Recurrence of IgM nephropathy in a renal allograft

Andrew H. J. Salmon, Dia Kamel and Peter W. Mathieson

Academic Renal Unit, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK

Correspondence and offprint requests to: Peter W. Mathieson, Academic Renal Unit, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK. Email: p.mathieson{at}bris.ac.uk

Keywords: allograft; IgM nephropathy; recurrence; renal



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
IgM nephropathy has been defined as ‘primary diffuse mesangioproliferative glomerulonephritis with IgM being deposited diffusely in the mesangium as the sole or dominant immunoglobulin on immunofluorescence examination’ [1]. IgM nephropathy was first described in 1978, in a series of 12 cases whose initial native renal biopsy specimens displayed mild glomerular mesangial hypercellularity on light microscopy, diffuse granular mesangial IgM deposition on immunofluorescence examination, and in whom systemic disease and other glomerulonephritides were excluded [2]. A series of 54 patients with IgM nephropathy used the same definition [1]. In both these series [1,2], a spectrum of clinical findings was noted, but the majority had heavy proteinuria with a normal creatinine at the time of original biopsy, and a poor response to prednisolone and immunomodulatory agents. Progression to end-stage renal failure was noted in a minority [1], only in patients whose repeat renal biopsy demonstrated focal segmental glomerulosclerosis (FSGS) with no significant change in immunofluorescence findings [1], and only in patients with nephrotic syndrome at presentation.

Other series of patients with ‘IgM nephropathy’ have included patients with FSGS [3] and normal glomeruli by light microscopy [4] on initial renal biopsy. The distinction between patients with IgM nephropathy as defined in the original report [2], and those with other renal biopsy findings, is an important one. Patients with immunofluorescence findings of IgM nephropathy, but normal glomeruli by light microscopy, typically display a clinical course similar to that of patients with minimal change disease [5], which is different from that described for patients with IgM nephropathy [1,2]. In addition, IgM deposition without accompanying glomerular abnormalities by light microscopy is reported to occur in up to 60% of normal kidneys donated for transplantation [6]. Patients with FSGS often have a poor prognosis, with frequent progression to end-stage renal disease. Inclusion of patients with FSGS on initial biopsy will skew data towards suggesting a poor outcome. It is important to adhere to strict pathological criteria in order to delineate those patients with true IgM nephropathy; the failure to identify IgM nephropathy as a distinct clinicopathological entity thus far may have resulted from failure to adhere to strict pathological criteria.

We present the case of a patient whose initial biopsy findings fulfil the criteria for IgM nephropathy, and in whom clinical and pathological features of IgM nephropathy recurred in a renal allograft, thus lending weight to the hypothesis that IgM nephropathy does constitute a distinct disease entity.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 9-year-old boy, with no significant past history, was admitted in May 1983 with nephrotic syndrome of 2 weeks duration. Serum albumin was 18 g/l, and urinary protein 3.5 g/day, without haematuria. Creatinine was normal, and there was no evidence of recent bacterial infection. A trial of prednisolone, alongside penicillin, fluid restriction and diuretics, was commenced for presumed minimal change disease. After 2 weeks, serum albumin was 32 g/l, proteinuria was 300 mg/day and weight had reduced by 5 kg.

Relapse of proteinuria occurred 4 months after cessation of prednisolone, following which persistent steroid dependent proteinuria was noted. Trials of cyclophosphamide (1 year duration) and levamisole (2 years duration) were introduced alongside prednisolone in 1987 and 1988, respectively, with no significant reduction in the frequency of relapses. In December 1990, at which time the patient was 16 years old, proteinuria persisted at 4.4 g/day, and a renal biopsy was undertaken. Eleven glomeruli were present, all with diffuse but mild mesangial cell proliferation and increased mesangial matrix, but none with sclerosis. Diffuse, granular IgM deposition, and to a lesser extent C1q deposition, was present in the mesangium, but without other immunoglobulins or complement components. Electron microscopy revealed occasional mesangial dense deposits (Figure 1A).



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Fig. 1. (A) Electron-dense deposits within the mesangium (arrow) in the first native renal biopsy (1990). Tissue was separated from the main core and processed for routine electron microscopy. Scale bar = 5000 nm. (B) Immunohistochemistry staining for IgM, showing granular and global deposition in sclerosed and non-sclerosed areas of a glomerulus, in the second native renal biopsy (1994). Original magnification x 250. (C) Haematoxylin and eosin staining of a 2 mm thick section of renal tissue demonstrating mild mesangial hypercellularity and increased mesangial matrix, in the fourth allograft renal biopsy (2001). Original magnification x 250.

 
Cyclosporin and lisinopril were added to prednisolone without effect; in March 1994, creatinine clearance had declined from the normal range to 70, and a second biopsy performed. On this occasion, nine of 10 glomeruli were completely or segmentally sclerosed, compatible with FSGS. Intact glomerular segments displayed mild mesangial hypercellularity and increased mesangial matrix. Immunoperoxidase examination in both sclerosed and non-sclerosed areas of glomeruli revealed dominant IgM staining in the same pattern as the previous biopsy (Figure 1B). Diffuse interstitial fibrosis, with mixed chronic inflammatory cells and foam cells were noted. Again, electron microscopy revealed mesangial dense deposits.

Renal function continued to decline inexorably, and both prednisolone and immunomodulatory agents were withdrawn in late 1995. Continuous ambulatory peritoneal dialysis was commenced in May 1996, with residual native urine output of ~1 l/day and proteinuria of 10.7 g/day. In August 1996, transplantation with a cadaveric renal allograft, with 0–0–0 mis-matching, was performed. Prednisolone and cyclosporin were initiated; initial graft function was good, and creatinine fell to 200 micromol/l.

Over the following 12 weeks, heavy proteinuria recurred and creatinine peaked twice; three allograft biopsies were undertaken. On all three occasions, interstitial inflammation and focal tubulitis consistent with acute cellular rejection were noted; in the third biopsy, mild venulitis and plump arteriolar endothelium associated with focal tubular loss suggested mild vascular rejection along with ongoing active cellular rejection. Glomeruli were normal by light microscopy on all three occasions. Immunofluorescence examination, performed on the last biopsy, revealed moderate, diffuse, granular mesangial IgM deposition, and to a lesser extent C1q deposition, with negative staining for IgA, IgG and C3c. No mesangial electron dense deposits were noted on electron microscopy of the third biopsy specimen. Pulses of methylprednisolone were administered on each occasion, and cyclosporin was converted to tacrolimus. Allograft function subsequently stabilized, with a creatinine of 180 micromol/l, serum albumin of ~40 g/l and proteinuria of 0.8 g/day.

In July 2001, proteinuria had risen to more than 10 g/day, and serum albumin had fallen to 25 g/l. Creatinine remained stable at 170 micromol/l. A further allograft biopsy was undertaken to assess for disease recurrence. All eight glomeruli present exhibited minor increases in both mesangial matrix and mesangial cellularity, without other light microscopic abnormalities (Figure 1C). Strong granular mesangial deposition of IgM was present, with lesser staining of C1q in the same distribution; IgA, IgG and C3c were negative. Electron microscopy revealed small dense deposits in the mesangium. Oral steroids were commenced alongside tacrolimus, leading to incomplete clinical resolution. Steroid-dependent nephrotic syndrome has ensued.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
We report a case of recurrent IgM nephropathy, in which immunopathological and clinical features concord with the literature [1,2]. Mesangial hypercellularity, increased mesangial matrix and diffuse granular mesangial IgM staining accompanied by electron dense deposits, suggestive of immune complex deposits, were demonstrated in the initial native biopsy, in non-sclerosed areas of the second native biopsy, and in the final allograft biopsy. Our case also resembles the clinical descriptions of previous reports of IgM nephropathy, in that the patient had nephrotic syndrome with a normal creatinine at the time of initial biopsy, and poorly responsive heavy proteinuria leading to end-stage renal failure.

Recurrence of IgM nephropathy in a renal allograft has been suggested twice previously. Myllymaki et al. [4] note one case of recurrent IgM nephropathy. However, patients with normal glomeruli by light microscopy were included in this study, and exact clinical and pathological details of the recurrent case are not provided. Solomon et al. [7] report a case of IgM nephropathy in which poorly responsive heavy proteinuria progressed to end-stage renal failure. They report recurrence 3 weeks after transplantation, similar in timing to that seen in cases of recurrence of FSGS; this is in contrast to recurrence at over 4 years in our case. The cases also differ with regard to pathological findings. Solomon et al. [7] acknowledge that, in their case, there were no glomeruli submitted for immunofluorescence in the initial biopsy, no glomeruli submitted for light microscopy or immunofluorescence in the renal allograft biopsy, and that these are ‘inadequate’ renal biopsy appearances. In contrast, we believe that our renal biopsy specimens confirm recurrent IgM nephropathy.

Heavy proteinuria was present in the first 2 weeks after transplantation in our case, and diffuse granular mesangial IgM deposition was noted in the third renal allograft biopsy. However, there were no glomerular abnormalities by light microscopy, nor electron dense deposits, in the first three allograft biopsies. Immunofluorescence examination often reveals IgM staining in renal allografts, but the significance of this finding in these circumstances is questionable without accompanying electron-dense deposits [8]. This suggests that the donor did not have IgM nephropathy, and that IgM nephropathy had not recurred at this time, as the aforementioned criteria for IgM nephropathy are not fulfilled. It is possible that proteinuria at this time represents residual proteinuria from the native kidneys. Proteinuria then resolved; when clinical features of IgM nephropathy reappeared, biopsies findings suggested recurrence of IgM nephropathy.

Many forms of glomerulonephritis are known to recur in renal allografts, but accurate diagnosis of ‘recurrent glomerulonephritis’ is essential. There are three ‘sine qua non’ which must be established before a diagnosis of recurrent glomerulonephritis can be made [9]. First, it is essential to have accurate pathological demonstration of the recipient's primary disease. Secondly, it is necessary to have an exact histological diagnosis of the disease which has occurred in the renal allograft. Thirdly, it is important to exclude the possibility that the renal allograft pathology was already present in the donor. We believe that all these criteria are satisfied in our patient.

Recurrence of a characteristic pathological lesion in a renal allograft, with appropriate clinical features, has been suggested to lend weight to the hypothesis that the disease which has recurred constitutes a distinct disease entity [10]. We believe that our case represents IgM nephropathy as described in the literature, and that the clinical and pathological features suggest recurrence of the disease following renal transplantation. This supports the notion that IgM nephropathy is a distinct disease entity. Our case correlates with the reports of previous authors, who have noted that patients with IgM nephropathy and nephrotic syndrome who develop FSGS have a less favourable prognosis than the remainder of patients with IgM nephropathy [1]. We add that there is a risk of recurrence of IgM nephropathy in patients who receive a renal allograft for end-stage renal failure as a consequence of progression of this disease.



   Acknowledgments
 
We thank Professor TG Feest for permission to report this patient under his care.

Conflict of interest statement. None.



   References
 Top
 Introduction
 Case
 Discussion
 References
 

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Received for publication: 18.11.03
Accepted in revised form: 28. 6.04





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