|Year : 2020 | Volume
| Issue : 4 | Page : 377-379
Plasma cell-rich rejection – The enigma revisited: Case report
Srikanth Gundlapalli, Sujeeth Reddy Bande, Venkateswar Rao Mulpuru
Department of Nephrology, Asian Institute of Nephrology and Urology, Hyderabad, Telangana, India
|Date of Submission||30-Dec-2019|
|Date of Acceptance||28-Mar-2020|
|Date of Web Publication||30-Dec-2020|
Dr. Srikanth Gundlapalli
Department of Nephrology, Asian Institute of Nephrology and Urology, Erramanzil Colony, Somajiguda, Hyderabad - 500 082, Telangana
Source of Support: None, Conflict of Interest: None
Plasma cell-rich rejection (PCRR) is a morphological pattern of rejection characterized by the presence of plasma cells constituting at least 10% of the cellular infiltrate. Clinical characteristics, therapeutic options, and its position in the Banff Classification for Allograft Rejection have not been clearly defined. Although morphologically discussed in close association with cellular rejection, histopathological advances and better availability of C4d helped us to understand the close relationship with the antibody-mediated rejection. T helper cell 2 predominant cellular infiltration has been identified in recent studies. Rational choices of drugs such as bortezomib have not shown outcomes as expected in various clinical trials. Newer therapeutic options directed at TH2 cytokines which are being tested in other disorders may open up new avenues of therapy. We discuss two cases of PCRR with varied presentation, one early and the other very late in the course of transplantation. Both of our patients had poor graft outcomes despite therapy.
Keywords: Bortezomib in plasma cell-rich rejection, delayed rejection, mixed rejection, plasma cell-rich rejection
|How to cite this article:|
Gundlapalli S, Bande SR, Mulpuru VR. Plasma cell-rich rejection – The enigma revisited: Case report. Indian J Transplant 2020;14:377-9
| Introduction|| |
Plasma cell-rich rejection (PCRR) is a distinct morphological form of renal allograft rejection, characterized by the presence of mature plasma cells that comprise more than 10% of the inflammatory cells. While the cause of PCRR remains unknown, it is noted in approximately 5%–14% of cases of biopsy-proven acute rejection. PCRR is associated with a poor treatment response, with most studies demonstrating 50% loss of allograft at 1 year.,, Although traditional understanding of the disease as a form of cellular rejection gained ground purely on the morphological pattern, recent evidence for humoral component of PCRR is on the upsurge. Banff classification is yet to include this form of rejection in the classification. With advancements in histopathological techniques, better understanding of the pathogenesis is opening up avenues for newer treatment options. Here, we report two cases of PCRR, which provide insight into the presentation and therapeutic response of PCRR.
| Case Reports|| |
A 59-year-old male, end-stage renal disease with diabetic nephropathy, underwent spousal transplant 7 months ago. He had good immediate graft function with nadir creatinine of 0.6 mg/dl. His baseline immunosuppression is cyclosporine, mycophenolate sodium, and prednisolone. Three months post renal transplantation, he developed pulmonary tuberculosis after which he was started on rifampicin-based antitubercular therapy with a dose adjustment of cyclosporine.
He was lost to follow-up for a period of 2 months after which he presented with severe graft dysfunction (serum creatinine: 5.2mg/dl and cyclosporine trough levels C0 <30 μg/L). Biopsy showed marked interstitial inflammation with tubulitis and early endarteritis, consistent with type IIA cellular rejection and mild peritubular capillaritis with strong circumferential C4d positivity suggesting a combined rejection. The interstitial infiltrate was predominant plasma cell infiltrate.
Donor-specific antibodies (DSAs) were high with a mean fluorescent index (MFI) of 8040. He received anti-thymocyte globulin (ATG) (thymoglobulin) to a total dose of 5 mg/kg in divided doses. He was planned for plasmapheresis and underwent one session of plasmapheresis, following which he had severe sepsis and metabolic acidosis. Further plasmapheresis was deferred as the patient and attendant not willing for it. His rifampicin was stopped and the dose of cyclosporine was optimized. His creatinine stabilized at around 3 mg/dl.
A 58-year-old male underwent a spousal transplant 7 years ago with basiliximab induction. Post transplant, the period was uneventful with a baseline creatinine of 1.0 mg%. Three years post transplant, he had an episode of acute rejection which was secondary to drug noncompliance. It was biopsy-proven cellular rejection, which responded to methyl prednisolone and ATG of 3 mg/kg. He was relatively well till 1 month ago when he presented with a creatinine of 4.5 mg/dl which quickly worsened to 5.8 mg/dl. He claims complete compliance with drugs. His allograft biopsy showed active antibody-mediated rejection with plasma cell-rich interstitial lymphocytic infiltrate. Interstitial fibrosis and tubular atrophy (IFTA) of 70% was reported. His DSA was positive in the titers of MFI more than 10,000.
His immunosuppression was optimized and he was started on intravenous immunoglobulin with plasmapheresis which was given for a total of five sessions followed by rituximab in the dose of 375 mg/m2. His creatinine worsened to 6.0 mg/dl and he is presently awaiting surgery for arteriovenous fistula.
| Discussion|| |
The earliest reports and understanding of PCRR stemmed from the pioneering work by Charney et al. who reported 27 cases of plasma cell-rich infiltrates causing graft dysfunction. Earlier to that, plasma cell infiltration was considered a part of viral/drug-induced infiltration causing allograft dysfunction. Plasma cell infiltration of the graft is not exclusively due to some kind of rejection. Other causes include viral infections, posttransplant lymphoproliferative disorder, and IgG4-related kidney disease.
PCRR is being increasingly reported as an important cause of graft loss, particularly with improving short-term outcomes. The incidence of PCRR reported has been 5%–15% of the biopsy-proven rejections,, and is probably increasing.
Most of the studies reported late-onset rejection, poor prognosis, and slight female preponderance as the unique features of this entity. Our cases had extremes of presentation, one within 7 months and the other after 7 years. Most of the initial reports of PCRR claimed cellular rejection, interstitial inflammation, and tubulitis, with only few polymorphs and lymphocytes in the glomeruli., The general consensus initially was that it was a form of cellular rejection.
The increasing availability of C4d and better morphological identification of patterns of injury in humoral rejection lead to increasing identification of humoral component as a part of PCRR.,, These cases however also reported significant chronicity and features of combined rejection. This peculiar clinical and morphological feature of PCRR made it difficult to accurately classify and fit in the system of Banff. The absence of PCRR in Banff is claimed as one of the major drawbacks of this system.
Our cases had combined features of T-cell mediated rejection (TCMR) and Antibody mediated rejection (ABMR), although predominant humoral component with C4d and DSA positivity compelled us to consider therapeutic options directed at antibody-mediated rejection. In addition to the chronicity on biopsy and vascular rejection, it is increasingly understood that DSA portends a worse prognosis in PCRR.
Whether PCRR with predominant morphology of acute cellular rejection is a different entity than DSA-positive and C4d-positive humoral rejection is an unanswered question. Work on these lines has been attempted by pathological and immunohistochemical analysis by Nishimura et al. They assessed the T-bet/GATA 3 ratio in the lymphocytes to distinguish Th1 versus Th2 cell phenotype. TH2 predominant lymphocytic infiltration leads to predominant interleukin 4 (IL-4)/IL-5 cytokine release, causing B-cell maturation into plasma cells. Pioneering work on the lymphocyte predominance to determine the type of rejection has been done by Sun et al.
The treatment of PCRR is not clearly defined due to the overall rarity of the disease. Literature talks about varied responses to different treatment options. None of the pathological parameters including the degree of plasma cell infiltrate or the Banff acute rejection grading seem to correlate with therapeutic outcomes.,,, Although response to methyl prednisolone is dismal, at least partial response has been reported with ATG., Therapies directed at antibody removal in the form of plasmapheresis reported better outcomes and improvement in graft function., Indian data from Gupta et al. also reported poor therapeutic responses in their series of eight cases.
Other than a few anecdotal reports, the systematic use of bortezomib for the management was only reported by Abbas et al. Bortezomib has been used in the treatment of Antibody mediated rejection (AMR) as well as desensitization protocols.,, With better understanding of the role of antibody-mediated rejection in PCRR and the direct effect of this drug on the proteasomes of plasma cells, it naturally forms a rational choice for this type of rejection. However not a very promising outcome was demonstrated in that study, the authors attribute nonresponse to the 80% IFTA in their allograft biopsies. With better understanding of PCRR, the type of cellular infiltrate, potential therapeutic targets are likely to open up. In fact, new drugs targeting Th2 cell cytokines are already in trials albeit for other disorders. Hopefully, these therapeutic approaches transform the outcomes in this otherwise notorious form of rejection.
| Conclusion|| |
PCRR remains a mystery which is yet to be solved. With advancement in histopathological techniques, clear pathogenic pathways may open up avenues for better therapies.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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