POST TRANSPLANT RECURRENCE OF MPGN WITH GRAFT LIMITED MONOCLONAL DISEASE- A UNIQUE ENTITY

Introduction:

Membrano Proliferative Glomerulonephritis (MPGN) remains an enigmatic disease with an elusive etiological work up . Advances in understanding the disease's pathogenesis have led to a revised classification, moving away from the traditional types I, II, and III. Comprehensive  workup for auto immune, infectious and monoclonal association is often productive ,however the monoclonal disease may sometimes be cryptic or an evolving problem that fails to be unmask during workup. This makes  renal transplantation in such a case a tough nut to crack . Therefore in patients who reach End stage Renal disease (ESRD) and have prospects of renal transplantation, the workup needs to be exhaustive to prevent a catastrophe of recurrent disease. Such a recurrence is associated with a high risk of graft loss and is influenced by factors such as living-related donations, preemptive transplantation, hypocomplementemia, and monoclonal gammopathy .Understanding and managing this recurrence is crucial for improving patient and graft outcomes.

  Monoclonal Gammopathy of Renal Significance (MGRS) encompasses renal diseases driven by monoclonal proteins that may not always be detectable in systemic circulation. There is no specific described entity with such features and it could be called Monoclonal Renal-Limited Disease. This is a subset where the renal damage is prominent despite the absence of systemic evidence of monoclonal gammopathy. We present a case manifesting as MPGN, with extensive secondary workup being negative. After reasonably being convinced that the disease is unlikely to recur he underwent a renal transplantation, Post transplant recurrence of the disease reflects the enigmatic nature of this disease and the need for more research in this field.

Methods:

A 28-year-old male presented with Rapidly Progressive Glomerulonephritis following which a  native kidney biopsy confirmed Immune Complex-mediated Crescentic MPGN with no monoclonal pattern  or light chain restriction on Immunofluorescence. His infectious disease and autoimmune workup were non-contributory, and complements were normal. Paraproteinemia was excluded with negative results on immunofixation electrophoresis, and urinary free light chain assay. He was thus classified as Idiopathic Immune Complex-mediated MPGN, his condition progressed to ESRD despite immunosuppressive therapy within few months.

Figure  :Light microscopy image , PAS stain showing single glomerulus appearing enlarged ,cellular with accentuation lobular tufts diffuse mesangial and endocapillary proliferation. The capillaries exhibit significant thickening and scattered capillary wall “splits” or “double contours “ discernible in silver methenamine sections. Twenty three of twenty eight glomeruli (82.1%) show crescents.

After 18 months on dialysis, he was considered for renal transplant with father as the donor. The chances of recurrence and associated complications was extensively discussed. Pre transplant rework up of Monoclonal association or Auto immunity did not mask any latent disease.  He underwent a successful ABO-compatible transplant with good immediate graft function that remained stable over the next year, with nadir creatinine at 0.8 mg/dl. However, routine follow-up revealed progressive proteinuria urine protein excretion of 2 grams/24 hours. Ultrasound and Doppler of the graft were normal.

Allograft biopsy showed features consistent with an MPGN pattern, with predominant deposits of kappa light chain and IgG which did not show up in the native kidney biopsy or the work up . Hence a post transplant  repeat workup for paraproteinemia, including free light chain assay, immunofixation electrophoresis, and bone marrow biopsy were done which  were negative. A whole body PET scan considering solitary plasmacytoma was also negative. Electron microscopy confirmed MPGN recurrence. He is currently on an Angiotensin Receptor Blocker for proteinuria ( recent 24 hr urine protein - 1.2grams ), on stable triple immunosuppression (Tacrolimus, mycophenolate mofetil, and steroids), and maintaining good graft function ( s creatinine - 1.2mg/dl).

Results:

DISCUSSION 

MPGN is a distinctive glomerular injury pattern characterized by mesangial expansion due to hyper cellularity and increased matrix, resulting in lobular accentuation of the glomerular tufts. It constitutes approximately 7-10% of all biopsy-confirmed glomerulonephritis. The clinical presentation is variable, ranging from asymptomatic hematuria and/or proteinuria to rapidly progressive glomerulonephritis. Treatment varies with the etiology.

Historically, MPGN has been classified into three types based on immune deposits observed under electron microscopy. A new classification system redefines MPGN by focusing on differences in pathogenesis and histological findings, enabling more precise assessment, including post-transplantation risks. This modern classification categorizes MPGN into immune complex-mediated (linked to infections, autoimmune diseases, or monoclonal gammopathies) and complement-mediated (caused by complement pathway dysregulation). While several observational studies have evaluated MPGN recurrence after renal transplantation, data on its natural course, impact on allografts, and treatment remain limited.

The overall reported recurrence rate of MPGN in allografts varies between 18% and 48%, representing a significant cause of graft loss .The highest recurrence rates are observed with Dense Deposit Disease and complement-mediated diseases. Recurrence after transplantation has been associated with living donor transplants, preemptive transplants, presence of monoclonal immunoglobulins, lower complement levels, higher proteinuria, and crescents in the original biopsy.

Treatment of post-transplant recurrence of MPGN is sparse more so with monoclonal restriction limited to graft alone .No  randomized controlled trials or established protocols are  available except for isolated case reports suggesting benefit with plasmapheresis and cyclophosphamide. Initial positive outcomes with rituximab have been noted in cases of post-transplant MPGN relapse, resulting in sustained remission for over a year . Alasfar et al. employed the updated MPGN classification system to evaluate diverse therapeutic interventions and reported a rituximab response rate of approximately 30%.

Our case is unique due to the lack of a conclusive diagnosis in the native kidney with MPGN and the recurrence of similar renal histopathology with newly diagnosed monoclonality post-transplant, despite no evidence of systemic monoclonal disease. This is an extremely rare phenomena and has not been recorded in literature so far .Potential explanations include de novo monoclonal gammopathy post-transplant, donor-derived clonal expansion, reactivation of a latent clone, or subclinical recurrence of the original disease.

Conclusions:

Monoclonal renal limited disease is a tough and a bizarre challenge for nephrology fraternity involving  diagnostic and therapeutic difficulties .Renal biopsy remains the  Achilles' heel  for identifying monoclonal protein-related pathology .This case emphasizes on the unique yet distinctive  presentation of the disease and underscores the need for further research to understand its pathogenesis and treatment aspects  in detail. 

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.