Saudi Journal of Kidney Diseases and Transplantation

CASE REPORT
Year
: 2016  |  Volume : 27  |  Issue : 2  |  Page : 381--385

Early recurrence of proliferative glomerulonephritis with monoclonal immunoglobulin deposits in a renal allograft


Rohit Tewari1, Kusum Joshi2, Ashwani Kumar2, CS Rayat2, Rajaram Iyer3, Vinay Sakhuja3, Mukut Minz4,  
1 Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Transplant Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:
Rohit Tewari
Department of Pathology, Armed Forces Medical College, Pune, Maharashtra
India

Abstract

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMIDs) is a clinico-pathologic entity, the recurrence of which in the renal allograft has only recently been described. A 55-year-old male presented with rapid deterioration of renal function. Light microscopy showed membranoproliferative glomerulonephritis with kappa light chain restriction and only one sub-class of IgG. He subsequently underwent renal transplant. Two months later, he developed acute graft dysfunction. Renal biopsy showed a recurrence of the disease. Work up for multiple myeloma was positive. Membranoproliferative pattern of injury in the posttransplant setting has a wide range of differential diagnosis, PGNMID being one of them.



How to cite this article:
Tewari R, Joshi K, Kumar A, Rayat C S, Iyer R, Sakhuja V, Minz M. Early recurrence of proliferative glomerulonephritis with monoclonal immunoglobulin deposits in a renal allograft.Saudi J Kidney Dis Transpl 2016;27:381-385


How to cite this URL:
Tewari R, Joshi K, Kumar A, Rayat C S, Iyer R, Sakhuja V, Minz M. Early recurrence of proliferative glomerulonephritis with monoclonal immunoglobulin deposits in a renal allograft. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Aug 15 ];27:381-385
Available from: http://www.sjkdt.org/text.asp?2016/27/2/381/178568


Full Text

 Introduction



There are a number of renal diseases associated with deposition of monoclonal immunoglobulins including light or heavy chain amyloidosis, monoclonal immunoglobulin deposition disease, type-1 cryoglobulinemia, immunotactoid glomerulopathy, and occasionally, fibrillary glomerulopathy. [1] Any of the renal compartments may be involved with deposition in the renal glomeruli, tubules, interstitium, or blood vessels. The etiology may range from conditions associated with monoclonal immunoglobulin production like malignant lymphoid or plasma cell neoplasm to monoclonal gammopathy of undetermined significance without identifiable underlying neoplasm at the time of renal biopsy, to cases which appear never to have an underlying neoplastic proliferation. [2] The light microscopic appearances of these conditions are also varied and may show changes mimicking membranoproliferative glomerulonephritis (MPGN), membranous glomerulonephritis, or nodular mesangial expansions mimicking diabetes. Immunofluorescence (IF), which includes different stains for light and heavy chains, is essential for diagnosis. Recently, a new entity was described with deposition of monoclonal immunoglobulins and a pattern of glomerular changes not compatible with any of the above conditions. This has been called proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID). [3] This entity has a propensity for early recurrence following renal transplant. [4]

 Case Report



A 55-year-old male, a known case of hypertension for 15-years and type II diabetes mellitus for five-years, presented with rapid deterioration of renal function with serum creatinine rising from 1.6 to 7.5 mg/dL over four months. Urine examination showed 2+ albumin, 8-10 pus cells, and 25-30 red blood cells in the sediment. Renal biopsy showed global sclerosis of 40% of the glomeruli [Figure 1]. The remaining glomeruli showed mesangial matrix expansion with thickening of the glomerular capillary walls. Direct IF studies showed intense (3+) granular positivity for IgG, C3, and C1q in the glomerular capillary walls and mesangium. Intense positivity (3+) was also seen for kappa light chains in the same location; however, IF for lambda light chains showed only 1+ positivity along the glomerular capillary walls. Electron microscopic (EM) examination showed the presence of thickening of the glomerular basement membrane with the thickness ranging from 653-870 nm with a mean of 701 nm. Extensive immune complex type of electron dense deposits were seen in the sub-endothelium and mesangial regions with focal remodeling of the glomerular basement membrane. In view of the presence of a proliferative pattern with immune complex deposition with C3 and C1q, a diagnosis of proliferative glomerulonephritis with diabetic nephropathy was made, and to rule out lupus nephritis in view of strong C1q positivity. All serological tests performed subsequently for systemic lupus erythematosus were negative. The renal function of the patient gradually worsened over the next 1½ years, and he was taken up for living unrelated donor renal allograft transplant. The immediate posttransplant period was unremarkable and he maintained a baseline serum creatinine of 1.1-1.2 mg/dL. However, two months later he developed a brain abscess, after which mycophenolate mofetil was stopped. He developed an increase in serum creatinine to 2.3 mg/dL when acute graft rejection was suspected and a renal biopsy was performed.{Figure 1}

Allograft biopsy showed enlarged glomeruli with thickening of the glomerular capillary walls along with mesangial expansion and increase in mesangial cellularity [Figure 2]. Focal endocapillary proliferation was present. There were no features to suggest acute rejection. Direct IF studies showed intense (3+) granular positivity for IgG and C3 along the glomerular capillary walls and mesangium. Lesser intense positivity in the same locations was also seen for kappa light chains (2+) and C1q (1+). Direct IF for IgA, IgM, and lambda light chains was negative. IF for IgG subclasses showed positivity for IgG3 only. A diagnosis of PGNMID was made. An initial work up for a plasma cell dyscrasia revealed no abnormality; however, a repeat work up after two months showed an M band on serum electrophoresis. The patient was subsequently managed with a hematopoietic stem cell transplantation and is now on follow-up with reduction in proteinuria.{Figure 2}

With the question as to whether the PGNMID was arising de novo or had recurred posttransplant, a review of the pre-transplant biopsy was carried out. On review of the previously stored images, it was noticed that the IF findings, interpreted earlier as 3+ positive for kappa and 1+ positive for lambda light chains, in fact showed positivity only for kappa light chains with the lambda light chain findings being limited to linear accentuation of the basement membranes often seen in a case of diabetic nephropathy. IF for IgG sub-classes was now performed and showed the presence of only IgG3. A final diagnosis of recurrence of PGNMID in a renal allograft was made.

 Discussion



PGNMID is a distinct entity, of which the defining criteria as enunciated by Nasr et al [5] are: (a) immune deposits staining for gamma heavy chain (IgG) with negativity for alpha and mu heavy chains (IgA and IgM), indicating restriction to a single immunoglobulin class; (b) positive staining for a single gamma (IgG) sub-class (IgG1, IgG2, IGg3, or IgG4); (c) positive staining for a single light chain isotype (kappa or lambda) indicating monoclonality; (d) predominantly granular electron dense deposits in mesangial, sub-endothelial, and/or sub-epithelial locations on EM, resembling immune complex glomerulonephritis; (e) absence of clinical or laboratory evidence of cryoglobulinemia. The case under discussion fulfills these diagnostic criteria.

The age at presentation ranges from 20 to 80 years with a female predominance of 2:1. The presentation is varied and ranges from nephritic range proteinuria in 70% of the cases to nephritic syndrome in 50%, hematuria and renal dysfunction in 65% of the cases. [3]

The morphologic patterns on light microscopy are heterogenous [3] with majority of the cases showing a membranoproliferative pattern (57%) with diffuse glomerular capillary wall thickening and duplication, mesangial matrix expansion and mesangial hypercellularity. Few cases show an endocapillary proliferative pattern (35%) and the remaining minority showing membranous or mesangial proliferative patterns. [6],[7] Up to 30% of the cases may have focal or diffuse crescents. The IF findings include granular mesangial and glomerular capillary wall staining for IgG and a monotypic light chain staining, with most cases showing restriction to kappa light chains. Simultaneously, a restriction to a single immunoglobulin sub-class is required for diagnosis with most cases showing only IgG3 restriction which is supportive of a monoclonal nature of the deposits. In addition, C3 is almost always present with most cases also having C1q. EM usually demonstrates predominantly mesangial and sub-endothelial immune complex type electron dense deposits. The deposits are usually amorphous with some cases showing organized deposits. The disease is only rarely associated with multiple myelomas with serum and urine monoclonal proteins identifiable in only about 30% of the cases. [3]

Idiopathic MPGN is expected to recur in the allograft with clinical signs of proteinuria in 20-50% of the cases usually within four years. [8] Graft failure is commonly seen years after the diagnosis in 10-50% of the cases. [9] Recurrence of PGNMID in the renal allograft has only recently been described. [10] Subsequently Nasr et al gave a detailed description of four cases, three females and one male with a mean age of 58.5 years who developed recurrence of PGNMID in the renal allograft. Recurrence was first documented by biopsy after a mean period of 3.8 months posttransplant. Myeloma work up, in the form of serum immunofixation performed in all the patients, serum-free light chain assay performed in two patients and urine immunofixation performed in three patients were negative for a monoclonal protein. The recurrent disease was treated with high dose prednisone and rituximab in three cases, high dose prednisone and cyclophosphamide in one case, and plasmapheresis and acute dialysis in one case. The duration of follow-up ranged from 11 to 83 months and all patients had a reduction in proteinuria and three showed a reduction in serum creatinine. [4]

The index case had presented three months after renal transplant with graft dysfunction and only traces of albumin in the urine suggesting a possibility of rejection, which is consistent with the described cases in the literature. [4] He had developed a brain abscess in the immediate posttransplant period due to which mycophenolate was stopped, which suggests that the occurrence of the disease was related to reduced immunosuppression. This is also highlighted in the study by Nasr et al where it was stressed that recurrent disease may respond to early aggressive immunosuppressive therapy with high-dose prednisone and rituximab. Their study had also found an association between the presence of underlying autoimmune disease and recurrence of PGNMID in the allograft. The index case in this report did not have any such history. The differential diagnosis in the posttransplant setting would include de novo postinfectious glomerulonephritis and recurrent or de novo primary MPGN, if the monoclonality is not picked up. In the absence of IF and EM, transplant glomerulopathy and thrombotic micro-angiopathy would also enter into the differential diagnosis.

Conflict of interest: None declared.

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