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![Page 1: The Double-Edged Sword: Long-Term Complications of ART and HIV Kidney conundrums: HIV and renal disease Mohamed G. Atta, MD, MPH Johns.](https://reader038.fdocuments.us/reader038/viewer/2022110208/56649ddb5503460f94ad21df/html5/thumbnails/1.jpg)
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www.aids2010.org
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
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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
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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