for subsequent 2 months. At every visit, the routine hemogram, serum urea, and serum creatinine levels are checked. Apart from this, every month, all the baseline parameters including viral titers, liver function tests, and renal function tests are monitored.

All allograft biopsies at our institute are essentially indicated biopsies and protocol biopsies are not followed. Biopsy is performed at any episode of graft dysfunction.

Follow-up criteria

Graft loss

This is defined as complete graft dysfunction or markedly elevated creatinine or dialysis dependence.

Persistent graft dysfunction

Patients having uremic symptoms or baseline creatinine more than 1.7 mg/dl.

Normal graft function

Absence of uremic symptoms and Serum creatinine of <1.5 mg/dl.

Statistical analysis

Statistical significance was calculated for long-term graft survival between EAR and LAR. The frequency of each category of renal disease was computed. All continuous parameters were expressed as mean and all qualitative variables as proportion. Chi-square test was used to compare graft function between EAR and LAR. Statistical analysis was done using Graph Pad Prism version 7 (La Jolla, CA, USA).

  Results Top

The median age of these 15 patients with LAR was 35 years with a range of 18–46 years. There was a male predominance with male: female ratio of 2:1 (10:5). Eleven of these were live related and only one was cadaver transplant. The details are shown in [Chart 1]. [Chart 2] depicts the posttransplant duration of all the patients and most were seen between 12 and 24 months of posttransplant duration.

The complete clinical details, biopsy findings, and outcome data of all the patients are depicted in [Table 1]. Of the 12 patients, 10 had associated features such as delayed graft function (DGF), noncompliance, infections, earlier rejection episodes, and tapering of immunosuppression. The subtype of rejection was cellular (acute cellular rejection [ACR], n = 1) including one of borderline cellular, isolated antibody mediated rejection (ABMR, n = 6) and combined ABMR + ACR (n = 7). Plasma cell-rich rejection was identified in four biopsies of which three were C4d positive. C4d was positive in all biopsies showing ABMR. Chronicity was seen in only two cases; both were only focal. DSAs were positive in 8 of the 12 patients.
Table 1: The entire clinicopathologic and follow-up details of all the patients

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Treatment and follow-up

Patients with ACR were treated with injection methylprednisolone and/or intravenous immunoglobulin (IVIG) whereas those with ABMR were treated with injection methylprednisolone, plasmapheresis, rituximab, and/or bortezomib and IVIG. Follow-up was available in ten patients. Majority had graft loss (n = 6) with one mortality. Four had persistent graft dysfunction with a creatinine of >2 mg/dl. The normal graft function posttreatment was achieved in only one patient. When the graft function was analyzed with respect to the type of rejection, it did not show statistical significance.

Statistical analysis

Applying Chi-square test showed statistical significance (P = 0.003) between EAR and LAR with respect to graft survival [Chart 3] and response to treatment which indicates that there is an association between the graft performance and the duration of acute rejection.

  Discussion Top

Acute rejection remains a potential threat to renal allografts in the early posttransplant period. With the advent of tacrolimus and MMF, the incidence of EAR in the 1st year of transplant has significantly dropped.[3] Even an overt rejection episode can be tackled with effective antirejection majors. However, the injury incited by any rejection episode stimulates tubulointerstitial chronicity which prevents long-term graft survival. Although the short-term graft survival has been taken care of, the incidence of LAR has not changed significantly.[24],[25] In this article, we have tried to put forth the risk factors, morphology, and prognosis of 15 biopsies of LAR that were reported in a short study period of 9 months.

Various authors have tried to study the factors influencing LAR. Eid et al. in their study of 23 patients of LAR observed that DGF and de novo DSA were associated with LAR. Ten of the 23 patients had DGF in their study.[3] DGF is responsible for EAR. However, its role in LAR has not been explained completely. Two of our patients had documented DGF where the induction protocol was intensified. The development of de novo DSA in the 1st year of transplant is another responsible factor.[9] However, DSAs are not regularly monitored at our institute, and we could not study this factor.

Noncompliance is an issue for long-term immunosuppressive protocol. It has been reported as major contributor to LAR in many series.[3],[4],[5],[8],[10],[11],[12],[13] Self-nonadherence to drugs and financial problems are the main reasons for noncompliance in Indian patients. Unfortunately, there are no standard guidelines for reassuring continuous drug adherence. Most of the acute rejections in patients with noncompliance are reported to be antibody mediated.[26] Seventeen percent of patients of late ABMRs had documented nonadherence to drugs in the study by Gupta et al.[27]

We have also done detailed analysis of the type of rejections as per the biopsy features. The ABMR was the dominant form of rejection either as isolated ABMR (n = 6) or as combined cellular and ABMR (n = 7). C4d was positive in all these cases, and vascular rejection was seen in four biopsies.

It is important to recognize that ABMRs can be “late acute” and these should not be confused as cases of chronic ABMR. There are distinct morphologic differences between features of acute and chronic ABMR. The presence of transplant glomerulopathy and interstitial fibrosis and tubular atrophy defines chronic antibody mediated rejection. Peritubular capillaritis, arteritis, glomerulitis along with positive C4d and DSA are diagnostic criteria for acute antibody mediated rejection.[23] Sun and Yang stressed the importance of differentiating late acute versus chronic ABMR in their review.[26] We found four biopsies with features of plasma cell-rich rejection. This form of rejection is seen more commonly in late transplant period and carries bad prognosis.[28]

There are definite differences in the long-term graft survival between EAR and LAR.[16],[17],[18],[19],[20],[21],[22] Agarwal et al. mentioned 46% graft loss at a median follow-up of 12 months in their patients of late ABMR.[29] Our study reconfirms this finding as we found statistical significance with graft loss following LAR as opposed to that of EAR.

There are no standard treatment protocols for LAR. It is better to prevent late episodes of acute rejection than to treat them. Rituximab, IVIG, and bortezomib have been used for the management of graft dysfunction in these patients. However, outcome data remain universally poor. Our own institute data showed that rituximab is not effective in treating late ABMR.[30]

  Conclusion Top

It is important to recognize late episodes of acute rejection with their risk factors. DGF, noncompliance, and infections were identified as major risk factors. Most of these were found to be antibody mediated. The prognosis was poor and most of the patients had documented graft loss.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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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. 27
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Agarwal G, Diskin CD, Williams TA, Kumar V. Late antibody-mediated rejection in kidney transplant recipients: Outcomes after intravenous immunoglobulin therapy. Clin Transpl 2016;32:111-8.  Back to cited text no. 29
Surendra M, Raju SB, Raju N, Chandragiri S, Mukku KK, Uppin MS, et al. Rituximab in the treatment of refractory late acute antibody-mediated rejection: Our initial experience. Indian J Nephrol 2016;26:317-21.  Back to cited text no. 30
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