Segmental Membranous Glomerulopathy in Adults

Abstract

Introduction: The clinicopathological features of segmental membranous glomerulopathy (SMGN) have not been well characterized. The aim of this study was to investigate the prevalence and clinicopathological features of SMGN in adults. Methods: Adult patients with biopsy-confirmed SMGN in the native kidney at our center between January 2017 to September 2020 were identified. The clinicopathological features of SMGN were collected. The glomerular deposition of IgG subclasses, M-type phospholipase A2 receptor 1 (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A) and neural epidermal growth factor-like 1 protein (NELL1) were tested. Clinical and pathologic features were comparable between NELL1-positive and NELL1-negative SMGN. Results: A total of 167 patients with biopsy-proven SMGN were enrolled. During the same period, 32,640 (33.0%) out of 98,939 renal biopsies were diagnosed with membranous nephropathy (MN) in adults. SMGN accounted for 0.17% of total kidney biopsies and 0.51% of MN in adults. One hundred and fifty (89.8%) cases were isolated SMGN and 17 (10.2%) cases were complicated with other kidney disease. Clinically, the median age of isolated SMGN patients was 41.5 years, with female (74%) predominance, and 33.1% had full nephrotic syndrome. Pathologically, IgG1 was the dominant subclass (92.5%), followed by IgG4 (45.0%). PLA2R and THSD7A staining were done in 142 and 136 isolated SMGN cases, respectively. In which, all the cases showed negative. NELL1 staining was done in 135 isolated SMGN cases, 58 cases (43.0%) showed positive. Fifty-eight patients (41.1%) had diffuse (≥90%) foot process effacement, 119 patients (83.8%) had either stage I (38.0%) or stage II (45.8%) membranous alterations in patients with SMGN. Most patients with NELL1-positive SMGN were female. Patients with NELL1-positive SMGN were more likely with lower prevalence of full nephrotic syndrome than NELL1-negative SMGN. Conclusions: SMGN is a relatively rare pathological type. Majority of patients with isolated SMGN were female, with a median age of 41.5 years, 33.1% had full nephrotic syndrome, absence of PLA2R and THSD7A, 43.0% with NELL1-positive, and mainly stage I or II MN (83.8%). NELL1 is the major target antigen of SMGN in adults.

NELL1 membranous nephropathy: clinical associations provide mechanistic clues

“…Another major underlying condition is malignancy, reported in in 0-33% of patients depending on study ( 13 , 27 , 36 ), substantially higher than that seen with PLA2R MN (~4%) ( 4 , 13 , 48 ). Of reported patients, 9 of 12 (75%) with oncologic remission also had remission of proteinuria ( 13 , 42 ), supporting this link.…”

“…Notably, series of NELL1 MN from India ( 36 ) and China ( 27 ) generally lack the associations with autoimmune disease or malignancy reported from the US, Europe, and Japan, and additional underlying genetic and/or environmental factors may contribute to disease development in different groups. Higher rates of remission tend to be seen in association with thiol or mercury exposures, and potentially with oncologic remission ( 13 ).…”

“…PLA2R and NELL1 are the most commonly implicated antigens in MN and have distinct clinical associations, but rare cases have been reported as dual positive (summarized in Table 2 ). Of seven cases, two describe patients with a low-titer ( 27 ) or borderline ( 50 ) serum anti-PLA2R antibodies at time of biopsy, one with positive tissue PLA2R ( 27 ), one with negative tissue PLA2R ( 50 ). The first went into remission but relapsed with high-titer anti-PLA2R antibodies (without anti-NELL1 antibodies) ( 27 ), and the second progressed to have a positive serum anti-PLA2R antibody (with persistent anti-NELL1 antibodies) ( 50 ).…”

“…Of seven cases, two describe patients with a low-titer ( 27 ) or borderline ( 50 ) serum anti-PLA2R antibodies at time of biopsy, one with positive tissue PLA2R ( 27 ), one with negative tissue PLA2R ( 50 ). The first went into remission but relapsed with high-titer anti-PLA2R antibodies (without anti-NELL1 antibodies) ( 27 ), and the second progressed to have a positive serum anti-PLA2R antibody (with persistent anti-NELL1 antibodies) ( 50 ). A third patient had an initial biopsy with PLA2R+ NELL1- MN (no serum available), treated conservatively, with relapse >10 years later and biopsy demonstrating dual PLA2R+ NELL1+ MN with corresponding serum antibodies to both PLA2R and NELL1 ( 37 ).…”

“…On presentation, patients with NELL1 MN have nephrotic range proteinuria (approximately 35-80%), often preserved kidney function (in 70-84%), and are usually adults with a median age in their 60's although adolescent cases have been reported (Table 1) (12,13,26,43). NELL1 MN has been reported in wide spectrum of racial and ethnic backgrounds; taken together, larger studies show a relatively similar male to female distribution although this varies significantly by study and underlying association (Table 1).…”