|Year : 2020 | Volume
| Issue : 3 | Page : 186-190
Combined membranous glomerulonephritis and plasma cell-rich acute rejection in renal transplant recipient presented as nephrotic syndrome: case report and review of literature
Osama Gheith1, Islam Elsawi2, Ayman Nagib1, Medhat A Halim2, Mohamed A El-Hameed2, Ahmad Altaleb3, Torki Al-Otaibi2
1 Department of Nephrology, Hamed Al-Essa Organ Transplant Center, Sabah Area; Nephrology Unit, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt, Kuwait
2 Department of Nephrology, Hamed Al-Essa Organ Transplant Center, Sabah Area, Kuwait
3 Department of Pathology, Faculty of Medicine, Kuwait
|Date of Submission||14-Apr-2020|
|Date of Acceptance||11-Jun-2020|
|Date of Web Publication||17-Jul-2020|
Dr. Osama Gheith
Mansoura Urology and Nephrology Center, Mansoura, 35511
Source of Support: None, Conflict of Interest: None
Despite the contentious trials to improve the rates of acute rejection episodes and improve the renal allograft survival with potent immunosuppressants, the occurrence of more than 10 % of the inflammatory cells infiltrating renal allograft as mature plasma cells is uncommon and was recognized as plasma cell rich acute rejection (PCAR). Combination of PCAR with other glomerulopathies has not been reported before. Here, we report a case of late-onset PCAR associated with membranous glomerulonephritis (MGN) diagnosed at an early stage (2 years after transplantation). A 58-year-old male patient had end-stage kidney disease secondary to diabetic nephropathy and he was maintained on hemodialysis for 2 years until he underwent overseas living kidney transplantation. He presented to our center in Kuwait on the sixth day postoperatively, with stable renal function. He was maintained on steroid, cyclosporine, and mycophenolate mofetil. Two years after transplant, he developed picture of nephritic syndrome. His graft biopsy showed plasma cell-rich interstitial infiltrate associated with mild edema and focal tubulitis (PCACR) in addition to MGN. Further immunohistochemistry tests revealed both B-cell and T-cell markers (CD20 and CD3) were expressed in the lymphoplasmacytic infiltrate with predominant T lymphocytes. The possibility of multiple myeloma was ruled out. He received pulse steroid 1 g od for 3 days. His maintenance immunosuppression was intensified to tacrolimus-based regimen. Cluster differentiated lymphocyte count showed high CD-19 cells; therefore, we gave him a single dose of rituximab (375 mg/m2). Follow-up graft biopsy (1 month later) revealed MGN with complete resolution of plasma cells. His proteinuria started to improve after 4 months of management. He is enjoying stable graft function with controlled diabetes mellitus. PCAR is a treatable form of acute cellular rejection, and its combination with MGN will need special care with specific CD20 ablation therapy.
Keywords: membranous GN, outcome, plasma cell rich acute rejection
|How to cite this article:|
Gheith O, Elsawi I, Nagib A, Halim MA, El-Hameed MA, Altaleb A, Al-Otaibi T. Combined membranous glomerulonephritis and plasma cell-rich acute rejection in renal transplant recipient presented as nephrotic syndrome: case report and review of literature. J Egypt Soc Nephrol Transplant 2020;20:186-90
|How to cite this URL:|
Gheith O, Elsawi I, Nagib A, Halim MA, El-Hameed MA, Altaleb A, Al-Otaibi T. Combined membranous glomerulonephritis and plasma cell-rich acute rejection in renal transplant recipient presented as nephrotic syndrome: case report and review of literature. J Egypt Soc Nephrol Transplant [serial online] 2020 [cited 2020 Sep 19];20:186-90. Available from: http://www.jesnt.eg.net/text.asp?2020/20/3/186/290010
| Introduction|| |
Continuous efforts are needed to reduce the rate of acute rejection episodes and to optimize allograft survival with potent immunosuppressive drugs. However, the occurrence of more than 10 % of the inflammatory cells infiltrating renal allograft as mature plasma cells is not common and was recognized as plasma cell-rich acute rejection (PCAR) . PCAR may represent a late variant of acute antibody-mediated rejection (ABMR), which could be classified separately from T-cell-mediated rejection and treated accordingly ,.
Although the cause of PCAR remains unknown, the cause is noted in nearly 5–14% of cases . Moreover, PCAR is associated with a poor treatment response, resulting in poorer graft survival than seen with other types of acute rejection ,. It has poor long-term outcome in renal transplant recipients, and little is known about its management . The management of PCAR is not uniformly standardized owing to its rarity in clinical experience. Classically, PCAR episodes are steroid resistant and may respond at least transiently to antithymocyte globulin ,.
The treatment protocols for PCAR have also evolved with this evolution in understanding of the pathogenesis of the process. Up to now, the emphasis of treatment lay on elimination of and neutralization of antibodies from the sera of recipients. Use of specific anti-B-cell therapy has also been reported .
In case–control studies, 50% of patients with PCAR lost graft function within six months after transplantation . Although therapies for ABMR and T-cell-mediated rejection have been established, there is no consensus on therapies for PCAR.
Combination of PCAR with other glomerulopathies was not reported before. Here, we report a case of late-onset PCAR associated with membranous glomerulonephritis (MGN) diagnosed 2 years after transplant.
| Aim|| |
We described management challenge and clinical outcome of kidney transplant recipient with biopsy-proven de-novo MGN and PCAR presented clinically with nephrotic syndrome and mild renal allograft dysfunction.
A 58-year-old male patient had end-stage kidney disease secondary to unknown cause. After getting patient informed consent to take data from his medical file, and getting approval from the local ethical committee of our center, we have reported this interesting case. He had type 2 diabetes and started therapy since a few years. He started hemodialysis for 2.5 years until he underwent overseas living kidney transplantation with smooth postoperative course. He landed to our center in Kuwait on the sixth day postoperatively. He was admitted to control his hypertension and uncontrolled type 2 diabetes. He was maintained on steroid, cyclosporine, and mycophenolate mofetil. His basal graft ultrasound and renogram were normal. He was investigated urologically for microhematuria, and he was kept on alpha blocker as a case of senile prostatic hyperplasia. His graft function was normal.
Two years after transplant, he developed pitting edema in both lower limbs, puffy face associated with heavy proteinuria, hypoalbuminemia and hypercholesterolemia. His graft function was stable around his baseline values (around 90 μmol/l). Virology screen finding including Cytomegalovirus and BK virus were negative. Doppler ultrasonography study of renal allograft showed mildly echogenic appearance with normal limit resistive index and no evidence of transplant renal artery stenosis. In view of his nephrotic range proteinuria, we decided to proceed for graft biopsy. His graft biopsy showed plasma cell rich interstitial infiltrate associated with mild edema and focal tubulitis (PCAR) in addition to MGN ([Figure 1]).
|Figure 1 Histopathologic section (before treatment) reveals plasma cell-rich interstitial infiltrate associated with mild edema. Focal tubulitis is also present (i2, t2, v0, g0, ptc0, C4d0, ci1, ct1, cv0, and cg0). The plasma cells comprised 20% of the cortical inflammatory cell infiltrate). (10×, H&E stain). Histopathologic section (before treatment) reveals plasma cell-rich interstitial infiltrate associated with mild edema. Focal tubulitis is also present (10×, H&E stain). H&E, hematoxylin and eosin.|
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The first biopsy was adequate with Banff score as follows: i2, t2, v0, g0, ptc0, C4d0, ci1, ct1, cv0, and cg0. The plasma cells comprised 20% of the cortical inflammatory cell infiltrate.
The plasma cells were easily identifiable by their characteristic histomorphology (‘clock-face’ nuclear chromatin, eccentric nuclei, with paranuclear pale zone). There was no evidence of viral cytopathic changes and SV-40 immunostain was negative. No morphologic changes suggestive of drug nephrotoxicity were present in the provided biopsy. No evidence of light chain restriction was identified using kappa and lambda immunostains. The membranous glomerulopathy component was identified by the presence of glomerular basement membrane deposits, which were positive for IgG (3+), IgM(1+),C3(2+), C4d (3+), and C1q (1+). However, no overt glomerular basement membrane thickening or alteration could be seen by light microscopy. The features were fully consistent with early membranous glomerulopathy ([Figure 1]).
The second biopsy was adequate, and it showed mild acute tubular injury with no evidence of graft rejection. Banff score was as follows: i0, t0, v0, g0, ptc0, C4d0, ci1, ct1, cv0, and cg0. Rare plasma cells are observed in the renal cortex (5%). For the membranous glomerulopathy component, the same findings of the first biopsy were present.
Bence-Jones protein, serum protein electrophoresis, and skeletal bone survey findings all came normal. So the possibility of multiple myeloma was ruled out. He received intravenous pulse steroid 1 g od for 3 days and then gradual tapering till his maintenance dose according to our protocol. His maintenance immunosuppression was intensified to tacrolimus-based regimen. His insulin requirement increased during that period. Cluster differentiated lymphocyte count was checked before giving him single dose of rituximab (375 mg/m2) to deplete CD-19 cells. His donor-specific antibody came negative. Follow-up graft biopsy (3 months later) revealed MGN with complete resolution of plasma cells. His proteinuria started to improve after 4 months of management (from 9.9 g to 0.22 g/24 h) until it came below 250 mg/24 h by the end of the first year after management. He is enjoying stable graft function with controlled diabetes mellitus.
| Discussion|| |
PCAR is an uncommon clinical entity (5% of patients with biopsy-proven acute rejection) independent of acute renal allograft rejection . The time of onset is variable. In a case series of 27 cases over 10 years, the majority of episodes were late post-transplant 55% (>6 months, mean: 37.3 months), which was in agreement with our patient who developed the PCAR after 24 months of transplant, whereas 45% developed early (<6 months, mean: 2.5 months) .
In our patient, we did not identify risk factors associated with PCAR, which were reported in one study as female sex, older age than 50 years, deceased donors, or simultaneous pancreas–kidney transplantation .
Apart from PCAR, plasmacytic infiltration has been reported to be associated with viral infection , AMR , post-transplant lymphoproliferative disease , monoclonal gammopathy , and patient nonadherence to immunosuppressive therapy . Fascinatingly, the manifestation of PCAR can also mimic IgG4-related kidney disease . In our patient, we have adopted Banff 2015 classification criteria to establish the diagnosis which was defined by the presence of more than 10% plasma cells among all the cortical inflammatory cell infiltrate. In the initial biopsy, the plasma cells comprised 20% of the cortical inflammatory cell infiltrate.
All the possibilities of plasma cell infiltration were assessed. We excluded viral infection-related disease by negative virology screen. We evaluated ABMR using a panel reactive antibody, and cross-match, and all results were negative at the time of initial biopsy. We could not detect C4d in peritubular capillaries in the two graft biopsies. Therefore, we disqualified the possibility that infiltration of plasma cells was not associated with ABMR. Moreover, our patient was adherent to his medications and follow-up visits (adequate trough levels during the follow-up period); his bone survey and serum protein electrophoresis were negative.
In a case series by Martin et al. , plasma cell infiltration was reported to be associated with development of chronic allograft dysfunction, but in our case, graft function was normal till the last follow-up even after management of rejection.
However, we did not observe any pathological findings suggestive of antibody-mediated element, and even PRA was negative, which were indicative of good compliance to immunosuppressive regimen. Recent literature also suggested that detection of donor-specific antibodies might be useful in determining whether the PCAR is of a subtype of AMR, which can be refractory to immunosuppression treatment with unfavorable outcome ,. Furthermore, our patient was responsive to steroid pulse therapy.
Therapy for PCAR has not been completely well established, and previous reports showed varied outcomes with different treatment modalities, which ranged from just baseline immunosuppression intensification, IV methyl-prednisolone pulses, IV immunoglobulin, and plasma exchange. The use of thymoglobulin, rituximab, and bortezomib has been reported in PCAR with T-cell, B-cell predominance, and monoclonal gammopathy, respectively .
The associated MGN and PCAR in our case obliged us to adopt combined therapy. The treatment of disease recurrence is largely extrapolated from treatment in the general population and classically includes a combination of antiproteinuric agents, corticosteroids, alkylating agents, calcineurin inhibitor (CNI), and rituximab . Therefore, we planned to give pulse steroid and rituximab and then to redo graft biopsy, and if plasma cell persisted, we added bortezomib. Our patient was maintained on angiotensin receptor blocker. Fortunately, after 1 month of pulse steroid, intensified maintenance immunosuppression, and single dose of rituximab, he responded well with complete resolution of plasma cells in the follow-up biopsy ([Figure 2]). Moreover, his proteinuria started to improve after the fourth month of management till it reached less than 250 mg per day by the end of the first year of management.We succeeded in managing such case adopting this management with satisfactory response, despite the previous reports portending a poor prognosis with high rate of graft loss or severe allograft dysfunction (1, 9, 16). We thought that timely diagnostic workup in addition to close collaboration with histopathologist followed by intensification of maintenance treatment was critical to prevent disease progression.
|Figure 2 Histopathologic section (after treatment) reveals complete resolution of the inflammation. Mild edema and acute tubular injury is seen (5×, H&E stain). H&E, hematoxylin and eosin.|
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| Conclusion|| |
PCAR is a treatable form of acute cellular rejection, and its combination with MGN will need special care with specific CD20 ablation therapy.
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Conflicts of interest
There are no conflicts of interest.
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