Case Presentation: An 18-year-old female with past medical history of benign primary hypergammaglobulinemic purpura of Waldenstrom presented with an acute kidney injury, nausea, and vomiting. On admission vital signs were significant for blood pressure elevated to 154/96. Physical exam was grossly normal. Notable laboratory studies included Hgb 8.7, Plt 393, BUN 16, creatinine 1.3 (baseline 0.7), GFR 53, FENa 4.8, and FEUrea 78.5. No schistocytes were seen on blood smear. Urinalysis was positive for blood and 24-hour urine collection produced 0.51g of protein. Urine microscopy showed mixed cellular casts with predominantly white blood cell casts and few red blood cells. Renal ultrasound showed echogenic kidneys with no evidence of obstruction. Rheumatology work up revealed ANA 2560 (speckled pattern), positive antiphospholipid panel, SSA+/SSB+, C3 144 (normal), C4 21 (normal). Anti-dsDNA, ANCA, and cryoglobulins were negative. Quantitative immunoglobulins measured IgG 2231 (elevated). Over the three-week admission period the patient had worsening nausea and vomiting, creatinine 1.1-1.2, and platelets dropped to 109. The patient was started on amlodipine 10mg daily but continued to have BP >140/90. Renal biopsy provided a diagnosis of C3 glomerulonephritis (C3GN). Light microscopy showed glomeruli with mild mesangial hypercellularity and some tubulointerstitial scarring. Immunofluorescence revealed C3 glomerular deposition and electron microscopy demonstrated some mesangial and subepithelial deposits. A few arteries showed chronic features of thrombotic microangiopathy (TMA). The patient was started on steroids with improvement in her nausea and vomiting.
Discussion: First described in 2007, C3GN is a disorder of alterative complement pathway (AP) regulation diagnosed by renal biopsy showing subendothelial, mesangial, or subepithelial C3 deposits without immunoglobulins. It is characterized by proteinuria, hematuria, and variable degrees of hypertension and azotemia. Serum C3 is usually normal suggesting local complement activation. There is no specific treatment and the disease tends to be progressive.
C3GN can be associated with TMA, which appears to be present in our patient given her microangiopathy on kidney biopsy, anemia, and subacute decline in platelets. The absence of schistocytes on smear may be explained by a well functioning spleen. We believe this microangiopathy may also underlie her gastrointestinal symptoms.
Patients with C3GN are thought to have a genetic predisposition but expression of the disease may require a second hit. Given her history of hypergammaglobulinemia, our patient likely produced autoantibodies against regulatory proteins of the AP. This is supported by the presence of other autoantibodies, particularly antiphospholipid antibodies which are known to be associated with increased complement activity, and by her positive response to steroids. Genetic testing for regulators of the AP is pending and may help us identify her predisposition to C3GN.
Conclusions: C3GN is a rare disorder of dysregulation of the AP presenting with proteinuria, hematuria, hypertension, and/or azotemia and can be associated with TMA. Development of the disease may require both a genetic predisposition and a second hit such as autoantibody production.