Question 1 Which of these pathophysiologic mechanisms best explains the renal lesions seen with each viral infection? A. Hepatitis B induced membranous GN is typically due to the deposition of HbsAg immune complexes in the subepithelial space. B. Hepatitis C causes Type I cryoglobulinemia which results in Type II MPGN. C. Research evidence suggests that HIV directly infects the podocytes cells leading to the development of the collapsing form of FSGS. D. Hepatitis B directly infects podocytes which leads to membranous GN. E. Hepatitis C associated GN is associated with the activation of the alternative pathway of complement.
Question 2 Case A 45 year old African American male with history of drug abuse, HIV+, and HCV+ presents with severe nephrotic syndrome and a recent rise of his serum creatinine from a baseline level of 1.0 mg/dl to 2.1 mg/dl. His BP 100/65, no peripheral edema. Renal ultrasound shows enlarged kidney with no obstruction or mass. What is likely his diagnosis?
A. B. C. D. E.
Classic FSGS Type II MPGN Cryoglobinemia GN HIVAN HIVICK
HIV-associated nephropathy • HIVAN is a collapsing form of focal segmental glomerulosclerosis (FSGS). • HIVAN classically presents with significant proteinuria and rapidly progressive kidney failure in the setting of normal blood pressure and normal to enlarged kidneys. • The incidence of HIVAN has been dramatically decreased with effective ART in USA (almost cured). However, the incidence remains high in Africa.
HIV-associated Nephropathy (HIVAN) Pathology • • •
Collapsing focal segmental glomerulosclerosis (FSGS) (D’Agati, Kidney Int. 1989): pseudo-crescent formation and loss of podocyte markers due to either dedifferentiation or apoptosis. Interstitial injury: interstitial nephritis with infiltration of inflammatory cells; tubular dilatation with microcystic formation. More classic FSGS cases are seen in HIV+ patients with ART treatment.
Wyatt, Klotman, & D’Agati. Seminars in Nephrology 2008
Pathogenesis of HIVAN The best studied viral disease Genetics • APOL1 (AA) (Odds: 29-89) • HIVAN1/HIVAN2
HIV infection in kidney cells
• • •
Viral entry Reservoir Latency
HIVAN Host Response • Podocyte loss or dedifferentiation? • Podocyte or PEC proliferation to form pseudo crescent • Tubular cell apoptosis • Inflammation, Fibrosis
Epigenetics • • •
Histone acetylation DNA methylation miRNA
Reversibility of HIVAN with ART
N Engl J Med. 2001 Jun 28;344(26):1979-84. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. Winston JA, Bruggeman LA, Ross MD, Jacobson J, Ross L, D'Agati VD, Klotman PE, Klotman ME.
Question 3 Continuation of the Case Patient started on a tenofovir-containing regimen as ART for 6 months and his viral load is now undetectable and CD4 count is back to normal. His proteinuria is reduced to 0.5g/day and renal function is back to normal. However, his serum Cr has been rising recently to 2.1 mg/dl. His Urine analysis shows a few WBC with trace proteinuria but no blood or RBC. His urine analysis also shows positive for glucose. His BP is 120/75 with no edema. What is likely cause of his recent rise of serum Cr? A. Relapse of HIVAN B. HCV-induced GN C. AKI due to HIVAN D. ART-induced nephrotoxicity E. Cocaine-induced nephropathy
AKI in HIV patients • Incidence of AKI: increased in HIV-positive patients compared with patients without HIV. • Risk factors for AKI: • Most risk factors for AKI among HIV-positive patients are similar to those for AKI in the general population (older age, DM, preexisting CKD, and liver disease). • However, some risk factors are specific to HIV (low CD4 count, high viral load, and co-infection with HCV. • Common causes of AKI in HIV-positive patients • Medication toxicity • Sepsis • HIVAN Nadkarni G AIDS 2015
Medication nephrotoxicity Patients with HIV infection are at risk for nephrotoxicity from ART • Protease inhibitors • Indinavir and atazanavir are protease inhibitors that can cause crystalluria and AKI. The use of ritonavir-boosted protease inhibitors has also been associated with increased risk of CKD. • Tenofovir disoproxil fumarate (TDF) • The risk of kidney toxicity with TDF has varied from 2-10%. • Tenofovir can cause AKI, proximal tubular dysfunction, or increased risk of CKD. • TDF should be avoided, if feasible, in patients with an eGFR25% decline of eGFR. • A newer prodrug, tenofovir alafenamide (TAF) achieves similar antiviral efficacy at much lower plasma concentrations of tenofovir, and has smaller nephrotoxicity
EM of proximal tubule cells in a kidney biopsy specimen from a patient with Fanconi syndrome secondary to tenofovir toxicity
(A) Mitochondrial size and morphologic characteristics are highly irregular, with (B) disruption of the normal cristae (arrows) and (C) occasional giant mitochondria. (Scale bars = 500 nm.)
Question 4 Continuation of the Case Over the course, patient developed diabetes and has been treated with oral anti-diabetes medications for several years. Patient was recently found to have more proteinuria but no hematuria. His renal function has been worsening slowly with a rise of serum Cr from a baseline 1.1 to 1.8 mg/dl. His viral load is undetectable. He still has HCV positive but negative for cryoglobulinemia. His complement levels are normal. HbA1c is 8.2%. What is likely cause of his increased proteinuria? A. HCV-induced MPGN B. Diabetic nephropathy C. HIVAN relapse D. Drug-induced nephropathy E. Classic FSGS
New Spectrum of Kidney Disease in HIV Patients
• HIV-associated Nephrology
• • • • •
HIV-Immune complex kidney disease Classic FSGS Drug-induced Nephropathy Interstitial Nephritis CKD (DKD, HTN) in HIV+ patients
Mallipattu S et al KI 2014
Effect of chronic HIV infection on the progression of DKD Progression to eGFR < 45 ml/min/1.73m2
No HIV/No DM
Medapalli R. et al JAIDS 2012
Question 5 Continuation of the Case This HIV+ and HCV+ positive patient develops now both hematuria and proteinuria and his renal function declines again. The serological test shows low complements and he is positive for cryoglobulinemia. His viral load is still undetectable and CD4 count is normal. What is the new diagnosis now for this patient? A. HIV-induced immune complex GN B. HCV-induced MPGN C. Classic FSGS D. IgA Nephropathy E. HIV induced interstitial nephritis
Glomerulonephritis due to HIV and hepatitis C virus co-infection
• HCV co-infection has been associated with the development of acute and chronic kidney disease in large cohort studies of HIV-positive patients. • MPGN is strongly associated with HCV infection in the general population and is a common alternative diagnosis in co-infected patients.
Glomerular diseases associated with HCV infection • Chronic hepatitis C virus (HCV) infection is associated with several glomerular diseases: • Mixed cryoglobulinemia with MPGN • Membranous nephropathy • Polyarteritis nodosa (PAN)
Mixed cryoglobulinemia syndrome • Mixed cryoglobulinemia syndrome is a systemic vasculitis. • The clinical manifestations include hematuria, proteinuria, and renal impairment. • Laboratory studies show low complement levels with C4 >C3 and cryoglobulinemia which are mostly type II, characterized by a polyclonal IgG and monoclonal IgM kappa rheumatoid factor. • There is evidence that HCV-containing immune complexes are directly involved in the pathogenesis of disease. • HCV RNA and HCV IgG antigen-antibody complexes are highly concentrated in the cryoprecipitate. • HCV antigens have been detected along the glomerular capillary walls and in the mesangium of patients with HCVrelated GN.
Cryoglobulin, anti-viral core-protein IgG antibodies provoke an IgM-rheumatoid factor antibody response, which fixes and activates classic complement pathway
MPGN in HCV-associated cryoglobulinemia
MPGN in HCV-associated cryoglobulinemia. (a) H&E stain showing capillary cryoglobulin thrombi (arrow), mesangial expansion with extrinsic inflammatory cellular infiltration; (b) Immunofluorescence showing IgM deposition along the glomerular capillary walls; c) Electron microphotograph showing dense subendothelial cryoglobulin deposits with typical fingerprinting appearance.
Question 6 Continuation of the Case This patient with both HIV and HCV develops severe MPGN associated with cryoglobulinemia. How should we treat this patient now? A. Start him on immunosuppressive medications and anti-viral treatment together. B. Start him on interferon-a and ribavirin. C. Direct Acting Antiviral drugs (DAA) could not be used in patients with renal failure D. Evidence from clinical trials confirms that DAA could improve HCV-induced MPGN. E. For kidney transplant patients, DAA could be given either prior or after transplantation.
RATIONALE FOR ANTIVIRAL TREATMENT • The main reason for antiviral treatment in patients with chronic HCV infection is to prevent liver complications. • In the patient with advanced chronic kidney disease who is a potential kidney transplant candidate, an additional reason is to prevent kidney transplant-related complications specific to HCV infection. • In the less common scenario of HCV related vasculitis and/or GN (mixed cryoglobulinemia), an additional rationale for antiviral treatment is to eradicate the immunologic stimulus (ie, HCV itself) for the vasculitis and/or glomerulonephritis.
Treatment of HCV in GN patients: supported by interferon-based regimen • Cure of HCV is associated with additional benefits in HCVinfected patients with renal disease. • In several studies of patients with MPGN with mixed cryoglobulinemia, improvements in the cutaneous vasculitis, cryoglobulin titers, proteinuria, and in the plasma creatinine concentration were observed in the majority patients who achieved HCV viral suppression on interferon-based treatment. • Much less is known about the extrahepatic effects of successful antiviral treatment of HCV associated GN without mixed cryoglobulinemia. • However, the evidence with new Direct-acting antiviral drugs (DAA) in HCV patients with cryoglobulinemia is still lacking.
Mechanisms of action of different anti-HCV drugs
NS3-4A protease inhibitors Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication Non-structural protein 5B (NS5B) is a HCV RNA-dependent RNA polymerase which is essential for viral replication
EXPEDITION-4 trial • The EXPEDITION-4 trial evaluated the safety and efficacy of 12 weeks of the pangenotypic NS3/NS4A protease inhibitor glecaprevir and the pangenotypic NS5A inhibitor pibrentasvir for genotype 1, 2, 3, 4, 5, or 6 infection. • This open-label study enrolled treatment-naive and experienced patients with CKD stage 4 or 5, including hemodialysis. • Baseline characteristics of the 104 patients enrolled in the study were 76% male; 25% black; 19% compensated cirrhosis; 40% treatment experienced; and 82% hemodialysis dependent. • The study reported ITT and mITT SVR12 rates of 98% and 100%, respectively.
Glecaprevir and Pibrentasvir in Patients with HCV and Severe Renal Impairment. AU Gane E, Lawitz E, Pugatch D, Papatheodoridis G, Bräu N, Brown A, Pol S, Leroy V, Persico M, Moreno C, Colombo M, Yoshida EM, Nelson DR, Collins C, Lei Y, Kosloski M, Mensa FJ SO N Engl J Med. 2017;377(15):1448.
C-SURFER trial • The C-SURFER trial evaluated the safety and efficacy of 12 weeks of the daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) versus placebo among genotype 1infected patients with CKD stage 4 or 5 (eGFR 90 mL/min); 2 = mild CKD (eGFR 60-89 mL/min); 3 = moderate CKD (eGFR 30-59 mL/min); 4 = severe CKD (eGFR 15-29 mL/min); 5 = end-stage CKD (eGFR
UPDATE ON VIRAL NEPHROPATHY John Cijiang He, MD/PhD Division of Nephrology Department of Medicine Mount Sinai School of Medicine