Nephropathy in the HIV-

Infected Patient
Oche Agbaji FMCP

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 1
Course_Jan 2022
 Outline
• Epidemiology of kidney disease in HIV infection
• Renal disorders in patients with HIV
• HIV-associated glomerular diseases
• HIVAN
• Pathophysiology
• Mechanism of renal injury
• Presentation
• Renal complications of HIV medications
• Tenofovir-associated nephrotoxicity
• Summary
NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 2
Course_Jan 2022
 Epidemiology of Kidney Disease in
HIV Infection
• Kidney disease is 4th leading cause of death among patients
with HIV
• Up to 30% of HIV patients in the US have CKD or proteinuria
• HIV is the leading cause of ESRD among African-American
men
• Burden of kidney disease among HIV patients not clear
worldwide and especially in sub-Saharan Africa
• Estimates of CKD prevalence among HIV patients range from
5% to 50%

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 3
Course_Jan 2022
 Epidemiology of HIV-Associated
Kidney disease
• Nigeria:
• 38% in Ile-Ife (2007) – Emem-Chioma P, Arogundade F, Sanusi A. et al
• 53.3% in Benin (2011) – Okafor UH, Unuigbe EI, and Oviasu E et al
• 23.8% in Jos (2011) – Agbaji OO, Adamu O, and Agaba P et al
• 23.5% in Lagos (2012) – Umeizudike T, Mabayoje M, and Okany C et al
• 30.8% in Jos (2018) – Abene E, Gimba Z, and Agbaji OO et al
• 15.8% in Calabar (2019) - Okpa HO, Bisong EM, and Effa EE et al

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 4
Course_Jan 2022
 Renal Disorders in Patients with HIV Infection
HIV-Associated nephropathy Focal segmental glomerulosclerosis
Minimal change disease
Membranoproliferative GN
Diffuse Proliferative GN
HUS/TTP
Amyloid

Unrelated diseases in HIV infected patients Heroin associated nephropathy

Obstructive uropathy

Acute renal failure Drugs, infection

HIV infection in RRT Blood transfusions, IVDA, sexual contacts

Allograft
 HIV-Associated Glomerular
Diseases
• Common
▪Focal segmental glomerulosclerosis
(“HIVAN”)
▪Mesangial proliferative GN
▪IgA nephropathy
• Uncommon
▪HUS/TTP
▪MPGN (HCV)
▪Membranous nephropathy
▪Amyloid and fibrillary/immunotactoid

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 6
Course_Jan 2022
 HIV-Associated
Glomerulonephritis
• IgA nephropathy in white or Asian
patients
• Course benign, at least over ~2-4
years

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 7
Course_Jan 2022
 HIV-Associated Renal
Disease
100
Prolif GN

80 FSGS
Other
60

40

20 Nochy, Nephrol Dial

Transplant 1993
0
Whites, N=21 Blacks, N=27

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 8
Course_Jan 2022
 HIV-Associated
Nephropathy (HIVAN)

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 9
Course_Jan 2022
 HIVAN-Incidence

Source: AIDS database and USRDS

NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 10
Course_Jan 2022
 Pathophysiology of HIVAN
• Genetic susceptibility
• African ancestry
• APOL1 gene
• MYH9 gene
• Direct Viral effects
• HIV DNA and mRNA found in kidney tissue
• nef gene-important for characteristic glomerular lesion
• vpr gene—Important for characteristic tubular pathology
• gag and pol genes- not involved
NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 11
Course_Jan 2022
 Mechanisms of Renal Injury
in HIVAN
• Opportunistic infection
• Infection of immune cells → cytokine
release
• Infection of renal cells
• Toxicity due to HIV accessory proteins
• Host response:  susceptibility in patients
of African descent

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 12
Course_Jan 2022
 • Podocyte injury
• Adhesion
• Capillary collapse
• Matrix expansion
• Filtrate misdirection

Kriz, Nephrol Dial

Transplant 1998

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 13
Course_Jan 2022
Primary Renal Pathology of HIVAN
• Collapsing FSGS
• Interstitial inflammation
• Tubular atrophy
• Microcystic tubular dilation
with proteinaceous casts,
and mild interstitial
inflammation.

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 14
Course_Jan 2022
 HIVAN: Presentation

• Affects predominantly patients of African

ancestry
• Can present early in HIV-1 infection but
typically presents when CD4 <200
• Oedema and hypertension typically
absent

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 15
Course_Jan 2022
 HIVAN: Presentation
• Massive proteinuria
• Micro-hematuria
• Azotemia
• Rapid progression to ESRD
• African American Patients
• CD4 count low
• Normotensive
• Large, echogenic kidneys on
ultrasound
 HIVAN: Presentation
• Natural History
• Malignant course
• ESRD within 3 to 4 months
• Less common now than 10 years ago
• Differential Diagnosis
• Heroin associated Nephropathy

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 17
Course_Jan 2022
 HIVAN: Case
• 39 year old black male
• Diagnosed with HIV
• CD4+ Cell count 12 cells/mm3
• Ankle edema
• Creatinine 221µmol/L
• Serologies-negative
• 24 hour urine protein 2 g/day
• Renal biopsy

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 18
Course_Jan 2022
 Treatment of HIVAN

• Treatment
• ART
• ACEIs, ARBs
• Sr. creatinine >790µmol/L
• Hemodialysis
• Kidney Transplantation

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 19
Course_Jan 2022
 HIVAN: ACEI Rx
9 Nephrotic patients (5 Lisinopril, 4 untreated)
Followed up for 24 weeks

Burns, Am J Kidney Dis 1997

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 20
Course_Jan 2022
 HIVAN: Steroid Rx

• N=20 (14 Biopsy Creatinine in 17 responders

proven FSGS)
▪ Uncontrolled
▪ Prednisone 2-11
weeks
▪ 17 improved renal
function
▪ 8 developed ESRD

Smith, Am J Med 1996

NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 21
Course_Jan 2022
 HIVAN ART Treatment: Case
Report
• Patient diagnosed with HIV, ESRD, renal biopsy
showed FSGS
• Treated with ART for 3 months
• Creatinine fell, dialysis stopped, renal biopsy
showed reversal of FSGS

Wali, Lancet 1998

Winston, NEJM 2001

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 22
Course_Jan 2022
 HIV-Associated Renal
Disease: Summary
• Black patients: FSGS
• White and Asian patients: immune
complex disease
• Host genetic factors likely contribute
to FSGS: APOL1, ACE and others

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 23
Course_Jan 2022
 Renal Complications of HIV Medication
Antibacterial, antiprotozoal
◼ Aminoglycosides ARF, Mg+ wasting
◼ Ciprofloxacin allergic interstitial nephritis
◼ Pentamidine rhabdomyolysis, ARF, hyperkalemia
◼ Rifampin ARF, proximal RTR, diabetes insipidus, AIN
◼ Sulfa azotemia (normal GFR), crystalluria, AIN
◼ Trimethoprim hyperkalemia

Antifungal
◼ Amphotericin B azotemia, ARF, K+, Mg+ wasting, distal RTA

Antiviral
◼ Tenofovir Proximal tubulopathy
◼ Acyclovir crystalluria
◼ Cidofovir, adefovir proximal RTA, ARF
◼ AZT rhabdomyolysis, lactic acidosis
◼ Indinavir stone, crystalluria, dysuria, interstitial nephritis
NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 24
Course_Jan 2022
 Tenofovir-Associated
Nephrotoxicity

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 25
Course_Jan 2022
 Tenofovir-Associated Nephrotoxicity
• Tenofovir Disoproxil Fumarate (TDF) is now widely
recommended as first-line HIV treatment in adolescents and
adults by WHO and Nigerian HIV treatment guidelines
• TDF is excreted in urine unchanged by a combination of
glomerular filtration and proximal tubular secretion

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 26
Course_Jan 2022
 Tenofovir and Kidney Function
• Systematic review and meta-analysis that included data from 17
studies
• Patients treated with TDF experienced a small but significant
loss of kidney function during the course of treatment
compared with controls (mean difference in eGFRs, 3.9
mls/min; 95% confidence interval [CI], 2.1–5.7)
• TDF-containing HAART is associated with a slight decline in the
medium term in CLcr compared with HAART regimens
containing alternative Nucleoside Reverse Transcriptase
Inhibitors

Cooper RD, Wiebe N, Smith N et al. Clin Infect Dis. 2010;51:496–505.

Agbaji OO, Agaba PA, Idoko JA et al. West Afr J Med. 2011 May-Jun, 30(3). 104-6

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 27
Course_Jan 2022
 Tenofovir and Kidney Function
Mean SCr in both groups over 48 wks
120

100
Mean SCr(µmol/L)

80
p,0.02
TDF
60
NRTI
40

20

0
wk0 wk12 wk24 wk48
Time on therapy (weeks)
25-Jan-22

Agbaji OO, Agaba PA, Idoko JA et al. West Afr J Med. 2011 May-Jun, 30(3). 104-6

NPMCN, Faculty of Internal Medicine General Medicine Update

28
Course_Jan 2022
 Tenofovir and Kidney Function
Mean CLcr in both groups over 48 wks
120

100

80

TDF
Mean CCr (ml/min)

60
NRTI

40
p= 0.02
20

0
wk0 wk12 wk24 wk48

25-Jan-22 Time on therapy ( weeks)

Agbaji OO, Agaba PA, Idoko JA et al. West Afr J Med. 2011 May-Jun, 30(3). 104-6
NPMCN, Faculty of Internal Medicine General Medicine Update
29
Course_Jan 2022
 Tenofovir and Kidney Function
• Fanconi syndrome in a 52 year old HIV-1 Infected female
on TDF; which resolved when TDF was discontinued
• Incidence and predictors of TDF-induced renal
impairment in HIV-infected Nigerians
• The incidence of TDF-induced renal impairment was 4.6%
• Predictors of renal impairment were:
• TDF use
• Older age
• Co-morbidities

Agbaji et al. Tropical Journal of Nephrology 6(2); 2011

Bazim et al. GERMS 8(2); 2018 NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 30
Course_Jan 2022
 Tenofovir and Kidney Function
• Long-term TDF exposure in a cohort of close to 5,000
HIV-1 patients at JUTH between 2006 and 2017 followed
for up for 144 weeks
• Showed the prevalence of renal impairment was found to be
45% in the TDF-exposed patients compared to 14% in the TDF-
unexposed patients
• This finding suggests that close to half of the patients on
a TDF-containing ART are likely develop renal
impairment after about 144 weeks of ART

Agbaji et al. Journal of the International Association of Providers of AIDS Care Volume 18: 1-9; (2019).

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 31
Course_Jan 2022
 50

45

Proportion of patients with renal

40

35
All patients

impairment
30
TDF exposed
25
TDF unexposed
20 Linear (All patients)
15 Linear (TDF exposed)

10 Linear (TDF unexposed)

0
Week 24 Week 48 Week 96 Week 144
Weeks of antiretroviral therapy

Figure 1: Prevalence of renal impairment*, overall, and by tenofovir exposure over 144 weeks of
antiretroviral therapy.
TDF,=tenofovir,
**Patient met one or more of the defined criteria for renal impairment based on eGFR <
60ml/min/1.73m2 or a doubling of scr from baseline

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 32
Course_Jan 2022
 Mechanisms of Tenofovir-Associated
Nephrotoxicity
• TDF enters proximal tubular cells across the basolateral
membrane through organic anion transporters (OAT), where it
competes for binding with didanosine, and exits the tubule
across the apical membrane through the multidrug resistance
protein transporter (MRP-4 and MRP-2) encoded by ABCC4
and ABCC2 genes respectively
• TDF toxicity of proximal tubular mitochondrial cells leads to
impaired reabsorption of low-molecular-weight proteins and
other solutes, with urinary wasting and the clinical features of
Fanconi syndrome

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 33
Course_Jan 2022
 Mechanisms of Tenofovir-Associated
Nephrotoxicity

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 34
Course_Jan 2022
 NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 35
Course_Jan 2022
 Pathology of Tenofovir-Associated
Nephrotoxicity
• The major renal biopsy finding is proximal tubular injury
• ranging from diffuse and severe to mild and localized
• Associated with varying degrees of chronic tubulo-interstitial
scarring (i.e. tubular atrophy and interstitial fibrosis)

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 36
Course_Jan 2022
 Spectrum of Tenofovir-Associated
Nephrotoxicity
• Proximal renal tubular dysfunction (Fanconi syndrome) with
preserved renal function
• Proximal renal tubular dysfunction associated with decreased
renal function
• Acute kidney injury (AKI)
• Chronic kidney disease (CKD)
• Decreased eGFR
• Fanconi syndrome (partial or complete)
• Hypophosphatemia
• Osteomalacia
• Etc.
NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 37
Course_Jan 2022
 Tenofovir-Associated Nephrotoxicity
• Predictors of renal function decline with TDF use:
• Pre-existing renal impairment
• Older age
• Advanced HIV disease
• Vasculo-metabolic disease
• Concomitant use of nephrotoxic drugs or protease inhibitors
(Ritonavir)
• Low body weight
• ABCC2 and ABCC4 genes (encoding the outward Tenofovir
transporter MRP-2 and MRP-4) polymorphisms
NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 38
Course_Jan 2022
 Prevention and Management of Tenofovir-
associated Nephrotoxicity
• Check baseline eGFR prior to initiation of Tenofovir
• Urine dipstick assays to identify early tubular damage
• Proteinuria
• Glycosuria
• Urinary Beta 2 microglobulin estimation
• Urinary Retinol binding protein or Cystatin C estimation
• Adjustment of TDF dose base on eGFR
• Tenofovir withdrawal leads to reversal of toxicity in majority of
patients
• Discontinue TDF if baseline eGFR <60mls/min-Substitute with
Abacavir
• Modification of the Tenofovir molecule : Tenofovir alefamide fumarate
(TAF)
• Avoid concomitant administration of nephrotoxic drugs
NPMCN, Faculty of Internal Medicine General Medicine Update
25-Jan-22 39
Course_Jan 2022
 Summary
• Kidney disease is 4th leading cause of death among patients
with HIV
• HIVAN is associated with genetic susceptibility
• African ancestry
• APOL1
• MYH9
• HIVAN is a form of collapsing FSGS that is potentially treatable
• Tenofovir is associated with nephropathy - reversible if
discontinued early

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 40
Course_Jan 2022
 Questions
???

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 41
Course_Jan 2022
 Thank You
oche.agbaji@npmcn.edu.ng

NPMCN, Faculty of Internal Medicine General Medicine Update

25-Jan-22 42
Course_Jan 2022