Kidney Biopsy Teaching Case Membranous Nephropathy as a Manifestation of Graft-VersusHost Disease: Association With HLA Antigen Typing, Phospholipase A2 Receptor, and C4d Cathryn J. Byrne-Dugan, MD,1 A. Bernard Collins, BS,2 Albert Q. Lam, MD,3,* and Ibrahim Batal, MD1,* Glomerulopathy is an uncommon but increasingly recognized complication of hematopoietic cell transplantation. It typically manifests as membranous nephropathy, less commonly as minimal change disease, and rarely as proliferative glomerulonephritis. There is evidence to suggest that these glomerulopathies might represent manifestations of chronic graft-versus-host disease. In this report, we focus on membranous nephropathy as the most common form of glomerulopathy after hematopoietic cell transplantation. We present a case of membranous nephropathy that developed 483 days post–allogeneic hematopoietic stem cell transplantation in a patient with a history of acute graft-versus-host disease. We also share our experience with 4 other cases of membranous nephropathy occurring after allogeneic hematopoietic stem cell transplantation. Clinicopathologic correlates, including the association with graft-versus-host-disease, HLA antigen typing, glomerular deposition of immunoglobulin G (IgG) subclasses, subepithelial colocalization of IgG deposits with phospholipase A2 receptor staining, C4d deposition along the peritubular capillaries, and treatment, are discussed with references to the literature. Am J Kidney Dis. 64(6):987-993. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Membranous nephropathy; glomerulonephritis; membranous; hematopoietic stem cell transplantation; receptor; phospholipase A2 (PLA2R); graft-vs-host disease; complement C4d; HLA serological subtypes.
INTRODUCTION Graft-versus-host disease (GVHD) is a potentially lethal condition in which transplanted donor leukocytes (graft) attack the recipient’s tissue (host).1 GVHD often occurs after hematopoietic cell transplantation (HCT), which includes hematopoietic stem cell transplantation and bone marrow transplantation. Acute GVHD occurs within 100 days of transplantation and typically affects the skin, gastrointestinal tract, and liver.2 Chronic GVHD presents more than 100 days posttransplantation, affects multiple organs (skin, eyes, mouth, esophagus, liver, etc), and often is associated with autoimmune features.2 Chronic GVHD can occur after a history of acute GVHD or as a de novo phenomenon. Acute and chronic kidney injury are frequent complications of HCT3,4 that often are attributed to overlapping causes.4-6 Glomerulopathies represent only a small proportion of such injury. They occur in 1% to 6% of HCT recipients7,8 and may represent manifestations of chronic GVHD. In a review of the literature, Hu9 showed that these glomerulopathies were classified as membranous nephropathy (MN; 64%), minimal change disease (19%), or other glomerulonephritis/glomerulopathies (17%). Because the number of patients undergoing HCT is growing,5 nephrologists and pathologists need to be familiar with such HCT complications. In this report, we concentrate on post-HCT MN. Characteristic features of post-HCT MN are compared with those of de novo Am J Kidney Dis. 2014;64(6):987-993
MN in the kidney transplant and primary MN in the native kidney9-21 (Table 1).
CASE REPORT Clinical History and Initial Laboratory Data A 44-year-old man underwent a single HLA-DQ–mismatched hematopoietic stem cell transplantation for acute myelogenous leukemia. The conditioning regimen of cyclophosphamide and total-body irradiation was instituted. GVHD prophylaxis initially consisted of methotrexate and tacrolimus, but later was transitioned
From 1Renal Pathology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School; 2Renal Pathology, Department of Pathology, Massachusetts General Hospital and Harvard Medical School; and 3Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. * A.Q.L. and I.B. contributed equally to this work. Received April 23, 2014. Accepted in revised form July 29, 2014. Originally published online October 7, 2014. Because the Feature Editor recused himself, the peer-review and decision-making processes were handled without his participation, and Dr Parmjeet Randhawa, MD, served as Acting Feature Editor. Details of the journal’s procedures for potential editor conflicts are given in the Information for Authors & Editorial Policies. Address correspondence to Dr Batal at his current affiliation: Ibrahim Batal, MD, Renal Pathology, Department of Pathology and Cellular Biology, Columbia University, 630 W 168th St, New York, NY 10032. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.09.001 987
Byrne-Dugan et al Table 1. Comparative Review of MN After HCT, De Novo MN in Kidney Transplant, and Primary MN in Native Kidney MN Post–Allogeneic HCTa
De Novo MN in Kidney Transplant
Primary MN in Native Kidney
Mostly matched
Often mismatched
Not applicable
Not studied
Not studied
Yes
Serum anti-PLA2R antibodies
Negative
Negative
Positive
In post-HCT MN, serum anti-PLA2R antibodies were detectable in up to 20% of patients (1/5 [20%] in 1 study12 and 2/13 [15%] in another study17); in de novo MN post–kidney transplantation, anti-PLA2R antibodies were undetectable in all patients (17/17)10; in contrast, w69% of patients with primary MN had detectable serum antibodies17
C4d along the peritubular capillaries
Negative
Variable
Negative
In post-HCT MN, no diffuse peritubular capillary C4d staining has been described. In de novo MN post–kidney transplant, C4d staining was positive in 10/17 (59%) of cases in 1 study11 but negative in all 12 cases in another study.13
Yes
No
Small proportion responded
In post-HCT MN, an in-depth review of the literature revealed that all 10 patients who were treated solely with steroids responded to treatment (complete response [n 5 6] and partial response [n 5 4])14; 0 of 12 patients with de novo MN post–kidney transplantation responded to steroids15; in primary MN, steroid treatment led to response in up to 36% (12% and 24% complete and partial response, respectively) in 1 study19 and much lower percentage in another study21
HLA antigen matching
DQ2.5 HLA complex (DQA1*05:01 & DQB1*02:01)
Response to steroid therapy
Notes
HLA antigen matching is important for HCT; thus, most post-HCT MN patients are HLA antigen matched; in de novo MN post–kidney transplantation, 2 HLA loci are mismatched on average11
Abbreviations: HCT, hematopoietic cell transplantation; MN, membranous nephropathy; PLA2R, phospholipase A2 receptor. a MN has been described only rarely after autologous HCT (only 2 cases described comprising w3% of published cases of MN postHCT9). Both cases were not characterized with regard to DQ2.5 HLA complex, PLA2R, or C4d staining. Treatment information was available for only 1 patient who responded to rituximab.16
to tacrolimus monotherapy. His serum creatinine (Scr) level remained at w0.8 mg/dL (corresponding to estimated glomerular filtration rate [eGFR] $ 60 mL/min/1.73 m2 as calculated using the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation), but his posttransplantation course was complicated by acute GVHD at day 36. A skin biopsy showed perivascular and lichinoid lymphocytic reaction with apoptotic keratinocytes consistent with grade II acute GVHD (Fig 1A and B), which resolved after 2 months of treatment with prednisone (2 mg/kg/d) and mycophenolate mofetil (1,000 mg twice daily). The patient’s posttransplantation course also was complicated by nausea and eye irritation, which were attributed to chronic GVHD. At 377 days posttransplantation, the patient was found to have proteinuria and microscopic hematuria. His Scr level had increased gradually to 1.6 mg/dL (eGFR, 47 mL/min/1.73 m2). Due to persistent hematuria and proteinuria (protein excretion, 2.3 g/24 h), the patient received a nephrology consultation at 440 days posttransplantation and was found to have serum albumin level of 3.3 g/dL, tested positive for antinuclear antibody (1:640), had mildly elevated transaminase levels (aspartate aminotransferase, 69 U/L; alanine aminotransferase, 60 U/L), and trace of cryoglobulins. His urine sediment showed a few 988
white blood cell casts. A kidney biopsy was performed at 483 days posttransplantation.
Kidney Biopsy The entire sample contained 61 glomeruli, 5 (8%) of which were globally sclerosed. By light microscopy, the peripheral glomerular capillary walls were mildly thickened and showed scattered double contours, occasional craters, but no overt spikes (Fig 1C). Approximately 30% of the parenchyma showed tubular atrophy and interstitial fibrosis with no significant inflammation. Arteries and arterioles showed moderate sclerosis. Immunofluorescence microscopy revealed diffuse finely granular deposition of immunoglobulin G (IgG; 31), C3 (11), C4d (31), k (21), l (21), IgM (11), C1q (trace), and IgA (trace) along the peripheral capillary walls and to a lesser degree in the mesangium. Staining for IgG subclasses showed codominance of IgG1 and IgG4 (Fig 2). Tubular basement membranes revealed focal granular deposition of IgG (21; Fig 2 [IgG4 (21), IgG1 (11), and IgG2 and IgG3 (trace)]), k (11), and l (11). C4d was undetectable along the peritubular capillaries. Am J Kidney Dis. 2014;64(6):987-993
Membranous Nephropathy Post–Stem Cell Transplantation
Figure 1. (A, B) Skin and (C-E) kidney biopsy specimens from patient 1. Skin biopsy reveals (A) an acute interface inflammation extending to the epidermis with associated dermal perivascular inflammation (hematoxylin and eosin; original magnification, 3200). (B) In addition to mononuclear cells, several apoptotic keratinocytes (arrowheads) are seen (hematoxylin and eosin; original magnification, 3600). (C-E) Kidney biopsy shows (C) a glomerulus with mild expansion of the mesangial matrix and minimal segmental mesangial proliferation. There is only mild thickening of glomerular basement membranes and scattered double contours (periodic acid–Schiff stain; original magnification, 3400). (D) Many subepithelial electron-dense deposits are seen (arrowheads). These electron-dense deposits are not associated with glomerular basement membrane reaction and spike formation. The subendothelial space is expanded by electron-lucent to finely granular material (electron microscopy; original magnification, 325,000). (E) Segmentally, glomerular basement membranes show more advanced remodeling with cellular interposition (electron microscopy; original magnification, 310,000).
To perform double staining for phospholipase A2 receptor (PLA2R) and IgG, 3 mm of frozen tissue sections were stained with a 1:40 dilution of rabbit anti-human fluorescein isothiocyanate– conjugated IgG (Dako) for 1 hour, then with a 1:50 dilution of rabbit anti-human PLA2R (Sigma) followed sequentially with a 1:50 dilution of biotinylated goat anti-rabbit IgG (Vector Labs) for 45 minutes and a 1:00 dilution of Cy3-streptavidin (GE Healthcare) for 45 minutes. Appropriate positive (primary MN) and negative controls were run. Double staining for PLA2R/IgG did not show significant colocalization (Fig 2). By electron microscopy, glomerular capillary walls contained many small nonorganized subepithelial electron-dense deposits not associated with basement membrane spikes (Fig 1D). There was extensive effacement of visceral epithelial cell foot processes. Glomerular endothelial cells showed segmental swelling and the subendothelial space was expanded by fluffy material with segmental cellular interposition (Fig 1D and E). The mesangium contained occasional electron-dense deposits. Tubular basement membranes revealed scattered electron-dense deposits.
Diagnosis The biopsy showed early MN (stage 1), with associated tubular basement membrane deposits. Secondary MN due to chronic GVHD was favored based on the patient’s history of HCT and acute GVHD and concurrent clinical signs of chronic GVHD. Supporting evidence against primary MN included negative IgG/ Am J Kidney Dis. 2014;64(6):987-993
PLA2R colocalization, intense IgG1 reactivity, and the presence of mesangial and extraglomerular deposits. The biopsy also showed thrombotic microangiopathy–like endothelial injury, which was attributed to chronic endothelial damage.
Clinical Follow-up The patient was treated with oral prednisone (60 mg/d) for 4 weeks and achieved partial remission with decreased proteinuria (protein excretion, 1.5 g/24 h) and increased serum albumin level (4.0 g/dL). His nausea and eye irritation resolved and liver function test results normalized. Sixteen months later, the patient experienced a relapse with protein excretion of 3.7 g/24 h. He was retreated with oral prednisone (60 mg/d) and 4 cycles of rituximab (375 mg/m2). His proteinuria improved and Scr level fluctuated between 1.4 and 1.9 mg/dL (eGFR, 55-39 mL/min/1.73 m2). At his last visit (889 days postbiopsy and 1,364 days posttransplantation), the patient was still in remission with protein excretion of 243 mg/ 24 h, serum albumin level of 4.1 g/dL, and Scr level of 1.6 mg/dL (eGFR, 47 mL/min/1.73 m2). Genetic studies have found that the single-nucleotide polymorphism rs2187668 of HLA-DQA1 is frequently encountered in patients with primary MN22,23 and is tightly linked to DQA1*05:01 and DQB1*02:01 alleles (DQ2.5 haplotype). The latter is a strong predisposing factor for autoimmune diseases and has been found to be associated with primary MN.18 Although single-nucleotide polymorphism analysis was not performed, HLA 989
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Figure 2. Immunofluorescence microscopy. Analysis of (upper row) immunoglobulin G (IgG) heavy chain subclasses reveals intense finely granular staining for IgG1 (31/41) and IgG4 (31/41) subclasses with less intense staining for IgG2 (11/41) and IgG3 (trace/41) subclasses (original magnification, 3200). (Left lower panel) Double staining for phospholipase A2 receptor (PLA2R; red) and IgG (green) reveals no significant colocalization (,5% colocalization as quantified by Image J software) along the peripheral capillary walls (original magnification, 3400). (Right lower panel) Finely granular IgG tubular basement membrane deposits are noted (original magnification, 3200).
typing by polymerase chain reaction with sequence-specific oligonucleotide probes detected no copies of the DQA1*05:01 and DQB1*02:01 alleles in our patient.
Additional Investigations This case led us to investigate the association of post-HCT MN with MN type, GVHD status, HLA antigen alleles, and C4d staining. In a retrospective review of all kidney biopsies from January 2011 to June 2013, we retrieved 4 additional cases of MN occurring after hematopoietic stem cell transplantation. This study was approved by the institutional review board (#2011P002692). Details for the 5 total cases (including the patient described in detail in this article) are provided in Table 2. All patients received allogeneic hematopoietic stem cell transplants and developed MN more than 100 days (765 6 620 days) posttransplantation with early stages of MN, polyclonal immune-type deposits, signs of endothelial cell injury manifested by subendothelial expansion with electron-lucent fluffy material and segmental endothelial swelling, and negative C4d staining along the peritubular capillaries (Table 2). Only one biopsy specimen (patient 5) was histologically consistent with the diagnosis of primary (idiopathic) MN due to the predominance of IgG4 subclass that colocalized with PLA2R (68% colocalization) and the absence of mesangial, subendothelial, or extraglomerular immune deposits. Interestingly, this patient did not have a history of acute GVHD and did not respond to steroid treatment. Furthermore, both donor and recipient had HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles. The other 4 patients were believed to have secondary MN. All these patients had undetectable PLA2R/IgG colocalization and none had HLA-DQA1*05:01 or HLA-DQB1*02:01 alleles. Furthermore, 2 patients had mesangial deposits, 2 had extraglomerular 990
immune-type deposits, 2 received hematopoietic stem cell transplants from an HLA antigen–mismatched donor, and 3 had a history of GVHD. These patients had dominance of IgG1 (n 5 1), IgG4 (n 5 1), or codominance of IgG1/IgG4 (n 5 2) subclasses. Patient 2 was given the diagnosis at autopsy and therefore was not treated. The other 3 patients achieved complete (n 5 2) or partial (n 5 1) remission after 4 weeks of prednisone treatment (Table 2).
DISCUSSION HCT is an increasingly recognized treatment for hematologic malignancies and other hematologic disorders, including sickle cell disease and aplastic anemia.2 Post-HCT glomerulopathies most often manifest as nephrotic syndrome caused primarily by MN or, less commonly, minimal change disease.9 The majority of patients with post-HCT MN had a history of acute (68%) or chronic (84%) GVHD.9,14 In our cohort, 75% of patients with secondary MN had a history of GVHD. Although the incidence of GVHD in patients with post-HCT MN (up to 84%) might be only slightly higher than that of the general HCT population (w50% of HCT recipients develop chronic GVHD),24 we believe that GVHD most likely is the cause of postHCT secondary MN for 3 additional supporting reasons. (1) There is an increased incidence of post-HCT MN compared to the general population (0.6%-3.8% Am J Kidney Dis. 2014;64(6):987-993
Membranous Nephropathy Post–Stem Cell Transplantation Table 2. Hematopoietic Stem Cell Transplant Recipients With Biopsies Showing Posttransplantation MN Patient 1a
Age (y)
44
Donors
Unrelated
Recipient/donor sex Reason for HSCT
HLA antigen mismatch
M/M Acute myelogenous leukemia 1 antigen (DQB)
Patient 2
35 2 umbilical blood donors M/M & Fb
Patient 3
Patient 4
73
50
71
Unrelated
Brother
Unrelated
F/F
F/M
Diffuse large B-cell Acute myelogenous Mixed phenotype lymphoma leukemia acute leukemia T/myeloid 2 antigens (DRB, DQB)
Patient 5
M/M Myelodysplastic syndrome
No
No
No
HLA-DQA1*05:01
No
No
No
No
Yes
HLA-DQB1*02:01
No
No
No
No
Yes
History of GVHD
Acute GVHD (clinical & biopsy); chronic GVHD (clinical)
Chronic GVHD (clinical)
No
Chronic GVHD (clinical & biopsy)
No
Time post-Tx (d)
483
268
1,834
689
539
Predominant IgG subclasses
IgG1/IgG4
IgG1
IgG1/IgG4
IgG4
IgG4
Extraglomerular Ig deposits Colocalization of PLA2R/IgGc
IgG along TBM
No
No
IgG in the interstitium
No
,5%
,5%
,5%
,5%
68% (IgG4)
Membranous staged
I
I
I-II
I
II
Subendothelial or mesangial depositsd Vascular sclerosis
Mesangial
Both
No
No
No
Moderate
Severe
Moderate
Severe
Moderate
Interstitial fibrosis and tubular atrophy (%)
30%
60%
20%
20%
10%
Prednisone (60 mg)
NAe
Prednisone (60 mg) Prednisone (60 mg)f
Prednisone (60 mg)
Partial remission
NAe
Complete remission Complete remission
No response
Additional treatment
Rituximab (375 mg/m2 weekly 34)
NAe
Current statusg
Complete remission
NAe
Initial treatment Response to treatment
None
None
Complete remission Complete remission
Rituximab (375 mg/m2 weekly 34) Partial remission
Note: Table based on retrospective review of biopsies accessioned in our institution from January 2011 to June 2013. For all patients, endothelial swelling, subendothelial expansion by fluffy material, and glomerular capillary wall remodeling were present; peritubular capillaries were negative for C4d; and there were no monoclonal deposits. Abbreviations: F, female; GVHD, graft-versus-host-disease; HSCT, hematopoietic stem cell transplantation; Ig, immunoglobulin; M, male; MN, membranous nephropathy; NA, not applicable; TBM, tubular basement membranes; Tx, transplantation. a Patient described as the case report of this article. b Umbilical cord blood donors: donor 1: male; donor 2: female. c Colocalization was assessed by Image J software. d As assessed by electron microscopy. e Diagnosis was made at time of autopsy. f This patient also was receiving intravenous immunoglobulin and rituximab for Stiff-Person syndrome. g Complete remission is defined as proteinuria with protein excretion , 0.5 g/d, albumin level $ 3.5 g/dL, and stable kidney function. Partial remission is defined as protein excretion $ 50% or ,2.5 g/d with albumin level . 3 g/dL and stable kidney function.31
over 1-10 years in post-HCT patients9 vs an annual incidence of 0.0012% in the general population25). (2) MN is encountered very rarely following autologous HCT (3% postautologous vs 97% postallogeneic HCT9). (3) Similar complications occur frequently in murine chronic GVHD; such mice develop lupus nephritis–like syndrome,26 which typically manifests as MN and/or proliferative glomerulonephritis.27 Am J Kidney Dis. 2014;64(6):987-993
Our cohort assessed several features of MN following GVHD that have not yet been well characterized. All our patients with secondary MN (patients 1-4) revealed no colocalization of PLA2R and IgG and half these patients showed extraglomerular deposits, a finding that has been noticed occasionally.28 Furthermore, HLA typing revealed that DQA1*05:01 and DQB1*02:01 were absent in all our patients with 991
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secondary MN, but present in our one patient with primary MN (patient 5). Endothelial cell damage frequently is seen postHCT in association with GVHD as a potential manifestation of an alloimmune response. However, endothelial injury often is multifactorial,29,30 and we cannot completely exclude that other factors (eg, infection, radiation dose, and tacrolimus toxicity) may trigger or aggravate such a lesion. Although the association between post-HCT MN and concurrent endothelial injury is not well defined, such endothelial injury was present in all our patients. Troxell et al16 also described the presence of microaneurysms with fibrin in 1 of 7 (14%) and arterial sclerosis in 4 of 7 (57%) of their patients with postHCT MN. Taken together, endothelial injury appears to be a relatively common lesion in this patient population. With regard to C4d staining, our study, as well as a prior study,16 demonstrated negative peritubular capillary C4d staining in all 10 patients (5 in each study) with post-HCT MN, excluding the presence of a specific humoral process that targets the peritubular capillaries. As opposed to primary MN, corticosteroids, which target GVHD, usually are the first line of treatment for post-HCT MN5,14,31 and often appear to be beneficial (Table 1). Notably, all our patients with secondary MN showed complete or partial response to steroid treatment, whereas our single patient with pathologic features suggestive of primary MN did not. In summary, although post-HCT MN commonly is secondary and likely to represent a manifestation of GVHD, primary MN should always remain in the differential diagnosis. An in-depth clinical, laboratory, and histologic assessment is warranted to rule out primary MN because the clinical course and response to treatment may be different.
ACKNOWLEDGEMENTS We thank Terri Woo and Helen Mah for excellent technical assistance. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
REFERENCES 1. Billingham RE. The biology of graft-versus-host reactions. Harvey Lect. 1966;62:21-78. 2. Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7(5):340-352. 3. Lopes JA, Jorge S. Acute kidney injury following HCT: incidence, risk factors and outcome. Bone Marrow Transplant. 2011;46(11):1399-1408. 4. Hingorani S. Chronic kidney disease in long-term survivors of hematopoietic cell transplantation: epidemiology, pathogenesis, and treatment. J Am Soc Nephrol. 2006;17(7):1995-2005. 5. Sawinski D. The kidney effects of hematopoietic stem cell transplantation. Adv Chronic Kidney Dis. 2014;21(1):96-105. 992
6. Jhaveri KD, Shah HH, Patel C, Kadiyala A, Stokes MB, Radhakrishnan J. Glomerular diseases associated with cancer, chemotherapy, and hematopoietic stem cell transplantation. Adv Chronic Kidney Dis. 2014;21(1):48-55. 7. Reddy P, Johnson K, Uberti JP, et al. Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2006;38(5):351-357. 8. Imai H, Oyama Y, Miura AB, Endoh M, Sakai H. Hematopoietic cell transplantation-related nephropathy in Japan. Am J Kidney Dis. 2000;36(3):474-480. 9. Hu SL. The role of graft-versus-host disease in haematopoietic cell transplantation-associated glomerular disease. Nephrol Dial Transplant. 2011;26(6):2025-2031. 10. Collins AB, Satoskar AA, Beck LH Jr, et al. De novo membranous glomerulonephritis (MGN) is immunologically distinct from idiopathic MGN and associated with C4d deposition and chronic humoral rejection [abstract]. Presented at: 11th Banff Conference on Allograft Pathology; June 2011; Enghien-les-Bains, France. 11. Honda K, Horita S, Toki D, et al. De novo membranous nephropathy and antibody-mediated rejection in transplanted kidney. Clin Transplant. 2011;25(2):191-200. 12. Huang X, Qin W, Zhang M, Zheng C, Zeng C, Liu Z. Detection of anti-PLA2R autoantibodies and IgG subclasses in post-allogeneic hematopoietic stem cell transplantation membranous nephropathy. Am J Med Sci. 2013;346(1):32-37. 13. Larsen CP, Walker PD. Phospholipase A2 receptor (PLA2R) staining is useful in the determination of de novo versus recurrent membranous glomerulopathy. Transplantation. 2013;95(10):1259-1262. 14. Niscola P, Tendas A, Luo XD, et al. The management of membranous glomerulopathy in allogeneic stem cells transplantation: updated literature. Cardiovasc Hematol Agents Med Chem. 2013;11(1):67-76. 15. Schwarz A, Krause PH, Offermann G, Keller F. Impact of de novo membranous glomerulonephritis on the clinical course after kidney transplantation. Transplantation. 1994;58(6): 650-654. 16. Troxell ML, Pilapil M, Miklos DB, Higgins JP, Kambham N. Renal pathology in hematopoietic cell transplantation recipients. Mod Pathol. 2008;21(4):396-406. 17. Ronco P, Debiec H. Pathogenesis of membranous nephropathy: recent advances and future challenges. Nat Rev Nephrol. 2012;8(4):203-213. 18. Vaughan RW, Tighe MR, Boki K, et al. An analysis of HLA class II gene polymorphism in British and Greek idiopathic membranous nephropathy patients. Eur J Immunogenet. 1995;22(2):179-186. 19. A controlled study of short-term prednisone treatment in adults with membranous nephropathy. Collaborative Study of the Adult Idiopathic Nephrotic Syndrome. N Engl J Med. 1979;301(24):1301-1306. 20. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21. 21. Black DA, Rose G, Brewer DB. Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br Med J. 1970;3(5720):421-426. 22. Stanescu HC, Arcos-Burgos M, Medlar A, et al. Risk HLADQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med. 2011;364(7):616-626. 23. Coenen MJ, Hofstra JM, Debiec H, et al. Phospholipase A2 receptor (PLA2R1) sequence variants in idiopathic membranous nephropathy. J Am Soc Nephrol. 2013;24(4):677-683. Am J Kidney Dis. 2014;64(6):987-993
Membranous Nephropathy Post–Stem Cell Transplantation 24. Fraser CJ, Bhatia S, Ness K, et al. Impact of chronic graftversus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood. 2006;108(8):2867-2873. 25. McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011;26(2):414-430. 26. Eisenberg RA, Via CS. T Cells, murine chronic graft-versushost disease and autoimmunity. J Autoimmun. 2012;39(3):240-247. 27. Foster AD, Haas M, Puliaeva I, Soloviova K, Puliaev R, Via CS. Donor CD8 T cell activation is critical for greater renal disease severity in female chronic graft-vs.-host mice and is associated with increased splenic ICOS(hi) host CD4 T cells and IL-21 expression. Clin Immunol. 2010;136(1):61-73.
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28. Ohsawa I, Ohi H, Fujita T, et al. Glomerular and extraglomerular immune complex deposits in a bone marrow transplant recipient. Am J Kidney Dis. 2000;36(1):E3. 29. Singh N, McNeely J, Parikh S, Bhinder A, Rovin BH, Shidham G. Kidney complications of hematopoietic stem cell transplantation. Am J Kidney Dis. 2013;61(5):809-821. 30. Changsirikulchai S, Myerson D, Guthrie KA, McDonald GB, Alpers CE, Hingorani SR. Renal thrombotic microangiopathy after hematopoietic cell transplant: role of GVHD in pathogenesis. Clin J Am Soc Nephrol. 2009;4(2):345-353. 31. Fraile P, Vazquez L, Caballero D, et al. Chronic graftversus-host disease of the kidney in patients with allogenic hematopoietic stem cell transplant. Eur J Haematol. 2013;91(2): 129-134.
993
INTRODUCTION Graft-versus-host disease (GVHD) is a potentially lethal condition in which transplanted donor leukocytes (graft) attack the recipient’s tissue (host).1 GVHD often occurs after hematopoietic cell transplantation (HCT), which includes hematopoietic stem cell transplantation and bone marrow transplantation. Acute GVHD occurs within 100 days of transplantation and typically affects the skin, gastrointestinal tract, and liver.2 Chronic GVHD presents more than 100 days posttransplantation, affects multiple organs (skin, eyes, mouth, esophagus, liver, etc), and often is associated with autoimmune features.2 Chronic GVHD can occur after a history of acute GVHD or as a de novo phenomenon. Acute and chronic kidney injury are frequent complications of HCT3,4 that often are attributed to overlapping causes.4-6 Glomerulopathies represent only a small proportion of such injury. They occur in 1% to 6% of HCT recipients7,8 and may represent manifestations of chronic GVHD. In a review of the literature, Hu9 showed that these glomerulopathies were classified as membranous nephropathy (MN; 64%), minimal change disease (19%), or other glomerulonephritis/glomerulopathies (17%). Because the number of patients undergoing HCT is growing,5 nephrologists and pathologists need to be familiar with such HCT complications. In this report, we concentrate on post-HCT MN. Characteristic features of post-HCT MN are compared with those of de novo Am J Kidney Dis. 2014;64(6):987-993
MN in the kidney transplant and primary MN in the native kidney9-21 (Table 1).
CASE REPORT Clinical History and Initial Laboratory Data A 44-year-old man underwent a single HLA-DQ–mismatched hematopoietic stem cell transplantation for acute myelogenous leukemia. The conditioning regimen of cyclophosphamide and total-body irradiation was instituted. GVHD prophylaxis initially consisted of methotrexate and tacrolimus, but later was transitioned
From 1Renal Pathology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School; 2Renal Pathology, Department of Pathology, Massachusetts General Hospital and Harvard Medical School; and 3Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA. * A.Q.L. and I.B. contributed equally to this work. Received April 23, 2014. Accepted in revised form July 29, 2014. Originally published online October 7, 2014. Because the Feature Editor recused himself, the peer-review and decision-making processes were handled without his participation, and Dr Parmjeet Randhawa, MD, served as Acting Feature Editor. Details of the journal’s procedures for potential editor conflicts are given in the Information for Authors & Editorial Policies. Address correspondence to Dr Batal at his current affiliation: Ibrahim Batal, MD, Renal Pathology, Department of Pathology and Cellular Biology, Columbia University, 630 W 168th St, New York, NY 10032. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.09.001 987
Byrne-Dugan et al Table 1. Comparative Review of MN After HCT, De Novo MN in Kidney Transplant, and Primary MN in Native Kidney MN Post–Allogeneic HCTa
De Novo MN in Kidney Transplant
Primary MN in Native Kidney
Mostly matched
Often mismatched
Not applicable
Not studied
Not studied
Yes
Serum anti-PLA2R antibodies
Negative
Negative
Positive
In post-HCT MN, serum anti-PLA2R antibodies were detectable in up to 20% of patients (1/5 [20%] in 1 study12 and 2/13 [15%] in another study17); in de novo MN post–kidney transplantation, anti-PLA2R antibodies were undetectable in all patients (17/17)10; in contrast, w69% of patients with primary MN had detectable serum antibodies17
C4d along the peritubular capillaries
Negative
Variable
Negative
In post-HCT MN, no diffuse peritubular capillary C4d staining has been described. In de novo MN post–kidney transplant, C4d staining was positive in 10/17 (59%) of cases in 1 study11 but negative in all 12 cases in another study.13
Yes
No
Small proportion responded
In post-HCT MN, an in-depth review of the literature revealed that all 10 patients who were treated solely with steroids responded to treatment (complete response [n 5 6] and partial response [n 5 4])14; 0 of 12 patients with de novo MN post–kidney transplantation responded to steroids15; in primary MN, steroid treatment led to response in up to 36% (12% and 24% complete and partial response, respectively) in 1 study19 and much lower percentage in another study21
HLA antigen matching
DQ2.5 HLA complex (DQA1*05:01 & DQB1*02:01)
Response to steroid therapy
Notes
HLA antigen matching is important for HCT; thus, most post-HCT MN patients are HLA antigen matched; in de novo MN post–kidney transplantation, 2 HLA loci are mismatched on average11
Abbreviations: HCT, hematopoietic cell transplantation; MN, membranous nephropathy; PLA2R, phospholipase A2 receptor. a MN has been described only rarely after autologous HCT (only 2 cases described comprising w3% of published cases of MN postHCT9). Both cases were not characterized with regard to DQ2.5 HLA complex, PLA2R, or C4d staining. Treatment information was available for only 1 patient who responded to rituximab.16
to tacrolimus monotherapy. His serum creatinine (Scr) level remained at w0.8 mg/dL (corresponding to estimated glomerular filtration rate [eGFR] $ 60 mL/min/1.73 m2 as calculated using the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation), but his posttransplantation course was complicated by acute GVHD at day 36. A skin biopsy showed perivascular and lichinoid lymphocytic reaction with apoptotic keratinocytes consistent with grade II acute GVHD (Fig 1A and B), which resolved after 2 months of treatment with prednisone (2 mg/kg/d) and mycophenolate mofetil (1,000 mg twice daily). The patient’s posttransplantation course also was complicated by nausea and eye irritation, which were attributed to chronic GVHD. At 377 days posttransplantation, the patient was found to have proteinuria and microscopic hematuria. His Scr level had increased gradually to 1.6 mg/dL (eGFR, 47 mL/min/1.73 m2). Due to persistent hematuria and proteinuria (protein excretion, 2.3 g/24 h), the patient received a nephrology consultation at 440 days posttransplantation and was found to have serum albumin level of 3.3 g/dL, tested positive for antinuclear antibody (1:640), had mildly elevated transaminase levels (aspartate aminotransferase, 69 U/L; alanine aminotransferase, 60 U/L), and trace of cryoglobulins. His urine sediment showed a few 988
white blood cell casts. A kidney biopsy was performed at 483 days posttransplantation.
Kidney Biopsy The entire sample contained 61 glomeruli, 5 (8%) of which were globally sclerosed. By light microscopy, the peripheral glomerular capillary walls were mildly thickened and showed scattered double contours, occasional craters, but no overt spikes (Fig 1C). Approximately 30% of the parenchyma showed tubular atrophy and interstitial fibrosis with no significant inflammation. Arteries and arterioles showed moderate sclerosis. Immunofluorescence microscopy revealed diffuse finely granular deposition of immunoglobulin G (IgG; 31), C3 (11), C4d (31), k (21), l (21), IgM (11), C1q (trace), and IgA (trace) along the peripheral capillary walls and to a lesser degree in the mesangium. Staining for IgG subclasses showed codominance of IgG1 and IgG4 (Fig 2). Tubular basement membranes revealed focal granular deposition of IgG (21; Fig 2 [IgG4 (21), IgG1 (11), and IgG2 and IgG3 (trace)]), k (11), and l (11). C4d was undetectable along the peritubular capillaries. Am J Kidney Dis. 2014;64(6):987-993
Membranous Nephropathy Post–Stem Cell Transplantation
Figure 1. (A, B) Skin and (C-E) kidney biopsy specimens from patient 1. Skin biopsy reveals (A) an acute interface inflammation extending to the epidermis with associated dermal perivascular inflammation (hematoxylin and eosin; original magnification, 3200). (B) In addition to mononuclear cells, several apoptotic keratinocytes (arrowheads) are seen (hematoxylin and eosin; original magnification, 3600). (C-E) Kidney biopsy shows (C) a glomerulus with mild expansion of the mesangial matrix and minimal segmental mesangial proliferation. There is only mild thickening of glomerular basement membranes and scattered double contours (periodic acid–Schiff stain; original magnification, 3400). (D) Many subepithelial electron-dense deposits are seen (arrowheads). These electron-dense deposits are not associated with glomerular basement membrane reaction and spike formation. The subendothelial space is expanded by electron-lucent to finely granular material (electron microscopy; original magnification, 325,000). (E) Segmentally, glomerular basement membranes show more advanced remodeling with cellular interposition (electron microscopy; original magnification, 310,000).
To perform double staining for phospholipase A2 receptor (PLA2R) and IgG, 3 mm of frozen tissue sections were stained with a 1:40 dilution of rabbit anti-human fluorescein isothiocyanate– conjugated IgG (Dako) for 1 hour, then with a 1:50 dilution of rabbit anti-human PLA2R (Sigma) followed sequentially with a 1:50 dilution of biotinylated goat anti-rabbit IgG (Vector Labs) for 45 minutes and a 1:00 dilution of Cy3-streptavidin (GE Healthcare) for 45 minutes. Appropriate positive (primary MN) and negative controls were run. Double staining for PLA2R/IgG did not show significant colocalization (Fig 2). By electron microscopy, glomerular capillary walls contained many small nonorganized subepithelial electron-dense deposits not associated with basement membrane spikes (Fig 1D). There was extensive effacement of visceral epithelial cell foot processes. Glomerular endothelial cells showed segmental swelling and the subendothelial space was expanded by fluffy material with segmental cellular interposition (Fig 1D and E). The mesangium contained occasional electron-dense deposits. Tubular basement membranes revealed scattered electron-dense deposits.
Diagnosis The biopsy showed early MN (stage 1), with associated tubular basement membrane deposits. Secondary MN due to chronic GVHD was favored based on the patient’s history of HCT and acute GVHD and concurrent clinical signs of chronic GVHD. Supporting evidence against primary MN included negative IgG/ Am J Kidney Dis. 2014;64(6):987-993
PLA2R colocalization, intense IgG1 reactivity, and the presence of mesangial and extraglomerular deposits. The biopsy also showed thrombotic microangiopathy–like endothelial injury, which was attributed to chronic endothelial damage.
Clinical Follow-up The patient was treated with oral prednisone (60 mg/d) for 4 weeks and achieved partial remission with decreased proteinuria (protein excretion, 1.5 g/24 h) and increased serum albumin level (4.0 g/dL). His nausea and eye irritation resolved and liver function test results normalized. Sixteen months later, the patient experienced a relapse with protein excretion of 3.7 g/24 h. He was retreated with oral prednisone (60 mg/d) and 4 cycles of rituximab (375 mg/m2). His proteinuria improved and Scr level fluctuated between 1.4 and 1.9 mg/dL (eGFR, 55-39 mL/min/1.73 m2). At his last visit (889 days postbiopsy and 1,364 days posttransplantation), the patient was still in remission with protein excretion of 243 mg/ 24 h, serum albumin level of 4.1 g/dL, and Scr level of 1.6 mg/dL (eGFR, 47 mL/min/1.73 m2). Genetic studies have found that the single-nucleotide polymorphism rs2187668 of HLA-DQA1 is frequently encountered in patients with primary MN22,23 and is tightly linked to DQA1*05:01 and DQB1*02:01 alleles (DQ2.5 haplotype). The latter is a strong predisposing factor for autoimmune diseases and has been found to be associated with primary MN.18 Although single-nucleotide polymorphism analysis was not performed, HLA 989
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Figure 2. Immunofluorescence microscopy. Analysis of (upper row) immunoglobulin G (IgG) heavy chain subclasses reveals intense finely granular staining for IgG1 (31/41) and IgG4 (31/41) subclasses with less intense staining for IgG2 (11/41) and IgG3 (trace/41) subclasses (original magnification, 3200). (Left lower panel) Double staining for phospholipase A2 receptor (PLA2R; red) and IgG (green) reveals no significant colocalization (,5% colocalization as quantified by Image J software) along the peripheral capillary walls (original magnification, 3400). (Right lower panel) Finely granular IgG tubular basement membrane deposits are noted (original magnification, 3200).
typing by polymerase chain reaction with sequence-specific oligonucleotide probes detected no copies of the DQA1*05:01 and DQB1*02:01 alleles in our patient.
Additional Investigations This case led us to investigate the association of post-HCT MN with MN type, GVHD status, HLA antigen alleles, and C4d staining. In a retrospective review of all kidney biopsies from January 2011 to June 2013, we retrieved 4 additional cases of MN occurring after hematopoietic stem cell transplantation. This study was approved by the institutional review board (#2011P002692). Details for the 5 total cases (including the patient described in detail in this article) are provided in Table 2. All patients received allogeneic hematopoietic stem cell transplants and developed MN more than 100 days (765 6 620 days) posttransplantation with early stages of MN, polyclonal immune-type deposits, signs of endothelial cell injury manifested by subendothelial expansion with electron-lucent fluffy material and segmental endothelial swelling, and negative C4d staining along the peritubular capillaries (Table 2). Only one biopsy specimen (patient 5) was histologically consistent with the diagnosis of primary (idiopathic) MN due to the predominance of IgG4 subclass that colocalized with PLA2R (68% colocalization) and the absence of mesangial, subendothelial, or extraglomerular immune deposits. Interestingly, this patient did not have a history of acute GVHD and did not respond to steroid treatment. Furthermore, both donor and recipient had HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles. The other 4 patients were believed to have secondary MN. All these patients had undetectable PLA2R/IgG colocalization and none had HLA-DQA1*05:01 or HLA-DQB1*02:01 alleles. Furthermore, 2 patients had mesangial deposits, 2 had extraglomerular 990
immune-type deposits, 2 received hematopoietic stem cell transplants from an HLA antigen–mismatched donor, and 3 had a history of GVHD. These patients had dominance of IgG1 (n 5 1), IgG4 (n 5 1), or codominance of IgG1/IgG4 (n 5 2) subclasses. Patient 2 was given the diagnosis at autopsy and therefore was not treated. The other 3 patients achieved complete (n 5 2) or partial (n 5 1) remission after 4 weeks of prednisone treatment (Table 2).
DISCUSSION HCT is an increasingly recognized treatment for hematologic malignancies and other hematologic disorders, including sickle cell disease and aplastic anemia.2 Post-HCT glomerulopathies most often manifest as nephrotic syndrome caused primarily by MN or, less commonly, minimal change disease.9 The majority of patients with post-HCT MN had a history of acute (68%) or chronic (84%) GVHD.9,14 In our cohort, 75% of patients with secondary MN had a history of GVHD. Although the incidence of GVHD in patients with post-HCT MN (up to 84%) might be only slightly higher than that of the general HCT population (w50% of HCT recipients develop chronic GVHD),24 we believe that GVHD most likely is the cause of postHCT secondary MN for 3 additional supporting reasons. (1) There is an increased incidence of post-HCT MN compared to the general population (0.6%-3.8% Am J Kidney Dis. 2014;64(6):987-993
Membranous Nephropathy Post–Stem Cell Transplantation Table 2. Hematopoietic Stem Cell Transplant Recipients With Biopsies Showing Posttransplantation MN Patient 1a
Age (y)
44
Donors
Unrelated
Recipient/donor sex Reason for HSCT
HLA antigen mismatch
M/M Acute myelogenous leukemia 1 antigen (DQB)
Patient 2
35 2 umbilical blood donors M/M & Fb
Patient 3
Patient 4
73
50
71
Unrelated
Brother
Unrelated
F/F
F/M
Diffuse large B-cell Acute myelogenous Mixed phenotype lymphoma leukemia acute leukemia T/myeloid 2 antigens (DRB, DQB)
Patient 5
M/M Myelodysplastic syndrome
No
No
No
HLA-DQA1*05:01
No
No
No
No
Yes
HLA-DQB1*02:01
No
No
No
No
Yes
History of GVHD
Acute GVHD (clinical & biopsy); chronic GVHD (clinical)
Chronic GVHD (clinical)
No
Chronic GVHD (clinical & biopsy)
No
Time post-Tx (d)
483
268
1,834
689
539
Predominant IgG subclasses
IgG1/IgG4
IgG1
IgG1/IgG4
IgG4
IgG4
Extraglomerular Ig deposits Colocalization of PLA2R/IgGc
IgG along TBM
No
No
IgG in the interstitium
No
,5%
,5%
,5%
,5%
68% (IgG4)
Membranous staged
I
I
I-II
I
II
Subendothelial or mesangial depositsd Vascular sclerosis
Mesangial
Both
No
No
No
Moderate
Severe
Moderate
Severe
Moderate
Interstitial fibrosis and tubular atrophy (%)
30%
60%
20%
20%
10%
Prednisone (60 mg)
NAe
Prednisone (60 mg) Prednisone (60 mg)f
Prednisone (60 mg)
Partial remission
NAe
Complete remission Complete remission
No response
Additional treatment
Rituximab (375 mg/m2 weekly 34)
NAe
Current statusg
Complete remission
NAe
Initial treatment Response to treatment
None
None
Complete remission Complete remission
Rituximab (375 mg/m2 weekly 34) Partial remission
Note: Table based on retrospective review of biopsies accessioned in our institution from January 2011 to June 2013. For all patients, endothelial swelling, subendothelial expansion by fluffy material, and glomerular capillary wall remodeling were present; peritubular capillaries were negative for C4d; and there were no monoclonal deposits. Abbreviations: F, female; GVHD, graft-versus-host-disease; HSCT, hematopoietic stem cell transplantation; Ig, immunoglobulin; M, male; MN, membranous nephropathy; NA, not applicable; TBM, tubular basement membranes; Tx, transplantation. a Patient described as the case report of this article. b Umbilical cord blood donors: donor 1: male; donor 2: female. c Colocalization was assessed by Image J software. d As assessed by electron microscopy. e Diagnosis was made at time of autopsy. f This patient also was receiving intravenous immunoglobulin and rituximab for Stiff-Person syndrome. g Complete remission is defined as proteinuria with protein excretion , 0.5 g/d, albumin level $ 3.5 g/dL, and stable kidney function. Partial remission is defined as protein excretion $ 50% or ,2.5 g/d with albumin level . 3 g/dL and stable kidney function.31
over 1-10 years in post-HCT patients9 vs an annual incidence of 0.0012% in the general population25). (2) MN is encountered very rarely following autologous HCT (3% postautologous vs 97% postallogeneic HCT9). (3) Similar complications occur frequently in murine chronic GVHD; such mice develop lupus nephritis–like syndrome,26 which typically manifests as MN and/or proliferative glomerulonephritis.27 Am J Kidney Dis. 2014;64(6):987-993
Our cohort assessed several features of MN following GVHD that have not yet been well characterized. All our patients with secondary MN (patients 1-4) revealed no colocalization of PLA2R and IgG and half these patients showed extraglomerular deposits, a finding that has been noticed occasionally.28 Furthermore, HLA typing revealed that DQA1*05:01 and DQB1*02:01 were absent in all our patients with 991
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secondary MN, but present in our one patient with primary MN (patient 5). Endothelial cell damage frequently is seen postHCT in association with GVHD as a potential manifestation of an alloimmune response. However, endothelial injury often is multifactorial,29,30 and we cannot completely exclude that other factors (eg, infection, radiation dose, and tacrolimus toxicity) may trigger or aggravate such a lesion. Although the association between post-HCT MN and concurrent endothelial injury is not well defined, such endothelial injury was present in all our patients. Troxell et al16 also described the presence of microaneurysms with fibrin in 1 of 7 (14%) and arterial sclerosis in 4 of 7 (57%) of their patients with postHCT MN. Taken together, endothelial injury appears to be a relatively common lesion in this patient population. With regard to C4d staining, our study, as well as a prior study,16 demonstrated negative peritubular capillary C4d staining in all 10 patients (5 in each study) with post-HCT MN, excluding the presence of a specific humoral process that targets the peritubular capillaries. As opposed to primary MN, corticosteroids, which target GVHD, usually are the first line of treatment for post-HCT MN5,14,31 and often appear to be beneficial (Table 1). Notably, all our patients with secondary MN showed complete or partial response to steroid treatment, whereas our single patient with pathologic features suggestive of primary MN did not. In summary, although post-HCT MN commonly is secondary and likely to represent a manifestation of GVHD, primary MN should always remain in the differential diagnosis. An in-depth clinical, laboratory, and histologic assessment is warranted to rule out primary MN because the clinical course and response to treatment may be different.
ACKNOWLEDGEMENTS We thank Terri Woo and Helen Mah for excellent technical assistance. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.
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6. Jhaveri KD, Shah HH, Patel C, Kadiyala A, Stokes MB, Radhakrishnan J. Glomerular diseases associated with cancer, chemotherapy, and hematopoietic stem cell transplantation. Adv Chronic Kidney Dis. 2014;21(1):48-55. 7. Reddy P, Johnson K, Uberti JP, et al. Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2006;38(5):351-357. 8. Imai H, Oyama Y, Miura AB, Endoh M, Sakai H. Hematopoietic cell transplantation-related nephropathy in Japan. Am J Kidney Dis. 2000;36(3):474-480. 9. Hu SL. The role of graft-versus-host disease in haematopoietic cell transplantation-associated glomerular disease. Nephrol Dial Transplant. 2011;26(6):2025-2031. 10. Collins AB, Satoskar AA, Beck LH Jr, et al. De novo membranous glomerulonephritis (MGN) is immunologically distinct from idiopathic MGN and associated with C4d deposition and chronic humoral rejection [abstract]. Presented at: 11th Banff Conference on Allograft Pathology; June 2011; Enghien-les-Bains, France. 11. Honda K, Horita S, Toki D, et al. De novo membranous nephropathy and antibody-mediated rejection in transplanted kidney. Clin Transplant. 2011;25(2):191-200. 12. Huang X, Qin W, Zhang M, Zheng C, Zeng C, Liu Z. Detection of anti-PLA2R autoantibodies and IgG subclasses in post-allogeneic hematopoietic stem cell transplantation membranous nephropathy. Am J Med Sci. 2013;346(1):32-37. 13. Larsen CP, Walker PD. Phospholipase A2 receptor (PLA2R) staining is useful in the determination of de novo versus recurrent membranous glomerulopathy. Transplantation. 2013;95(10):1259-1262. 14. Niscola P, Tendas A, Luo XD, et al. The management of membranous glomerulopathy in allogeneic stem cells transplantation: updated literature. Cardiovasc Hematol Agents Med Chem. 2013;11(1):67-76. 15. Schwarz A, Krause PH, Offermann G, Keller F. Impact of de novo membranous glomerulonephritis on the clinical course after kidney transplantation. Transplantation. 1994;58(6): 650-654. 16. Troxell ML, Pilapil M, Miklos DB, Higgins JP, Kambham N. Renal pathology in hematopoietic cell transplantation recipients. Mod Pathol. 2008;21(4):396-406. 17. Ronco P, Debiec H. Pathogenesis of membranous nephropathy: recent advances and future challenges. Nat Rev Nephrol. 2012;8(4):203-213. 18. Vaughan RW, Tighe MR, Boki K, et al. An analysis of HLA class II gene polymorphism in British and Greek idiopathic membranous nephropathy patients. Eur J Immunogenet. 1995;22(2):179-186. 19. A controlled study of short-term prednisone treatment in adults with membranous nephropathy. Collaborative Study of the Adult Idiopathic Nephrotic Syndrome. N Engl J Med. 1979;301(24):1301-1306. 20. Beck LH Jr, Bonegio RG, Lambeau G, et al. M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21. 21. Black DA, Rose G, Brewer DB. Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br Med J. 1970;3(5720):421-426. 22. Stanescu HC, Arcos-Burgos M, Medlar A, et al. Risk HLADQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med. 2011;364(7):616-626. 23. Coenen MJ, Hofstra JM, Debiec H, et al. Phospholipase A2 receptor (PLA2R1) sequence variants in idiopathic membranous nephropathy. J Am Soc Nephrol. 2013;24(4):677-683. Am J Kidney Dis. 2014;64(6):987-993
Membranous Nephropathy Post–Stem Cell Transplantation 24. Fraser CJ, Bhatia S, Ness K, et al. Impact of chronic graftversus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood. 2006;108(8):2867-2873. 25. McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011;26(2):414-430. 26. Eisenberg RA, Via CS. T Cells, murine chronic graft-versushost disease and autoimmunity. J Autoimmun. 2012;39(3):240-247. 27. Foster AD, Haas M, Puliaeva I, Soloviova K, Puliaev R, Via CS. Donor CD8 T cell activation is critical for greater renal disease severity in female chronic graft-vs.-host mice and is associated with increased splenic ICOS(hi) host CD4 T cells and IL-21 expression. Clin Immunol. 2010;136(1):61-73.
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28. Ohsawa I, Ohi H, Fujita T, et al. Glomerular and extraglomerular immune complex deposits in a bone marrow transplant recipient. Am J Kidney Dis. 2000;36(1):E3. 29. Singh N, McNeely J, Parikh S, Bhinder A, Rovin BH, Shidham G. Kidney complications of hematopoietic stem cell transplantation. Am J Kidney Dis. 2013;61(5):809-821. 30. Changsirikulchai S, Myerson D, Guthrie KA, McDonald GB, Alpers CE, Hingorani SR. Renal thrombotic microangiopathy after hematopoietic cell transplant: role of GVHD in pathogenesis. Clin J Am Soc Nephrol. 2009;4(2):345-353. 31. Fraile P, Vazquez L, Caballero D, et al. Chronic graftversus-host disease of the kidney in patients with allogenic hematopoietic stem cell transplant. Eur J Haematol. 2013;91(2): 129-134.
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