Hepatitis C and renal disease

Dr. Mohamed Abbass

Nephrologist

PGDD, CARDIFF, UK

Hepatitis C virus infection is associated with many renal diseases. Renal disease caused by

Virus itself Drugsused for treatment of hepatitis c Associated condition with hepatitisadvanced liver cell failure.

A. The renal disease associated with hepatitis c due to advanced liver

cell failure: Prerenal (Hypovolemia , shock and hepatorenal syndrome ) ATN ( sepsis or shock) B. Drugs used for treatment of hepatitis c: Interstitial nephritis secondary to Interferon C. Hepatitis c itself

o Hepatitis c is RNA flavivirus( single strand) o Has extrahepatic manifestation like arthritis, DM, cryglobulinemia

and glomerulonephritis o Renal diseases associated with hepatitis C

1. The most common types is MPGN with cryoglobulinemia 2. Others are

MPGN without cryoglobulinemia Membranous nephropathy (MN) Focal segmental glomerulosclerosis IgA nephropathy Fibrillary glomerulopathy Immunotactoid glomerulopathy Thrombotic microangiopathy Amyloid Vasculitis Interstitial nephritis secondary to virus HCV-associated PAN

Pathogenesis: There are many methods of renal diseases in hepatitis c patients:

1- Formation of immune complexes 2- Formation of mixed cryoglobulinemia

3- Direct injury HCV has the ability to bind and penetrate the parenchyma cells by the CD 81 and SR-B1 receptors HCV endocytosis!

4- Some time the HCV RNA causes podocytes injury! 5- HCV react with Toll –like receptors (TLR3) IL6, IL8! 6- HCV causes hyperisulinemia and insulin resistance increases the IGF-1

(insulin like growth factor -1) and TGF-B (transforming growth factors beta- 1) increase the oxidative stress!

There are some suggested methods of renal disease in HCV patients

The immune complexes mechanism: The HCV escape from immune system this leading to chronic viremia immune complex will be formed will deposit in glomeruli attract the platelets, neutrophils, and macrophages complement activation with chemokine generation and leukocyte adhesion molecule expression Capillary wall damage Cytokine and growth factor Stimulation of mesangial cells Proteinuria Mesangial cell proliferation The formation of mixed cryoglobulinemia: The chronic infection of HCV leads to excessive proliferation and stimulation of B cells and formation of type II cryoglobulin type II mixed cryoglobulinemia

Deposition of cryoglobulin in the glomerular capillary and mesangium Causes vasculitis and fibrinoid necrosis

Mechanism of renal disease in HCV patients

Immune complexes

Mixed cryoglobulinemia

Direct injury CD 81 !

Injury to podocytes !

Toll –like receptors !

Hyperisulinemia and IR !

Cryoglobulin can cause nephrotoxicity by attack the cellular fibronectin in the mesangial matrix

Cryoglobulins cause vasculitis by deposition in the small-sized arteries fix complement cause local inflammation and injury

Clinical pictures of renal diseases due to HCV:

Patients with chronic hepatitis c Proteinuria Hematuria (microscopic) Deterioration of kidney functions HTN Triad of purpura , asthenia , arthralgia ( GN with cryoglobulinemia) The purpura is palpable , which consists of leukocytoclastic vasculitis, this

lesions mostly found in the lower limb or can found anywhere, this represent small vessel vasculitis

Low serum C4 ,C1q and CH50 but normal C3 There are different presentation of renal disease according to types of

glomerulonephritis Diagnosis Laboratory tests +Renal biopsy Anti-HVC antibody and HCV RNA in serum Elevated serum transaminase in > 70% of patients Cryoglobulin can be detected in > 50% of patients Rheumatoid factors may be +ve

Pathology Renal biopsy show changes according to type of glomerulonephritis Membranoproliferative glomerulonephritis type I is the most common Or any other types

The Membranoproliferative glomerulonephritis type I Light microscopy: Glomerular hypercellularity Increased matrix and mesangial proliferation Splitting of capillary basement membranes (double contouring- tram

tracks ( Intracapillary thrombosis due to cryoglobulin deposition Vasculitis and fibrinoid necrosis.

Immunofluorescence: Deposits of IgG, IgM, and C3 in granular capillary wall distribution and the

mesangium

EM: Large subendothelial deposits (different from idiopathic MPGN where the

subendothelial deposits are much smaller ) These subendothelial deposits are so large they may protrude into the

capillary lumen, causing thrombosis.

Treatment: The policy of treatment depend on the renal function In non- nephrotic , normal renal function interferon alfa In nephrotic syndrome , renal impairment or with cryoglobulinemia

pegylated interferon alfa (1 ug/kg week )+ ribavirin(15 mg/kg/day) for 12 months then short course of low-dose corticosteroids

In Rapidly progressive renal failure: methylprednisolone (1 g/ day) for 3 days, followed by oral prednisone (60 mg/day) with slow taper over 2-3 months

Plasma exchange to remove cryoglobulins (3/week for 2 – 3 weeks) Rituximab to stop further B cell production (375mg/m 2 weekly for 4

weeks) or in resistance cases Cyclophosphamide for 2 – 4 months ) 1.5 – 2.0mg/kg daily orally) Use erythropoietin to keep Hb>110 g/L (ribavirin causes red cell

fragility) ACE-1/ARB to reduce proteinuria ( uPCR<50 mg/mmol) also to control

blood pressure ( aim < 130/80mmHg)