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The Double-Edged Sword: Long-Term Complications of ART and HIV
Kidney conundrums: HIV and renal disease
Mohamed G. Atta, MD, MPH
Johns Hopkins
Baltimore, MD, USA
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Objectives
Review implications of kidney disease in HIV infected individuals
Discuss pros and cons of deferred vs. early HAART in this population: Renal perspectives
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Multivariate Hazard Ratios for primary outcome in HOPE
0 1 2
Microalbuminuria
CAD
Diabetes
Cr.>1.4mg/dl
Male
Age
Ramipril
1.59
1.51
1.42
1.4
1.2
1.03
0.79
Hazard Ratio
Adapted from the HOPE study: N Engl J Med 2000, 342: 145-153
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All-cause and cardiovascular mortality according to eGFR and categorical albuminuria
Chronic Kidney Disease Prognosis Consortium, Lancet, May 18, 2010
105,872 from 14 studies
1, 128,310 from 7 studies
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Kidney Function and the Risk of Cardiovascular Events in HIV-1 Infected Patients
Nested, matched, case-control study
315 HIV-infected patients (63 cases who had cardiovascular events and 252 controls).
eGFR (CKD-EPI formula/MDRD), and proteinuria were the primary exposures of interest
George et. al AIDS, January 2010
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Kidney Function and the Risk of Cardiovascular Events in HIV-1 Infected Patients
eGFR of <60: unadjusted OR 15·9 for cardiovascular event (p<0·001).
Adjusted OR (eGFR 10 ml/min ): 1.2 (95% CI 1·1–1·4) for cardiovascular event
Prevalence of proteinuria: 51% in cases vs. 25% in control, p<0·001).
Proteinuria: unadjusted OR 3·6 (95% CI 1·9–7·0) and adjusted OR 2·2 (95% CI 1·1–4·8).
George et. al AIDS, January 2010
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Relationship between eGFR and cardiovascular event status HIV-1 infected patients
George et. al AIDS, January 2010
Mean eGFR was 68·4 in cases vs. 103·2 ml/min, in control p<0·001
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VA study of 17,264 patients
1194 with eGFR < 60 (MDRD)
GFR by MDRD
Urine albumin by dipstick
Outcome: 1) Incident CVD, defined as coronary, cerebrovascular, or
peripheral arterial disease, and
2) Incident heart failure
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Choi et al, Circulation, January 2010
Incident event rates stratified by eGFR and Dipstick Proteinuria
eGFR = Event rates Events with albuminuria
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Microalbuminuria Is Associated With All-Cause Mortality in women
1547 HIV-infected women (WIHS)
Confirmed microalbuminuria
Unconfirmed albuminuria
Confirmed proteinuria
No albuminuria
Wyatt et al. JAIDS 2010
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HAART toxicities
Metabolic derangements
HIVAN
Early treatmentDeferred treatment
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HIVAN: Pathogenesis
Direct role of HIV-1 in the development of HIVAN
Transgenic mouse models
Detection of HIV-1 RNA and DNA in renal epithelial cells
Reports of clinical and pathological reversal of HIVAN w/ HAART
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HIVAN:“Classic” clinical characteristics
Exclusive disease of Africans
Proteinuria (often nephrotic range) Atta et al. Am J Med, 2005
Detectable viremia or detectable Proviral DNA Estrella et al. Clin Infect Dis 2006Izzedine et al. NDT (July, 2010)
Normal size echogenic kidneys on ultrasoundAtta et al. J Ultrasound Med, 2004
Progressive renal failure (weeks to months)
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Genome-wide admixture analysis and chromosome 22 gene localization (Kopp Nature Genetics 2008)
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Frequencies of the candidate genotypes for the MYH9 SNPs (Kopp et al. Nature Genetics 2008)
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HIVAN Prevention and Treatment
Dia
lysi
s-fr
ee S
urv
ival
(%
)
(n=26)
No ARV
P = (0.025)
ARV Treatment
(n=10)
10000 2000 3000
0
25
50
75
100
Time (days)
Hopkins Nephrology HIV CohortARV Treatment of HIVAN:
Cas
es p
er 1
000
per
son
-yea
rs
0
5
10
15
20
25
30
35
40
45 No Antiretroviral Therapy
Nucleoside Reverse Transcriptase Inhibitor Therapy
Highly Active Antiretroviral Therapy
Presumed HIV-Associated Nephropathy Incidence Stratified by AIDS Status and Antiretroviral Use
0
Lucas GM, et al. AIDS. 2004;20:18(3):541-546.
No AIDS
Atta et al., Nephrol Dial Transpl, 2006
AIDS
26.3
14.4
6.82.6 5
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Recommendations for Initiating ART in the US
Symptomatic HIV disease
Asymptomatic
• CD4<350• CD4>350
• Rapid decline in CD4 count• High risk of CVD• Active hepatitis B or C coinfection• HIVAN
August, 2008
Risks of early HAART:Renal perspective
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Diabetes in Multicenter AIDS Cohort Study
Impaired glucose-sensing by β-cells
Glut-4 transporter inhibition
Increased insulin resistance
HCV co-infection?
Brown et al Arch Intern Med. 2005, Koster et.al. Diabetes 52, 2003. Murata et.al. J Bio Chem 275, 2000. Justman et.al. JAIDS 32, 2003. Visnegarwala et.al. J Infection 50,2005.
Brown et.al. Arch Intern Med 165, 2005.
DM incidence 4x more in HIV-+ individuals on HAARTPIs associated w/ 3-fold increase risk in DM
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Hypertension in MACS
Seaberg et al. AIDS 19, 2005.
5578 men 1984-2003HAART exposure >2 yrs associated w/ systolic HTN
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Crystalluria and stone formation
IndinavirAtazanavir Indinavir
crystals
A: Kopp, J. Ann Intern Med 1997; B: courtesy of Perazella M, Yale University.
Atazanivir crystalsCouzigou et al. CID 2007
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Tenofovir renal toxicity
Acute renal failure
Fanconi syndrome
Nephrogenic diabetes insipidus
. . .
Chronic kidney disease?
Atta et al. Seminars in Nephrology, 6, 2008
Izzedine et.al. AJKD 45, 2005.
Winston, et.al. HIV Med 7, 2006.
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Model of organic anion transporters in kidney proximal tubule
Russel et al. Annu. Rev. Physiol. 2002. 64:563–94
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Blood Urine
Courtesy of Gilbert DerayPierre et Marie Curie University, Paris, France
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Chronic kidney disease and antiretroviral drug use in HIV-positive patients
Mocroft et al. AIDS 2010, EuroSIDA Study Group
3.3% over a median follow-up of 3.7
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Incidence of CKD and increasing exposure to antiretrovirals
Mocroft et al. AIDS 2010, EuroSIDA Study Group
Mocroft et al. AIDS 2010, EuroSIDA Study Group
Hazard of CKD incidence
Tenofovir 1.16 1.06-1.25
Indinavir 1.121.06-1.18
Atazanavir 1.21 1.09-1.34
Lopinavir/r 1.08 1.01-1.16
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Age and Kidney Function on Tenofovir1031 HIV clinic patients on tenofovir 2002-2009
100
110
120
130
140
150
eG
FR
ml/m
in
0 500 1000 1500 2000 2500
days on tenofovir
100
120
140
160
eG
FR
ml/m
in0 500 1000 1500 2000
days on tenofovirAge<30 Age 30-45Age>45
30011th International Workshop on Clinical Pharmacology of HIV Therapy,Sorrento, Italy, 2010
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Suggested Recommendations• No evidence of benefit from the renal standpoint
for early HIV treatment.
• In treated or untreated HIV,• Screen all patients with GFR/urine
protein/albumin
• For high risk patients, monitor kidney disease
regularly
• For those with (non HIVAN) kidney disease, new
studies are needed to determine benefits
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Acknowledgements Derek M. Fine, USA
Gregory M. Lucas, USA
Michelle Estrella, USA
Joel Gallant, USA
Richard Moore, USA
Hassane Izzedine, France
Gilbert Deray, France
Elizabeth George, India
