HIV Related Kidney Disease in Jamaican...

HIV Related Kidney Disease in Jamaican Children

Professor Russell Pierre

Faculty of Medical Sciences

The University of the West Indies, Mona, Jamaica

3rd Jamaican Paediatric Nephrology Conference 2018

“What’s New in Paediatric Nephrology and Urology”

Knutsford Court Hotel – Kingston, Jamaica

Sunday, October 21st 2018

Disclosures

• None to declare

Objectives

• Background

• Paediatric HIV in Jamaica

• HIV-related renal problems by timeline

• Summary

Background

• Epidemiology of kidney disease in HIV+ individuals, including children has evolved over the years

• Driving forces: genetic susceptibility, race, age, comorbid conditions, HIV infection, access to ART

• Key point: kidney is a vascular organ

• Microalbuminuria: in HIV associated with ↑ risk renal-related morbidity/mortality

Szczech LA, et al. Microalbuminuria predicts overt proteinuria among patients with HIV infection. HIV Med. 2010 Aug;11(7):419-26. doi: 10.111/j.1468-1293.2009.00805.x. Epub 2010 Jan 4. Wyatt CM, et al. Microalbuminuria is associated with all-cause and AIDS mortality in women with HIV infection. J Acquir Immune Defic Syndr. 2010 Sep;55(1):73-7. doi: 10.1097/QAI.0b013e3181cc1070. George E, et al. Kidney function and the risk of cardiovascular events in HIV-1-infected patients. AIDS. 2010 Jan 28;24(3):387-94. doi: 10.1097/QAD.0b013e3283359253.

Spectrum of Renal Disease in HIV

Background

• Clinical symptoms – vague and non-specific (decreased appetite, “not feeling right”, fatigue

• More specific – new onset hypertension, swelling

• Screening for early alterations in kidney function is essential 2 x year, esp in high-risk groups

• Urinary albumin/protein; serum creatinine; estimate of GFR

• Others: serum phosphorus, uric acid, bicarbonate, potassium (tubular function)

Risk Factors for Kidney Disease (include) Low birth weight Family history of kidney disease Urinary tract infections Lower urinary tract obstruction Urolithiasis Recovery from ARF Comorbid conditions (HBP, DM, autoimmune) Drugs (………….)

Lucas et al. 2014 Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 Nov 1;59(9):e96-138. doi:10.1093/cid//ciu617. Epub 2014 Sep 17.

Background • Renal involvement in HIV first described in adults and children in 1984

• Overall kidney disease in ~ 30% of HIV infected individuals

• USA: Data from 30 areas with mandatory reporting in 2002 children • 2-5% estimated incidence of Kidney disease

• 6% may have renal disease determined principally by laboratory evaluation

Strauss J et al. Renal Problems. In: Pizzo PA, Wilfert CM, eds. Paediatric AIDS: The Challenge of HIV Infection in Infants, Children and Adolescents. 3rd ed. Williams and Wilkins;1998;395-401. Guidelines for the management of Chronic Kidney Disease in HIV-Infected Patients: Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America http://www.journals.uchicago.edu/doi/pdf/10.1086/430257.

Background Paediatric and Adolescent HIV/AIDS in Jamaica

Background

• First case of pediatric AIDS identified in 1986, Jamaica

• Public access to treatment was not available until ~20031

• Kingston Paediatric & Perinatal HIV/AIDS Programme (KPAIDS)2

established in 2002 provided: • Coordinated management for

paediatric & perinatal HIV • Commencement of ARVs

• Implementation and uptake of antiretroviral therapy (ART) for affected children and adolescents in Jamaica has transitioned over the last 15 yrs influenced by:

• Treatment guidelines • Availability of ART • Access to ART

1Pierre RB, Steel-Duncan JC, Evans-Gilbert T, Rodriguez B, Moore J, Palmer P, Smikle MF, et al. Effectiveness of antiretroviral therapy in treating paediatric HIV/AIDS in Jamaica. West Indian Med J. 2008;57(3): 223–30.

2Christie CDC. A paediatric and perinatal HIV/AIDS leadership initiative in Kingston, Jamaica. West Indian Med J. 2004;53(5): 283–92.

Timeline of key events in Paediatric HIV – Jamaica

1986 --------› 1999 2000----› 2002 2003 ---------› --------› 2007

Increased

access to ART2

Mustard Seed

Community

start hospice

First case

Paediatric

AIDS

Family Centre

initiated at University

Hospital of the West

Indies

Accelerated access

to laboratory

monitoring

KPAIDS

established1

Maturing

Cohort

1 Christie CDC. A paediatric and perinatal HIV/AIDS leadership initiative in Kingston, Jamaica. West Indian Med J. 2004;53(5): 283–92.

2 Pierre RB, Steel-Duncan JC, Evans-Gilbert T, Rodriguez B, Moore J, Palmer P, Smikle MF, et al. Effectiveness of antiretroviral therapy in treating paediatric HIV/AIDS in Jamaica. West Indian Med J. 2008;57(3): 223–30.

Changing epidemiology of paediatric HIV in Jamaica

•Palliative care

•Frequent hospitalizations

•Natural history of infection-

related complications → death

•Chronic disease care

•Ambulatory visits

•Emergence of long-term

problems – target organ

specific, adverse drug effects

Key Achievements

Increase in ART uptake

Decreased hospitalizations

Reduction in HIV-related morbidity

Improved survival and quality of life

History of Paediatric HIV in Jamaica Summary – HIV Related Renal Disease

< 2000

Pre-ART Era

No ART available

Treatment of clinical complications, mainly infections

Mortality was high

2000-’04

Early ART Era

Treatment based on clinical criteria

Sequential uptake of ART and CD4 public access

UTI main renal-related problem

2004-’08

ART Era

Treatment based on immunological criteria (CD4 threshold)

HIV viral load public access

↑ Occurrence of HIVAN

2008-’18

2nd Line ART

HIV Viral Load Monitoring

↑ % on 2nd line ART → 3rd line

Adverse ART-related renal effects

ESRD

>2018

Future

Transition to adult care

Anticipated ↑:

HIVAN in maturing cohort

Adverse long-term effects of ART

012

Jamaica Paediatric and Adolescent HIV /AIDS Programme

21 October 2018

Kidney Disease in HIV Jamaica Paediatric Perspective

Spectrum – Kidney Disease in Paediatric HIV

• Recurrent Urinary Tract Infections (UTIs)

• HIVAN

• Nephrotic Syndrome

• Drug – induced

Kidney Disease – UTIs

• Described the CDC defined diseases of the initial cohort (included recurrent UTIs)

• E. coli was the most common organism (34% of urinary isolates)

• Mainly gram negative pathogens

• Important consideration in etiology of gram negative sepsis

• One death in the first year due to urosepsis


• Renal manifestations of the cohort of 196 children followed longitudinally during Sept 2002- Aug 2005

• 57 UTIs identified in 33 children

• E. coli was the most common pathogen


• Reviewed antibiotic resistance pattern in Jamaican children living with HIV/ AIDS

• 52 UTIs (70.3% of infections) were identified

• 41.8% urinary isolates – E. coli

• All E. coli isolates were resistant to cotrimoxazole; 90% to ampicillin

Kidney Disease – HIVAN

• 6 cases identified; 5 male

• CDC category C (5) children; category B (1)

• Nephrotic range proteinuria-all

• Chronic renal impairment (3)

• One had renal biopsy-FSGS

• Treatment: • All were commenced on ART and

ACE Inhibitor • 3 received steroids - no noticeable

improvement

• Co-managed with Paediatric Nephrologist

• 3 died over 3 years: 1 HIVAN; 2 complications of advanced HIV

Classic HIVAN showing typical global collapse of the glomerular tuft with loss of luminal patency and hypertrophy and hyperplasia of the overlying glomerular epithelial cells, some of which contain intracytoplasmic protein

resorption droplets

Kidney Disease – Drug Induced

• 7 children were commenced on Indinavir

• 4 had renal complications

• Indinavir use has been discontinued

Kidney Disease – Metabolic Swaby K, Pierre RB, Evans-Gilbert T, Miller M, Moore J, Lewis K, Christie CDC, “Metabolic complications in virally-suppressed perinatal HIV-infected children and adolescents on tenofovir disoproxil fumarate”. Presentated at the 9th IAS Conference on HIV Science, July 23-26, 2017, Paris, France [Abstract WEPEB0538]

ARV Regimens in Jamaican Children

• First line

• Zidolam-N (AZT/ 3TC/ NVP) - Majority

• Combivir/Alluvia (AZT/ 3TC, RTNvr/ LPvr)

• Atripla (TDF/ 3TC /EFV)

• Second Line

• Alluvia & Truvada (TDF/3TC);

• Alluvia & Abacavir

• Truvada, Ritonavir/ Atazanavir

• Third Line

• Darunavir/Ritonavir, Etravarine, Raltegravir, Truvada

• Truvada, Darunavir/Ritonavir, Raltegravir

Boosted PIs and Tenofovir DF have been associated with significant declines in renal function in combination and individually Goicoechea M et al. J Infect Dis. 2008 Jan 1;197(1):102-8. doi:10.1086/524061 Morlat et al. PloS One. 2013 Jun 12;8(6):e66223. doi:10.1371/journal.pone.0066223

Background

• 30% are on second line therapy: PI with Tenofovir Disoproxil Fumarate and Lamivudine backbone

• Many have been exposed to ARVs for up to 10 years

• Therefore identification and management of long term ARV side effects and chronic HIV are a priority

Background

• Tenofovir Disoproxil Fumarate is an NRTI shown to have nephrotoxic effects in both the adult and pediatric population including:

1. Renal phosphate wasting

2. Proximal tubular dysfunction (Fanconi Syndrome)

3. Acute Kidney Injury

4. Chronic Kidney Disease

5. Distal Tubular Defects (less commonly)

Gupta SK. Tenofovir-Associated Fanconi Syndrome: Review of the FDA Adverse Event Reporting System. AIDS patient care and STDs. 2008;22(2):99-103.

Background: The Jamaica Experience

• First Case: Identified in 2010/11

• Young teen with recurrent pathologic fractures

• Investigation revealed elevated alkaline phosphatase

• Presumed diagnosis of metabolic bone disease

• Subsequently a few other cases presented with bone pain or pathologic fractures and were found to have renal tubular dysfunction

Lewis K., Pierre RP, Moore J., Christie CDC. Fractures in adolescents on Highly Active Antiretroviral Therapy, Poster, Caribbean HIV Conference, Nassau, Bahamas, November, 2011.

Characteristics of 14 children identified with probable metabolic complications of TDF

Characteristic Value / Parameter

Age

Median (range) yrs

14.5

(8.68 – 20.62)

Gender

n/%

Male

8/57

Transmission

n/%

MTCT

14/100

CDC Clinical Category

n/%

CDC C

8/57

Total time on ARV

Median (range) yrs

11.56

(7.21 – 15.44)

Time on TDF

Median (range) yrs

2.31

(0.30 – 5.25) Swaby K et al. “Metabolic complications in virally-suppressed perinatal HIV-infected children and adolescents on tenofovir disoproxil fumarate”. 9th IAS Conference on HIV Science, July 23-26, 2017, Paris, France [Abstract WEPEB0538]

Clinical abnormalities identified in children with metabolic complications of TDF Therapy

Clinical Features n %

Asymptomatic 4 28.6

Bone Pain 7 50.0

Limp 5 38.5

Altered Gait 5 38.5

Fracture 5 35.7

Swaby K et al. “Metabolic complications in virally-suppressed perinatal HIV-infected children and adolescents on tenofovir disoproxil fumarate”. 9th IAS Conference on HIV Science, July 23-26, 2017, Paris, France [Abstract WEPEB0538]

Summary of laboratory findings identified in children with metabolic complications of TDF Therapy

Laboratory (N=14) n %

Hyponatremia 6 42.9

Hypokalemia 7 50.0

Hypophosphatemia 11 78.6

Hypocalcemia 5 35.7

Metabolic acidosis 9 64.3

Elevated Alk Phos 11 84.6

Elevated BUN 1 8.3

Elevated Creat 7 58.3

Decreased GFR 7 58.3

Urine Studies n %

Proteinuria 5 / 6 83.3

Glycosuria 4 / 6 66.7

Phosphaturia 5 / 6 83.3

Calciuria 3 / 5 60

Sodium Wasting 4 / 4 100

Potassium Wasting 4 / 4 100

Abnormal BMD was only done in one patient and was positive for osteopenia


Renal Impairment Identified

• Based on the RIFLE Classification for Acute Kidney Injury

• Risk: 4 patients

• Fall in GFR >25% and rise in Creat > 1.5x baseline

• Injury: 1 patient • Fall in GFR of 54.3%

• Rise in Creatinine by 2.39x baseline

• Failure: 2 patients

• Fall in GFR of 77.8% and 69.3%

• Rise in Creatinine by 4.67x and 4.30x baseline respectively


Radiological n %

X-Rays Performed 10 71.43

Results:

Normal 3 30

Osteopenia 3 30

Pathologic Fractures

4 40

Radiologic abnormalities identified in children with metabolic complications of TDF Therapy


n %

Renal Tubular Dysfunction 9 64.3

Acute Kidney Injury 3 21.4

Presumed Metabolic Bone Disease 13 92.9

Adverse Outcomes identified in patients with metabolic complications of TDF Therapy

• 1 patient had chronic kidney disease Not secondary to TDF use.


Management

• Interventions for these patients included: • Optimized Anti-retroviral agents

(substitute ABC for TDF)

• Orthopedic referral and care

• Renal referral and follow up • Replacement for renal losses:

• Calcium, Potassium, Phosphate and Sodium • ACE-inhibitors (for reduction in proteinuria)


Management

• Use of Tenofovir Alafenide Fumarate: • Prodrug of tenofovir • Produces higher intracellular levels and lowever plasma levels of

tenofovir (compared to TDF) • Decreased risk of nephrotoxicity • Preferred ART – IAS USA Guidelines

Gallant et al. Lancet HIV. 2016 Apr;3(4):e158-65. doi: 10.1016/S2352-3-18(16)00024-2. Epub 2016 Mar 14 Saag et al. JAMA. 2018 Jul 24;320(4):379-396. doi: 10.1001/jama.2018.8431

Tenofovir Induced Nephrotoxicity

• Fanconi syndrome – most commonly reported event: tubular proteinuria, aminoaciduria, phospaturia, glycosuria, bicarbonate wasting

Verhelst D, Monge M, Meynard J-L, Fouqueray B, Mougenot B, Girard P-M, et al. Fanconi syndrome and renal failure induced by tenofovir: A first case report. American Journal of Kidney Diseases.40(6):1331-3.

• Mechanism: Mitochondrial dysfunction • Inhibition of mitochondrial DNA polymerase-gamma • Induction of oxidative stress

• Renal biopsy findings: • Acute tubular damage • Flattening of epithelium • Interstitial oedema • Giant misshapen mitochondria in the proximal tubule cells

Hall AM, Hendry BM, Nitsch D, Connolly JO. Tenofovir-Associated Kidney Toxicity in HIV-Infected Patients: A Review of the Evidence. American Journal of Kidney Diseases.57(5):773-80.

Proteinuria

Glycosuria

Phosphaturia (Hypophosphatemia)

Proximal Tubular dysfunction

Increased Bone Turnover (Elevated Alk. Phos)

Osteopenia (Decreased BMD)

Pathologic Fractures

Hypokalemia

Hypercalciuria

Proximal tubular cell apoptosis

Decreased mtDNA content

Inhibits Mitochondrial DNA Polymerase γ

Tenofovir

AKI CKD

Impaired Reabsorption

Transported into PTC by OAT1&3 Actively secreted into tubular lumen by MRP-2 & 4

Vitamin D-binding protein

β2 microglobulin Aminoaciduria

Uricosuria

Persistent PTC Injury

Impaired SLGT2

Hyponatremia

Hypochloremia

Metabolic Acidosis Na, K, Cl, HCO3 wasting


Risk Factors Identified: 1. Use greater than 3 years * 2. Genetics (point mutation in renal transporter gene ABCC2)* 3. Concomitant use of nephrotoxic drugs 4. Older age 5. Decreased body mass 6. Pre-existing renal disease

Purswani M, Patel K, Kopp JB, Seage GR, 3rd, Chernoff MC, Hazra R, et al. Tenofovir treatment duration predicts proteinuria in a multiethnic United States Cohort of children and adolescents with perinatal HIV-1 infection. The Pediatric infectious disease journal. 2013;32(5):495-500. Hall AM, Hendry BM, Nitsch D, Connolly JO. Tenofovir-Associated Kidney Toxicity in HIV-Infected Patients: A Review of the Evidence. American Journal of Kidney Diseases.57(5):773-80.

*Children


• Prospective Case Controlled trials have identified renal phosphate wasting and changes in bone mineral density in the pediatric population

• Giacomet et al – Case Control Trial with TDF for 132mo.

• After 72 months identified 17 cases of phosphaturia - 14 had a mutation in the ABCC2 Renal transporter gene

• These clinical trials however have not identified progression to Fanconi syndrome or Renal impairment

Giacomet V, Nannini P, Vigano A, Erba P, Benincaso A, Bedogni G, et al. Long-term renal effects of tenofovir-disoproxil-fumarate in vertically HIV-infected children, adolescents, and young adults: a 132-month follow-up study. Clinical drug investigation. 2015;35(7):419-26.

Conclusion

Recommendations – workup for kidney disease in HIV infected individuals • Serum chemistry panel

• Complete urinalysis

• Albuminuria quantitation

• Assessment of temporal trends in eGFR (in at risk persons)

• Evaluation of markers of proximal tubular dysfunction (esp. in individuals on tenofovir DF)

• Renal ultrasound

• Review all medications for potential nephrotoxicity

• Consult a nephrologist

Lucas et al. 2014 Clinical practive guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014 Nov 1;59(9):e96-138. doi:10.1093/cid//ciu617. Epub 2014 Sep 17.

The Future for Paediatric/Adolescent HIV and renal disease • Prevalence of kidney disease is associated a disproportionately high

prevalence of cardiovascular disease among the adult population…. [US Renal Data System. Available at:http://www.usrds.org ]

• Rigorous management of HBP – better outcomes with ACE-inhibitors [James et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eight Joint National Committee. JAMA. 2014 Feb 5;311 (5):507-20. doi:10.1001/jama.2013.284427]

• Use of screening for and treating proteinuria regardless of GFR (ACE inhibitor)

• Identify HIVAN (biopsy) – at risk for progression to ESRD

• Identify and manage co-morbidities

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HIV Related Kidney Disease in Jamaican...

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