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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2016  |  Volume : 27  |  Issue : 2  |  Page : 381-385
Early recurrence of proliferative glomerulonephritis with monoclonal immunoglobulin deposits in a renal allograft


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

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Date of Web Publication11-Mar-2016
 

   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;27:381-5

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 2019 Dec 11];27:381-5. Available from: http://www.sjkdt.org/text.asp?2016/27/2/381/178568

   Introduction Top


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 Top


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: A panel of photomicrographs of the first (native) renal biopsy. (a) Glomerulus showing mesangial matrix expansion with thickening of the glomerular capillary walls (H and E, ×100). (b) Extensive sub-endothelial and mesangial immune complex type electron dense deposits (Electron photomicrograph, ×13300). (c) Immunofluorescence for IgG antisera showing intense positivity along the glomerular capillary walls and mesangium. (d) Immunofluorescence for C3 antisera showing intense positivity along the glomerular capillary walls and mesangium.

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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: A panel of photomicrographs of the second (allograft) renal biopsy. (a) Enlarged glomerulus with accentuated lobulation, thickening of the glomerular capillary walls (thin arrow) along with mesangial expansion and increase in mesangial and endocapillary cellularity (block arrow) (H and E ×40). (b) Another glomerulus showing capillary wall thickening, focal reduplication (thin arrow), and mesangial matrix expansion (block arrow) (periodic-acid Schiff ×40). (c) Immunofluorescence for IgG antisera showing intense granular mesangial and capillary wall staining. (d) Immunofluorescence for kappa antisera showing intense granular mesangial and capillary wall staining. (e) Immunofluorescence for lambda antisera showing no staining. (f) Immunofluorescence for IgG1, IgG2, IgG3, and IgG4 antisera showing positivity only for IgG3.

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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 Top


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.

 
   References Top

1.
Markowitz GS. Dysproteinemia and the kidney. Adv Anat Pathol 2004;11:49-63.  Back to cited text no. 1
    
2.
Lin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immunoglobulin deposition disease: The disease spectrum. J Am Soc Nephrol 2001;12:1482-92.  Back to cited text no. 2
    
3.
Nasr SH, Satoskar A, Markowitz GS, et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol 2009;20:2055-64.  Back to cited text no. 3
    
4.
Nasr SH, Sethi S, Cornell LD, et al. Proliferative glomerulonephritis with monoclonal IgG deposits recurs in the allograft. Clin J Am Soc Nephrol 2011;6:122-32.  Back to cited text no. 4
    
5.
Nasr SH, Markowitz GS, Stokes MB, et al. Proliferative glomerulonephritis with monoclonal IgG deposits: A distinct entity mimicking immune-complex glomerulonephritis. Kidney Int 2004;65:85-96.  Back to cited text no. 5
    
6.
Komatsuda A, Wakui H, Ohtani H, Nimura T, Sawada K. Steroid-responsive nephrotic syndrome in a patient with proliferative glomerulonephritis with monoclonal IgG deposits with pure mesangial proliferative features. NDT Plus 2010;3:357-9.  Back to cited text no. 6
    
7.
Masai R, Wakui H, Komatsuda A, et al. Characteristics of proliferative glomerulonephritis with monoclonal IgG deposits associated with membranoproliferative features. Clin Nephrol 2009;72:46-54.  Back to cited text no. 7
    
8.
Floege J. Recurrent glomerulonephritis following renal transplantation: An update. Nephrol Dial Transplant 2003;18:1260-5.  Back to cited text no. 8
    
9.
Lorenz EC, Sethi S, Leung N, Dispenzieri A, Fervenza FC, Cosio FG. Recurrent membranoproliferative glomerulonephritis after kidney transplantation. Kidney Int 2010;77:721-8.  Back to cited text no. 9
    
10.
Albawardi A, Sataskar A, Brodsky S, Nadasdy GM, Nadasdy T. Proliferative glomerulonephritis with monoclonal IgG deposits recurs or may develop de novo in renal allografts [Abstract]. Mod Pathol 2010;23:337A.  Back to cited text no. 10
    

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Correspondence Address:
Rohit Tewari
Department of Pathology, Armed Forces Medical College, Pune, Maharashtra
India
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DOI: 10.4103/1319-2442.178568

PMID: 26997395

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