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HIV and the Kidney
Marianne Harris, MD, CCFP
Clinical Assistant Professor, Dept. of Family Practice
Associate Member, Division of AIDS, Dept. of Medicine
Faculty of Medicine, UBC
Outline
• HIV epidemiology
• Impact of highly active antiretroviral therapy
(HAART)
• Kidney disease in HIV
– Role of antiretroviral drugs
Total: 36.7 million [34.0–39.8 million]
http://www.who.int/gho/hiv/en/
HIV in Canada
• 80,469 reported HIV cases as of 2014
6%
10%
9%
49%
10%
0.1%
13%
3%
• 25% women
• 16% aboriginal (vs. 4% of Canadian population)
HIV and AIDS in Canada: Surveillance Report to Dec. 31, 2014
Public Health Agency of Canada. www.phac-aspc.gc.ca
Number of reported HIV cases by year of
test– Canada 1996-2014
Public Health Agency of Canada. www.phac-aspc.gc.ca
All-age HIV diagnosis rate (per 100,000 population) by
province/territory - Canada, 2014
HIV and AIDS in Canada: Surveillance Report to Dec. 31, 2014
Public Health Agency of Canada. www.phac-aspc.gc.ca
New HIV Diagnoses per Year, Canada
R Hogg, V Lima, J Nakagawa, et al. 2016
Sexual risk behaviour not declining
BC CDC, Annual HIV and STI report, 2014
New HIV Diagnoses in BC 1996-2012
Updated from Montaner et al, Lancet, 2010
HIV in BC
Total = 7174
M =84%, F = 16%
Median age 51 years
www.cfenet.ubc.ca
DTP Monthly Report, November 2016
Number of reported HIV cases by age group and
year of test - Canada, 2009-2014
22% of new HIV diagnoses are in people aged 50 and over
Public Health Agency of Canada. www.phac-aspc.gc.ca
Life Expectancy with HIV
A 20-year old
HIV+ person on
HAART in the US
or Canada is
expected to live
into their 70s, a
life expectancy
approaching
that of the
general
population.
Samji et al., PLoS ONE 2013
Impact of HAART in BC
Hogg et al., AIDS 2006.
CVD
Osteoporosis
Non-AIDS cancers
Depression
Diabetes mellitus
Chronic liver disease
Frailty
Cognitive disorders
Chronic kidney disease
Chronic Kidney Disease
(CKD) in HIV
• CKD is becoming more common in the general
population, and in people living with HIV
• Related to aging and other risk factors
• People with HIV develop CKD at a younger age, and
are more likely to have rapid progression and
complications
• People with one or more risk factors for CKD are
more likely to develop kidney injury from drugs
(nephrotoxicity)
Causes of CKD in HIV+ patients
Traditional risk
factors
HIV
replication
Antiretroviral
therapy
Causes of CKD in HIV+ patients
Traditional risk
factors
HIV
replication
Antiretroviral
therapy
Recreational
drug use
Diabetes
Family history
of kidney
disease
Proteinuria
Risk Factors
For CKD in
HIV
HBV/HCV
co-infection
Orange = non-modifiable
Blue = modifiable
Established
CVD
Smoking
AfricanAmerican
descent
Dyslipidemia
Hypertension
Family history
of CVD
Older age
Use of
nephrotoxic
medications
Causes of CKD in HIV+ patients
Traditional risk
factors
HIV
replication
Antiretroviral
therapy
In situ hybridization for HIV-1 mRNA in kidney biopsies.
Wyatt C M , and Klotman P E CJASN 2007;2:S20-S24
©2007 by American Society of Nephrology
HIV-associated nephropathy (HIVAN)
– Direct infection of kidney epithelial cells with HIV
– Rapidly progressive kidney failure and death
– Advanced, untreated HIV (high viral load, low CD4)
– Genetic disposition in blacks of west African or
Haitian descent
– Bilateral enlarged kidneys
.
Types of kidney disease
Glomerular
• Severe proteinuria “nephrotic
syndrome”
• Normally most protein is
filtered out of urine, and the
little that gets through is
reabsorbed by the tubules
• If glomerular basement
membrane is damaged, ++
protein in urine
• E.g. HIVAN, Diabetic
nephropathy
Tubular
• Amino acids and protein in urine
(lower levels than with glomerular
damage and occurs later)
• Lose water – dilute urine
(diabetes insipidus) →
dehydration
• Sugar in urine despite normal
blood sugar
• Inability to secrete H+ ions and
reabsorb HCO3- → acid builds up
in blood (metabolic acidosis)
• Phosphate wasting in urine → low
blood phosphate
• Inability to reabsorb K+ ions → low
blood potassium
Recreational
drug use
Diabetes
Family history
of kidney
disease
Proteinuria
LowCD4 #
HBV/HCV
co-infection
Orange = non-modifiable
Blue = modifiable
Established
CVD
Risk Factors
For CKD in
HIV
Smoking
AfricanAmerican
descent
Dyslipidemia
Hypertension
Family history
of CVD
Older age
Use of
nephrotoxic
medications
Causes of CKD in HIV+ patients
Traditional risk
factors
HIV
replication
Antiretroviral
therapy
1987
• AZT monotherapy
• 1000 - 1500 mg per day
• 5-6 doses per day
+ meds for
• Thrush
• PCP
• Pain
• Nausea
• Diarrhea
• Etc.
Targets for HIV Inhibition
Non-Nucleoside
Reverse Transcriptase
Inhibitors
(NNRTIs)
Protease
Inhibitors
Entry
Inhibitors
Nucleoside Reverse
Transcriptase Inhibitors
(NRTIs)
Maturation
Inhibitors
Integrase
Inhibitors
2007-2016
Benefits of antiretroviral therapy
• Prevent progression of HIV disease to AIDS
– preserve/restore immune function
• Prevent morbidity and mortality due to “nonAIDS” conditions
– Cardiovascular disease
– Liver, kidney, and bone disease
– Neurocognitive disorders
– Cancers
Kidney stones
• Indinavir (Crixivan®)
• Atazanavir (Reyataz®)
• Drugs that are insoluble in
urine precipitate as crystals in
the kidney tubules
• Can form stones which cause
obstruction anywhere in the
urinary tract
• Acute pain, blood in urine
• Risk increased with
dehydration, reduced GFR
Indinavir Crystal
Nephropathy
Indinavir.
Tashima KT et al. N Engl J Med 1997;336:138-140.
Kidney biopsy:
Collecting ducts in the medulla
(A) and cortex (B) contain
aggregates of crystals.
Interstitial fibrosis, tubular
atrophy, and chronic
inflammation.
Proximal tubule is susceptible to injury e.g. from drugs, heavy metals
Kidney tubule electronic microscopy
HIV- control
Benign recurrent hematuria
mtDNA/nDNA ratio: 19.1
HIV+ on tenofovir/ddI
Acute tubular necrosis
mtDNA/nDNA ratio: 4.4
Cote, Magil, Harris et al., Antiviral Therapy 2006.
Types of kidney disease
Glomerular
• Severe proteinuria “nephrotic
syndrome”
• Normally most protein is
filtered out of urine, and the
little that gets through is
reabsorbed by the tubules
• If glomerular basement
membrane is damaged, ++
protein in urine
• E.g. HIVAN, Diabetic
nephropathy
Tubular
• Amino acids and protein in urine
(lower levels than with glomerular
damage and occurs later)
• Lose water – dilute urine
(diabetes insipidus) →
dehydration
• Sugar in urine despite normal
blood sugar
• Inability to secrete H+ ions and
reabsorb HCO3- → acid builds up
in blood (metabolic acidosis)
• Inability to reabsorb K+ ions → low
blood potassium
• Phosphate wasting in urine → low
blood phosphate
Chronic renal tubular dysfunction
• can be caused by long-term exposure to drugs
such as tenofovir DF (e.g. Truvada®, Atripla®)
• Chronic phosphate wasting
→ hypophosphatemia
Daily Phosphorus Balance
Dietary intake
(meat, eggs, dairy
products, chocolate,
etc.)
Secretion
0.2 g


Absorption
1.1 g
Intracellular
compartment
58 g
Extracellular
compartment
0.6 g
Filtered
7g
Reabsorbed
6.1 g
Deposition


Reabsorption
0.4 g
Hypophosphatemia etiology
↓ Intestinal P absorption
• ↓ dietary intake
• Chronic diarrhea or
malabsorption
• Antacids – magnesium,
aluminum, calcium
• Vitamin D deficiency
↑ Renal P excretion
(↓ reabsorption)
• Hyperparathyroidism
• Vitamin D deficiency
• Tubular drug toxicity
Hypophosphatemia: consequences
– Short term:
• Asymptomatic, or muscle weakness or bone pain
– Long term:
• ↓ bone mineral density → osteoporosis
Effects of HIV drugs on the kidney
• Atazanavir (N ~ 1600 in BC)
– Concentrated in the urine and can cause kidney
stones and possibly chronic kidney disease
• Tenofovir DF (N ~ 4100 in BC)
–
–
–
–
can damage kidney tubules
chronic kidney disease
can cause acute or chronic phosphate loss
can lead to bone disease after many years
• Overall, antiretroviral therapy ↓ kidney disease
BC-CfE HIV/AIDS Drug Treatment Program,
Monthly Report, November 2016; www.cfenet.ubc.ca
Treatment as Prevention® (TasP)
• Giving highly active antiretroviral
therapy (HAART) to HIV+ individuals
• Reduces amount of HIV (viral load)
in plasma and other body fluids,
rendering that person less
infectious and therefore less likely
to transmit HIV to others
• Mother to child transmission
• Injection drug use
• Sexual transmission
www.unaids.org
British Columbia’s UNAIDS 90-90-90 Target Trajectory,
by Fiscal Year, from 2014/2015 to 2019/2020
By 2014:
83% Diagnosed
81% on ART
96% Suppressed
By 2020:
93% Diagnosed
91% on ART
97% Suppressed
VD Lima, et al. Achieving the 90-90-90 Target by 2020: The Experience in British Columbia,
Canada (CROI 2017, poster 1042)
Take-home messages
• HIV testing is now recommended for all sexually
active adults – “risk groups” no longer apply
• No cure yet, but can be considered a chronic
manageable disease
• HIV affects all organs, both directly and indirectly
– via chronic inflammation and medication side
effects
• HIV-related death and new HIV infections are
decreasing where antiretroviral therapy is widely
available
www.cfenet.ubc.ca