Navigating the seronegative gap: a review of rapidly progressive glomerulonephritis with absent biomarkers

Rapidly progressive glomerulonephritis is a nephrological emergency defined by a swift decline in renal function and crescentic injury on biopsy. Its classical framework relies on serological classification into three immunopathological types: anti-glomerular basement membrane antibody disease, immune-complex-mediated nephritis, and pauci-immune antineutrophil cytoplasmic antibody-associated vasculitis. However, a clinically significant subset presents with histological evidence of severe glomerular injury in the absence of any detectable serological marker, a diagnostic and therapeutic challenge termed the “seronegative gap.” This review systematically addresses the full spectrum of seronegative crescentic nephritis. We examine entities where seronegative variants are well-recognized, including seronegative antineutrophil cytoplasmic antibody-associated vasculitis, seronegative anti-glomerular basement membrane disease, and lupus nephritis, alongside conditions that are inherently diagnosis-by-biopsy, such as immunoglobulin A nephropathy and poststreptococcal glomerulonephritis, as well as renal involvement from small-vessel vasculitides, including cryoglobulinemic and rheumatoid vasculitis. For each entity, we discuss the proposed mechanisms of seronegativity, a structured diagnostic algorithm, histopathological classification, and current management strategies. We emphasize that early renal biopsy, not serological confirmation, must drive treatment initiation. Recognition of this seronegative spectrum is essential to prevent irreversible nephron loss.