Thrombospondin type-1 domain-containing 7A-related membranous nephropathy associated with glomerular AL amyloidosis

Abstract

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a systemic severe disease that predominantly affects the kidneys and the heart, with cardiac amyloidosis as a major determinant of outcome. Renal involvement typically manifests with nephrotic syndrome and/or deterioration of kidney function, with amyloid deposits mainly observed within the glomeruli and vessel walls. It usually occurs in patients with plasma cell clones but may also result, in rare cases, from Waldenström macroglobulinaemia (WM) and other B-cell lymphoproliferative disorders. Autologous stem cell transplantation (SCT) associated with high dose chemotherapy has improved haematological response and survival in selected patients with AL amyloidosis. Organ response is often delayed after a favourable haematological response, with organ recovery strongly associated with the depth of the haematological response achieved.1Muchtar E. Dispenzieri A. Leung N. et al.Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria.Leukemia. 2018; 32: 2240-2249Crossref PubMed Scopus (52) Google Scholar,2Kaufman G.P. Dispenzieri A. Gertz M.A. et al.Kinetics of organ response and survival following normalization of the serum free light chain ratio in AL amyloidosis.Am J Hematol. 2015; 90: 181-186Crossref PubMed Scopus (60) Google Scholar Even in cases of successful haematological response, patients with AL amyloidosis can experience a progressive decline of renal function and a worsening of proteinuria.1Muchtar E. Dispenzieri A. Leung N. et al.Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria.Leukemia. 2018; 32: 2240-2249Crossref PubMed Scopus (52) Google Scholar,3Angel-Korman A. Jaberi A. Sanchorawala V. Avasi A. The utility of repeat kidney biopsy in systemic immunoglobulin light chain amyloidosis.Amyloid. 2020; 27: 17-24Crossref PubMed Scopus (7) Google Scholar Iterative kidney biopsies may show the persistence of or increases in renal amyloid deposits3Angel-Korman A. Jaberi A. Sanchorawala V. Avasi A. The utility of repeat kidney biopsy in systemic immunoglobulin light chain amyloidosis.Amyloid. 2020; 27: 17-24Crossref PubMed Scopus (7) Google Scholar, 4Roth R.M. Benson D. Hebert L.A. et al.Progressive renal light chain amyloidosis with the absence of detectable free monoclonal light chains after an autologous hematopoietic stem cell transplant for amyloid light chain amyloidosis.Arch Pathol Lab Med. 2013; 137: 1304-1308Crossref PubMed Scopus (7) Google Scholar, 5Zeier M. Perz J. Linke R.P. et al.No regression of renal AL amyloid in monoclonal gammopathy after successful autologous blood stem cell transplantation and significant clinical improvement.Nephrol Dial Transplant. 2003; 18: 2644-2647Crossref PubMed Scopus (43) Google Scholar without identifying recent amyloid deposits, and thus may not be helpful in the therapeutic management. We report a patient who presented with nephrotic syndrome 5 years after autologous SCT for systemic AL amyloidosis related to WM. Strikingly, renal biopsy demonstrated Thrombospondin type-1 domain-containing 7A (THSD7A)-related membranous nephropathy (MN) associated with glomerular AL amyloidosis. In 2011, a 56-year-old man was diagnosed with biclonal WM, with monoclonal IgM lambda (32 g/L) and IgG lambda (12 g/L) spikes associated with a decrease in free light chain ratio [kappa/lambda (κ/λ) ratio = 0.18; normal range 0.26–1.65] on immunonephelometric assays. At the time of WM diagnosis, whole-body magnetic resonance imaging revealed diffuse infiltration of the retroperitoneal and mesenteric adipose tissue due to biopsy-proven AL-lambda amyloidosis. Amyloid deposits were also observed on bone marrow and bladder biopsies. Magnetic resonance imagery showed left ventricular wall thickening (septum 19 mm) with heterogeneous late gadolinium enhancement, suggestive of cardiac amyloidosis. No renal biopsy was performed at the time of WM diagnosis, because renal function was not altered [serum creatinine concentration 0.83 mg/dL; estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease–Epidemiology Collaboration (CKD-EPI) equation 114 mL/min/1.73 m2] with no significant proteinuria [urine protein/creatinine ratio (UPCR) 46 mg/mmol]. In 2012, after several lines of chemotherapy with no satisfactory haematological response, the patient received an autologous SCT leading to a normalisation of free light chain ratio (κ/λ ratio = 0.44) and a decrease in the monoclonal IgM and IgG lambda spikes to below the threshold for quantification. UPCR and albumin levels at lymphoma diagnosis and during follow-up are summarised in Fig. 1. The patient was referred to our Nephrology Department in November 2017. At admission, he presented with nephrotic syndrome (UPCR 522 mg/mmol and albumin concentration 2.3 g/dL) and microscopic haematuria (104/mL) on urine sediment analysis. Physical examination revealed neither organomegaly nor palpably enlarged lymph nodes. Laboratory investigations revealed a decrease in eGFR to 74 mL/min/1.73 m2, and detectable but non-quantifiable monoclonal IgG and IgM lambda spikes (<1 g/L) on immunoelectrophoresis. Immunonephelometric assays showed the presence of free lambda light chains at a concentration of 35.7 mg/L (normal range 5.71–26.30 mg/L) with a normal κ/λ ratio of 0.79. Proteinuria was composed mostly of albumin (urine albumin/creatinine ratio 410 mg/mmol). Urine immunoelectrophoresis revealed the presence of small amounts of IgG lambda and free lambda light chains. Serum complement levels were within the normal range. Renal ultrasonography findings were unremarkable, and positron emission tomography-computed tomography (PET-CT) did not identify any hypermetabolic lesions. A kidney biopsy was performed to explore this nephrotic syndrome in a patient previously diagnosed with extrarenal AL amyloidosis but with non-quantifiable monoclonal spikes 5 years after autologous SCT. The renal biopsy specimen consisted of renal cortex tissue, with 16 glomeruli. All the glomeruli displayed large mesangial Congo red-positive amyloid deposits, with apple-green birefringence (Fig. 2A,B). Immunofluorescence showed that anti-λ light chain antibody stained predominantly the amyloid deposits and revealed bright granular capillary wall IgG deposits with polytypic (kappa- and lambda-positive) subepithelial deposits (Fig. 2C–E). An analysis of the subepithelial IgG subclass distribution revealed positive staining for IgG1 and IgG4 (data not shown), suggesting primary MN. Consistent with light microscopy and immunofluorescence analysis findings, electron microscopy demonstrated amyloid fibrils within the mesangium and subepithelial non-organised deposits (Fig. 3). Immunohistochemistry with anti-phospholipase A2 receptor 1 (PLA2R) antibody was negative (not shown), whereas subepithelial deposits were stained with anti-THSD7A antibody (Fig. 2F). Circulating THSD7A antibodies were detected in the serum (1/50). The definitive pathological diagnosis was a co-occurrence of AL amyloidosis and THSD7A-related MN.Fig. 3Electron microscopy findings. Ultrastructural analysis revealed randomly unbranched amyloid fibrils within the mesangium (A, arrow and B) and subepithelial non-organised deposits (A, arrowheads and C, arrowheads). A, ×15,000, scale bar = 1 μm. B, ×50,000, scale bar = 500 nm. C, ×40,000, scale bar = 500 nm.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Our patient was treated with two doses of intravenous rituximab (375 mg/m2), 2 weeks apart. Two weeks after the second infusion of rituximab, circulating anti-THSD7A antibodies were no longer detectable, and we observed a significant decrease in UPCR associated with an increase in albumin concentration (Fig. 1). Two years later, with no additional treatment, our patient was in complete remission from the nephrotic syndrome with sustained haematological disease remission (normal κ/λ ratio of 1.12) (Fig. 1). MN, one of the major causes of nephrotic syndrome in adults, is histologically characterised by granular IgG deposits in the subepithelial region of the glomerular basement membrane. Since the recent discovery of autoantibodies directed against a podocyte surface antigen, primary MN has been reclassified as an autoimmunity-mediated glomerular disease. Circulating antibodies against PLA2R and THSD7A were the first to be identified, and account for about 70–80% and 2–5% of primary MN cases, respectively. A broad spectrum of medical conditions may be associated with the occurrence of MN and the recent identification by laser microdissection and mass spectrometry of new target antigens in MN has highlighted an antigen-based classification.6Sethi S. New 'antigens' in membranous nephropathy.J Am Soc Nephrol. 2021; 32: 268-278Crossref PubMed Scopus (62) Google Scholar Circulating anti-THSD7A antibodies have been previously identified in the setting of solid tumour-associated MN, with expression of THSD7A in tumoural cells.7Hoxha E. Wiech T. Stahl P.R. et al.A mechanism for cancer-associated membranous nephropathy.N Engl J Med. 2016; 374: 1995-1996Crossref PubMed Scopus (109) Google Scholar In our case, extensive screening (colonoscopy, oesophagogastroscopy and PET-CT) for potential underlying cancer was negative. Secondary MN is one of the most frequent glomerular diseases occurring after allogeneic haematopoietic SCT8Troxell M.L. Pilapil M. Miklos D.B. et al.Renal pathology in hematopoietic cell transplantation recipients.Mod Pathol. 2008; 21: 396-406Crossref PubMed Scopus (51) Google Scholar and may be included in the spectrum of clinical manifestation related to chronic graft-versus-host-disease (GVHD). Chronic GVHD is associated with a loss of B-cell tolerance, with the production of antibodies to both allo- and auto-antigens, notably targeting surface membrane antigens. By contrast, secondary MN after autologous SCT remains poorly described.8Troxell M.L. Pilapil M. Miklos D.B. et al.Renal pathology in hematopoietic cell transplantation recipients.Mod Pathol. 2008; 21: 396-406Crossref PubMed Scopus (51) Google Scholar, 9Mrabet S. Aicha N.B. Abdessayed N. et al.Membranous nephropathy succeeding autologous hematopoietic stem cell transplant: a case report.BMC Nephrol. 2018; 19: 57Crossref PubMed Scopus (4) Google Scholar, 10Abudayyeh A. Truong L.D. Beck Jr., L.H. et al.Membranous nephropathy in autologous hematopoietic stem cell transplant: autologous graft-versus-host disease or autoimmunity induction?.Clin Kidney J. 2015; 8: 440-444Crossref PubMed Scopus (11) Google Scholar In these four previously reported cases, analysis of the glomerular IgG subclasses distribution was not performed and no circulating anti-PLA2R antibodies were detected in two patients.9Mrabet S. Aicha N.B. Abdessayed N. et al.Membranous nephropathy succeeding autologous hematopoietic stem cell transplant: a case report.BMC Nephrol. 2018; 19: 57Crossref PubMed Scopus (4) Google Scholar,10Abudayyeh A. Truong L.D. Beck Jr., L.H. et al.Membranous nephropathy in autologous hematopoietic stem cell transplant: autologous graft-versus-host disease or autoimmunity induction?.Clin Kidney J. 2015; 8: 440-444Crossref PubMed Scopus (11) Google Scholar The association of biopsy-proven renal amyloidosis and concomitant polytypic MN remains an exceptional finding. We report here the first case, to our knowledge, of simultaneous renal AL amyloidosis associated with THSD7A-related MN after a favourable haematological response. As no kidney biopsy was performed at initial presentation, we cannot accurately determine when fibril deposition in renal tissue began, or its kinetics. The presence of diffuse extra-renal amyloid deposits (retroperitoneum, bone marrow, and bladder) at the time of WM diagnosis and the successful treatment of the haematological disease suggest that amyloid deposits may have also involved the kidney at the time of initial presentation, although our patient had no significant proteinuria and normal eGFR. Amyloidosis burden in kidney biopsy may not correlate to proteinuria level at diagnosis in AL amyloidosis patients.11Rubinstein S. Cornell R.F. Du L. et al.Novel pathologic scoring tools predict end-stage kidney disease in light chain (AL) amyloidosis.Amyloid. 2017; 24: 205-211Crossref PubMed Scopus (7) Google Scholar In AL amyloidosis patients achieving a favourable haematological response, iterative kidney biopsies may also reveal a regression of the immunoglobulin component12Safadi S. Saad A. Quint P.S. et al.Disappearance of immunoglobulins from persistent renal amyloid deposits following stem cell transplantation for heavy-and light-chain amyloidosis.Nephrol Dial Transplant. 2015; 30: 1151-1155Crossref PubMed Scopus (10) Google Scholar suggesting that, beyond the amyloid bulk, the amyloidogenic monoclonal light chain may display direct tissue toxicity. In our patient, despite the persistence of lambda light chain within amyloid deposits on immunofluorescence study, the voluminous glomerular amyloid deposits remain asymptomatic with a normal range of proteinuria 2 years after rituximab infusion, one of the cornerstones of the therapeutic management of primary MN. The rapid improvement of proteinuria and albumin levels after two infusions of rituximab, without the need for additional haematological chemotherapy, and the sustained complete remission of nephrotic syndrome after 2 years of follow-up, strongly suggest that the nephrotic-range proteinuria was mostly due to glomerular damage related to MN rather than to AL amyloid deposits. In conclusion, optimal management of renal progression in patients with AL amyloidosis remains challenging after haematological treatment. Careful nephrological investigations, in addition to the standard haematological tests, are required in patients with successful treatment of AL amyloidosis and worsening of laboratory renal parameters. In such patients, kidney biopsy should be systematically discussed to investigate potential alternative glomerular diseases.