Autoimmunity in membranous nephropathy

Membranous nephropathy (MN, also membranous glomerulonephritis) is a chronic inflammatory disease of the kidney corpuscles (glomeruli) characterised by thickening of the glomerular capillary walls due to deposits of immune complexes (see illustration). The deposits damage the podocytes and impair the permeability of the glomerular basement membrane in the glomeruli, leading to proteinuria. If protein excretion in the urine increases significantly (>3.5 g/24 h), nephrotic syndrome with reduced protein concentration in the blood (hypoproteinaemia), increased blood lipid levels (hyperlipidaemia) and oedema may develop.¹

CONCLUSION: Since the treatment of the two disease forms differs significantly, the diagnostic differentiation between primary and secondary MN is of greatest clinical importance.⁴ In sMN, the therapy focuses on the underlying disease, whereas patients with pMN are mainly treated with immunosuppressives. Therefore, correct and fast diagnosis may prevent unnecessary diagnostic procedures or drug treatment.

In 2009, David J. Salant and colleagues discovered PLA2R, a185-kDa glycoprotein, as a specific autoantigen for antibodies that could be detected in 70-80% of all patients with MN without secondary cause.³ In 2014, a second antigen was described in connection with primary MN, THSD7A.⁵ The prevalence of antibodies against THSD7A is given with values of up to 10%. Although antibodies against PLA2R and THSD7A can occur in parallel in rare cases, anti-THSD7A antibodies have been found predominantly in anti-PLA2R seronegative pMN patients.⁶ In patients with sMN, both autoantibodies against PLA2R and THSD7A could not be detected.
The antigens are expressed on the surface of the podocytes. They bind circulating autoantibodies and immune-complex deposits are formed.

The pathogenic mechanism of the development of pMN is not yet fully understood. However, scientists agree that the thickening of the glomerular capillary walls is caused by deposited immune complexes. These trigger local complement activations, which lead to a degradation of the cytoskeleton of the podocytes via the involvement of various mediators. The impaired podocytes lose their filter function and secrete additional factors that have a negative effect on the glomerular basement membrane.¹ This causes a progressive impairment of the filter function and thus an increase in the amount of protein in the primary urine (proteinuria). This leads to the development of oedema and a compensatory increase in lipoprotein synthesis, which can result in nephrotic syndrome.

The relevance of autoantibodies in the pathogenesis of pMN was shown in 2017 for THSD7A in the mouse model. Injection of antibodies directed against THSD7A induced severe nephrotic syndrome with proteinuria and hyperlipidaemia in mice.⁷

While the pathogenesis triggered by the autoantibodies is the same regarding the mechanism, differences have been observed in the clinic of anti-PLA2R and anti-THSD7A-positive pMN patients. A study by Hoxha et al. (2016) showed a higher incidence of malignant tumours in anti-THSD7A-positive patients.⁸ 

¹Ronco et al., Nat Rev Dis Primers 7, 69 (2021)
²KDIGO, Kidney inter. 100 (Suppl.): 1–276 (2021)
³Beck et al., N Engl J Med 361, 11-21 (2009)
⁴Trujillo et al., Nephron. 144, 261-271 (2020)
⁵Tomas et al., N Engl J Med 371, 2277-2287 (2014)
⁶Tomas et al., J Am Soc Nephrol 28, 3262-3277 (2017)
⁷Larsen et al., Mod Pathol 29, 421-426 (2016)
⁸Hoxha et al., J Am Soc Nephrol 28, 520-531 (2017)