Current status and issues of C1q nephropathy

Abstract

C1q nephropathy, first proposed by Jennette and Hipp [Am J Clin Pathol 83:415-420, 1985; Am J Kidney Dis 6:103-110, 1985], was described as a distinct glomerular disease entity characterized by extensive mesangial deposition of C1q, with associated mesangial immune complexes, and the absence of any clinical and laboratory evidence of systemic lupus erythematosus. Now, 20 years since the first report, the disease entity is gradually attaining recognition, particularly in the field of pediatrics. C1q is the subcomponent of C1 in the classical pathway of complement activation. Generally, C1q deposition is caused by the activation of C1 by immunoglobulin G (IgG) and IgM; therefore, C1q nephropathy is considered as an immune complex glomerulonephritis. However, in C1q nephropathy, it remains unclear whether the deposition of C1q in the glomeruli is in response to the deposition of immunoglobulin or immune complex, or whether deposition is non-specific trapping that accompanies increased glomerular protein trafficking associated with proteinuria. Since not only the pathogenesis of C1q deposition in glomeruli but also its significance are still uncertain, it has not yet been established as an independent disease. From recent publications of the clinical and pathological characterizations, C1q nephropathy has been thought to be a subgroup of primary focal segmental glomerular sclerosis. However, many reports describe different symptoms, histopathologies, therapeutic responses and prognoses, suggesting that C1q nephropathy is not a single disease entity, but that it may be a combination of several disease groups. There are many uncertain areas requiring further investigation, though it is hoped that a detailed examination of future cases will clarify the subgroups making up C1q nephropathy and their clinicopathological characteristics, and will lead to the establishment of C1q nephropathy as an independent disease entity.

Resolution of clinical and pathologic features of C1q nephropathy after rituximab therapy

“…A rapid decline in serum creatinine and proteinuria was seen following therapy with rituximab, so that hemodialysis could be stopped, and prednisone tapered laboratory evidence of SLE. Clinical manifestations range from asymptomatic proteinuria and/or hematuria with normal renal function to severe nephrotic syndrome with variable progression to ESRD [1,3,9,10]. Our two patients depict this heterogeneity; one an adolescent with moderate renal impairment and massive proteinuria, and the other an elderly woman with rapidly progressive glomerulonephritis necessitating dialysis.…”

“…Our two patients depict this heterogeneity; one an adolescent with moderate renal impairment and massive proteinuria, and the other an elderly woman with rapidly progressive glomerulonephritis necessitating dialysis. Morphologically, two variants of C1qN have been described, the minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) variant and the immune complex glomerulonephritis (GN) variant [1,10]; however, the pathogenesis and role of C1q in this lesion are unclear. In one series, Markowitz et al [3] described C1qN in 19 renal biopsies, of which 17 also demonstrated FSGS including 6 with CG, and 2 had MCD features; they suggested C1qN is a variant of FSGS.…”

“…Predominantly seen in adolescence or young adulthood, the clinical presentation of C1qN varies widely, but the outcome is usually unfavorable; the majority respond poorly to corticosteroids and progress to end-stage renal disease (ESRD) [1,2]. The disease pathogenesis is unclear, as is the role of C1q deposition [3].…”

C1q nephropathy in the pediatric population: pathology and pathogenesis

“…The co-localization of C1q and IgG suggests that mesangial deposition is likely Fc-mediated, although direct cell surface interactions or non-specific trapping cannot be excluded. It has been argued that the heterogeneity of histological findings seen by light microscopy in C1q nephropathy is similar to that found in IgA nephropathy, and thus the pathological classification should be determined largely on the basis of C1q staining [11,34]. While the comparison may prove to be an apt one, the acceptance of IgA nephropathy as a distinct clinicopathological disease was facilitated by the high incidence of IgA nephropathy, the publication of an exceptional number of manuscripts on the clinical and pathological aspects of IgA nephropathy (there were nearly 2,000 publications on IgA nephropathy within 25 years of the initial description by Berger), experimental structural data supporting the direct pathogenic role of IgA, as well as animal models, although these have been shown to have limited homology to human disease [68][69][70][71][72].…”

“…The purpose of this review is to evaluate potential pathogenic mechanisms underlying C1q nephropathy and provide a current appraisal of the published case series from a pediatric perspective. For a broader discussion of C1q nephropathy the reader is referred to recent papers by Mii et al and Vizak et al [11,12].…”