Hepatitis C virus infection and renal disease after renal transplantation

doi:10.1016/j.transproceed.2004.03.041

Transplantation Proceedings

Volume 36, Issue 3, April 2004, Pages 760-762

https://doi.org/10.1016/j.transproceed.2004.03.041 Get rights and content

Abstract

Hepatitis C virus (HCV) infection is the main cause of chronic liver disease after renal transplantation (RT). It is considered in some series to be a risk factor for graft loss and patient death. Also, HCV has been implicated in the pathogenesis of glomerular diseases in native and transplanted kidneys. The presence of membranoproliferative (MP) or membranous (M) glomerulonephritis (GN) in HCV-positive patients has been well documented after RT, but there is no clear data concerning the real prevalence of HCV-induced glomerulonephritis. MPGN with or without cryoglobulinemia and MGN have been described in HCV RNA-positive patients in general without severe liver disease. Also, there is a possible association between HCV infection and acute/chronic transplant glomerulopathy. Renal thrombotic microangiopathy has been described in HCV-positive patients with positive anti-cardolipin antibodies. The pathogenesis of MPGN and MGN in HCV patients after RT seems to be similar to that which occurs in native kidneys: the deposition of immune complexes containing HCV proteins in the glomeruli. Renal biopsy, using light microscopy, immunofluorescence techniques, and electron microscopy, is useful to achieve a correct diagnosis. Unfortunately, interferon is not recommended due to the significant risk of rejection. The possibility of pegylated interferon needs to be tested. Ribavirin can improve proteinuria but HCV RNA remains positive. Finally, recent data suggest that the use of interferon in HCV patients on dialysis can negate HCV RNA and prevent associated glomerulonephritis after RT.

Section snippets

HCV infection, graft survival and proteinuria after renal transplantation

RT is the best therapy for end-stage renal disease patients on dialysis who display anti-HCV antibodies.2, 3 However, HCV can influence the long-term results of renal transplantation.2, 3, 4 In fact, HCV infection has been considered in several but not all studies to be an independent risk factor for graft survival and patient death.2, 3 A recent study from Spain during the period 1990 to 1998 showed that the presence of anti-HCV antibodies in the recipient was significantly associated in

Glomerular lesions associated with HCV infection after renal transplantation

The presence of of glomerular lesions such as MPGN and MGN in HCV-positive patients has been well documented after RT.1, 2, 3 Unfortunately, there is no clear data concerning the prevalence of HCV-induced glomerulonephritis after renal transplantation.

Membranoproliferative glomerulonephritis without cryoglobulinemia

Roth et al provided the first report on five HCV-positive patients with HCV viremia who developed de novo MPGN after RT.⁷ All presented with nephrotic range proteinuria, two patients with hypocomplementemia, and none with cryoglobulinemia. Renal histology was similar to that of idiopathic MPGN. Other authors corroborate these findings. Hammoud et al also demonstrated that the proportion of patients who developed MPGN was higher among HCV-positive. (7 of 115; 5.9%) than HCV-negative patients (8

Membranoproliferative glomerulonephritis with cryoglobulinemia

Cruzado et al published six cases of cryoglobulinemic MPGN in HCV-positive patients with detectable HCV RNA in the serum (genotype 1b).⁹ All presented with proteinuria, microhematuria, positive cryoglobulins, low serum levels of immune complexes, hypocomplementemia C3 and C4, antinuclear antibodies, and positive perinuclear antineutrophil cytoplasmic autoantibody. Notably, HCV RNA was found in higher concentrations in the cryoprecipitate than in the serum. They also observed MPGN in 20 (45.8%)

Membranous glomerulonephritis

Among 409 anti-HCV-positive patients within a total cohort of 2045 patients transplanted in two centers in Spain between 1980 and 1994, 15 (3.6%) developed MGN after RT.¹⁰ All showed detectable HCV RNA in the serum and none exhibited cryoglobulinemia, hypocomplementemia, or positive rheumatoid factor. The clinical presentation (nephrotic proteinuria), outcomes (progressive worsening of renal function in patients with persistent proteinuria), and histological picture were similar to

Acute and chronic transplant glomerulopathy

Gallay et al described two HCV-positive patients with features of MPGN and transplant glomerulopathy.¹¹ Notably, it was impossible to clearly distinguish the lessions. They suggested a possible association between HCV infection and chronic transplant glomerulopathy. Cosio et al also reported that patients with acute and chronic transplant glomerulopathy (CTG) have a high prevalence of HCV infection, suggesting an association between this infection and glomerulopathy lesions.¹² They also

Renal thrombotic microangiopathy

Baid et al recently described five HCV patients who displayed an association of the infection with the development of de novo renal thrombotic microangiopathy (RTMA) in the graft, particularly patients with pretransplant anticardiolipin antibodies.¹⁴ This hypothesis is supported by the observation that anticardiolipin antibodies were not found in HCV-negative patients who presented with RTMA in the graft. Clinical manifestations and pathological changes appeared between 5 and 120 days after

Pathogenesis of HCV-induced glomerular lesions

The pathogenesis of MPGN and MGN in HCV-positive patients after RT seems to be similar to that which occurs in native kidneys: the deposition of immune complexes containing HCV proteins in the glomeruli.1, 2 Why these HCV-positive patients develop glomerular lessions despite immunosuppressive therapy is unknown. A possible explanation could be that immunosuppression increases HCV viremia and decreases immunoglobulin synthesis. These changes could produce an imbalance in the antigen-antibody

Diagnosis of HCV-induced glomerular lessions

The presence of glomerular lesions should be suspected. Among patients with HCV infection and persistent or nephrotic range proteinuria with microhematuria.1, 2 The definitive diagnosis is established by renal biopsy using light microscopy, immunofluorescence techniques, and electron microscopy (EM).2, 11

Differential diagnosis of MPGN after RT should be performed with CTG. Immunological and serological studies, particularly cryoglobulins, can be useful, especially in cryoglobulinemic MPGN.

Treatment

Unfortunately, there is no well-established treatment for patients with HCV-induced glomerular disease after RT. Interferon (IF) alpha cannot be recommended in these patients due to the significant risk of acute rejection or renal dysfunction. Interferon also may exacerbate proteinuria in some cases.

Ribavirin in low doses effectively controlled proteinuria in liver transplant recipients with nephrotic syndrome, although the viremia remains unchanged. This fact suggests that the effect of

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Cited by (31)

Recurent and De Novo Membranous Glomerulopathy After Kidney Transplantation
2009, Transplantation Proceedings
Citation Excerpt :
It showed a prevalence of about 2.5% of MG among kidney transplants, which increased over time. This prevalence has been estimated between 2% and 4% in previous studies including patients with unknown diagnosis in the native kidneys and/or with lupus nephropathy.2,4,6 In this series, de novo MG was more frequent than recurrent MG (65% vs 35% of all MG on transplants), as already reported.7,8
The aim of this study was to compare the clinical characteristics of recurrent and de novo membranous glomerulopathy (MG) among a cohort of 614 recipients transplanted between 1989 and 2006. Lupus nephritides were excluded. The diagnosis was established on protocol biopsies performed 1, 2, 4, or 8 years after transplantation or because of proteinuria/nephrotic syndrome and/or an increased serum creatinine level. HCV infection, cryoglobulinemia, monoclonal gammopathy, skin cancers, Kaposi sarcoma, diabetes mellitus, anti-HLA antibodies, and graft survival were not significantly different between the groups. Seventeen MG were diagnosed in 15 patients (2.45% of the whole group), including 6 recurrent MG (35%) and 11 de novo MG (75%). Recurrent MG occurred earlier than de novo MG (15.58 ± 19.13 vs 49.27 ± 32.71 months). Recipients with de novo MG were more frequently infected with HCV, which seemed to be the main etiologic factor for de novo MG, and may be linked to a Th2 polarization of the immune response.
Introduction
2008, Kidney International
Hepatitis C Virus Infection and Outcome of Renal Transplantation
2007, Transplantation Proceedings
Citation Excerpt :
The influence of each immunosuppressive agent is still a matter of debate.16,17 Treatment of HCV infection in renal transplanted patients is associated with an increased risk of acute graft rejection.18 Standard interferon monotherapy is associated with a high sustained virologic response (SVR) in dialysis patients (33% to 37%).19,20
Chronic hepatitis B and C viruses (HBV and HCV) are common problems in renal transplant patients. There is no uniform agreement regarding their influence on graft outcomes and patient survival. We evaluated the influence of anti-HCV and hepatitis B surface antigen-positive status; gender; age > 49 years at the time of transplantation; alanine aminotransferase elevation; acute rejection; type of graft; number of transplants; and maintenance/induction immunosuppressive treatment on both graft and patient survivals among a population transplanted in our center between 1991 and 2004.
Univariate analysis showed that anti-HCV–positive status, three-drug immunosuppressive therapy, and one or more episodes of acute rejection were associated with diminished graft survival. Over the age of 49 years at the time of transplantation, anti-HCV–positive status, cadaveric donor, kidney–pancreas transplantation, and three-drug immunosuppressive therapy were associated with diminished patient survival. Upon multivariate analysis, reduced patient survival was associated with the same variables as in the univariate analysis: anti-HCV–positive status, three-drug immunosuppressive therapy, and one or more episodes of acute rejection were associated with diminished graft survival. In our experience, anti-HCV–positive compared with anti-HCV–negative status was associated with a reduced graft (56% vs. 75%; P = .0002) and patient survival (68% vs. 83%; P = .0028).
Different Impacts of Hepatitis B Virus and Hepatitis C Virus on the Outcome of Kidney Transplantation
2007, Transplantation Proceedings
Citation Excerpt :
Some studies showed a negative association with patient survival,4,5,10 whereas other studies reported that survival of hepatitis C-positive patients was not worse than that of HCV negative patients.11,12 Although our study did not detect an effect of HCV infection on patient survival, we did observe that HCV infection presented a risk for graft loss, which was consistent with previous findings.4,5,13 Interestingly, our multivariate analysis showed that HCV (+) was a stronger predictor of low graft survival compared with HBV (+), diabetes mellitus, donor type and delayed graft function.
Previous studies had shown that HBV and HCV infections lead to increased morbidity and mortality after kidney transplantation when compared with the nonhepatitis group. However, few studies have compared the impact among a population with a high prevalence of HBV and HCV infections. We studied the outcomes of 346 recipients including 23 HBsAg (+) patients (6.6%; group 1), 22 patients with anti-HCV+ (6.3%, group 2), and 301 nonhepatitis patients (group 3) in a single center during a 6-year period. No patient had evidence of precirrhosis or cirrhosis before transplant. The primary end point was graft and patient survival rates. Secondary end point was the rate of progression of chronic allograft, nephropathy. The median follow-up time was 3.7 (0.5–6.8) years. Five-year actuarial graft survival was 80% for group 1, 61% for group 2, and 88 % for group 3 (P = .005). Cox regression showed HCV (hazards ratio 2.96; 95% CI = 1.03–8.51) and acute rejection episode (HR 3.01; 95%CI = 1.86–4.87) to be significant predictors of graft survival. Actuarial 5-year patient survival of group 1 was significantly lower than group 2 or group 3 (79 % vs 89% and 96%; P = .003). Cox regression revealed that the hazards ratio of HBV for death was 7.63 (95%CI = 1.88–30.86; P = .004). In contrast, HCV infection had no significant effect on patient survival (HR 1.59; 95%CI = 0.28–9.02). The rate of chronic allograft nephropathy progression was significantly faster in group 1 (−6.74 mL/min per year) and group 2 (−6.14 mL/min per year) than the controls. We concluded that HBV infection decreased patient survival earlier than HCV and that HCV decreased graft survival more significantly than HBV. Both HBV and HCV were associated with rapid progression of chronic allograft nephropathy. HBV was the strongest risk factor for mortality compared with HCV, with acute rejection episode, with diabetes mellitus, or other hazardous factors.
Chapter 12 Renal Disease in Cryoglobulinemic Vasculitis
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Although cryoglobulinemic GN may recur after renal transplantation (Hiesse et al., 1989), most patients are asymptomatic and cryoglobulinemia does not appear to affect graft function (Sens et al., 2005). However, transplant glomerulopathy (Morales, 2004) and chronic allograft dysfunction might be more frequent in HCV-positive renal transplant recipients, particularly in those with complement activation (Weiner et al., 2004). Antiviral therapy is problematic in HCV-positive renal transplant patients.
This chapter discusses the renal disease in cryoglobulinemic vasculitis. Cryoglobulins are immunoglobulins (Ig) that precipitate as serum is cooled below body temperature and dissolve after rewarming at 37ºC. They are classified into three types, on the basis of their Ig composition: Type-I cryoglobulins are entirely made up of a monoclonal Ig. Type-I cryoglobulinemia is usually observed in the context of lymphoplasmacytic proliferation, mainly Waldenstrom's macroglobulinaemia, chronic lymphocytic leukemia, or multiple myeloma. Type II (or mixed) cryoglobulins are composed of two distinct components: a monoclonal Ig (usually IgMk, less frequently IgG) that displays a specific antibody activity against the polyclonal component of the cryoglobulin. Type III cryoglobulins are composed of one or several classes of polyclonal Ig. They are observed in various pathologic conditions with immune complex formation, including infectious diseases, autoimmune disorders, malignancies, or even in apparently healthy individuals.
Treatment of hepatitis C in hemodialysis patients and renal transplant recipients
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Renal transplantationHepatitis C virus infection and renal disease after renal transplantation

Abstract

Section snippets

HCV infection, graft survival and proteinuria after renal transplantation

Glomerular lesions associated with HCV infection after renal transplantation

Membranoproliferative glomerulonephritis without cryoglobulinemia

Membranoproliferative glomerulonephritis with cryoglobulinemia

Membranous glomerulonephritis

Acute and chronic transplant glomerulopathy

Renal thrombotic microangiopathy

Pathogenesis of HCV-induced glomerular lesions

Diagnosis of HCV-induced glomerular lessions

Treatment

Am J Kid Dis

Am J Kid Dis

Am J Kid Dis

Curr Opin Nephrol Hypertension

J Am Soc Nephrol

J Am Soc Nephrol

Renal transplantation
Hepatitis C virus infection and renal disease after renal transplantation