Saturday, June 14, 2014

C1q Nephropathy: What You Need to Know

I saw a 20 year old African American male in clinic with nephrotic range proteinuria, reduced GFR and no signs or symptoms of a systemic disease. His mother developed ESRD at age 36 and his brother, aged 26, has CKD Stage 4. A full laboratory workup including complement proteins and ANA was unremarkable. Renal biopsy demonstrated an FSGS pattern of injury with a full house picture on immunofluorescence but with dominant C1q staining. A diagnosis of C1q Nephropathy (C1QN) was made. 

Jennette et al described C1QN in 1985 in 15 patients without evidence of lupus who had dominant mesangial C1q deposition, often with C3 and Ig’s also. The mean age at presentation was almost 18 years, with a similar male: female ratio and average proteinuria of 7.5g/day. Another series from Columbia University included 19 patients who were predominantly African American (73%), young and female (73%) with nephrotic range proteinuria. Renal outcomes across the series’ (including this European series) are mixed but would suggest immunosuppressive treatment directed against the primary pathology should be considered.
C1QN may be considered an independent pathological entity, although this has been controversial, with some classing it as a subtype of FSGS or minimal change disease (MCD). The prevalence varies (0.2-16%) but is more common in children. The predominant light microscopic appearance may be MCD, FSGS or a proliferative glomerulonephritis. While C1q deposition (predominantly in the mesangium; see image) is dominant or co-dominant by definition, a full house pattern of IgM, IgG, IgA, C1q and C3 may be observed, more commonly with a proliferative glomerulonephritis. As for treatment, the case series are small and largely uninformative. Some patients appear to remit with or without immunosuppressive treatment whereas others have a rapid course towards ESRD. Patients with an FSGS pattern may do worse than other types. For what it’s worth, my patient had no response to 6 months of steroids and mycophenolate and a plan for cyclosporine was made. The fact he likely has a genetic element to his disease adds complexity. Some would argue that immunosuppressive therapy in these cases is not likely to be of benefit but we see from our hereditary FSGS cohort that this is not necessarily the case. Cyclosporine and Rituximab in particular appear to have a directly beneficial effect on podocyte function (also see case report of Rituximab treatment in C1QN).
As for the pathogenesis and significance of the C1q deposits, we have much to learn. Are the C1q deposits pathogenic or merely markers of injury? We do know that C1q binds to the basement membrane via laminin and C1q receptors enhance binding of immune complexes to mesangial cells where it combines with other complement proteins to form C1 protease. This in theory allows activation of the classical complement cascade. Despite this, serum C4 levels are generally normal and I can find no reports of complement directed therapy (Eculizumab or C1-Inhibitors) in C1QN.
Bottom line: C1QN is likely an under recognized entity which can have varying clinical and histological presentations. Renal outcomes are also variable and it may have a different prognosis compared to traditional MCD (& FSGS?). One to keep in mind for the boards.

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