Hepatitis C in Renal Disease, Hemodialysis and Transplantation

J. M. Morales

• Publisher: S. Karger
• Year: 2012
• ISBN:
  9783805598217
• Topic: Medicine
• Subtopic: Nephrology

Hepatitis C virus (HCV) infection is a major health problem worldwide, with currently over 150 million HCV-infected people on the five continents. Although there have been important advances in the diagnosis, prevention and therapy, the infection remains an important health problem in most countries.HCV infection is considered a systemic disease: Not only does it affect the liver, it can induce autoimmune, dermatological and renal disease. Moreover, soon after the discovery of HCV as the major cause of non-A non-B hepatitis, HCV infection was recognized as an important cause and consequence of chronic kidney disease. The publication at hand is an update on the most important topics concerning HCV infection, renal disease and problems with dialysis in the general population as well as in renal transplant patients. Also included is a chapter on the emerging problem of renal complications associated with HCV virus in patients with HIV infection.Containing contributions from a panel of internationally acclaimed experts, this publication is a timely update on HCV infection and the kidney.

Morales JM (ed): Hepatitis C in Renal Disease, Hemodialysis and Transplantation.
Contrib Nephrol. Basel, Karger, 2012, vol 176, pp 10-23

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Hepatitis C and Renal Disease: Epidemiology, Diagnosis, Pathogenesis and Therapy

Jose M. Morales^a · N. Kamar^b,c · L. Rostaing^b,c

^aDepartment of Nephrology, Hospital 12 de Octubre, Madrid, Spain; ^bDepartment of Nephrology, Dialysis, and Organ Transplantation, CHU Rangueil, ^cINSERM U563, IFR-30, Toulouse, France

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Abstract

There is an increased evidence for the association between hepatitis C virus (HCV) infection and kidney diseases. Recent epidemiological studies strongly suggest that HCV infection is a risk factor for proteinuria and/or impaired renal function. Type I membranoproliferative glomerulonephritis (MPGN) associated with type II cryoglobulinemia is the most frequent renal disease, and non-cryoglobulinemic MPGN and membranous glomerulonephritis are less frequently associated with active HCV infection. The pathogenesis of these lesions are related to the deposition of immune complexes in the glomeruli, and recently it has been described that toll-like receptor 3 could have a pathogenic role establishing a link between viral infection and glomerulonephritis. Patients with HCV-related glomerulopathies should be treated with angiotensin-converting enzyme inhibitors in association or not with angiotensin receptor blockers, as well as with anti-HCV therapy. The latter relies on a combined antiviral therapy of standard or pegylated interferon-α and ribavirin. We recommend the treatment of patients for at least 48 weeks, and the continuation of antiviral therapy, even in the absence of a decrease in HCV RNA concentration of 2-log at week 12. Ribavirin doses should be adapted according to creatinine clearance in order to avoid its main side effect, i.e. hemolytic anemia. Combined antiviral therapy and immunosuppression (cyclophosphamide or rituximab with steroids) may be the treatment of choice for patients with severe renal disease, i.e. nephrotic syndrome and/or progressive renal failure, or diseases that are refractory to anti-HCV therapy alone.

Copyright © 2012 S. Karger AG, Basel

Patients with hepatitis C virus (HCV) infection can develop chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Several extrahepatic complications have also been associated with HCV infection, including hematological, dermatologic, autoimmune and kidney diseases [1]. There is an increasing evidence for the association between HCV infection and glomerular disease in both native and transplanted kidneys [2, 3]. Type I membranoproliferative glomerulonephritis (MPGN) associated with type II cryoglobulinemia is the more frequent renal disease, and non-cryoglobulinemic MPGN and membranous glomerulonephritis (MGN) are less frequently described to be associated with HCV infection [2–4].

In this chapter, we will review the literature concerning the increased risk of chronic kidney disease (CKD) in HCV-positive patients, the most important kidney diseases associated with HCV infection as well as their clinical manifestations, pathogenesis and therapy.

Epidemiology of Chronic Kidney Disease in Patients with HCV Infection

HCV-infected patients, including those with kidney or liver transplants, have an increased risk of glomerular lesions leading to CKD. These alterations have been described in the presence or absence of significant liver disease: however, all patients with HCV-associated GN are HCV RNA positive in the serum [2–4].

Fabrizi et al. [5] reported that the prevalence of HCV seropositivity in case series of patients with MPGN is about 10 times greater than the reported prevalence in HCV-negative patients. This elevated prevalence of MPGN comparing general population was also described in both live and autopsy series [6, 7]. Recently, several epidemiologic studies reporting CKD prevalence and its clinical significance in patients with HCV infection have been described. In a study from the US, 18,002 patients with HCV infection were identified and compared with 25,137 controls with estimated glomerular filtration rate (eGFR) >60 ml/m/1.73 m² at baseline [8]. Notably, HCV infection was associated with a higher risk of developing CKD stages 3–5. As expected, increasing age, hypertension and diabetes were associated with significantly higher risks of developing CKD in HCV-positive patients and controls. Decompensated liver disease was a strong predictor of CKD in both groups and, remarkably, HCV-infected patients had a shorter time to CKD. Although information of proteinuria was absent, this study clearly demonstrated that HCV infection is associated with higher risk and shorter time to CKD. In another study, 552 anti-HCV-positive patients were compared with 313 HCV-negative patients. CKD was defined as eGFR <60 ml/m/1.73 m² and/or persistence of proteinuria >6 months on urine analysis by dipstick. The prevalence of CKD was significantly higher in HCV patients (9.6 vs. 5.1%), and these patients showed a shorter time to develop CKD and end-stage renal disease. Interestingly, a higher baseline viral load was an independent predictor of CKD [9].

A cross-sectional analysis of the NHANES III data demonstrated an agedependent association between HCV seropositivity and albuminuria (adjusted odds ratio of 1.84 for ages 40–59 years and 1.27 for ages ≥60 years) [10]. In the ≥60 years group, 46% of HCV-positive individuals had albuminuria compared with 24% of those who where HCV antibody negative. However, this study found no significant association between HCV seropositivity and low estimated GFR. In a cross-sectional analysis from Taiwan, non-diabetic patients who were anti-HCV positive had a high prevalence of proteinuria (>1 positive dipstick) than the seronegative group (8.3 vs. 5.1%, p = 0.002) [11]. In multivariable analysis, the association between HCV status and proteinuria had an odds ratio of 1.84, although there was no association with low eGFR.

In a study from Italy in 320 predialysis patients, the incidence of HCV infection was 6.25%, which is much higher than that expected for Europe, i.e. 0.2– 3.5% [12]. As an example of this geographic variation, authors from Norway including a prospective cohort study of 1,010 HCV-positive patients diagnosed between 1990 and 2000, demonstrated that renal failure caused by MPGN occurred in 0.2% [13]. Therefore, all these data described above strongly suggest that HCV infection is a risk factor for proteinuria and/or impaired renal function.

The main clinical manifestations of glomerular disease in HCV-positive patients are the presence of proteinuria and microscopic hematuria with or without impaired kidney function [2]. Therefore, it has been recommended by international guidelines that HCV-infected patients be tested at least annually for proteinuria, hematuria and eGFR [3]. This is especially important particularly in patients with cryoglobulinemia. Guidelines also recommended that a kidney biopsy be performed in HCV-infected patients with clinical evidence of glomerulonephritis (GN) [3]. Early diagnosis and therapy of HCV-associated GN may improve clinical outcomes [4].

Diagnosis of Glomerular Diseases Associated with HCV Infection

Mixed Cryoglobulinemia and Cryoglobulinemic Glomerulonephritis

Clinical and Laboratory Findings

HCV infection is the major cause of mixed cryoglobulinemia (MC), a systemic vasculitis characterized by arthralgias, arthritis, Raynaud phenomena, purpura, peripheral neuropathy, hypocomplementemia and kidney disease.

The presence of cryoglobulins is essential for the diagnosis, and usually HCV RNA is present in the serum [14, 15]. Hypocomplementemia and positive rheumatoid factor can also be observed. Some patients exhibited normal or only mild elevation of liver enzyme values. Clinical manifestations of kidney disease include nephrotic or non-nephrotic proteinuria, hematuria and variable degrees of reduced eGFR. Notably, acute nephritic syndrome or nephrotic syndrome can be the clinical presentation in 25 and 20% of these patients, respectively. Clinical signs of MC, such as purpura, arthralgias or neuropathy, can precede in several years the presence of kidney disease [14, 15].

HCV infection is mainly associated with type II MC, and type I MPGN, also called cryoglobulinemic GN, is the more frequent kidney lesion.

Pathology

Cryoglobulinemic GN typically includes evidence of immune complex deposition in the glomeruli and changes of type I MPGN. On light microscopy, glomeruli may demonstrate prominent hypercellularity as a result of massive infiltration of glomerular capillaries with mononuclear and polymorphonuclear leukocytes. Glomeruli show accentuation of lobulation of the tuft architecture, and may have a combination of increased matrix and mesangial cells, capillary endothelial swelling, splitting of capillary basement membrane, intracapillary thrombi and accumulation of eosinophilic material representing precipitated immune complexes or cryoglobulins. Vasculitis of the small and mediumsized renal arteries can also be present. Immunofluorescence usually demonstrates deposition of IgM, IgG and C3 in the mesangium and capillary walls. Subendothelial immune complexes are usually observed on electron microscopy and may also have a fibrillar or immunotactoid pattern suggestive of cryoglobulin deposits [3, 14, 15].

Clinicopathological Correlation

The presence of massive intraluminal thrombi, vasculitis or both is more commonly observed in patients with acute nephritic syndrome and rapid progression to kidney failure. Exsudative or lobular MPGN are associated with nephrotic and/or nephritic syndrome, whereas mesangioproliferative GN is associated with proteinuria and microscopic hematuria with normal renal function [3].

Outcome

Clinical course is variable; in the majority of patients, renal disease slowly progresses but does not progress to kidney failure in spite of the presence of proteinuria and some degree of renal impairment. Even some patients with cryoglobulinemic MPGN with massive thrombi and vasculitis can spontaneously reverse. Risk factors to develop end-stage renal disease are: older age, recurrent purpura, elevated cryocrit, hypocomplementemia and high serum creatinine at diagnosis [2, 3].

Non-Cryoglobulinemic Membranoproliferative Glomerulonephritis

Some patients with HCV infection can develop MPGN without exhibited cryoglobulins in the serum. The clinical picture, pathologic findings and laboratory data characteristically are indistinguishable from idiopathic type I MPGN except the presence of HCV antibodies and HCV RNA in the serum [2]. On electron microscopy, subendothelial and mesangial immune complexes can be detected without a distinctive substructure.

Membranous Glomerulonephritis

MGN is also associated with HCV infection. Clinical manifestations, outcome and pathology are similar to those of idiopathic MGN. All patients have serum HCV RNA-positive status accompanied by normal serum complement and negative cryoglobulins and rheumatoid factor [2–4, 16]. The characteristic finding on light microscopy is a diffuse thickening of the glomerular basement membrane without mesangial proliferation. The immunofluorescence demonstrates diffuse and granular deposits of IgG, C3 and IgA. Electron microscopy identifies diffuse subepithelial immune deposits....

Table of contents

• Cover Page
• Front Matter
• Hepatitis C: Epidemiology, Diagnosis, Natural History and Therapy
• Hepatitis C and Renal Disease: Epidemiology, Diagnosis, Pathogenesis and Therapy
• Hepatitis C-Induced Renal Disease in Patients with AIDS: An Emergent Problem
• Hepatitis C in Hemodialysis: Epidemiology and Prevention of Hepatitis C Virus Transmission
• Hepatitis C- Related Liver Disease in Dialysis Patients
• Treatment of Hepatitis C in Dialysis Patients
• Selection and Management of Hepatitis C Virus- Infected Patients for the Kidney Transplant Waiting List
• Kidney Transplantation in the Patient with Hepatitis C Virus Infection
• Treatment of Hepatitis C Virus Infection after Kidney Transplantation
• Immunosuppression in Hepatitis C Virus- Infected Patients after Kidney Transplantation
• Impact of Extrahepatic Complications (Diabetes and Glomerulonephritis) Associated with Hepatitis C Virus Infection after Renal Transplantation
• Renal Transplantation from Donors with a Positive Serology for Hepatitis C
• Author Index
• Subject Index