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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 6  |  Page : 1111-1114
Late acute antibody mediated rejection after nine years of renal transplantation

1 Hamed Alessa Organ Transplantation Center, Mubarak Al-Kabeer Hospital, Kuwait
2 Histopathology Department, Mubarak Al-Kabeer Hospital, Kuwait

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Date of Web Publication4-Nov-2010


Acute Antibody Mediated Rejection (AMR) is rarely reported as a long-term com­plication of renal transplantation, and it can present on top of another chronic pathology affecting the graft. A 45-year-old gentleman with chronic kidney disease due to unknown etiology received renal transplantation from his sister with 4 HLA mismatches. He received antithymocte globulin induction therapy and was maintained on steroids, azathioprine (AZA) and cyclosporine A (CsA). Up to eight years post-transplantation he was clinically and biochemically stable. He lost follow­up for about one year, and then presented with nephritic nephrotic syndrome and rise of serum creatinine (SCr.) to 210 μmol/L. Graft biopsy revealed picture suggestive of acute AMR on top of de novo membranoprolipherative glomerulonephritis (MPGN) with focal crescent formation, diffuse immune complex deposition and peri-tubular capillaries C4d positivity. Anti-HLA donor specific antibodies were highly positive for B and T cells class I and class II. The patient was treated with intravenous immunoglobulin, plasma exchange and anti-CD20 (rituximab). AZA was changed to mycophenolate mofetil and CsA to tacrolimus. He had partial response, but SCr. continued at 220 μmol/L.

How to cite this article:
Halim MA, Al-Otaibi T, Al-Waheeb S, Tawab KA, El Kholy O, Nair P, Said T, Narayanan Nampoory M R. Late acute antibody mediated rejection after nine years of renal transplantation. Saudi J Kidney Dis Transpl 2010;21:1111-4

How to cite this URL:
Halim MA, Al-Otaibi T, Al-Waheeb S, Tawab KA, El Kholy O, Nair P, Said T, Narayanan Nampoory M R. Late acute antibody mediated rejection after nine years of renal transplantation. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2022 Aug 7];21:1111-4. Available from: https://www.sjkdt.org/text.asp?2010/21/6/1111/72300

   Introduction Top

Acute antibody mediated rejection (AMR) is rarely reported as a long-term complication of renal transplantation. [1],[2],[3],[4] Anti-HLA donor-spe­cific antibodies (DSA) constitute a serious risk to renal allograft function. [1],[2],[3],[4] As the sensitivity of techniques for the detection of anti-HLA antibodies has increased, moving from com­plement-dependent cytotoxicity (CDC), to anti­human globulin augmented CDC, to flow cyto­metry (FC), the ability to detect de novo post­transplantation anti-HLA DSA has greatly im­proved. [5] Aiding in the diagnosis of antibody­mediated rejection has been the identification of the complement degradation product C4d in the peritubular capillaries (PTC) and glomeruli of allografts experiencing rejection by this mechanism. [2],[3],[4] We report a recipient of a living related renal transplant who presented with nephritic nephrotic syndrome due to acute AMR on top of de novo membranoproliferative glomerulonephritis (MPGN) with high titer of anti-HLA DSA nine years post-transplant.

   Case History Top

A 45-year-old gentleman with chronic kidney disease due to unknown etiology had a history of hypertension and hepatitis B virus (HBV) infection with mild non-specific reactive hepa­titis on liver biopsy done before transplan­tation. He was on hemodialysis for one month till he received renal transplantation from his sister with 4 HLA mismatches. He received antithymocyte globulin induction therapy and was maintained on steroids, azathioprine (AZA), and cyclosporine A (CsA) as maintenance im­munosuppressive therapy, which 8 years post­transplantation consisted of prednisolone 5 mg daily, AZA 50 mg daily, and CsA 50 mg twice daily with adequate blood level of about 75 ng/L. He was clinically and biochemically sta­ble with serum creatinine 95 μmol/L. He lost follow-up for about one year till he developed nephritic nephrotic state with high blood pre­ssure, generalized edema, bilateral pleural ef­fusion, ascitis, microhematuria, proteinuria 6.6 gm/day, hypoalbuminemia 19 gm/L and high s. creatinine 210 μmol/L. The hematological profile revealed normocytic normochromic ane­mia (hemoglobin 99 gm/L). Liver function tests were within normal. The patient had positive HBVs antigen and HBVe antibody, while HBV-DNA, HBVe antigen, HCV-PCR, cryo­globulines, anti Ds-DNA, ANA, and ANCA were negative. He had normal coagulation pro­file, tumor markers, serum protein electropho­resis and C4, but low C3. An ultrasound of the renal transplant showed normal vessels and no hydronephrosis. Graft biopsy revealed: 3 glo­bally sclerosed glomeruli, 7 normal glomeruli, and 3 glomeruli that showed proliferation of the visceral epithelial cells in Bowman's space with collapse of the glomerular tuft. There was also diffuse mesangeal hypercellularity asso­ciated with a mild increase in the amount of extracellular matrix and prominent double contours in the glomerular peripheral capillary walls; Bowman's capsular basement membrane was disrupted in the crescentic areas. Tubules revealed focal atrophy with thickening of their basement membranes. Many of areas of capil­laritis were observed. The interstitium showed patchy areas of fibrosis and interstitial infla­mmation associated with mononuclear inflam­matory cellular infiltration. Approximately 40% of the sample showed tubular and interstitial fibrosis, as evidenced on the trichrome stains (AFOG). Arteries and arterioles revealed mo­derate sclerosis and hyalinosis of the vessel walls, respectively. There were no features sug­gestive of vasculitis. C4d was done with im­munoproxidase technique (IP) and was dif­fusely positive in the PTC. IP staining showed immunoglobulin (Ig) G 2+, IgA 2+, IgM 1+, C3 1+ in the mesangium and peripheral ca­pillary walls. Electron microscopic evaluation of the biopsy showed prominent mesangial interpositioning of the glomerular basement membranes and subendothelial electron dense deposits. Complete effacement of podocyte foot processes was also noted. In view of the "full house" Ig deposition pattern seen by IP, the possibility of Lupus nephritis was excluded clinically and serologically and cryoglobulines were negative. These histopathological and im­munopathological findings were cross matched with the kidney donor was done. The anti­HLA DSA were negative by CDC but highly positive by FC for B and T cells class I and class II with his sister who donated the kidney 9 years back. These criteria strongly suggest a superimposed acute AMR (Banff I) to a MPGN pattern of injury and focal crescents. He was treated with intravenous Ig (2 gm/kg), plasma exchange (5 sessions), and anti-CD20 (rituxi­mab). An angiotensin converting enzyme inhi­bitor (ACEI) and an angiotensin receptor bloc­ker (ARB) (captopril and valsartan) were ad­ded to control blood pressure and proteinuria. To intensify his immunosuppressive regime, AZA was changed to mycophenolate mofetil (1 gm BID) and CsA to tacrolimus. He deve­loped acute gastro-intestinal bleeding due to antral ulcers and gastro-duodenitis as shown by upper gastro-intestinal endoscopy. He was treated conservatively and stabilized clinically and biochemically. Two months later he was clinically stable and his graft function was within the same range (s. creatinine 220 umol/ L) with improvement of his blood pressure and nephrotic state (s. albumin 28 gm/L and protei­nuria became 2.2 gm/L).

   Discussion Top

Antibody mediated rejection should be con­sidered in renal allograft dysfunction at all stages of the post-transplant course. [6] The pre­sent patient developed de novo anti-HLA anti­bodies with his living related donor. His anti­donor B and T lymphocyte antibodies were not detectable by CDC, but were identified by FC. Recently, human, but not murine, renal peritu­bular glomerular capillaries have been shown to constitutively express Class II major histo­compatibility antigens at high levels. [7] The pre­sence of the Class II HLA antigens in addition to Class I HLA antigen renders the renal micro­vasculature a target for antibody directed against B lymphocytes as well as T lympho­cytes. [7] Post-transplantation development of anti-HLA antibodies has become a more im­portant and recognizable form of allograft rejection with the routine use of FC cross­matching rather than the less sensitive CDC. [5],[7] In the absence of pregnancy or blood trans­fusions after transplantation, the development of anti-HLA antibodies is related to HLA incompatibilities in the allograft. Our patient is a male and has no history of blood transfusion. Numerous previous reports have focused on the appearance of these antibodies in the early transplant period, and others have extended the identification of these antibodies more than ten years after transplantation. [7] Deposition of C4d in PTC and glomeruli is further evidence for a humoral mechanism of allograft rejection. [2],[4] C4d staining was correlated with an increased risk for graft loss and also was significantly associated with recipient history of pretrans­plantation sensitization and high levels of panel-reactive antibodies. [2],[3],[4] C4d deposition in PTC is found in only a few instances of renal disease in native kidneys. AMR may have different patterns forms, either predominantly thrombotic microangiopathy or PTC pattern of injury. [6] Lupus nephritis may have bright, gra­nular deposits along the PTC, corresponding to the immune complex deposits. [6] Our patient had no other clinical or serological signs sup­porting lupus nephritis diagnosis.

Thrombotic microangiopathy is negative for C4d in PTC, as shown in published cases of recurrent hemolytic uremic syndrome in a transplant, as well as unpublished experiences. [6] This is particularly helpful, because AMR is always in the differential diagnosis of throm­botic microangiopathy. [6] This patient had pre­dominant PTC pattern of injury with C4d de­position rendering hemolytic uremic syndrome diagnosis unlikely.

Our patient presented with low serum C3 and C3 deposits in the graft biopsy. C3 is the next component in the classic pathway sequence after C4; therefore, its cleavage products should indicate more complete complement active­tion. [6] C3d was found in conjunction with C4d in sensitized patients, but it added little diag­nostic value to C4d in positive cross-match grafts that showed histologic features of AMR. [6]

Transplant glomerulopathy is strongly asso­ciated with circulating antibodies to donor HLA antigens and poor prognosis. [6] The histopatho­logical findings of MPGN can be confused with transplant glomerulopathy but the presence of immune complex deposition in the graft biopsy supports MPGN diagnosis. MPGN can be secondary to hepatitis infection. Our patient had a history of mild HBV, but he had no evidence of active hepatitis serologically and histopathologically. He was not infected by HCV either, and cryoglobulines were negative.

The literature review showed no direct corre­lation between acute AMR and MPGN, which supports our impression that this patient deve­loped de novo MPGN, when he lost follow-up, then AMR developed acutely at the time of presentation.

Therapy of AMR is plasmapheresis or immu­noadsorption and intravenous Ig combined with intensive immunosuppression (typically tacro­limus and mycophenolate mofetil). For those who fail this treatment, other measures include anti-CD20 antibody and splenectomy. [6] Treat­ment modalities for de novo MPGN with cres­centic formation may need the same measures in addition to ACEI and ARB, which were added. Adding antiplatelet aggregation drugs were not possible due to upper gastro-intestinal tract hemorrhage. He received the appropriate treatment and will need strict control of blood pressure with frequent assessment of his cli­nical and laboratory parameters.

We conclude that our patient developed late acute AMR on top of de novo MPGN 9 years post-renal transplantation, which is a rare com­plication. Acute AMR was diagnosed by posi­tive anti-HLA DSA, histopathological findings and diffusely positive C4d staining in PTC. He received aggressive anti-rejection treatment and his condition could be stabilized. He needs close follow-up to maintain his renal function.

   References Top

1.Terasaki PI. Humoral theory of transplantation. Am J Transplant 2003;3:665-73.  Back to cited text no. 1
2.Feucht HE. Complement C4d in graft capillaries­the missing link in the recognition of humoral alloreactivity. Am J Transplant 2003;3:646-52.  Back to cited text no. 2
3.Racusen LC, Colvin RB, Solez K, et al. Anti­body-mediated rejection criteria-an addition to the Banff '97 classification of renal allograft rejection. Am J Transplant 2003;3:708-14.  Back to cited text no. 3
4.Halloran PF. The clinical importance of allo­antibody-mediated rejection. Am J Transplant 2003;3:639-40.  Back to cited text no. 4
5.Braun WE. Laboratory and clinical management of the highly sensitized organ transplant reci­pient. Hum Immunol 1989;26:245-60.  Back to cited text no. 5
6.Colvin RB. Antibody-mediated renal allograft rejection: Diagnosis and pathogenesis. J Am Soc Nephrol 2007;18:1046-56.  Back to cited text no. 6
7.Weinsteina D, Brauna WE, Cookb D, McMahonc JT, Mylesc J, Protivaa D. Ultra­late antibody-mediated rejection 30 years after a living-related renal allograft. Am J Transplant 2005;5:2576-81.  Back to cited text no. 7

Correspondence Address:
Medhat Abdel Halim
Hamed Al-Essa Organ Transplantation Centre, Ibn Sina Hospital, P.O. Box 25427, 13115 Safat
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Source of Support: None, Conflict of Interest: None

PMID: 21060182

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