The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.

AIDS CLINICAL ROUNDS

Renal Disease in HIV/AIDS

Theodoros Katsivas, M.D. Assistant Clinical Professor; UCSD Owen Clinic

Robyn Cunard, M.D., FRCP

Assistant Professor, Nephrology

Shira Abeles, M.D. ID Fellow, UCSD Owen Clinic

AIDS Clinical Rounds, UCSD AVRC

Jan 4, 2013

Renal disease in HIV infection Prevalence of renal disease in European HIV cohorts

ranges 0.31% – 0.5%

US cohorts report higher rates with incidence ranging 3-8 per 1,000 patient-years

Burden of renal disease expected to increase as the HIV infected population survival rates increase

Renal disease in HIV infection Acute kidney injury (AKI) Pre-renal states (hypovolemia, cirrhosis) Acute tubular necrosis Ischemic Sepsis IV contrast Nephrotoxic

Post-renal causes Nephrolithiasis Cancer Infectious

Interstitial nephritis HIV associated thrombotic microangiopathy

Medication nephrotoxicity in HIV infection

Antiretrovirals PIs: indinavir, atazanavir NRTIs: tenofovir

Other antivirals: acyclovir, foscarnet, cidofovir, adefovir

Other antibiotics: SMX/TMP, pentamidine, aminoglycosides

Antifungals: amphotericin

Renal disease in HIV infection Chronic kidney disease (CKD) HIV associated nephropathy Immune complex mediated GN (HIVICK) Hepatitis C co-infection related renal disease Post infectious GN Membranous GN Membranoproliferative GN IgA nephritis Lupus like diseases Cryoglobulinemic GN Thrombotic microangiopathy HTN nephrosclerosis DM nephropathy

Advanced renal disease in HIV infection

Ryom, JIAS, 2012, Advanced renal disease, end-stage renal disease and renal death among HIV-positive individuals in Europe

• N=8817 with median f/u 4.5 years • ARD: advanced renal disease: eGFR<30 ml/min • ESRD: HD or PD >1 mo or renal transplant

Renal disease and HIV progression or AIDS death

In a cohort with 5,824 person years of follow-up

22% were female, 34% African American, 38% on HAART, and 3% had CKD at baseline

CKD at presentation was not independently associated with increased risk of AIDS defining illness or AIDS related death

(Alves, Clin Nephrol, 2012)

Advanced renal disease in HIV infection

Most studies suggest improved mortality in HD patients receiving ART

Kidney transplant recipients infected with HIV and receiving ART now have survival rates that are similar to uninfected allograft recipients.

Antiretroviral treatment in HIVAN and advanced renal disease

No RCTs on use of ARVs for HIVAN

Observational studies show cART benefit, but not clear on: Which agents are more beneficial? Magnitude of beneficial effect? Durability of beneficial effect?

Limited dosing options for renally adjusted ARVs combinations

Case Presentation: HPI

45 yo M with HIV, Hep C, DM2, and HTN who presented after leaving prison for care of HIV and medical issues

2009 diagnosed with HIV and Hep C, CD4 was 50s VL Unknown; Started on atripla

Developed disseminated Tb (lungs, gut, renal, sinuses) in Jan 2010, M. bovis; stenotic L ureteral orifice, ? Tb – stent placed (ultimately removed 6/2011)

HPI cont’d

10/2011 released from jail, began care at San Ysidro – no acute issues. On atripla and insulin regimen Cr 1.3, 3+ protein in urine

11/2011 developed L CVAT and found to have hydronephrosis, Cr 1.4

Seen by urology

3/2012 Creatinine 1.5 Underwent cystoscopy – stent placed, AFB cultures

negative

HPI cont’d SBO 4/23 – biopsies of ileocecal valve c/w chronic

active ileocolitis – no cultures of biopsies sent (CMV staining negative), AKI with this, Cr 3.07, resolved

Atripla changed to Efavirenz/Abacavir/3TC

Following switch, Cr bumped 1.3 -> 1.8 (resolved)

Referred to renal

Followed by urology for stenotic L ureteral orifice with reflux

PMH HIV CD4 412, VL UD, dx in 2009 with AIDS

RF ? exposure while nurse in Mexico vs MSM, last neg HIV test 1999

Disseminated TB dx 2010 - M. Bovis, possibly in kidneys/ L ureter. He was hospitalized at Alvarado for 1 1/2 months, treated for 1 year 4 meds/then 2 med.

CKD with proteinuria

Ileocecal SBO, iliocolitis

HCV (1a), VL 292k - dx in 2009, no tmt

DM2 - since 1999, on insulin since 2008, + diabetic retinopathy s/p laser tmt, + PN in hands and feet

HTN - dx 2012

HL - dx 1999

Hydronephrosis: Stenotic left ureteral orifice, dilated with stent, removed the stent in 5/12, first dilatation in 2010, stent left in for 6 months

History cont’d NKDA

Meds: Atripla, gemfibrozil, bactrim ppx, azithro ppx, insulin, citalopram

Fam Hx: No renal disease

Soc Hx: From Monrovia, CA; in MCC (prison) 21 months 2009-2011, CA-1 9/2011, then in half-way house. Has a cat. No other travel, MSM, no IV drugs, not currently sexually active

PE Exam notable for BP 138/86

Thin, well-appearing

Otherwise unremarkable, no peripheral edema

Pertinent Studies CD4 418, VL UD

BUN 34, Cr 1.6, K 4.6; A1c 7.5

>3g proteinuria; protein/cr ratio 10,903

UA gluc 1+, 3+ protein, 2+ occ blood but no RBCs or WBCs

Renal US - unremarkable

Renal Biopsy 1) Review some normal histology slides

2) Review our patients’ pathology

Renal Biopsy

EM

Discussion: HIV and Renal Disease HIV often combined with DM, HTN, Hep C

ARF and CKD more likely in HIV than non-HIV ARF HIV-related RF include AIDS/AIDS-defining illness,

high VL, or use of indinavir, tenofovir, nevaripine CKD HIV-related RF higher VL and lower CD4, use of

tenofovir or indinavir

Immune activation – inflammatory cascades and Ig complex deposition, some IL enhance viral replication (IL-6, TNFα)

Glomerular disorders associated with HIV

1) HIVAN Form of FSGS with collapse of entire glomerular tuft (not focal) but

podocytes proliferate instead of atrophy/die Dilated/microcystic tubules, various levels of fibrosis and edema immune cell infiltrates – CD4 and CD8 cells and macrophages

2) HIVICK (HIV-immune complex kidney disease), immune complex glomerulonephridities Subepithelial and/or subendothelial immune deposits of HIV Ags,

Ig complexes (IgA), complement Glomerular lesions w mesangial expansion w crescents Immune cell infiltrates mostly B cells

3) Thrombotic microangiopathy Rare. Damage to glomerular microvascular endothelium, occurs

often with thrombocytopenia or hemolytic anemia.

HIVAN: Clinical Features Typically in setting of high VL

Rarely in acute HIV infection or in 1st few months

Typically rapid decline in renal function with significant proteinuria – nephrotic range

Typically lack peripheral edema, HTN

UA typically bland

US with b/l echogenic & enlarged kidneys

Dx requires bx

HIVAN: Epi

EPI: more common in African descent Of 102 HIVAN cases, 97 in black pts (Laradi et al 1998) Of 17 cases of HIV and renal disease, 7 with HIVAN, all of

African origin (Williams et al 1998) 120 autopsies of Caucasian AIDS pts: 68% with renal

disease, 0% HIVAN (Monga et al, 1997)

Inrig et al. Renal Complications of HIV Infection. AIDS 2013

HIVAN Pathogenesis: HIV in renal cells

Bruggerman – murine model: HIV-1 expression in renal epithelial cells necessary for devpt of HIVAN Since mice don’t develop AIDS, shows independent of

immune suppression and suggested viral gene expression in renal cells important (proteins)

Also showed that in HIV+ pts with HIVAN, HIV infected tubular and glomerular epithelial cells

Unclear how HIV enters epithelial cells PCR suggests CD4 and CXCR4 can be detected in

cultured renal epithelial cells

HIVAN Pathogenesis Marras – renal tubular cells supported viral replication

and subsequent divergence (separate from blood)

Winston – renal parenchymal cells can serve as reservoir for HIV, can persist in glomerular and tubular epithelial cells despite ART

HIVAN: Pathogenesis

Note – HIV DNA seen in glomeruli even in absence oh HIVAN so another factor involved Viral expression: Nef Genetic predisposition

HIVAN Pathophysiology: Nef Nef implicated; interferes with host signaling pathways

in renal cells

Nef – accessory protein involved in modulation of host immune system by controlling T cell receptor responses, downregulation of CD4 and CD28

In mice, Nef production results in phenotypic changes seen in HIVAN likely from Nef’s effects on host cell transduction pathway

involving Src Kinases and STAT3 and activation of NF-kB Induces podocyte dysfunction

HIVAN – Genetic RF Almost exclusively in African Americans Associated with gene MYH9 which codes for non-muscle myosin

on chromosome 22 Genome-wide association analysis using >1million SNPs in AAs

and European Americans with FSGS. Variants in 60kb area on chromosome 22 containing MYH9 and Apolipoprotein L1 (ApoL1) genes were strongly associated with increased risk for FSGS in Aas only.

DNA sequence in larger cohort showed 2 ApoL1 variants (G1 and G2) associated with FSGS, not MYH9. G1 and G2 variants absent in European Am genomes.

ApoL1 encodes serum factor that lyses Trypanosoma brucei Subspps (gambiense and rhodesiense) produce ApoL1 inhibitors;

inhibited by G1 and G2 ApoL1 mutations

Genovese et al. Science 2010

Antiretroviral treatment in HIVAN and advanced renal disease

No RCTs on use of ARVs for HIVAN

Observational studies show cART benefit, but not clear on: Which agents are more beneficial? Magnitude of beneficial effect? Durability of beneficial effect?

Limited dosing options for renally adjusted ARVs combinations

HIVAN: Treatment Prior to ART, patients progressed to ESRD within 1-4

months of dx, now slower with ART Increased risk of worsening renal function with Low CD4 Elevated Serum Cr Increased proteinuria Higher VL Hep C coinfection

In general worse renal survival compared with non-HIVAN

HIVAN: Treatment Other therapies ACE-I – improved renal survival in early disease Steroids – unclear benefit, high infectious complications –

not recommended Dialysis Renal transplant

Points of Discussion Patient Diagnosis

Patient management Hep C treatment Antiretroviral choices

Thank you! Thank you Boris Shlopov of pathology for taking pics of

slides

Thank you Robyn Cunard of nephrology