HIV Related Kidney Disease in Jamaican Children

Transcription

1 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

2 Disclosures None to declare

3 Objectives Background Paediatric HIV in Jamaica HIV-related renal problems by timeline Summary

4 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 Aug;11(7): doi: /j 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 Sep;55(1):73-7. doi: /QAI.0b013e3181cc1070. George E, et al. Kidney function and the risk of cardiovascular events in HIV-1-infected patients. AIDS Jan 28;24(3): doi: /QAD.0b013e

5 Spectrum of Renal Disease in HIV

6 Background Clinical symptoms vague and non-specific (decreased appetite, not feeling right, fatigue Risk Factors for Kidney Disease (include) Low birth weight More specific newfamily onset hypertension, history of kidney disease swelling Urinary tract infections Screening for early alterations inobstruction kidney function is essential 2 x year, Lower urinary tract esp in high-risk groups Urolithiasis Recovery from ARF Urinary albumin/protein; estimate of GFR Comorbid serum conditionscreatinine; (HBP, DM, autoimmune) Drugs (.) Others: serum phosphorus, uric acid, bicarbonate, potassium (tubular function) Lucas et al 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 Nov 1;59(9):e doi: /cid//ciu617. Epub 2014 Sep 17.

7 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; 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

8 Background Paediatric and Adolescent HIV/AIDS in Jamaica

9 Background First case of pediatric AIDS identified in 1986, Jamaica Public access to treatment was not available until ~ 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 1 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): Christie CDC. A paediatric and perinatal HIV/AIDS leadership initiative in Kingston, Jamaica. West Indian Med J. 2004;53(5):

10 Timeline of key events in Paediatric HIV Jamaica First case Paediatric AIDS Mustard Seed Community start hospice Increased access to ART 2 Maturing Cohort Family Centre initiated at University Hospital of the West Indies KPAIDS established 1 Accelerated access to laboratory monitoring 1 Christie CDC. A paediatric and perinatal HIV/AIDS leadership initiative in Kingston, Jamaica. West Indian Med J. 2004;53(5): 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):

11 Changing epidemiology of paediatric HIV in Jamaica Palliative care Frequent hospitalizations Natural history of infectionrelated 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

12 History of Paediatric HIV in Jamaica Summary HIV Related Renal Disease < >2018 Pre-ART Era Early ART Era ART Era 2nd Line ART Future No ART available Treatment based on clinical criteria Treatment based on immunological criteria (CD4 threshold) HIV Viral Load Monitoring Transition to adult care % on 2nd line ART 3rd line Anticipated : Treatment of clinical complications, mainly infections Mortality was high Sequential uptake of ART and CD4 public access UTI main renalrelated problem HIV viral load public access Occurrence of HIVAN Adverse ARTrelated renal effects HIVAN in maturing cohort Adverse long-term effects of ART ESRD Jamaica Paediatric and Adolescent HIV /AIDS Programme 21 October

13 Kidney Disease in HIV Jamaica Paediatric Perspective

14 Spectrum Kidney Disease in Paediatric HIV Recurrent Urinary Tract Infections (UTIs) HIVAN Nephrotic Syndrome Drug induced

15 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

16 Kidney Disease UTIs Renal manifestations of the cohort of 196 children followed longitudinally during Sept Aug UTIs identified in 33 children E. coli was the most common pathogen

17 Kidney Disease UTIs 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

18 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

19 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

20 Kidney Disease Drug Induced 7 children were commenced on Indinavir 4 had renal complications Indinavir use has been discontinued

21 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]

22 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 Jan 1;197(1): doi: / Morlat et al. PloS One Jun 12;8(6):e doi: /journal.pone

23 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

24 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):

25 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.

26 Characteristics of 14 children identified with probable metabolic complications of TDF Characteristic Age Median (range) yrs Gender n/% Transmission n/% CDC Clinical Category n/% Total time on ARV Median (range) yrs Time on TDF Median (range) yrs Value / Parameter 14.5 ( ) Male 8/57 MTCT 14/100 CDC C 8/ ( ) 2.31 ( ) 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]

27 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 Bone Pain Limp Altered Gait Fracture

28 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 Hypokalemia Hypophosphatemia Hypocalcemia Metabolic acidosis Elevated Alk Phos Elevated BUN Elevated Creat Decreased GFR Urine Studies n % Proteinuria 5 / Glycosuria 4 / Phosphaturia 5 / Calciuria 3 / 5 60 Sodium Wasting 4 / Potassium Wasting 4 / Abnormal BMD was only done in one patient and was positive for osteopenia

29 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 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]

30 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] Radiologic abnormalities identified in children with metabolic complications of TDF Therapy Radiological n % X-Rays Performed Results: Normal 3 30 Osteopenia 3 30 Pathologic Fractures 4 40

31 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] Adverse Outcomes identified in patients with metabolic complications of TDF Therapy n % Renal Tubular Dysfunction Acute Kidney Injury Presumed Metabolic Bone Disease patient had chronic kidney disease Not secondary to TDF use.

32 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] 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)

33 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 Apr;3(4):e doi: /S (16) Epub 2016 Mar 14 Saag et al. JAMA Jul 24;320(4): doi: /jama

34 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): 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):

35 Tenofovir Transported into PTC by OAT1&3 Actively secreted into tubular lumen by MRP-2 & 4 Inhibits Mitochondrial DNA Polymerase γ Decreased mtdna content CKD AKI Persistent PTC Injury Proximal tubular cell apoptosis Impaired Reabsorption Proximal Tubular dysfunction Pathologic Fractures Osteopenia (Decreased BMD) Increased Bone Turnover (Elevated Alk. Phos) Phosphaturia (Hypophosphatemia) Hypercalciuria Hyponatremia Hypokalemia Hypochloremia Metabolic Acidosis Vitamin D-binding protein β2 microglobulin Glycosuria Proteinuria Aminoaciduria Uricosuria Impaired SLGT2 Na, K, Cl, HCO3 wasting

36 Tenofovir Induced Nephrotoxicity 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 *Children 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): 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):

37 Tenofovir Induced Nephrotoxicity 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):

38 Conclusion

39 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 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 Nov 1;59(9):e doi: /cid//ciu617. Epub 2014 Sep 17.

40 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: ] Rigorous management of HBP better outcomes with ACE-inhibitors [James et al 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 Feb 5;311 (5): doi: /jama ] 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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