Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Membranous nephropathy and lupus-like syndrome after hematopoietic cell transplantation: a case report

  • Kostas Stylianou1Email author,
  • Stavros Stratakis1,
  • Vasiliki Mavroeidi1,
  • Ioannis Petrakis1,
  • Dimitris Xydakis1,
  • Eleftheria Vardaki1,
  • Spyros Stratigis1,
  • Kostas Perakis1,
  • Theodora Katsarou1,
  • Peggy Kanellou2,
  • Irene Xylouri2,
  • Constantina Petraki3,
  • Michael Alexandrakis2 and
  • Eugene Daphnis1
Journal of Medical Case Reports20104:303

https://doi.org/10.1186/1752-1947-4-303

Received: 8 November 2009

Accepted: 10 September 2010

Published: 10 September 2010

Abstract

Introduction

The kidney is increasingly recognised as a target organ of chronic graft-versus-host disease after hematopoietic cell transplantation in the context of the development of the nephrotic syndrome. Chronic graft-versus-host disease is associated with autoimmune phenomena similar, but not identical, to those observed in various rheumatologic disorders, implicating autoimmunity as an important component of the disease.

Case presentation

We report the case of a 57-year-old Caucasian man who developed the nephrotic syndrome due to membranous nephropathy in association with recurrent chronic graft-versus-host disease, along with a lupus-like syndrome manifested with pancytopenia, hair loss, positive anti-DNA antibodies and sub-epithelial and mesangial immune deposits. To the best of our knowledge, this is the first case reported in the literature. The nephrotic syndrome subsided soon after he was treated with a short course of cyclosporin with steroids. Unfortunately he died seven months later due to a relapse of leukemia.

Conclusions

Our case report confirms the notion that chronic graft-versus-host disease is characterized by the appearance of autoimmune phenomena similar, but not identical, to those seen in autoimmune diseases. The decision for more immunosuppression has to be weighed against the need for preservation of the graft versus leukemia phenomenon.

Introduction

Acute graft-versus-host disease (aGVHD) has traditionally been defined as a syndrome occurring during the first 100 days following allogeneic hematopoietic cell transplant (HCT). aGVHD occurs in 9 to 50 percent of patients who receive HCT, despite intensive prophylaxis with immunosuppressive agents [1].

Chronic graft-versus-host disease (cGVHD), by definition, appears over 100 days after HCT and is associated with autoimmune phenomena [2]. Auto-antibodies found in patients with cGVHD are similar, but not identical, to those observed in various rheumatologic disorders, implicating autoimmunity as an important component of cGVHD [3].

The kidney is increasingly recognised as a target organ of cGVHD in the context of the development of the nephrotic syndrome (NS) [49]. We report the case of a man who developed NS due to membranous nephropathy (MN), three years after HCT, along with clinical and laboratory findings resembling systemic lupus erythematosus (SLE).

Case presentation

A 57-year-old Caucasian man was referred to our renal ward when he was found to have developed NS. Five years earlier, he had been diagnosed with acute myelogenous leukemia (AML-M2) for which he received induction therapy with cytarabine and idarubicin followed by mitoxantrone and VP-16, with complete response. One year later he underwent HCT from his HLA-identical sister at his first relapse. Their compatibility was complete for HLA A1,24, B8,35, CW4,7, BW6, DR11, DRW52, DRB1, DRB2 and the transplant came from peripheral blood stem cells. Busulfan and cyclophosphamide were given as a conditioning regimen and cyclosporin plus methotrexate as a prophylaxis for GVHD. Methotrexate was discontinued at day 30 and cyclosporin was gradually tapered until it was stopped at six months. Despite prophylaxis, he developed extensive cGVHD with widespread skin eruption and elevated liver enzymes eight months after HCT. He was then restarted on cyclosporin for two months and prednisone which was discontinued 12 months later when all signs and symptoms of cGVHD had subsided. After cessation of the immunosuppressants, he gradually developed hypertension, proteinuria (2 g/d), mild creatinine elevation (133 μmol/L) and elevated liver enzymes (SGOT 200 U/L, SGPT 207 U/L, ALP 197 U/L, LDH 479 U/L). Reinstitution of prednisone resulted in a clinical improvement but six months after the cessation of steroids he developed NS with anasarca, proteinuria (4 g/d), hypoalbuminemia (1.7 g/dl), and elevated serum creatinine (150.3 μmol/L). An attempt by the treating physicians to obtain kidney tissue by a biopsy was not successful at this time so he was empirically commenced on furosemide (80 mg/d), enalapril (10 mg/d) and methylprednisolone (48 mg/d) with subsequent improvement of proteinuria and his renal function.

One year later, when steroids had been withdrawn due to a worsening cataract, he presented with pancytopenia, alopecia and a relapse of NS. At this point he was referred to the renal ward of our hospital for the first time. On clinical examination, he was apyrexial with pitting edema in both of his legs, loss of hair in his armpits and on his head, and poikiloderma lesions on his arms and trunk. A laboratory investigation showed the following: hemoglobin 9 g/dl; white blood cell count 4800/μl (28 percent neutrophils, 60 percent lymphocytes, 12 percent monocytes, no blasts); platelets 98000/μl; serum creatinine 212 μmol/L; increased liver enzymes (SGOT 97 U/L, SGPT 51 U/L, ALP 235 U/L, LDH 578 U/L); and nephrotic range proteinuria 4.3 g/d. Urine analysis showed increased erythrocytes (20/HPF, 70 percent dysmorphic), few mixed casts (consisting of white blood cells, tubular epithelial cells and rare erythrocytes), few oval fat bodies and plenty of hyaline casts. Virology tests for human immunodeficiency virus (HIV), cytomegalovirus (CMV), hepatitis B virus (HBV) and hepatitis C virus (HCV) were negative. His serum immunoglobulins, C3, C4, rheumatoid factor, anti-mitochondrial antibodies and anti-nuclear cytoplasmic antibodies (ANCA) were all normal. A direct Coomb's test was negative, anti-nuclear antibodies (ANA) were positive (1/320 diffuse staining) and anti-dsDNA antibodies were also positive by enzyme-linked immunosorbent assay (ELISA) (74 IU/ml). However, the crithidia luciliae immunofluorescence test (CLIFT) was negative.

A bone-marrow biopsy did not display any recurrence of the leukemia, while a chimerism analysis showed complete donor-type cells. At this point, a renal biopsy was performed to elucidate the underlying cause of proteinuria. The kidney specimen contained 31 glomeruli. Six of them were globally sclerotic and three had segmental sclerosis. The remaining 22 showed mild thickening of the capillary walls with segmental spike formation. Immunohistochemistry revealed diffuse deposits of IgG and C3 on the outer aspect of his glomerular capillary wall and segmental mesangial IgM deposits. Electron microscopy showed diffuse sub-epithelial deposits and foot processes fusion. These findings were consistent with MN stage I, accompanied by focal sclerotic lesions (Figure 1).
Figure 1

A. Mild thickening and rigidity of the glomerular capillary walls with slight dilatation of the capillary lumens [JMSx400]; B. Focus of tubular atrophy and interstitial fibrosis (white arrow), global wrinkling and sclerosis of a glomerulus (white arrowhead) [JMSx200]; C. IgG immunohistochemical expression in glomerular capillary walls (black arrows) [IgGx400]; D. Sub-epithelial dense deposits (white arrow), effacement of epithelial foot processes and segmental spike formation (×13000).

Complete resolution of the NS, improvement of his renal function (serum creatinine 168 μmol/L) and a restoration of pancytopenia were achieved within two months of treatment with cyclosporin (150 mg/d) and methylprednisolone (36 mg/day) with subsequent tapering.

Six months later, he manifested a relapse of acute leukemia. He refused to undergo a second transplant with a reduced intensity preparative regimen, so an attempt was made to achieve remission by chemotherapy alone. Unfortunately he died of sepsis one month later.

Discussion

Most cases of NS post HCT develop a few months after minimization or cessation of a GVHD prophylaxis regimen [610]. The principal histological entity reported is MN followed by minimal change disease, while other diagnoses are very rare. Almost all patients have presented some kind of GVHD (acute or chronic) prior to the development of proteinuria. The treatment of the NS post HCT is achieved mainly by steroids and cyclosporin [610].

To the best of our knowledge, this is the first reported case of a patient with MN post HCT fulfilling the clinical and laboratory criteria for the diagnosis of SLE (pancytopenia, glomerulonephritis, high anti-dsDNA titres and hair loss). Another reported patient with positive anti-dsDNA antibodies was a 12-year old girl who developed minimal change disease (MCD) after an umbilical-cord blood transplantation, without other manifestations of SLE [11]. The presence of segmental IgM deposits in the mesangium supports the diagnosis of secondary MN which, in connection with the positive anti-dsDNA antibodies, raises the possibility of a membranous nephropathy secondary to lupus. Nevertheless, alopecia and immune cytopenias are both well-known features of cGVHD, while IgM deposits in the mesangium have been reported in few other cases of glomerulonephritis post HCT [7]. Moreover, the temporal association of proteinuria with recurrent cGVHD manifestations, the rapid resolution of NS after a short course of cyclosporin and steroids, the diffuse ANA staining pattern and the negative CLIFT test, reduce the possibility of a true lupus MN and make more likely the diagnosis of an MN secondary to cGVHD with associated lupus-like manifestations.

Finally, our case report also raises the possibility that a more intensive blockade of the renin-angiotensin system with less immunosuppression may be more appropriate for the treatment of NS post HCT.

Conclusions

NS post HCT is a late complication usually presenting after withdrawal of GVHD prophylaxis therapy. cGVHD is characterized by the appearance of autoimmune phenomena similar, but not identical, to those seen in autoimmune diseases. The decision for more immunosuppression has to be weighed against the need for preservation of the graft versus leukemia phenomenon.

Consent

Written informed consent was obtained from the patient's next-of-kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Abbreviations

aGVHD: 

acute graft-versus-host disease

AML: 

acute myelogenous leukemia

ANA: 

anti-nuclear antibodies

ANCA: 

anti-nuclear cytoplasmic antibodies

cGVHD: 

chronic graft-versus-host disease

CLIFT: 

crithidia luciliae immunofluorescence test

CMV: 

cytomegalovirus

ELISA: 

enzyme-linked immunosorbent assay

HBV: 

hepatitis B virus

HCV: 

hepatitis C virus

HCT: 

hematopoietic cell transplantation

HIV: 

human immunodeficiency virus

HLA: 

human leukocytes antigen

HPF: 

high power field

MCD: 

minimal change disease

MN: 

membranous nephropathy

NS: 

nephrotic syndrome

SLE: 

systemic lupus erythematosus.

Declarations

Authors’ Affiliations

(1)
Nephrology Department, Heraklion University Hospital
(2)
Hematology Department, Heraklion University Hospital
(3)
Department of Pathology, Evaggelismos Hospital

References

  1. Reddy P: Pathophysiology of acute graft-versus-host disease. Hematol Oncol. 2003, 21: 149-161. 10.1002/hon.716.View ArticlePubMedGoogle Scholar
  2. Higman M, Vogelsang GB: Chronic graft versus host disease. Br J Haematol. 2004, 125: 435-454. 10.1111/j.1365-2141.2004.04945.x.View ArticlePubMedGoogle Scholar
  3. Tyndall A, Dazzi F: Chronic GVHD as an autoimmune disease. Best Pract Best Pract Res Clin Haematol. 2008, 21: 281-289. 10.1016/j.beha.2008.03.003.View ArticlePubMedGoogle Scholar
  4. Rao PS: Nephrotic syndrome in patients with peripheral blood stem cell transplant. Am J Kidney Dis. 2005, 45: 780-785. 10.1053/j.ajkd.2005.01.003.View ArticlePubMedGoogle Scholar
  5. Srinivasan R, Balow JE, Sabnis S, Lundqvist A, Igarashi T, Takahashi Y, Austin H, Tisdale J, Barrett J, Geller N, Childs R: Nephrotic syndrome: an under-recognised immune-mediated complication of non-myeloablative allogeneic haematopoietic cell transplantation. Br J Haematol. 2005, 131: 74-79. 10.1111/j.1365-2141.2005.05728.x.View ArticlePubMedGoogle Scholar
  6. Brukamp K, Doyle AM, Bloom RD, Bunin N, Tomaszewski JE, Cizman B: Nephrotic syndrome after hematopoietic cell transplantation: do glomerular lesions represent renal graft-versus-host disease?. Clin J Am Soc Nephrol. 2006, 1: 685-694. 10.2215/CJN.00380705.View ArticlePubMedGoogle Scholar
  7. Chang A, Hingorani S, Kowalewska J, Flowers ME, Aneja T, Smith KD, Meehan SM, Nicosia RF, Alpers CE: Spectrum of renal pathology in hematopoietic cell transplantation: a series of 20 patients and review of the literature. Clin J Am Soc Nephrol. 2007, 2: 1014-1023. 10.2215/CJN.01700407.View ArticlePubMedGoogle Scholar
  8. Troxell ML, Pilapil M, Miklos DB, Higgins JP, Kambham N: Renal pathology in hematopoietic cell transplantation recipients. Mod Pathol. 2008, 21: 396-406. 10.1038/modpathol.3801011.View ArticlePubMedGoogle Scholar
  9. Chan GS, Lam MF, Au WY, Chim S, Tse KC, Lo SH, Fung SH, Lai KN, Chan KW: Clinicopathologic analysis of renal biopsies after haematopoietic stem cell transplantation. Nephrology (Carlton). 2008, 13: 322-330. 10.1111/j.1440-1797.2007.00915.x.View ArticleGoogle Scholar
  10. Lin J, Markowitz GS, Nicolaides M, Hesdorffer CS, Appel GB, D'Agati VD, Savage DG: Membranous glomerulopathy associated with graft-versus-host disease following allogeneic stem cell transplantation. Report of 2 cases and review of the literature. Am J Nephrol. 2001, 21: 351-356. 10.1159/000046273.View ArticlePubMedGoogle Scholar
  11. Lee JH, Kwon BS, Ha IS, Cheong HI, Moon KC, Ahn HS, Choi Y: Nephrotic syndrome in a child after umbilical-cord-blood transplantation. Pediatr Nephrol. 2006, 21: 1312-1317. 10.1007/s00467-006-0171-x.View ArticlePubMedGoogle Scholar

Copyright

© Stylianou et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.