Early-onset lupus nephritis

Abstract

Early-onset systemic lupus erythematous (SLE) is a distinct clinical entity characterized by the onset of disease manifestations during childhood. Despite some similarities to patients who are diagnosed during adulthood, early-onset SLE typically displays a greater disease severity, with aggressive multiorgan involvement, lower responsiveness to classical therapies, and more frequent flares. Lupus nephritis is one of the most severe complications of SLE and represents a major risk factor for long-term morbidity and mortality, especially in children. This review focuses on the clinical and histological aspects of early-onset lupus nephritis, aiming at highlighting relevant differences with adult patients, emphasizing long-term outcomes and discussing the management of long-term complications. We also discuss monogenic lupus, a spectrum of conditions caused by single gene variants affecting the complement cascade, extracellular and intracellular nucleic acid sensing and processing, and occasionally other metabolic pathways. These monogenic forms typically develop early in life and often have clinical manifestations that resemble sporadic SLE, whereas their response to standard treatments is poor.

Keywords: interferonopathy; lupus nephritis; monogenic lupus; paediatric lupus.

Figure 1:

Comparison of clinical features and laboratory findings between early-, adult-, and late-onset SLE. The heatmap highlights the different frequency of individual characteristics and clinical manifestations, as well as of haematological and serological markers, across different age-based subgroups of patients with SLE. The data used to generate this heatmap largely come from references [17, 19, 22–25].

Figure 2:

Pathophysiology of LN. Upper panel shows the defects in the clearance of apoptotic debris together with an excessive production of NETs trigger the autoimmune response against nuclear antigens, eventually leading to the production of circulating immune complexes (CICs) composed mainly of autoreactive antibodies capable of binding and activating complement. Autoantigens are captured by plasmacytoid dendritic cells (pDC), which represent the main source of interferon alpha (INFα). IFNα orchestrates the immune response and is responsible for the activation of a broad range of immune cells, including dendritic cells (DC), T helper (Th) cells, cytotoxic T lymphocytes (CTL), and B cells. A variety of cytokines and other stimulating factors induce the maturation of B cells, eventually leading to the generation of autoreactive plasma cells (PC). Lower panel shows that, in LN, glomerular injury is caused by a massive deposition of CICs, usually occurring in the mesangial, subendothelial, and sub-epithelial space (red lines). These induce complement (purple pentagons) activation, which contributes to tissue damage in addition to cytotoxicity deriving from lymphocytes, pro-inflammatory cytokines, and INFα (blue lines), the latter primarily targeting podocytes, endothelial, and parietal epithelial cells. PMN: polymorphonuclear leukocyte; DC: dendritic cell; pDC: plasmacytoid dendritic cell; Th: T helper; CTL: cytotoxic T lymphocyte; PC: plasma cell; IFNα: interferon alpha.

Figure 3:

Kidney histological findings of lupus not included in the ISN/RPS classification. (a) Lupus podocytopathy. Ultrastructural image of a glomerular capillary loop showing complete podocyte foot process effacement (arrows). This came from a patient with new-onset nephrotic syndrome, systemic lupus manifestations and a normal appearance of kidney histology on light microscopy. (b) Thrombotic microangiopathy. Jones’ methenamine-silver-stained slide showing a glomerulus with global intracapillary proliferation and a mixed fibrin and cellular thrombus in the hilum (asterisk). Thrombotic microangiopathy in this patient coexisted with a diagnosis of international society of nephrology and renal pathology society (ISN/RPS) class IV LN. Antiphospholipid antibodies were negative. (c) Antiphospholipid nephropathy. Periodic acid Schiff-stained slide showing a large arteriole with near-complete occlusion due to massive fibrointimal hyperplasia with sparse cells admixed in the proliferating subintimal matrix. Such a lesion is typical of antiphospholipid nephropathy and coexisted in a patient with a diagnosis of ISN/RPS class II LN. Antiphospholipid syndrome was secondary to lupus. (d) Lupus vasculopathy. Masson's trichrome stained slide showing an arteriole (asterisks) completely occluded with massive subendothelial fuchsinophilic deposits, which were positive for IgG, IgA, IgM, C3, and C1q on immunofluorescence, consistent with a diagnosis of lupus vasculopathy. This patient had a concomitant ISN/RPS class III proliferative LN.