55 year-old man with Hepatitis C, chronic renal insufficiency and proteinuria

CLINICAL PRESENTATION

55 year-old Caucasian man presents with chronic renal insufficiency and proteinuria. Past medical history is significant for Hepatitis C (first diagnosed 9 months ago), chronic nose bleeds, stomach ulcers, excessive alcohol intake and hypertension for several years. His initial renal presentation was approximately 2 years ago when he presented with acute renal failure and a serum creatinine of 3.1 mg/dL. Since that time creatinine has ranged from 2.6 to 3.0 mg/dL. His medications include famciclovir, hydralizine, lisinopril, amlodipine and a proton pump inhibitor. He recently presented to the hospital with a nose bleed. Physical exam revealed blood pressure of 115/73 and no rash or edema.  He was found to have creatinine of 3.3 mg/dL, BUN 63, creatinine clearance 21 cc/min, 24-hour urine protein 5.4 g, albumin 2.3 g/dL. Urinalysis revealed 3+ protein, 1+ blood, 2-4 RBC/hpf, and no WBCs or casts. Serologic work-up revealed positive ANA, positive anti-DNA, positive Hepatitis C antibody, positive Hepatitis C RNA, and normal complement levels. SPEP and UPEP were negative for monoclonal proteins. Rheumatoid factor (used as a surrogate for cyroglobulin testing) was negative.
Renal biopsy was performed.

RENAL BIOPSY FINDINGS

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PATHOLOGY DIAGNOSIS

Fibrillary glomerulonephritis with membranoproliferative features, moderate to severe (HCV-associated/clinical)

DISCUSSION

Hepatitis C is associated with a variety of glomerular diseases, including membranoproliferative glomerulonephritis (most often seen in the context of cryoglobulinemia), membranous nephropathy, and fibrillary glomerulonephritis. Fibrillary glomerulonephritis (FGN) is a relatively rare form of glomerulonephritis diagnosed in 0.5% to 1% of native kidney biopsies.  While an association between Hepatitis C infection and the development of FGN has been observed, the pathogenesis of this entity and the relationship between the two diseases is unclear. It has been hypothesized that in cases of hepatitis C-associated FGN, the fibrillary deposits may result from accumulation of oligoclonal immune deposits that are part of the immune response to hepatitis C infection.
 
Clinically, FGN is most often seen in middle-aged to older patients (mean age 55-60 yrs) who present with proteinuria, renal insufficiency and microhematuria. The largest series of Hepatitis C-associated FGN was published by Markowitz et.al.in 1998 and included 6 cases.  Renal presentation in five of the six patients included nephrotic range proteinuria (range 2.4 to 24 g/day) but only 2 patients had full nephrotic syndrome with edema, hypercholesterolemia and hypoalbuminemia. At diagnosis, creatinine was elevated in 5 of 6 patients. Microhematuria (but no red cell cast formation) was seen in 5 of 6 patients and three had reduced C3 and CH50 (none had reduced C4). Only one of the six patients had a detectable cryoglobulin, and it was low titer and found in only 1 of 3 assays.  
 
The pathologic diagnosis of FGN requires light microscopy, immunofluorescence and electron microscopy. The light microscopic appearance of FGN is heterogeneous, ranging from mild mesangial proliferation to a fully expressed membranoproliferative pattern that looks similar to MPGN. Immunofluorescence typically shows mesangial and glomerular capillary wall deposits with a “smudged” quality that are IgG dominant, without evidence of monoclonality (both kappa and lambda light chains were present). Interestingly, in cases where IgG subclass typing has been performed, fibrillary deposits stain predominantly for IgG1 and IgG4, a finding of uncertain significance. Electron microscopy is essential to confirm the diagnosis of fibrillary GN. The characteristic appearance is that of randomly oriented fibrils, usually ranging between 18 and 24 nm in diameter, infiltrating the mesangium and glomerular capillary walls. Electron microscopy helps differentiate fibrillary GN from amyloid (which has randomly oriented fibrils that typically range from 8-12 nm in diameter) and immunotactoid glomerulopathy (which features microtubular structures usually ranging from 35-50 nm). The differentiation of FGN from amyloidosis is of primary clinical importance, and FGN is not typically associated with lymphoproliferative disorders.
 
Prognosis and treatment of FGN was examined in a series of 61 patients published by Rosenstock et.al. In this series, 45% progressed to ESRD over a mean of 23 months follow-up. Serum creatinine at presentation and severity of interstitial fibrosis on biopsy significantly correlated with outcome. Among these patients, 36% received immunosuppressive therapy, but the use of therapy did not correlate with outcome parameters including incidence of ESRD or time to ESRD. The optimal treatment for patients with FGN remains unknown. In patients with hepatitis C-associated glomerulonephritis, treatment decisions are further complicated due to the potential for viral exacerbation with immunosuppressive therapy and the unfavorable side-effect profile of ribavirin-based anti-viral therapy in patients with CKD and impaired renal function.

REFERENCES

1. Markowitz GS, Cheng JT, Colvin RB, Trebbin WM, D’Agati VD: Hepatitis C Viral Infection is Associated with Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy. J Am Soc Neprhol 9: 2244-2252, 1998.

2. Alpers CE, Kowalewska J: Fibrillary Glomerulobephritis and Immunotactoid Glomerulopathy. J Am Soc Nephrol 19: 34-37, 2008.

3. Rosenstock JL, Markowitz GS, Valeri AM, Sacchi G, Appel GB and D’Agati VD: Fibrillary and Immunotactoid Glomerulonephritis: Distince entities with different clinical and pathologic features. Kidney Int 63: 1450-1461, 2003.

4. Guideline 5: Diagnosis and management of kidney diseases associated with HCV infection. Kidney International (2008) 73 (Suppl 109), S69–S77.

CORRESPONDANCE

Leal Herlitz MD, Department of Pathology, Columbia University Medical Center

Haroon Rashid MD, Department of Nephrology, Palisades Medical Center, North Bergen, NJ

Jai Radhakrishnan MD, Associate Professor of Clinical Medicine, Department of Nephrology, Columbia University Medical Center