ARCHIVIO CASI


Membranous Glomerulonephritis After Bone
Marrow Transplantation for Multiple Myeloma

Licia Rossi, Francesca Cardarelli, Maria L. Vampa, Carlo Buzio, Giorgio Olivetti1

Dipartimenti di Clinica Medica, Nefrologia e Scienze della Prevenzione e di Patologia e Medicina di Laboratorio1, Sezione di Anatomia Patologica, Università degli Studi, Parma, Italy

Key words: graft-versus-host disease; membranous glomerulonephritis; nephrotic syndrome; transplantation; cyclosporine.

Abstract             
Renal involvement during graft-versus-host disease following haematopoietic cell transplantation for multiple myeloma has never been described.  We report a case of a recipient who developed  nephrotic syndrome and membranous glomerulonephritis 22 months after the graft and six months after Cyclosporine withdrawal. Symptoms resolved  when  immunosuppressive therapy was reinstituted.

Introduction
The occurrence of  renal disorders after haematopoietic cell transplantation (HCT) and graft-versus-host disease (GVHD) is a rare event SYMBOL 91 \f "Symbol" \s 12 [ Table 1SYMBOL 93 \f "Symbol" \s 12 ] and has been described in a limited number of patients SYMBOL 91 \f "Symbol" \s 12 [ 1-9SYMBOL 93 \f "Symbol" \s 12 ] .  In general,  important alterations of the glomerular permeability occur and all the patients develop heavy proteinuria and/or nephrotic syndrome.  The renal damage seems to be the consequence of antibodies induced by GVHD although the precise mechanism that may alter glomerular  capillaries is still unknown.  Symptoms develop irrespective of  the original illness.  Interestingly, in some cases renal involvement  has  been detected after Cyclosporine (CsA) withdrawal and the glomerular leakage of proteins decreased or disappeared after the reinstitution of the immunosuppressive therapy.

In the present report we describe a patient who received HCT for multiple myeloma and developed membranous glomerulonephritis (MG) with nephrotic syndrome.


p. Case
A 54-year-old man underwent a non T cell depleted HCT from his HLA- identical brother for treatment of multiple myeloma IgGSYMBOL 108 \f "Symbol" \s 12 l on February 1997. At that time although Bence-Jones protein (SYMBOL 108 \f "Symbol" \s 12 l light chain) was present in the urine, there was not evidence of renal impairment since serum creatinine and 24 h proteinuria were within normal limits.   He was conditioned with melphalan followed by cyclophosphamide and total body irradiation. To prevent GVHD, from day -1 CsA and methotrexate at high dosage were administered.  A few days after HCT he developed a Grade I GVHD of the skin requiring the addition to the treatment of methyl-prednisolone subsequently discontinued on May 1997.   The initial dose of CsA was 100 mg twice a day then gradually tapered off and finally withdrawn in June 1998.  The patient remained without therapy and free of symptoms until the end of December 1998 when he was admitted to our Hospital for the appearance of nephrotic syndrome with pedal edema and a gain of 4 Kg in body weight.  Arterial blood pressure was 150/105 mmHg.  A normochromic and normocytic moderate anaemia (haemoglobin 9.4 g/dl; hematocrit 27.3%; RBC 3.030.000/mm3 ), mainly  related to the conditioning therapy, was present. White blood cell count was 7770/SYMBOL 109 \f "Symbol" \s 12 m L, platelet count 408000/SYMBOL 109 \f "Symbol" \s 12 m L, serum creatinine 1.8 mg/dl, urea 59 mg/dl, albumin  2.5 g/dl, cholesterol 277 mg/dl.  Proteinuria was 7 g/24-hour.  Immunoglobulins were: IgG 512 mg/dl,   IgA 65mg/dl  IgM 59mg/dl. No evidence of monoclonal band was seen in the serum electrophoresis, but the persistence of a minimal disease was indicated by a SYMBOL 107 \f "Symbol" \s 12 k /SYMBOL 108 \f "Symbol" \s 12 l ratio of  0.74.

On February 1999 a percutaneous renal biopsy was performed to establish the underlying disease.  On light microscopy 22 glomeruli were seen, 8 of them completely sclerotic. In the remaining 14 different findings were found in different glomeruli.  Most of the glomeruli had a normal appearance without significant alterations.  In others a segmental damage with enlargement of the mesangial regions was apparent SYMBOL 91 \f "Symbol" \s 12 [ Figura 1 ]. In all glomeruli  the  basement membranes were thin and the silver stain did not revealed any  “spikes”.  Focal areas of tubular atrophy, fine interstitial fibrosis with a small number of chronic inflammatory cells were also present. The wall of small arterioles was moderate thickened. Congo Red staininig for amyloid was negative. By immunofluorescence a granular deposition of antisera against IgG [Figura 2], IgA, C3 and SYMBOL 107 \f "Symbol" \s 12 k and SYMBOL 108 \f "Symbol" \s 12 l chains along the external side of the basement membrane was detected in all glomeruli.  The intensity of the fluorescence was approximately similar for immunoglobulins and light chains. By electron microscopy the capillary wall was altered for the presence of electron dense globular material in the sub-epithelial aspect of the basement membrane  [Figura 3]. Furthermore, large areas of effacement of foot process in several capillaries  were present.  In   addition,  the mesangium   was   moderately    enlarged with an increased number of cells and matrix. By the combination of light and electron microscopy a diagnosis of  membranous glomerulonephritis at an early stage of development was made. The large number of sclerotic glomeruli that may indicate a preexisting renal disease was attributed to the coexistence of hypertension. 

Approximately one month after renal biopsy,  the patient was readmitted for treatment. Serum creatinine was 1.5 mg/dl and  urea 59 mg/dl.  Proteinuria was 6.5 g/24 h.  The search for antinuclear antibodies, antibodies to native DNA, cryoglobulins and immune-complexes was negative; C3 and C4 levels were within the normal range. Seventy-five days after the onset of the nephrotic syndrome 100 mg twice a day of CsA and 25 mg/day of prednisone were given. Thereafter, CsA was adjusted at a dosage of 150 mg/day to maintain serum level between 100 and 200 ng/ml, and prednisone was decreased to 12.5 mg/day and then withdrawn 2 months later.  After 26 weeks of treatment,  the proteinuria decreased to 190 mg/24 h and the nephrotic syndrome completely  recovered. Anaemia was still present in last controls.

Discussion 
In Table 1 the major characteristics of patients in which renal involvement developed after allogeneic HCT are listed. Most of the patients were affected by  lymphoma or leukemias.  The development of GVHD was either immediate or lasting several months after the transplantation. MG was the prevailing pathologic finding  although minimal change disease with nephrotic syndrome was also found SYMBOL 91 \f "Symbol" \s 10 [ 1;5SYMBOL 93 \f "Symbol" \s 10 ] . The high frequency of positive ANA seen in five out of ten patients may be explained by the variety of autoantibodies detected during GVHD [10].

The role played by CsA is intriguing. Renal symptoms develop either during full dose therapy SYMBOL 91 \f "Symbol" \s 10 [ 3SYMBOL 93 \f "Symbol" \s 10 ] , during tapering SYMBOL 91 \f "Symbol" \s 10 [ 4SYMBOL 93 \f "Symbol" \s 10 ] or after discontinuation of  the drug SYMBOL 91 \f "Symbol" \s 10 [ 2SYMBOL 93 \f "Symbol" \s 10 ] . CsA  affects  cell-mediated immunity,  is nephrotoxic  with involvement of  tubules and arterioles, but the occurrence of  MG has never been described.  The possibility may be advanced that withdrawal or insufficient immunosuppression may enhance the production of antibodies and the genesis of renal damage. This hypothesis is supported by the efficacy of CsA treatment on the disappearance of proteinuria in recipients of HCT or in patients with idiopathic MG SYMBOL 91 \f "Symbol" \s 10 [ 1-9; 11SYMBOL 93 \f "Symbol" \s 10 ] . However, a cell-mediated immune injury cannot be completely excluded because a defect in T-cell populations has been detected in MG and in minimal change nephrotic syndrome SYMBOL 91 \f "Symbol" \s 10 [ 11; 12SYMBOL 93 \f "Symbol" \s 10 ].
 
GVHD is a life-threatening very complex disease involving several tissues and organs, more often the skin, gastrointestinal tract and the liver mimicking biological and clinical symptoms of systemic lupus erythematosus or other immune-complex mediated disorders SYMBOL 91 \f "Symbol" \s 10 [ 13SYMBOL 93 \f "Symbol" \s 10 ] .  It appears to be induced by the presence of autoantibodies against major histocompatibility complex minor antigens produced by the interaction between donor’s alloreactive T-helper cells and recipient’s autoreactive B-cells SYMBOL 91 \f "Symbol" \s 10 [ 2;4;6SYMBOL 93 \f "Symbol" \s 10 ].
 
GVHD has an acute or chronic evolution and it is one of the most important causes of morbidity and mortality following HCT.  The renal involvement in GVHD is occasional and may be attributed to deposition on glomerular capillaries of immune-complexes as hypothesised in idiopathic forms of MG.  Alternatively, antibodies may bound to antigens already planted on the epithelial aspect of the glomerular basement membrane, as demonstrated with tubular antigens in experimental models of MG SYMBOL 91 \f "Symbol" \s 10 [ 3;14SYMBOL 93 \f "Symbol" \s 10 ] .  In this regard a number of reports have demonstrated that IgG4 predominates in idiopathic or secondary MG [15;16] suggesting that the initiating glomerular antigen may predominantly stimulate a Th2-type nephritogenic  immunoresponse  [17].

On the basis of available information MG in our patient was interpreted as renal manifestation of chronic GVHD.  This conviction is also supported by the results obtained in the murine model of GVHD in which parental-strain lymphocytes injected into F1 hybrid recipients produce a lupus-like nephropathy with glomerular alterations reminiscent of MG, nephrotic syndrome and different classes of autoantibodies including anti native-DNA and anti renal tubular antigens SYMBOL 91 \f "Symbol" \s 10 [ 4SYMBOL 93 \f "Symbol" \s 10 ].

Genetic influences in the occurrence of MG may be excluded since the HLA aplotype of our patient  (A2, A3; B51(5), BW4; DR W 13(W6), DR W 8, DR W 52; DQ W 1, DQ W4) is not considered to be susceptible to develop MG [18].
 
It is tempting to speculate that in our patient different classes of antibodies induced by GVHD may have elicited glomerular lesions and activated the processes responsible for the development of MG which involves Th2 lymphocytes and IgG4 formation. CsA therapy by blocking T helper cells proliferation may have reduced IgG4 production and the consequent glomerular damage.

Acknowledgement
We wish to give special thanks to Dr. F. Pilato, Dipartimento di Anatomia Patologica,  Dr L. Allegri and Dr L. Carnevali, Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università degli Studi, Parma, Italy.

 

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