Clarice P. Lin1 and Richard C. Chou2, 1University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Department of Medicine, Buffalo, NY, 2University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Division of Allergy, Immunology, & Rheumatology, Department of Medicine, Buffalo, NY
Background/Purpose: Kidney disease is a common manifestation of systemic lupus erythematosus (SLE); when it presents as glomerulonephritis also known as lupus nephritis (LN), it predicts an aggressive SLE disease course. Conventional nephrotic-range proteinuria is typically associated with Class III, IV, and V LN; however, a patient can have both nephrotic proteinuria and lupus with a rare and distinctive histopathology not characteristic of these three LN classes. Lupus podocytopathy (LP) is characterized by widespread podocyte foot process effacement without endocapillary proliferation, mesangial deposits, or lupus-associated sub-endothelial and sub-epithelial immune-complex deposition present in the glomerular capillary wall seen on electron microscopy. However, the contribution of LP to the pathophysiology of lupus kidney disease and its relationship to LN is unknown. In this review, we systematically outline the molecular mechanisms of LN and LP to provide a framework for better understanding the difference in the pathogenesis, clinical presentation, and treatment outcomes in both LN and LP.
Methods: A comprehensive electronic database search was conducted to identify studies involving patients with LN or LP. Previous observational studies and experimental trials on LN and LP published from inception to May 22, 2022 were included; a total of 68 full-text articles in English language were analyzed for review.
Results: LP has been shown to be pathogenically independent of the widely accepted immune complex deposition and cytokine production characteristic of podocyte injury pathway of LN. The proposed mechanisms of LP suggest that dysregulation of interleukin-13 decreases the expression of structural podocyte proteins, and upregulation of angiopoietin-like 4 changes intermediate filament and actin-binding proteins found in the podocyte cytoskeleton, ultimately causing cytoskeleton damage and diffuse foot process effacement. Renal biopsy and subsequent histopathology should differentiate between LN and LP; many urinary biomarkers have been proposed, but not one has been demonstrated as strong enough to validate its usefulness in clinical practice and replace the kidney biopsy. In addition, the treatment responsiveness to glucocorticoid therapy is noticeably different between LN and LP. Recent studies have advocated for further breakdown of categorization of LP into minimal change disease type, mesangial proliferation type, and focal segmental glomerulosclerosis (FSGS) type of LP; further breakdown into subtypes of LP may explain the difficulty of early diagnosis, prompt treatment of symptoms, and predict their responsiveness to certain immunosuppressive treatments.
Conclusion: LP is emerging as a unique and independent type of LN, and targeted therapy of LP should be designed accordingly. More research is needed to elucidate the differences in pathogenesis and treatment in LN and LP. Renal biopsy and histopathology should guide management of LP. Although podocyte injury does not fully explain the pathogenesis of LP, immunosuppressive therapies known to treat podocyte injury in minimal change disease and FSGS (diseases not seen with concurrent lupus) should be further explored for LP.
Disclosures: C. Lin, None; R. Chou, Sun Pharmaceuticals Industries Limited.
