In a recent article in the American Journal of Kidney Diseases, Fabrizi et al review hepatitis C virus and kidney disease with focus on cryoglobulinemia. The following questions will test your knowledge on hepatitis C virus–associated kidney diseases:

1. A 41-year-old woman with recent diagnosis of hepatitis C infection was found to have an elevated serum creatinine of 2.3 mg/dL (eGFR 23 mL/min). She developed 2+ lower extremity edema and 2.7 g/24 h proteinuria with microscopic hematuria (10-25 RBCs/high power field). C4 was undetectable and C3 was 27 mg/dL. The rheumatoid factor was 3748 IU/mL. Other serologies, including ANA, anti-GBM antibody, and ANCA, are negative. A kidney biopsy was performed. What is the most likely diagnosis?

A. Active proliferative lupus nephritis with large sub-endothelial deposits

B. Waldenström macroglobulinemia

C. Cryoglobulinemic glomerulonephritis secondary to type II cryoglobulinemia

D. Thrombotic microangiopathy

A: PAS stain of a representative glomerulus; original magnification, x600. B: Glomerular staining for IgG by direct immunofluorescence; original magnification, x400 (similar staining was noted for IgM). C: High magnification EM image taken of a glomerular deposit; original magnification, x80,000. Images courtesy of Dr Tibor Nadasdy.

2. A 59-year-old woman was diagnosed with hepatitis C virus infection five years before this biopsy and was treated with pegylated interferon. This therapy was discontinued two years ago. She now presents with 3 g/day proteinuria, 3+ microscopic hematuria, low serum C4 level, and normal serum C3 level. Her hepatitis C viral load is elevated and her serum cryoglobulin test is negative (confirmed). Serum creatinine is 1.3 mg/dL (eGFR 36 mL/min). Based on the images, what is the most likely diagnosis?

A. Pauci-immune crescentic and necrotizing glomerulonephritis

B. Proliferative glomerulonephritis with a membranoproliferative pattern secondary to hepatitis C virus infection

C. Interferon-induced glomerulopathy with proteinuria

D. C3 glomerulopathy

A: H&E stain of representative glomerulus; original magnification, x400. B: Immunofluorescence with an antibody to IgG; original magnification, x400 (similar mild segmental granular staining was noted for IgM, kappa and lambda light chains, and C3). Images courtesy of Dr. Tibor Nadasdy.

3. A 42-year-old morbidly obese woman with metabolic syndrome and asthma is being evaluated for a sub-acute rise in serum creatinine. She has a long history of hepatitis C virus infection, which has been under good control but no recent viral load is available. One month ago, she had been on a tapered dose of steroids for her asthma. Liver biochemical and functional profile is normal. She presents with upper respiratory complaints and shortness of breath for several weeks. A chest x-ray, bronchoscopy, and bronchioalveolar lavage indicate an infectious process. She rapidly develops acute kidney injury with a serum creatinine of 4.29 mg/dL (eGFR 12 mL/min). Urinalysis shows 3+ proteinuria and 2+ blood. Serum complement levels are normal. She has an elevated white blood cell count while ANCA and ANA serologies are negative. A kidney biopsy is performed. Based on the images, what is the most likely diagnosis?

A. Proliferative glomerulonephritis secondary to an underlying infection (probably staphylococcus infection)

B. Cryoglobulinemic glomerulonephritis related to the hepatitis C virus infection

C. Mesangial IgA deposits secondary to liver cirrhosis

D. Acute post-streptococcal glomerulonephritis

A: Representative glomerulus from the H&E-stained paraffin section; original magnification, x400. B: Granular, somewhat segmental IgA staining in a representative glomerulus. Direct immunofluorescence; original magnification, x200 (similar C3 staining was also noted in the glomeruli). C: Ultrastructural examination revealed mesangial and subepithelial (shown on the image) electron-dense immune-type deposits; original magnification, x8000. Images courtesy of Dr. Tibor Nadasdy.

4. A 36-year-old African American man with hemophilia A was diagnosed with HIV and hepatitis C virus infection in 1990. HIV disease has been treated, and he exhibits no signs of opportunistic infections. His most recent viral load was 89,599 copies and his CD4 count was 214 cells/mm³. His hepatitis C viral load is high with 17,000,000 copies. He had normal kidney function in the past with a serum creatinine between 0.6 and 0.7 mg/dL (eGFR 154 mL/min). Now he presents with 6 g/day proteinuria and a serum creatinine of 2.9 mg/dL (eGFR 30 mL/min). ANA, rheumatoid factor, and cryoglobulin serologies are negative. His serum complements are within normal range. A kidney biopsy is performed. Based on the images, what is the most likely diagnosis?

A. HIV-associated nephropathy

B. Cryoglobulinemic glomerulonephritis

C. Idiopathic membranous glomerulonephritis

D. Membranous glomerulonephritis secondary to hepatitis C virus infection

Immunofluorescence showed strong diffuse granular glomerular capillary immune complex deposits for IgG. The immunofluorescence images show reactions with antibodies to the IgG subclasses (each panel: original magnification, x200). The right panel shows an electron micrograph taken from a glomerular capillary. L: Glomerular capillary lumen. B: Bowman space; original magnification, x8000. Images courtesy of Dr. Tibor Nadasdy.

5. A 48-year-old woman has a long history of hepatitis C virus infection. Her follow up has been poor and no recent hepatitis C viral loads are available. She presents with nephrotic syndrome and 5 g/day proteinuria. Her serum creatinine is up to 1.5 mg/dL (eGFR 45 mL/min) from 0.8 mg/dL (eGFR 93 mL/min) in the past. She does not have hematuria. She has normal blood pressure. C3 and C4 are within the normal range. ANA and serum immunofixation are negative. A kidney biopsy is performed. Based on the images, what is the most likely diagnosis?

A. Cryoglobulinemic glomerulonephritis

B. Fibrillary glomerulonephritis

C. Membranous glomerulonephritis related to hepatitis C infection

D. IgG4 heavy chain amyloidosis

A: Representative glomerulus from the H&E-stained paraffin section; original magnification, x400. B: Glomerular immunofluorescence with an antibody to IgG4; original magnification, x400. C: Representative ultrastructural image taken from a mesangial area; original magnification, x50,000. Images courtesy of Dr. Tibor Nadasdy.

Post prepared by Tibor Nadasdy, MD, eAJKD Contributor and AJKD Kidney Biopsy Teaching Case Advisory Board member; and Kenar Jhaveri, MD, eAJKD Blog Editor.

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