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Conference Reports

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HCV-Related Renal Disease after Liver Transplantation

Raymond T. Chung, MD

Chronic HCV infection has been causally or circumstantially associated with a number of distinct allograft pathologic entities following transplantation of the kidney, including de novo or recurrent membranoproliferative glomerulonephritis (MPGN), membranous nephropathy, renal thrombotic microangiopathy, and acute and chronic transplant glomerulopathy. However, the association of HCV with renal disease in the liver transplant (LT) recipient has been less fully characterized. The best available evidence indicates a strong association with immune complex-mediated MPGN. Because of the strong association of MPGN with mixed cryoglobulinemia (Type II and III), an association of post-LT renal disease with cryoglobulinemia has been postulated. However, because MPGN can occur without detectable cryoglobulins, and vice versa, the true incidence of post-LT renal disease can at this juncture only be inferred.

In view of the underlying immune complex pathogenesis of MPGN, consideration of the natural history of post-LT HCV infection is instructive. Induction immunosuppression with high-dose corticosteroids, antilymphocyte therapy, calcineurin inhibition, and azathioprine produces marked increases in post-LT HCV RNA levels, between 16 and 100-fold. On one hand, given the state of relative antibody excess, this dramatic increase in circulating antigen could be conjectured to drive immune complex formation and worsening of cryoglobulin/MPGN disease. On the other hand, it is also reasonable to speculate that the lympholytic properties of induction and chronic immunosuppressive therapy may counteract these increases in antigen by limiting available antibody for complex formation and suppress disease.

A number of reports of HCV-associated glomerular disease with nephrotic syndrome and cryoglobulinemia after LT have suggested that the early increase in viremia following repopulation of the allograft may acutely exacerbate these conditions (Table). All patients who developed post-LT MPGN with cryoglobulinemia who had pre-LT data available tested positive for cryoglobulins. While the number of patients described has been small, these findings suggest that pre-LT assessment in the HCV ( + ) recipient should include routine testing for cryoglobulins.

A large longitudinal study of 91 HCV RNA (+) and 106 HCV RNA (-) LT recipients was conducted to compare incidence of renal disease (Kendrick et al). No significant differences were seen in pre-LT creatinine clearance between groups. By 3 months post-LT, mean creatinine clearance decreased by one third and remained relatively stable to the 36 month follow up in both groups. However, a significantly larger portion of HCV(+) vs. HCV(-) (p = 0.05) excreted >2g protein/day post-LT. Among HCV(+) recipients, proteinuria was not associated with recurrent allograft HCV, diabetes, or hypertension. MPGN was demonstrated in 4 of 10 HCV( +) patients undergoing biopsy but not observed in any of the 7 biopsies from HCV(-) recipients. The association between proteinuria and cryoglobulins was not studied. These data suggest that while HCV is clearly associated with a specific risk for MPGN and increased proteinuria, that in the short term the overall frequency of clinically meaningful renal dysfunction is modestly increased (4-5%). This study and others in post-LT cryoglobulinemia-MPGN have also demonstrated that effec- tive antiviral therapy wit~ interferon alfa decreases proteinuria and stabilizes but does not reverse renal dysfunction. In this regard, interferon therapy performs as it does in immunocompetent hosts with cryoglobulinemia.

We sought to define the frequency of post-LT cryoglobulinemia and significant renal complications from our cohort (Abrahamian et al). We conducted a cross- sectional analysis of patients transplanted at our institution from 1991 to 1998. Of the 53 HCV(+) recipients, 22 either died or were not available for evaluation. The remaining 31 were characterized for clinical, immunologic and virologic parameters and compared to an unselected contemporaneous group of 21 HCV(-) LT recipients. Baseline characteristics (induction and maintenance immunosuppression, creatinine, age, gender) were similar between groups. Both groups were analyzed at a mean 30-34 months post-LT. Six (19%) of the HCV (+) group and none of the HCV (-) group had cryoglobulins (3 type II, 2 type III, 1 indeterminate). No significant differences in HCV viremia, genotype, renal function, or complement levels were seen between those with and without cryoglobulins. Three of these 6 patients had symptomatic cryoglobulinemia (palpable purpura and vasculitis). Creatinine clearance between groups was comparable at the time of evaluation, but proteinuria (> 1 g/d) was present in 7/31 HCV(+) vs. 0/21 HCV(-) patients (p = 0.02). Of these 7, glomerulonephritis was identified in 4 (biopsy-proven in two), cyclosporine toxicity with focal sclerosis in 1, diabetes in 1, and indeterminate in 1.

We have recently performed long term follow up of this patient group. Of the 6 patients with cryoglobulinemia, one patient died of severe cryoglobulinemic vasculitis of the CNS and skin 9 years post-LT. One patient died of recurrent hepatocellular carcinoma. Another has begun hemodialysis 5 years post-LT after developing MPGN. The remaining three have had stable hepatic and renal function on intermittent courses of interferon therapy at 6 years of followup. Of the 4 patients with glomerulonephritis, 2 of who were cryoglobulin (+), 1 died with renal failure (8 months post-LT) and 2 were initiated on hemodialysis (5 and 7 years post-LT). The remaining patient had GN and skin vasculitis and has been managed successfully with antiviral therapy. Taken together, with longer follow up of a small but unselected group of HCV(+) LT recipients, the frequency of symptomatic cryoglobulinemia was 10% and of clinically meaningful renal disease 10%. The finding of glomerulonephritis with or without cryoglobulins was associated with particularly accelerated adverse outcomes.

While the overall frequency of cryoglobulinemia after LT among HCV( +) recipients is not appreciably different than that seen in non-transplant patients, the frequency of clinically important renal dysfunction attributable to HCV-related GN is considerably higher. This may be a result of several fac- tors, including the interactions of HCV with calcineurin inhibitors and the higher rates of diabetes and hypertension after LT. Longer term prospective studies are needed to define the precise magnitude of the risk of pre and post- LT cryoglobulins for development of subsequent renal dysfunction. In the meantime, careful monitoring of proteinuria as an early index of HCV-related renal disease should be performed in post-LT patients. A renal biopsy in patients with evidence of more overt renal dysfunction prior to LT should be considered. In the event of the discovery of HCV-related GN, the merits of proceeding with liver transplantation should be carefully weighed against the risk of progressive renal disease. Protocol studies of combined liver and kidney transplantation for HCV-related hepatic and renal disease will be of interest in this regard. Renal transplant for ESRD after LT has been performed with some long-term success. The success of antiviral therapies in bringing about parallel virologic, immunologic, and renal improvements suggests that patients with either symptomatic cryoglobulinemia or early evidence of renal involvement should be strongly considered for treatment with interferon-ribavirin regimens after LT.

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References

1. Abrahamian GA, Cosimi AB, Farrell ML, Schoenfeld DA, Chung RT, Pascual M. Prevalence of hepatitis C virus-associated mixed cryoglobulinemia after liver transplantation. Liver Transplantation 2000;6:185-90.

2. Burstein DM, Rodby RA. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. J Am Soc Nephrology 1993;4:1288-93.

3. Davis CL, Gretch DR, Perkins JD, et al. Hepatitis C-associated glomerular disease in liver transplant recipients. Liver Transplantation Surg 1995;1:166-175.

4. Gournay J, Ferrell LD, Roberts JP, Ascher NL, Wright TL, Lake JR. Cryoglobulinemia presenting after liver transplantation. Gastroenterology 1996;110:265-70.

5. Kendrick EA, McVicar JP, Kowdley KV, et al. Renal disease in hepatitis C-positive liver transplant recipients. Transplantation 1997;63:1287-93.

6. Molmenti EP, Jain AB, Shapiro R, et al. Kidney transplantation for end-stage renal failure in liver transplant recipients with HCV infection. Transplantation 2001;71:267-71.

7. Pascual M, Thadhani, Chung RT, et al. Nephrotic syndrome after liver transplantation in a patient with hepatitis C virus-associated glomerulonephritis. Transplantation 1997;64:1073-76.

8. Safadi R, Shouval D, Eid A Ilan Y; Turkaspa R, Jurim O. Hepatitis C- associated cryoglobulinemia after liver transplantation. Transplant Proc 1997 ;29:2684-86.

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