Hepatitis C and renal diseaseHepatitis C and renal disease

Dr. Mohamed Abbass Dr. Mohamed Abbass Nephrologist Nephrologist

PGDD, CARDIFF, UKPGDD, CARDIFF, UK

Hepatitis C virus infection is associated with many Hepatitis C virus infection is associated with many renal diseases. renal diseases. Renal disease caused by :Renal disease caused by :•Virus itself •Virus itself •Drugs used for treatment of hepatitis c •Drugs used for treatment of hepatitis c •Associated condition with hepatitis → •Associated condition with hepatitis → advanced liver cell failure. advanced liver cell failure.

1–The renal disease associated with hepatitis c due to advanced liver cell failure:

•Prerenal →(Hypovolemia , shock and hepatorenal syndrome)

•ATN →(sepsis or shock)2– Drugs used for treatment of hepatitis c:Interstitial nephritis secondary to interferon

3–Hepatitis c itself:3–Hepatitis c itself:••Hepatitis c is RNA flavivirus(single strand) Hepatitis c is RNA flavivirus(single strand) •Has extrahepatic manifestation like arthritis, DM, •Has extrahepatic manifestation like arthritis, DM, cryglobulinemia and glomerulonephritis cryglobulinemia and glomerulonephritis

11 . .The most common types is The most common types is MPGN with cryoglobulinemia 2. Others are: 2. Others are: MPGN without cryoglobulinemia MPGN without cryoglobulinemia Membranous nephropathy (MN) Membranous nephropathy (MN) Focal segmental glomerulosclerosis Focal segmental glomerulosclerosis IgA nephropathy IgA nephropathy Fibrillary glomerulopathy Fibrillary glomerulopathy Immunotactoid glomerulopathy Immunotactoid glomerulopathy Thrombotic microangiopathy Thrombotic microangiopathy Amyloid Amyloid VasculitisVasculitis Interstitial nephritis secondary to virus Interstitial nephritis secondary to virus HCV-associated PANHCV-associated PAN

There are many methods of renal diseases in hepatitis c: There are many methods of renal diseases in hepatitis c: 1- 1- Formation of immune complexes Formation of immune complexes 2- Formation of mixed cryoglobulinemia 2- Formation of mixed cryoglobulinemia 3- 3- Direct injury→ HCV has the ability to bind and penetrate the Direct injury→ HCV has the ability to bind and penetrate the parenchyma cells by the CD 81 and SR-B1 receptors → HCV parenchyma cells by the CD 81 and SR-B1 receptors → HCV endocytosis! endocytosis! 4- Some time the HCV RNA causes podocytes injury! 4- Some time the HCV RNA causes podocytes injury! 5- HCV react with Toll –like receptors (TLR3)→ IL6, IL8! 5- HCV react with Toll –like receptors (TLR3)→ IL6, IL8! 6- HCV causes hyperisulinemia and insulin resistance → increases the 6- HCV causes hyperisulinemia and insulin resistance → increases the IGF-1 (insulin like growth factor -1) and TGF-B (transforming growth IGF-1 (insulin like growth factor -1) and TGF-B (transforming growth

factors beta- 1)→ increase the oxidative stressfactors beta- 1)→ increase the oxidative stress ! !

Mechanism of renal disease in HCV patientsMechanism of renal disease in HCV patients↓↓

1-Immune complexes

2-Mixed cryogulobinemia

3-Direct injury CD 81

4-Injury to podocytes

5-Toll –like receptors

6 -Hyper isulinemia and IR

The immune complexes mechanism:The immune complexes mechanism:The HCV escape from immune system this leading to chronic The HCV escape from immune system this leading to chronic viremia viremia →→immune complex will be formed immune complex will be formed →→ will deposit in will deposit in glomeruliglomeruli→→ attract the platelets, neutrophils, and attract the platelets, neutrophils, and macrophages macrophages →→ complement activation with chemokine complement activation with chemokine generation generation and leukocyte adhesion molecule expressionand leukocyte adhesion molecule expression

Capillary wall damage Cytokine and growth factorCapillary wall damage Cytokine and growth factor Stimulation of mesangial cells Stimulation of mesangial cells

Proteinuria Mesangial cell proliferationProteinuria Mesangial cell proliferation

The formation of mixed cryoglobulinemia:The formation of mixed cryoglobulinemia:The chronic infection of HCV leads to excessive proliferation and The chronic infection of HCV leads to excessive proliferation and stimulation of B cells and formation of type II cryoglobulin→ type II stimulation of B cells and formation of type II cryoglobulin→ type II mixed cryoglobulinemiamixed cryoglobulinemia1-1-Deposition of cryoglobulin in the glomerular capillary and mesangiumDeposition of cryoglobulin in the glomerular capillary and mesangium2-2-Causes vasculitis and fibrinoid necrosisCauses vasculitis and fibrinoid necrosis3-3-Cryoglobulin can cause nephrotoxicity by attack the cellular fibronectin Cryoglobulin can cause nephrotoxicity by attack the cellular fibronectin in the mesangial matrixin the mesangial matrix4- 4- Cryoglobulins cause vasculitis by deposition in the small-sized Cryoglobulins cause vasculitis by deposition in the small-sized arteries arteries → fix complement →cause local inflammation and injury→ fix complement →cause local inflammation and injury

Clinical pictures of renal Clinical pictures of renal

diseases due to HCVdiseases due to HCV

Patients with chronic hepatitis c may has Patients with chronic hepatitis c may has 1-Proteinuria1-Proteinuria2-Hematuria (microscopic)2-Hematuria (microscopic)3-Deterioration of kidney functions3-Deterioration of kidney functions4-HTN4-HTN5-Triad of purpura , asthenia , arthralgia ( GN with cryoglobulinemia)5-Triad of purpura , asthenia , arthralgia ( GN with cryoglobulinemia)6-The purpura is palpable , which consists of leukocytoclastic vasculitis, 6-The purpura is palpable , which consists of leukocytoclastic vasculitis, this lesions mostly found in the lower limb or can found anywhere, this this lesions mostly found in the lower limb or can found anywhere, this represent small vessel vasculitisrepresent small vessel vasculitis7-Low serum C4 ,C1q and CH50 but normal C37-Low serum C4 ,C1q and CH50 but normal C38-There are different presentation of renal disease according to types of 8-There are different presentation of renal disease according to types of glomerulonephritisglomerulonephritis

Diagnosis

Laboratory tests +Renal biopsyLaboratory tests +Renal biopsy1-Anti-HVC antibody and HCV RNA in serum1-Anti-HVC antibody and HCV RNA in serum2-Elevated serum transaminase in > 70% of patients2-Elevated serum transaminase in > 70% of patients3-Cryoglobulin can be detected in > 50% of patients3-Cryoglobulin can be detected in > 50% of patients4-Rheumatoid factors may be +ve4-Rheumatoid factors may be +ve

PathologyPathology

11--Renal biopsy show changes according to type of Renal biopsy show changes according to type of glomerulonephritisglomerulonephritis2-Membranoproliferative glomerulonephritis type I is 2-Membranoproliferative glomerulonephritis type I is the most commonthe most common3-Or any other types3-Or any other types

The Membranoproliferative glomerulonephritis type IThe Membranoproliferative glomerulonephritis type ILight microscopy:Light microscopy:1-Glomerular hypercellularity1-Glomerular hypercellularity2-Increased matrix and mesangial proliferation2-Increased matrix and mesangial proliferation3-Splitting of capillary basement membranes (double 3-Splitting of capillary basement membranes (double contouring- tram tracks )contouring- tram tracks )4-Intracapillary thrombosis due to cryoglobulin deposition4-Intracapillary thrombosis due to cryoglobulin deposition5-Vasculitis and fibrinoid necrosis5-Vasculitis and fibrinoid necrosis..

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

EM:EM:1-Large subendothelial deposits (different from 1-Large subendothelial deposits (different from idiopathic MPGN where the subendothelial deposits idiopathic MPGN where the subendothelial deposits are much smaller)are much smaller)2-These subendothelial deposits are so large they 2-These subendothelial deposits are so large they may protrude into the capillary lumen, causing may protrude into the capillary lumen, causing thrombosisthrombosis..

TreatmentTreatment

The policy of treatment depend on the renal function

1-In non- nephrotic , normal renal function 1-In non- nephrotic , normal renal function →→ interferon alfainterferon alfa2-In nephrotic syndrome , renal impairment or with cryoglobulinemia → 2-In nephrotic syndrome , renal impairment or with cryoglobulinemia → pegylated interferon alfa pegylated interferon alfa (1 ug/kg week )+ (1 ug/kg week )+ ribavirinribavirin(15 mg/kg/day) for 12 (15 mg/kg/day) for 12 months then short course of low-dose corticosteroidsmonths then short course of low-dose corticosteroids3-In Rapidly progressive renal failure: 3-In Rapidly progressive renal failure: methylprednisolonemethylprednisolone (1 g/ day) for (1 g/ day) for 3 days, followed by 3 days, followed by oral prednisone oral prednisone (60 mg/day) with slow taper over 2-3 (60 mg/day) with slow taper over 2-3 monthsmonths4-4-Plasma exchange Plasma exchange to remove cryoglobulins (3/week for 2 – 3 weeks)to remove cryoglobulins (3/week for 2 – 3 weeks)

5-5-RituximabRituximab to stop further B cell production to stop further B cell production (375mg/m 2 weekly for 4 weeks) or in resistance (375mg/m 2 weekly for 4 weeks) or in resistance casescases6-6-CyclophosphamideCyclophosphamide for 2 – 4 months ) 1.5 – for 2 – 4 months ) 1.5 – 2.0mg/kg daily orally)2.0mg/kg daily orally)7-Use 7-Use erythropoietinerythropoietin to keep Hb>110 g/L (ribavirin to keep Hb>110 g/L (ribavirin causes red cell fragility)causes red cell fragility)8-8-ACE-1/ARBACE-1/ARB to reduce proteinuria ( uPCR<50 to reduce proteinuria ( uPCR<50 mg/mmol) also to control blood pressure ( aim < mg/mmol) also to control blood pressure ( aim < 130/80mmHg130/80mmHg

ThanksThanks

Dr. M. Dr. M. AbbassAbbass