Disclosures. Viral Nephritides Including HIV and Hepatitis. Objectives HIV 7/20/2015. Advisory board

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1 Disclosures Viral Nephritides Including HIV and Hepatitis Advisory board Merck Jai Radhakrishnan, MD, MS Professor of Medicine at Columbia University Medical Center Objectives Epidemiology, pathogenesis, clinical features and treatment of viral-related glomerular disease HIV HCV HBV CMV HIV 1

2 ARS Case 1: Adults and children estimated to be living with HIV year-old African American male with history of injection drug use presents with edema. He is known to be HIV positive on cart Physical Exam: normal BP, thin, 1+ edema Labs: HIV VL: zero copies/ml.cd4 300/µl Urine 3+ protein, 2+ blood. Micro: RBC/HPF. Urine prot/creat: 4.5 S Creatinine 3.1, S Albumin 2.2g/dL. CBC normal except for Hb8.8g/dL C3 and C4 complements are low. ANA 1:320 His renal biopsy is likely to show 1. Collapsing glomerulopathy 2. Proliferative glomerulonephritis 3. Interstitial nephritis 4. Fibrin thrombi in the microvasculature HIV Related Renal disease HIV Associated Nephropathy Collapsing glomerulopathy Immune Complex Disease Thrombotic microangiopathy Combined anti-retroviral treatment (cart) nephropathy Relative Prevalence of HIV-Associated Renal Disease (biopsy) OTHERS 25% FSGS 22% HIVICK 18% HIVAN 35% Am. J. Nephrol. 28, (2008). 2

3 Clinical Presentation of HIVAN Black race >90% Untreated, advanced stage of HIV disease (CD4<200, high VL) Proteinuria Nephrotic range (rarely subnephrotic) Hematuria Microscopic / macroscopic Normal BP (HTN present in 12-20%) Normal to large size echogenickidneys (microcysts) Rapid course of progression to ESRD in untreated patients (3 6 months) HIVAN Involves all Renal Compartments GLOMERULAR Collapsing Glomerulopathy TUBULAR Microcystic dilatation Atrophied tubular epithelium INTERSTITIAL Lymphocytic infiltrate Interstitial fibrosis Immunofluorescence: Nonspecific Electron microscopy: Tubuloreticular inclusions Int J STD AIDS, November 2008 vol. 19 no Pathogenesis of HIVAN Treatment of HIVAN Genetic susceptibility APOL1 homozygosity/ double heterozygosity for high risk alleles G1/G2 HIV is directly and indirectly involved in nephropathy Initiate combined anti retroviral therapy Renin angiotensin system inhibitors Trial of corticosteroids for rapid progression of renal failure despite cart. Renal transplantation in patients with VL zero and CD4>200 on cart. Nature Reviews Nephrology 11, (2015) 3

4 Impact of Highly Active Antiretroviral Therapy Renal Transplantation: Patient and Graft Survival and First Acute Kidney-Allograft Rejection. AIDS-related mortality incidence of HIV-related ESRD mortality in patients with HIV and ESRD Wyatt C M, Klotm`an P E CJASN 2007;2:S20-S by American Society of Nephrology Stock PG et al. N Engl J Med 2010;363: Immune Complex Glomerulonephritis in HIV HIVICK : HIV-associated immune complex diseas Lupus-like GN IgA Nephropathy Membranous Nephropathy MPGN Mesangial proliferative GN Infection related GN Immunotactoid/fibrillary GN HIVICK Duration of HIV 10 years Nephrotic syndrome 71% Hematuria 100% HTN 79% Hepatitis C 50% Decreased C3 40% Positive ANA 21% TRI 100% ESRD within 1 year of Dx 70% (Despite cart) Global mesangial hyperplasia, Mes/paramesangial eosinophilic deposits IF: Varying Ig/Complement; some full house Haas M, et al. Kidney Int 67;1381,2005 Subepithelial'ball-in-cup' deposit 4

5 HIV-associated Thrombotic microangiopathy Usually seen in advanced HIV disease Incidence declining with cart Low ADAMTS13 levels associated with response to PLEX/plasma/steroids and better prognosis cart Related Nephropathy Reverse Transcriptase Inhibitors (RTI) (MITOCHONDIAL DYSFn) Nucleotide analog RTI (NtRTI) Tenofovir AKI/CKD, Fanconi Syndrome Protease inhibitors (crystal-induced nephropathy) Indinavir Nephrolithiasis papillary necrosis Interstitial /intratubular crystals -Atazanavir Malak Scand J Immunol Sep;68(3): Azatanvir Nephropathy: Crystal associated AIN (also nephrolithiasis) Am J Kidney Dis. 2004;44(5):e81 4. Kidney International (2010) 78, AIDS Nov 12;21(17):

6 Key Message Renal diagnoses in HIV+ patients cart-naïve, full NS HIVAN likely On cart, full NS Other GNs, notably FSGS On cart, nephritic, +/- low complements Immune complex disease On cart, CKD/subnephrotic +/- Fanconi cart nephropathy ARS Case 1: ANSWER 32-year-old African American male with history of injection drug use presents with edema. He is known to be HIV positive on cart Physical Exam: normal BP, thin, 1+ edema Labs: HIV VL: zero copies/ml.cd4 300/µl Urine 3+ protein, 2+ blood. Micro: RBC/HPF. Urine prot/creat: 4.5 S Creatinine 3.1, S Albumin 2.2g/dL. CBC normal except for Hb8.8g/dL C3 and C4 complements are low. ANA 1:320 His renal biopsy is likely to show 1. Collapsing glomerulopathy 2. Proliferative glomerulonephritis 3. Interstitial nephritis 4. Fibrin thrombi in the microvasculature ARS Case 2 HEPATITIS-C 34-year old S Asian male, recently diagnosed hepatitis C (IVDA) LE edema, dyspnea and abdominal distension, + dark urine Laboratory: S Creatinine =3.6 mg/dl S Albumin =1.7 g/dl Urine: 3+ protein, 3+ blood, WBC 20-49, RBC >50; UPCR=17 Renal U/S normal Serologies: C3 low, C4 normal, ANA 1:40, + IgM kappa on SPEP Negative anti-dsdna, GBM, ANCA, RPR, HIV and HBV Rheumatoid factor +ve. Cryoglobulins +ve, IgM kappa HCV Ab +. HCV PCR + for genotype 1a, Viral Load 2 million 6

7 ARS Case 2 (cont) Renal Biopsy IgM ARS Case 2 (cont) What treatment would you advise at this time? Steroids + Rituximab Steroids + cyclophosphamide + plasmapheresis IFN/Ribavirin Sovaldi(Sofosbuvir)+ Olysio(simeprevir) MPGN, acute severe 10% crescents Severe interstitial edema/inflammation 30% fibrosis Major Autoimmune Syndromes Associated with HCV Strong Intermediate Low Cryoglobulinemic Vasculitis Glomerulonephritis Neuropathy Lymphoma Sjogren s Syndrome Diabetes Porphyria cutanea tarda Thyroid disease Corneal ulcers Lichen planus Fibromyalgia Pulmonary fibrosis HCV-Associated Renal Disease Mixed cryoglobulinemic syndrome Other glomerulonephritides [MPGN without cryo]? Membranous nephropathy Fibrillary/Immunotactoid GN Polyarteritis Nodosa 7

8 Renal Diagnoses in HCVAb +, HCV RNA+ patients Cryoglobulins Rheumatoid Factor activity: Complement activation Coccoli P, et al. Dig Liver Dis 39:supp1, S83-86,2007 Am J Med Mar 30. pii: S (15) Cryoglobulin Meltzer triad: purpura, arthralgia, and weakness Orphanet J Rare Dis Sep 16;3:25 8

9 HCV-Cryoglobulinemic GN Laboratory features Renal Biopsy in Cryoglobulinemic GN Light Microscopy Asymptomatic proteinuria/hematuria, nephrotic syndrome, CKD, RPGN Low C4 complement, sometimes C3 Rheumatoid factor positive Aminotransferase elevations in 70% MPGN Prominent macrophage infiltration Capillary microthrombi Am J Kidney Dis Oct;42(4): Renal Biopsy in Cryoglobulinemic GN Immunofluorscence Microscopy Renal Biopsy in Cryoglobulinemic GN Electron Microscopy IgM, IgG and Complement deposits Fingerprint pattern 9

10 Survival in HCV-mixed cryoglobulinemia HCV-Associated Membranous Nephropathy Association with HCV controversial Normal complements Negative cryoglobulins & rheumatoid factor PLA2R Ab may be positive in 2/3 Modern Pathology(2013) 26, Roccatello D Am J Kidney Dis Jan;49(1):69-82 Am J Kidney Dis 1996 Nov;28(5): HCV-Associated Fibrillary and Immunotactoid Glomerulonephritis 4 cases of fibrillary GN 2 cases of immunotactoid GN Clinical presentation Nephroticproteinuria, hematuria, renal insufficiency Low complement in 50% Hepatitis C virus-associated polyarteritis nodosa % of 161 patients with HCV-related vasculitis More severe/acute presentation Fevers and wtloss Severe HTN GI involvement Mononeuritis multiplex CRP elevation Higher remission rate (79 vs 56% with Mixed Cryoglobulinemia) J Am Soc Nephrol Dec;9(12): Saadoun D...Arthritis Care Res (Hoboken) Mar;63(3):

11 Pathogenesis/Treatment Strategies in Cryoglobulinemic Vasculitis Rituximab in HCV Glomerulonephritis : Pooled Clinical Studies (n = 43 patients) HCV Replication Antiviral therapy Poly- and monoclonal B cell activation Rituximab, Cyclophosphamide Cryoglobulins Plasmapheresis Inflammation Corticosteroids Saadoun D.. Curr Opin Rheumatol Jan;20(1):23-8 Approved Regimens For Hepatitis C Genotype 1 Triple Therapy [Peginterferon with Ribavirin for 48 weeks] Peginterferon with Ribavirin plus Boceprevir for 24 or 48 weeks Peginterferon with Ribavirin plus Telaprevir for 24 or 48 weeks Peginterferon with Ribavirin and Simeprevir for 12 weeks (total duration 24 weeks) Peginterferon with Ribavirin and Sofosbuvir for 12 weeks Sofosbuvir-Ledipasvir (Harvoni ) FDC for 12 weeks (First all oral regimen- approved October 10 th, 2014) Sofosbuvir (Sovaldi )-Simeprevir (Olysio ) for 12 weeks (approved November 5 th, 2014) ombitasvir, paritaprevirand ritonavir tablets co-packaged with dasabuvirtablets (Viekira Pak ) [egfr >30 for Sofosbuvir] HCV Antiviral Therapy: The Stepwise Increase in Sustained Virological Response Rates in the Past 25 Years Nature Reviews Immunology 13, (2013) 11

12 HCV-GN: Treatment Strategies by Severity` ARS Case 4 (cont) What treatment would you advise at this time? HCV Cryo-GN Asymptomatic hematuria or proteinuria Active GN, stable CKD and subnephrotic Nephrotic Syndrome Rapidly Progressive GN Antivirals Antivirals (Rituximab or Cyclophosphamide) + Steroids. Antivirals PEX +steroids Rituximab or CYC Antivirals Steroids + Rituximab Steroids + cyclophosphamide + plasmapheresis IFN/Ribavirin Sovaldi(Sofosbuvir)+ Olysio(simeprevir) Patient was treated with Rituximab, steroids, then sofosbuvir+simeprevir Viral load undectable 2 weeks after antiviral Follow-up SCr1.35, PCR 2 Key Messages HCV is associated is typically assocated with cryoglobulinemic vasculitis and MPGN kidney biopsy of HCV+ patients more commonly show other diagnoses) Immunosupression needs to be tailored to the clinical severity Successful antiviral therapy is associated with remission HEPATITIS B 12

13 Renal Diseases Associated with HBV Infection Membranous nephropathy Membranoproliferative GN Immune Complex-Associated Polyarteritis nodosa?iga nephropathy?fsgs HBV-associated Membranous Nephropathy Pediatric patients Overt liver disease absent Mild CKD with nephrotic syndrome Good prognosis Adult patients Overt liver disease more frequent CKD, HTN frequent Poor prognosis Pathogenesis Viral proteins in immune complexes (PLA2R ab may be positive) Nature Clinical Practice Nephrology(2006) 2, Treatment of HBV-associated GN Optimal therapy is not known Antiviral therapy (lamivudine) has shown to reduce proteinuria High rates of resistance Monotherapy with corticosteroids ineffective Immunosuppression (especially rituximab) associated with HBV reactivation Treatment Guidelines: Recommendations for First-Line Therapy in Patients Without Cirrhosis HBeAg Positive or Negative Chronic HBV Preferred Alternative Not Preferred Tenofovir DF Adefovir Lamivudine Entecavir Peg-IFN alfa-2a Telbivudine* *HBV DNA must be undetectable at 24 weeks to continue (Keeffe). AASLD guidelines: lamivudine and telbivudine not preferred due to relatively high rate of resistance. Adefovir not preferred due to weak antiviral activity and relatively high rate of resistance in HBeAg-negative studies. World J Gastroenterol2010; 16(6): Nature Clinical Practice Nephrology(2006) 2, Lok AS, et al. Hepatology. 2009;50: Available at: Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:

14 Key Messages: HBV GN OTHER VIRUSES Membranous nephropathy is the commonest GN related to HBV PLA2 R ab may be positive Antiviral therapy may be associated with improvement of proteinuria/ckd progression Immunosuppression may be associated with HBV reactivation and severe liver disease (unknown if IS helps control the disease) Hantavirus Hemorrhagic fever with renal syndrome (Europe/Asia) Cardiopulmonary syndrome (Americas) Small mammals are the reservoir Worldwide distribution Flulike symptoms, followed by shock, low platelets AKI in up to 90% of patients. 5-15% mortality Direct endothelial damage and interstitial inflammation Ribavirin may reduce mortality Kidney International (2013) 83, 23 14