Test Your Knowledge: The Rise of C3 Glomerulopathies

In a recent article published in the American Journal of Kidney Diseases, Sandhu et al describe a case of C3 glomerulopathy masquerading as acute post-infectious glomerulonephritis. Test your knowledge on this novel entity of C3 glomerulopathy.

1. A 60-year-old man with no significant past medical history presents with increasing fatigue and worsening lower extremity edema for the past 4 weeks. He is hypertensive on exam and has 3+ pitting edema. His labs reveal acute kidney injury, hypoalbuminemia, and a urine protein/creatinine ratio of 6 g/g. Urinalysis reveals an active sediment with dysmorphic red blood cells. Serum C3 is low and C4 is normal with an elevated anti-streptolysin O antibody. Given the patient’s acute kidney injury and nephrotic range proteinuria, a kidney biopsy is performed showing the following:

Light microscopy revealed a diffuse proliferative and exudative glomerulonephritis. Immunofluorescence revealed granular global mesangial and capillary wall deposits which stained 3+ for C3, 1+ for C1q and IgM, and +/- focal for lambda. Electron microscopy revealed global mesangial and subendothelial electron dense deposits, rare segmental subepithelial deposits, and complete foot process effacement.

A diagnosis of acute post-infectious glomerulonephritis is made. Lisinopril and furosemide are initiated. On monthly follow-up visits, there is no improvement in the patient’s clinical status, and he continues to have significant nephrotic syndrome.

What is your next step in the management of this patient?

A. Admit to the hospital for pulse dose steroid administration
B. Start course of antibiotics
C. Start losartan 50 mg daily
D. Repeat kidney biopsy

2. In the above patient, a repeat kidney biopsy was performed revealing:

Light microscopy showed a diffuse proliferative glomerulonephritis. Immunofluorescence revealed global mesangial and capillary wall deposits which stained 3+ for C3. No significant staining for IgG, IgM, C1q, kappa, and lambda light chains. Electron microscopy revealed global mesangial and segmental subendothelial and intramembranous electron dense deposits. 

Given the above biopsy results, which diagnosis is most likely?

A. Post-infectious glomerulonephritis
B. Membranoproliferative glomerulonephritis (MPGN) associated with monoclonal gammopathy
C. C3 glomerulonephritis
D. Class IV lupus nephritis

3. You are evaluating a patient who reports foamy urine. He became concerned as he has numerous family members on dialysis, and they all complained of similar symptoms early in their lives. A kidney biopsy reports a diffuse proliferative glomerulonephritis, with IF staining of the mesangial and capillary wall for C3. There was no other significant staining. EM showed subendothelial and mesangial electron-dense deposits. The final diagnosis was C3 glomerulonephritis. Upon further questioning of the patient, you discover that his family originates from the Troodos Mountains of Cyprus.

A genetic testing in this individual would likely reveal a mutation in:

A. Podocin
B. Complement factor H-related protein 5 (CFHR5)
C. Platelet-activating factor acetylhydrolase
D. TRPC6 channel

4. A 35-year-old Hispanic man with a history of hypertension presents with hematuria and proteinuria. A kidney biopsy (EM) is shown below. IF revealed deposits of C3 along the glomerular, tubular, and Bowman capsule basement membranes, with no significant immunoglobulin deposition. What is the most likely diagnosis?

EM, uranyl acetate – lead citrate; original magnification, x8000. Image courtesy of Dr. Tibor Nadasdy.

A. MPGN type 1
B. Dense deposit disease
C. C3 glomerulonephritis
D. CFHR5 nephropathy

5. Which of the following is NOT likely to be found with the above lesion?

A. Low C3
B. Low C4
C. Low factor H levels
D. C3 convertase stabilizing autoantibody (C3 nephritic factor)

Post prepared by Sean Kalloo, MD, MBA, eAJKD Contributor, and Tibor Nadasdy, MD, eAJKD Contributor and AJKD Kidney Biopsy Teaching Case Advisory Board member.

To see answers, please click here.

To view the article abstract or full-text (subscription required), please visit AJKD.org.

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