• 1.

    Brukamp K, et al. Nephrotic syndrome after hematopoietic cell transplantation: Do glomerular lesions represent renal graft-versus-host disease? Clin J Am Soc Nephrol 2006; 1:685694. doi: 10.2215/CJN.00380705.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Murphy WJ. Revisiting graft-versus-host disease models of autoimmunity: New insights in immune regulatory processes. J Clin Invest 2000; 106:745747. doi: 10.1172/JCI11088

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Hu SL. The role of graft-versus-host disease in haematopoietic cell transplantation-associated glomerular disease. Nephrol Dial Transplant 2011; 26:20252031. doi: 10.1093/ndt/gfq645.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Beck LH Jr, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361:1121. doi: 10.1056/NEJMoa0810457

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Tomas NM, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014; 371:22772287. doi: 10.1056/NEJMoa1409354

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Sethi S, et al. Hematopoietic stem cell transplant-membranous nephropathy is associated with protocadherin FAT1. J Am Soc Nephrol [published online ahead of print March 23, 2022]. doi: 10.1681/ASN.2021111488; https://jasn.asnjournals.org/content/early/2022/03/23/ASN.2021111488

    • Search Google Scholar
    • Export Citation
  • 7.

    Kudose S, et al. NELL1-associated membranous glomerulopathy after hematopoietic stem cell transplantation. Kidney Int Rep 2021; 6:19921995. doi: 10.1016/j.ekir.2021.04.033.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Nasr SH, et al. Membranous nephropathy with extensive tubular basement membrane deposits following allogeneic hematopoietic cell transplant: A report of 5 cases. Am J Kidney Dis [published online ahead of print September 8, 2021]. doi: 10.1053/j.ajkd.2021.07.021; https://www.ajkd.org/article/S0272-6386(21)00840-4/fulltext

    • Search Google Scholar
    • Export Citation
  • 9.

    Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med 2016; 374:22562267. doi: 10.1056/NEJMra1404711

  • 10.

    Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med 2017; 377:25652579. doi: 10.1056/NEJMra1703472

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Mattei D, et al. Long-term results of rituximab treatment for membranous nephropathy after allogeneic hematopoietic SCT: A case report. Bone Marrow Transplant 2010; 45:11111112. doi: 10.1038/bmt.2009.276

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Jodele S, et al. Complement blockade for TA-TMA: Lessons learned from a large pediatric cohort treated with eculizumab. Blood 2020; 135:10491057. doi: 10.1182/blood.2019004218

    • Search Google Scholar
    • Export Citation

Glomerular Diseases Associated with Stem Cell Transplant

  • 1 Ala Abudayyeh, MD, is Associate Professor with the Division of Internal Medicine, Section of Nephrology, The University of Texas MD Anderson Cancer Center, Houston, TX. Rimda Wanchoo, MD, is Professor of Medicine with the Division of Kidney Disease and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY.
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A llogeneic stem cell transplant (SCT) is used to cure several hematological disorders. The incidence of both acute kidney injury and chronic kidney disease (CKD) post-SCT remains high. A rare cause of CKD post-allogeneic SCT is development of glomerular disease, which by many is considered to be a manifestation of chronic graft-versus-host disease (GVHD) affecting the kidney (1). Based on mouse models, it has been proposed that GVHD could be a direct T cell-mediated injury or that the chronic systemic inflammatory state of GVHD leads to autoimmune induction and glomerulopathy (2). The incidence of nephrotic syndrome

A llogeneic stem cell transplant (SCT) is used to cure several hematological disorders. The incidence of both acute kidney injury and chronic kidney disease (CKD) post-SCT remains high. A rare cause of CKD post-allogeneic SCT is development of glomerular disease, which by many is considered to be a manifestation of chronic graft-versus-host disease (GVHD) affecting the kidney (1). Based on mouse models, it has been proposed that GVHD could be a direct T cell-mediated injury or that the chronic systemic inflammatory state of GVHD leads to autoimmune induction and glomerulopathy (2). The incidence of nephrotic syndrome post-allogeneic SCT is reported to range from 0.4% to 6%, with a median onset after 100 days and up to 12 months post-allogeneic SCT (3). Based on case reports and retrospective studies, it has been reported that nephrotic syndrome appears shortly after cessation or tapering of immunosuppression, with or without chronic GVHD (1, 2).

The most common histological lesion seen is membranous nephropathy (MN), followed by minimal change disease. Other lesions that have been reported are focal segmental glomerulosclerosis, IgA nephropathy, and mesangial proliferative disease (1). In patients with proteinuria, it is recommended to assess for secondary causes, such as infections, drugs, and malignancy, and to do a kidney biopsy when safe (Figure 1).

Figure 1
Figure 1

Glomerular diseases in stem cell transplant patients

Citation: Kidney News 14, 5

In the last decade, we have started to recognize specific antibodies associated with primary MN, such as anti-M-type phospholipase A2 receptor (anti-PLA2R) in 70% of primary MN and anti-thrombospondin type-1 domain-containing 7A (anti-THSD7A) in 1%−5% of primary MN (4, 5). Other rare antigens have also been described in primary MN, such as neural tissue-encoding protein (NELL-1), semaphorin 3B (SEMA3B), protocadherin 7 (PCDH7), and serine protease HTRA1. Secondary MN has been associated with exostosin 1/exostosin 2 (EXT1/EXT2) and neural cell adhesion molecule (NCAM1) (6). For recognizing specific antigens associated with MN in SCT patients, both PLA2R- and NELL-1-associated MNs have been reported (7). In a recent study by Sethi et al. (6), protocadherin (FAT1) was identified as a unique antigen in MN associated with SCT, especially PLA2R-negative MN. All control cases, which included 15 time 0 kidney transplant biopsies, 73 other glomerulopathies, and 28 PLA2R-positive MN cases, were negative for FAT1 (6). In another case series by Nasr et al. (8), five patients with MN were noted to have extensive tubular basement membrane (TBM) deposits of IgG, C3, κ, and λ following allogeneic SCT. Only one patient had PLA2R, and the others were negative for PLA2R, THSD7A, EXT1/EXT2, NELL-1, PCDH7, and SEMA3B, which suggests that there are other unknown antibodies to the TBM leading to the injury as a form of renal GVHD (8).

Although podocyte diseases are rare, renal-limited thrombotic microangiopathy (TMA) post-SCT is not uncommon and remains a challenging topic from a mechanistic, diagnostic, and treatment aspect. However, there have been data indicating that the injury of renal vascular endothelium is analogous to renal GVHD, with C4d staining eluding to the presence of antibody and complement activation (9). Another finding connecting endothelial injury and TMA to GVHD includes elevated markers of endothelial injury, such as ST2 protein (receptor for interleukin-33), as well as angiopoietin 2, in patients with steroid refractory GVHD (10).

Treatment of glomerular diseases post-SCT has been guided by case reports and case series. Typically, treating with steroids initially and reinitiating immunosuppressive therapy, such as calcineurin inhibitors, mycophenolate mofetil, or cyclophosphamide, have been the standard of care. Rituximab has been used to treat SCT-associated MN and has proven to be effective (11). Treatment for renal TMA is challenging and often requires use of rituximab or anti-complement therapy. Data are sparse and mostly in the pediatric nephrology literature (12).

References

  • 1.

    Brukamp K, et al. Nephrotic syndrome after hematopoietic cell transplantation: Do glomerular lesions represent renal graft-versus-host disease? Clin J Am Soc Nephrol 2006; 1:685694. doi: 10.2215/CJN.00380705.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Murphy WJ. Revisiting graft-versus-host disease models of autoimmunity: New insights in immune regulatory processes. J Clin Invest 2000; 106:745747. doi: 10.1172/JCI11088

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Hu SL. The role of graft-versus-host disease in haematopoietic cell transplantation-associated glomerular disease. Nephrol Dial Transplant 2011; 26:20252031. doi: 10.1093/ndt/gfq645.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Beck LH Jr, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361:1121. doi: 10.1056/NEJMoa0810457

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Tomas NM, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med 2014; 371:22772287. doi: 10.1056/NEJMoa1409354

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Sethi S, et al. Hematopoietic stem cell transplant-membranous nephropathy is associated with protocadherin FAT1. J Am Soc Nephrol [published online ahead of print March 23, 2022]. doi: 10.1681/ASN.2021111488; https://jasn.asnjournals.org/content/early/2022/03/23/ASN.2021111488

    • Search Google Scholar
    • Export Citation
  • 7.

    Kudose S, et al. NELL1-associated membranous glomerulopathy after hematopoietic stem cell transplantation. Kidney Int Rep 2021; 6:19921995. doi: 10.1016/j.ekir.2021.04.033.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Nasr SH, et al. Membranous nephropathy with extensive tubular basement membrane deposits following allogeneic hematopoietic cell transplant: A report of 5 cases. Am J Kidney Dis [published online ahead of print September 8, 2021]. doi: 10.1053/j.ajkd.2021.07.021; https://www.ajkd.org/article/S0272-6386(21)00840-4/fulltext

    • Search Google Scholar
    • Export Citation
  • 9.

    Hingorani S. Renal complications of hematopoietic-cell transplantation. N Engl J Med 2016; 374:22562267. doi: 10.1056/NEJMra1404711

  • 10.

    Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med 2017; 377:25652579. doi: 10.1056/NEJMra1703472

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Mattei D, et al. Long-term results of rituximab treatment for membranous nephropathy after allogeneic hematopoietic SCT: A case report. Bone Marrow Transplant 2010; 45:11111112. doi: 10.1038/bmt.2009.276

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Jodele S, et al. Complement blockade for TA-TMA: Lessons learned from a large pediatric cohort treated with eculizumab. Blood 2020; 135:10491057. doi: 10.1182/blood.2019004218

    • Search Google Scholar
    • Export Citation
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