Proliferative glomerulonephritis with monoclonal IgG deposits manifesting as a nephrotic syndrome recently has been described as a renal disease with the pathological features of mesangial and subendothelial deposits of monoclonal IgG. Eight cases of recurrent proliferative glomerulonephritis with monoclonal IgG deposits after a renal transplant have been reported. Almost all of these patients had a certain remission of proteinuria by steroids alone or with cyclophosphamide, and had further remission through other special treatments (ie, rituximab and plasmapheresis).

We present a case of recurrent proliferative glomerulonephritis with monoclonal IgG deposits of the IgG3κ subtype after a renal transplant, which was insensitive to pulse intravenous methyl-prednisolone and cyclophosphamide remitted by double filtration plasmapheresis. This case report reveals that recurrent proliferative glomerulo-nephritis with monoclonal IgG deposits may be insensitive to intravenous pulse therapy of methylprednisolone and cyclophosphamide. We advocate double filtration plasmapheresis as an effective treatment of proliferative glomerulo-nephritis with monoclonal IgG deposits on remission of proteinuria.

Key words : Biopsy, Blood purification treatment, IgG3κ subtype, Recurrent renal disease, Renal allograft

Introduction

Renal transplant is one of the most effective renal replacement therapies for end-stage renal disease, of which most are primary or secondary glomer-ulonephritis. Golgert and associates¹ reported that the recurrent rate of glomerulonephritis of native kidney was 10% to 20%, and nearly 50% of these patients lost their renal grafts because of the recurrence.

Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID), which was first reported in 2004 by Nasr and associates,² has been a recently described renal disease with a morbidity rate of 0.17% (34/about 20 000),³ accounting for 0.07% (4/5443) of the diagnoses by renal biopsy.⁴

The main clinical manifestation of PGNMID is a nephrotic syndrome accompanied by varying degrees of microscopic hematuria, hypertension, and hypocomplementemia. Most notably, PGNMID has a pathological feature of mesangial and subendothelial deposits of monoclonal IgG. As with the other glomerulonephritis, PGNMID may recur after a renal transplant. Only 8 cases of recurrent PGNMID have been reported to date.^5-8 Almost all these patients had a remission of proteinuria after receiving therapy containing steroids alone or combined with cyclophosphamide; they had further remission through other special treatments, such as intravenous immunoglobulin and rituximab. We present a case of recurrent PGNMID of the IgG3κ subtype after a renal transplant, which was insensitive to pulse intravenous methylprednisolone and cyclophosphamide remitted by double filtration plasmapheresis (DFPP).

Case Report

A 41-year-old Chinese man with proteinuria of 1 year’s duration after a renal transplant was admitted to Jinling Hospital in Nanjing, China, in October 2012. Before the renal transplant, he underwent a native renal biopsy twice because of a nephrotic syndrome.

In August 2008 and August 2009, the patient underwent 2 renal biopsies at our center; the first was because of a nephrotic syndrome with normal renal function, and the second was because of recurrence of proteinuria with renal dysfunction after remission under treatment with steroids. All pathological findings revealed mesangial and subendothelial proliferation and deposits of IgG (Figures 1 A1-2, B1-2, C1-2, and F1-2). In the absence of immunofluorescence staining data of the IgG subclass, we made a diagnosis of type III membrano­proliferative glomerulonephritis. In September 2009, the patient received continuous ambulatory peritoneal dialysis because of progressive irreversible chronic renal dysfunction.

In September 2010, at another hospital, the patient underwent an ABO-compatible, living-related donor renal transplant with a kidney donated from his younger brother, who had no kidney disease. Intravenous basiliximab was given as inductive immunosuppressive therapy, and the maintenance immunosuppressants used initially were mycophenolate mofetil, cyclosporine, and prednisone. His serum creatinine (SCr) level decreased to normal on the fifth day after the renal transplant. In October 2011, after continuous proteinuria was detected, the patient received pulse therapy of intravenous methylprednisolone (500 mg/d × 3 d) and cyclo-sporine was replaced by tacrolimus, but the proteinuria did not remit.

In April 2012, the patient was admitted to our center for the duration of proteinuria after the renal transplant. The pathological manifestation of a graft biopsy was similar to the 2 native renal biopsies (Figures 1 A1-3, B1-3, C1-3, and F1-3). Because of prominent granular mesangial and capillary loops seen on staining of κ light chain on immuno-fluorescence microscopy (Figure 1 E3), we performed immunofluorescence staining of IgG subclass, which showed the deposits were monotypic with IgG3 (Figure 1 D3).

The retrospective analysis of the 2 native renal biopsies revealed the same results as the graft biopsy (Figures 1 D1-3 and E1-3). Thus, we confirmed a diagnosis of recurrent PGNMID of the IgG3κ subtype. We then added Tripterygium wilfordii Hook F (an immunosuppressant extracted from a traditional Chinese herb called Tripterygium wilfordii Hook F with potent anti-inflammatory properties), which led us to treat several autoimmune diseases (eg, rheumatoid arthritis, nephritis, and systemic lupus erythematosus) to previous immuno-suppressants (mycophenolate mofetil, tacrolimus, and methylprednisolone combined with amlodipine, and valsartan).

In July 2012, because there was no remission of proteinuria, the patient underwent pulse therapy of intravenous cyclophosphamide (1.0 g/mo × 3 mo) at the hospital where he received the renal transplant, but there was still no remission of proteinuria.

In October 2012, the patient visited our center again for further treatment. On admission, his laboratory findings included proteinuria of 4.05 g/24 hours, albumin of 25.6 g/L, SCr of 83.98 μmol/L, estimated glomerular filtration rate of 92.86 mL/min/1.73 m² (Modification of Diet in Renal Disease Study Equation), blood urea nitrogen of 10.92 mmol/L, and hemoglobin of 92 g/L. During hospitalization, he underwent treatment of DFPP on 3 occasions with an additional complement of plasma and intravenous immunoglobulin. With these therapies, he was discharged with proteinuria of 1.33 g/24 hours, albumin of 43.1 g/L, SCr of 54.81 μmol/L, estimated glomerular filtration rate of 151.95 mL/min/1.73 m², blood urea nitrogen of 5.03 mmol/L, and hemoglobin of 94 g/L.

In January 2013, the patient died of severe pulmonary infection with a functioning renal allograft. His clinical course is shown in Figure 2.

Discussion

As mentioned, the first description of PGNMID was in 2004, when Nasr and associates² presented a group of 10 cases with this disease. Light microscopy showed proliferative glomerulonephritis, whereas immunofluorescence microscopy revealed mesangial and capillary loops staining of monoclonal IgG and light chain (4 IgG3κ, 2 IgG1κ, 1 IgGλ, 1 IgG1λ, 1 IgG2λ, and 1 IgG3λ); electron microscopy showed mesangial and subendothelial electron-dense deposits. Without immunofluorescence staining of IgG subclass and light chain, it is difficult to distinguish PGNMID from membranoproliferative glomerulonephritis. Recently, PGNMID has been reported more often because of the gradual recognition of this disease and the extensive application of immunofluorescence staining of IgG subclass, but the number of cases is limited.

The pathogenesis of PGNMID is unknown. The disease may result from an immune response activated by endogenous or exogenous antigens during which monoclonal immunoglobulins produced by B cells are deposited in glomeruli owing to self-aggregation. Proliferative glomerulonephritis with monoclonal IgG deposits of the IgG3 subtype are the most common, which probably result from the special properties of IgG3: IgG3 has the highest isoelectric point of all isotypes, giving it the strongest affinity to glomerular basement membranes, and it has the largest molecular weight and ability of self-aggregation by Fc-Fc interaction—2 features that promote its deposition in glomeruli and increase the filtration difficulty by the glomerular filtration barrier. Furthermore, IgG3 has the greatest complement-fixing activity, which makes it stimulate proliferation of glomerular cells and the infiltration of inflammatory cells recruited by the activation of inflammatory mediators.

So far, 10 cases of PGNMID after a renal transplant have been reported,^5-8 from which 8 are recurrent cases and 2 are de novo cases (Table 1). The overall prognosis is poor: 4 cases lost the renal graft, from which 2 died. The major therapeutic regimens of recurrent PGNMID are based on pulse treatment of steroids. Nasr and associates5 have described 3 cases with therapy containing rituximab, or combining therapy with plasmapheresis, and 1 case with treatment containing oral cyclophosphamide. Ranghino and associates7 treated a patient with plasmapheresis, and in both these studies, the patients had remission of proteinuria and graft dysfunction.

We present a case of recurrent PGNMID of the IgG3κ subtype after a renal transplant, which was insensitive to intravenous pulse therapy of methylprednisolone and cyclophosphamide. Double filtration plasmaphereses as a treatment with a more efficient clearance of pathogenic immunoglobulin and a minimal loss of nonpathogenic substance has been widely used to remove autoantibodies in vasculitides⁹ and systemic lupus erythematosus.¹⁰ Therefore, we chose DFPP to treat this patient. Although he had a partial remission of proteinuria with normal graft function after the DFPP (Figure 2), he died of severe infections with a functioning renal allograft. We believe the pulse intravenous cyclophosphamide might have been the primary cause of the severely immunocompromised status of the patient.

In conclusion, the present case reveals that recurrent PGNMID of IgG3κ subtype after a renal transplant may be insensitive to intravenous pulse therapy of methylprednisolone and cyclophos-phamide. We advocate that DFPP may be an effective treatment of PGNMID for remission of proteinuria, despite the possible delay of previous pulse therapies. Also, we believe that the immediate application of DFPP after diagnosing PGNMID may make better curative effects and reduce the risk of severe infections caused by some intensive immunosuppressive therapies. To elucidate the definite pathogenesis, effective prevention and treatment of recurrent PGNMID after a renal transplant, additional studies of large samples are needed.

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