renal disease in hiv/aids
DESCRIPTION
Theodoros Katsivas, MD (UC San Diego Owen Clinic), Shira Abeles, MD (UC San Diego Owen Clinic) and Robyn Cunard, MD (UC San Diego) present "Renal Disease in HIV/AIDS"TRANSCRIPT
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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
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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
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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
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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
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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
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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
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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
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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)
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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.
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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
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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)
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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
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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
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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
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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
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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
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Renal Biopsy 1) Review some normal histology slides
2) Review our patients’ pathology
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Renal Biopsy
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EM
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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)
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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.
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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
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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
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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
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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
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HIVAN: Pathogenesis
Note – HIV DNA seen in glomeruli even in absence oh HIVAN so another factor involved Viral expression: Nef Genetic predisposition
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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
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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
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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
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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
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HIVAN: Treatment Other therapies ACE-I – improved renal survival in early disease Steroids – unclear benefit, high infectious complications –
not recommended Dialysis Renal transplant
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Points of Discussion Patient Diagnosis
Patient management Hep C treatment Antiretroviral choices
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Thank you! Thank you Boris Shlopov of pathology for taking pics of
slides
Thank you Robyn Cunard of nephrology