Presentation on theme: "1 Nephrology Department, General Hospital of Rhodes, Rhodes, Greece, 2 1 st Department of Internal Medicine, General Hospital of Rhodes, Rhodes, Greece."— Presentation transcript:
1 Nephrology Department, General Hospital of Rhodes, Rhodes, Greece, 2 1 st Department of Internal Medicine, General Hospital of Rhodes, Rhodes, Greece
C3 glomerulonephritis (C3GN) is a rare glomerular disease characterised by glomerular deposition mainly of C3 protein with little or no immunoglobulins. Acquired or genetic defects of complement’s regulatory proteins lead to uncontrolled activation of the alternative pathway (AP) of complement’s cascade with subsequent glomerular injury. Occassionally AP may also be activated by an infection resulting in glomerular lesions similar to those observed in C3 GN. We present a case of a proliferative GN with dominant C3 deposits secondary to a respiratory infection.
A 71 year-old male patient was admitted in our hospital due to pneumonia with pleural effusion. During his hospitalization he presented acute renal failure (urea 143 mg/dl, creatinine 2,9mg/dl), proteinuria of 6,3 gr/24h, microscopic hematuria and arterial hypertension. Administration of Moxifloxacin and Piperacillin/Tazobactam iv for 14 days led to clinical improvement and the patient was discharged presenting normal renal function and proteinuria of subnephrotic level. Three months later he was readmitted due to full- blown nephrotic syndrome(12,4gr/ ) with generalised oedema. His renal function was still normal. Immunologic blood testing revealed the presence of autoantibodies (ANA 1/640, Ra-test 24,8 IU/ ml) and low levels of complement’s protein C3 (2 mg/dl, normal 82-175 mg/dl). Serum levels of C4 were within normal range. Control for the presence of other autoantibodies (anti-dsDNA, c- ANCA, p-ANCA, anti-ENA), serum tumor markers, HBV, HCV and monoclonal gammopathy was negative. The patient underwent a kidney biopsy which showed endocapillary proliferation,mild mesangial expansion, focal thichening of glomerular basement membranes and intersitial inflammation. Immunofluorescence revealed massive granular, “hump-like” deposits of C3 in the glomerular basement membranes.Fig1,2. Staining for IgM, IgG, IgA, C1q, κ and λ light chains was negative. Further laboratory testing revealed the presence of C3NeF (0,18 IU, range 0,00-0,30), while the serum levels of CFH were normal (375 μg/ml, normal 160-412 μg/ml). Specific immunosuppressive treatment with cyclosporine (3mg/kg/d) and low-dose methylprednisolone (16mg/day) was initiated. Two months later the patient had normal renal function, proteinuria 222 mg/24hours while C3 serum levels were 62 mg/dl.
Fig.1: Lobulated glomerulus with mild endocapillary hypercellularity, increased mesangial matrix and segmental thickening of the glomerular basement membranes. Fig. 2. Interstitial infiltration with inflammatory leucocytes
C3 glomerulopathy includes a group of rare glomerular diseases (dense deposit disease, C3GN and CFHR5 nephropathy) with the common histologic feature of glomerular deposition of C3 with little or no immunoglobulines . Pathogenesis of these GN relies on the uncontrolled avtivation of the AP of the complement’s cascade. Genetic defects of the regulatory proteins of the AP (CFH, CFI, MCP/CD46) as well as autoantibodies (C3 NeF, anti-CFH) lead to glomerular accumulation of C3. C3 GN is usually diagnosed in adults with proteinuria, sometimes of nephrotic range, hematuria, arterial hypertension or renal failure. The most common histological appearance of C3 GN on light microscopy is the mesangioproliferative or membranoproliferative pattern . In our case we observe a postinfectious GN (PIGN) with atypical clinical and laboratory course and histologic features suggestive of C3 GN. Although resolution of pneumonia was associated with normalization of renal function and decline of proteinuria, the patient presented full-blown nephrotic syndrome 3 months later. In addition, serum levels of C3 were very low. In typical cases of PIGN they return to normal within 8 weeks of therapy .
C3NeF is an autoantibody which directs against C3 convertase of the AP and stabilizes the convertase against the effect of CFH. As a result altered regulation of the AP leads to uncontrolled C3 activation and low C3 serum levels. The findings of intracapillary and interstitial inflammation on light microscopy as well as the “hump-like” deposits were suggestive of a classic postinfectius GN but they were accompanied by C3 deposits exclusively without immunoglobulines. There is a degree of overlap between C3GN and the classic PIGN but their distinction will be based on the abovementioned atypical features. Although the treatment of C3 GN using immunosuppressive agents has given contradictory results in the literature, in this case the administration of cyclosporine and low-dose cortisone led to rapid resolution of nephrotic syndrome and stabilization of C3 serum levels.
C3 GN should be taken in consideration for differential diagnosis in patients with postinfectious acute renal injury. Cyclosporine-based regimen may lead to early remission. REFERENCES: 1.Fakhouri F, Fremeaux-Bacchi V, Noel LH et Al. C3 glomerulopathy: a new classification. Nat Rev Nephrol 2010; 6: 494-499 2. Barbour TD, Pickering MC, Cook HT. Recent insights into C3 glomerulopathy. Nephrol Dial Transplant 2013; 28: 1685-1693 3. Sethi S, Fervenza FC, Zhang Y et al. C3 glomerunephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up. Kidney International 2012; 82: 465-473 4. Payne D, Houtman P, Browning M. Acute post- streptococcal glomerulonephritis associated with prolonged hypocomplementaemia. J Clin Path 2008; 61(10): 1133-1135 5. Sethi S, Fervenza FC, Zhang Y et al. Atypical post- infectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney International 2013; 83(2): 293-299 6. Pickering MC, D’Agati VD, Nester CM et al. C3 glomerulopathy: consensus report. Kidney International 2013; 84: 1079-1089