Clinical and Pathophysiological Insights Into Immunological Mediated Glomerular Diseases in Childhood

Abstract

The kidney is often the target of immune system dysregulation in the context of primary or systemic disease. In particular, the glomerulus represents the anatomical entity most frequently involved, generally as the expression of inflammatory cell invasion or circulant or in situ immune-complex deposition. Glomerulonephritis is the most common clinical and pathological manifestation of this involvement. There are no universally accepted classifications for glomerulonephritis. However, recent advances in our understanding of the pathophysiological mechanisms suggest the assessment of immunological features, biomarkers, and genetic analysis. At the same time, more accurate and targeted therapies have been developed. Data on pediatric glomerulonephritis are scarce and often derived from adult studies. In this review, we update the current understanding of the etiologic events and genetic factors involved in the pathogenesis of pediatric immunologically mediated primitive forms of glomerulonephritis, together with the clinical spectrum and prognosis. Possible new therapeutic targets are also briefly discussed.

Anti-glomerular basement membrane disease in children: a brief overview

“…Cases of dual ANCA and anti-GBM antibody positivity are widely reported (17% of reported cases in children) and it has been suggested that the initial presence of ANCA may be the trigger responsible for exposing the epitope in the alpha-3 chain [8]. Dual positivity is associated with a poorer prognosis, and thus, early, aggressive treatment is recommended [18]. Patients may also present with features overlapping with membranous nephropathy at a higher rate than would be expected by chance and atypical presentations of this disease are reported [19].…”

Rapidly progressive glomerulonephritis in children

“…This final fibrous stage is unlikely to respond to immunosuppressive therapy and has a high risk of ESKD. 1,13,14 Types of Crescentic Glomerulonephritis: Three mechanisms of glomerular injury are known that can result in activation of podocytes and epithelial proliferation to form crescents. Type-I: Anti-GBM (Goodpasture syndrome)constitutes circulating antibodies IgG directed against the non-collagenous domain of alpha-3 chain of type IV collagen, present in the GBM and/or alveolar basement membrane.…”

“…It accounts for 10%-15% of all diffuse crescentic GN and may present as GN alone or in combination with pulmonary hemorrhage (Goodpasture syndrome) and as ANCA associated "dual antibody disease". 14 Reported pediatric cases are very rare (n=31) with a higher prevalence in girls (M/F ratio 1:4). 15 Type-II: Immune complex mediated injury-Multiple stimuli lead to crescentic proliferative GN including infections, systemic diseases, and preexisting primary GN.…”

“…Ten percent of patients with GPA or MPA may have ANCA-negative GN limited to the kidneys and are taken under this spectrum with similar clinical features, biopsy findings and prognosis. 13,14 The histological classification: focal (50% normal glomeruli), crescentic (>50% cellular crescents), sclerotic (>50% sclerotic glomeruli) and mixed (any other combination) has significant prognostic value. Validation studies have confirmed the predictive value of this system in adults and in children.…”

“…18 RPGN in older children may present more commonly with complications like hypertensive emergencies, volume overload, pulmonary edema and cardiac failure. 14 There may be features of underlying systemic diseases with skin (vasculitic rash), joint (arthritis), nervous system (convulsions and altered sensorium) and upper airway (sinusitis, septal perforation) /pulmonary involvement (hemoptysis and pulmonary hemorrhage). 11,14,19 Anti-GBM RPGN is rare in children.…”