HIV and Renal Health

1. HIV and Renal Health Dr. Patrice JunodClinique médicale l’Actuel This activity is supported by an educational grant from:

2. Program Development Principle Content Development Content Contributors Anita Rachlis Ali Zahirieh David Fletcher Gord Arbess Jean-Guy Baril Mélanie Hamel Brian Conway Chris Fraser Marianne Harris Christine Hughes Patrice Junod Marek Smieja Graham Smith Rachel Therrien Alice Tseng Sharon Walmsley Consultant Linda Robinson

3. Conflict of Interest Declaration This program was developed with consultants through an educational grant from Janssen Inc. The faculty members received financial compensation for developing & presenting this program.

4. Faculty Disclosures • Abbvie • Gilead • Janssen • Merck • ViiV

5. Discuss factors that can impact renal health in HIV patients List which renal lab tests are the most clinically relevant and how often they should be performed Present a practical tool for the management of declining renal function Apply these learnings using interactive patient case examples Objectives

6. Background: HIV and the Kydney

7. Kidney disease is an important complication of HIV infection in the era of antiretroviral therapy1 In a retrospective study of 487 consecutive HIV positive patients with normal renal function, the initial prevalence of CKD was 2%2 After 5 years of follow-up, 6% had progressed to CKD Older age was a multivariate predictor of CKD for this cohort Renal Disease in HIV Positive Patients 1 Gupta SK, et al. Clinical Infectious Disease 2005;40:1559-1585.2 Gupta SK, et al. Clinical Nephrology 2004;61:1-6.

8. The spectrum of kidney disease in HIV includes: HIV-associated nephropathy Immune complex kidney disease Medication nephrotoxicity Kidney disease related to co-morbid conditions Diabetes, hypertension, and hepatitis virus co-infection Kidney Disease in HIV Positive Patients Wyatt CM. AJM 2007;120:488-49.

9. Risk Factors for Kidney Disease in the HIV Positive Population Ethnicity Age Family History CKD Risk HIV Hyper- tension Nephrotoxic medication Diabetes = Modifiable = Nonmodifiable Hepatitis C Gupta SK, et al.Clinical Infectious Disease 2005;40:1559-1585.

10. Prevalence 3-15% Race and other genetic factors Hypertension Diabetes mellitus Hepatitis C virus infection Decreased CD4 cell count Increased viral load Nephrotoxic Drugs Chronic Kidney Disease in HIV

11. Medications and Renal Disease TMP/SMX: trimethoprim and sulfamethoxazole Adapted from: Guo X, Nzerue C. Cleve Clin J Med 2002;69:289-312.

12. Acute Kidney Injury (AKI) is more common in individuals with HIV infection Chronic Kidney Disease (CKD) is more common in individuals with HIV infection Proteinuria is more common in individuals with HIV infection Proximal tubular dysfunction is more common in individuals with HIV infection HIV & The Kidney: Summary

13. Classification of CKD Levey A. KI 2010;80: 17.

14. Glomerular Filtration Rate (GFR) Proteinuria Proximal Tubular Function Three Important Measures

15. Glomerular Filtration Rate (GFR) Proteinuria Proximal Tubular Function Three Important Measures

16. Gold standard: inulin clearance iothalamate clearance Iohexol “Practical” serum creatinine 24-hr urine collection for creatinine clearance (cumbersome!) equations, equations, equations How Do We Measure GFR?

17. Serum creatinine Metabolism of creatine in skeletal muscle and from dietary meat intake Production tied to muscle mass Age, weight, sex, amputations, corticosteroid use Modestly influenced by diet Filtered by glomerulus and secreted by proximal tubule Proportionally increased secretion with reduced GFR Creatinine may not increase until up to 50% of GFR is lost Secretion inhibited by drugs including cimetidine, trimethoprim, dapsone, cobicistat Large intra-person and intra-laboratory variation Intra-person variation 7−20% Poor intra-laboratory calibration particularly affecting higher GFRs Renal Function Measurement Krop JS, et al.Arch Intern Med 1999;159:1777-1783. Coresh J, et al.Am J Kidney Dis 2002;39:920-929.

18. Serum Creatinine 110 μmol/L

19. The same serum creatinine represents very different GFRs in these two individuals Serum Creatinine 110 μmol/L 140 ml/min 40 ml/min

20. CrCl = weight x (140 – age) / (serum Cr x 49)* Estimates CrCl (not GFR) Derived from a study of 249 white Canadian hospitalized veterans who had 2 similar 24-hr urine CrCl measurements Validated for renal dosing of drugs * X 0.8 if female Cockcroft-Gault Equation

21. MDRD GFR (mL/min/1.73m2) = 175 x [serum creatinine(µmol/L)/88.4]-1.154 x (Age) -0.203 x (0.742 if female) x (1.21 if African American) Estimates Glomerular Filtration Rate Derived from 1070 individuals with advanced chronic kidney disease 60% male, 88% white, 6% DM MDRD Equation

22. Newest Equation of the three Non-linear based equation More accurate in estimating GFR in those with mild CKD CKD-EPI Levey et al.Ann Intern Med 2009;150: 604-612.

23. Glomerular Filtration Rate (GFR) Proteinuria Proximal Tubular Function Three Important Measures

24. Normal < 150 mg/day of proteinuria < 30 mg/day of albuminuria Quantification strategies: Dipstick Measure ONLY albumin at a CONCENTRATION > 300 mg/L 24-hr urine collection Helpful if patient performs a ‘complete’ collection Spot urine albumin:creatinine (or protein:creatinine) Can increase sensitivity for detecting proteinuria in a convenient fashion Quantifying Proteinuria

25. A typical man produces roughly 15 mmol of creatinine/day A typical woman produces roughly 10 mmol of creatinine/day The protein:creatinine (PCR) or albumin:creatinine (ACR) tell you how much protein/albumin is present in the urine per mmol of Cr Thus multiplying the ACR by 10 in woman and by 15 in men will give you an estimate of that individual’s 24hr excretion of albumin (the exact same applies to PCR) Practical Point

26. A marker of increased risk of CV events Increased risk of CKD progression (notably when > 1g/day protein or 200mg/day albumin) Implications of Proteinuria

27. Glomerular Filtration Rate (GFR) Proteinuria Proximal Tubular Function Three Important Measures

28. “Reabsorption” Water Electrolytes Bicarbonate Glucose Filtered proteins Secretion Organic Anions/Cations Drugs Metabolic Byproducts Creatinine Tubular Functions Ernst M, Moser M. N Engl J Med 2009;361:2153-2164.

29. Proximal Tubular Function • Protein Reabsorption • Phosphate Reabsorption • Glucose Reabsorption • Amino Acid Reabsorption • Creatinine Secretion • Bicarbonate • “reabsorption” Ernst M, Moser M. N Engl J Med 2009;361:2153-2164.

30. Some Evidence of Proximal Tubular Injury Urine: glucosuria in absence of diabetes Non-albumin based proteinuria measure both albuminuria & proteinuria high urinary β2-microglobulin excretion Evidence of ATN (hemegranular casts) Serum: non-anion gap metabolic acidosis, creatinine rise Hypophosphatemia & high urinary phosphate excretion Calculate the Fractional Excretion of Phosphate* (Urinary PO4/Ur Cr) / (Serum PO4/Serum Cr) Abnomal = greater than 10% in setting of hypophosphatemia “What Are You Looking For?”

31. Aquitaine Cohort 399 patients in a cross sectional analysis Overall prevalence of PRTD was high at 6.5 % 29.6 % stage 1 or 2 kidney disease 5.3 % stage 3 to 5 kidney disease Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy F-A Dauchy et al. Kidney International 2011;80:302-309.

32. Multivariate Analysis showed significant independent associations Age (OR 1.28 per 5 year increase) TDF (OR 1.23 per year) ATZ (OR 1.28) Primary tubular abnormalities can be missed even when severe and can lead to decline in GFR Early screening is necessary to avoid them Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy F-A Dauchy et al. Kidney International 2011;80:302-309.

33. Guidelines

34. IDSA Guidelines: Evaluating and Monitoring CKD in HIV All patients at the time of HIV diagnosis should be assessed for existing kidney disease Calculated estimate of renal function and Screening for proteinuria Dipstick, protein/creat ratio or albumin/creat ratio? If there is no evidence of kidney disease at initial evaluation, patients at high risk for the development of proteinuric renal disease should undergo annual screening African American persons CD4+ cell counts <200 mL or HIV RNA levels >4000 copies/mL Diabetes mellitus Hypertension Hepatitis C virus coinfection Patients without risk factors for kidney disease should be followed clinically and reassessed based on the occurrence of signs and symptoms or as clinical events dictate Gupta SK et al. Clin Infect Dis 2005;40:1559-1585.

35. IDSA Initial Evaluation Recommendations Obtain baseline GFR: All patients at the time of HIV diagnosis should be assessed for existing kidney disease with a screening urinalysis for proteinuria and a calculated estimate of renal function Annual screening: If there is no evidence of proteinuria at initial evaluation, patients at high risk for the development of proteinuric renal disease should undergo annual screening Renal function should be estimated on a yearly basis to assess for changes over time When to consider a nephrology consult: Additional evaluations and referral to a nephrologist are recommended for patients with proteinuria of grade ≥1+ by dipstick analysis or GFR<60 mL/min per 1.73m2 Gupta SK, et al.Clinical Infectious Disease 2005;40:1559-1585.

36. DHHS Recommendations Table 3. Laboratory Monitoring Schedule for Patients Before and After Initiation of Antiretroviral Therapy Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/Adultand

37. Kidney Stones Chronic Kidney Disease (CKD) Emerging Evidence

38. Renal stones are risk factor for chronic kidney disease (CKD) Urolithiasis well-known side effect of indinavir Considered to be drug crystallization in urine Urolithiasis also associated with atazanavir Probably similar etiology Renal Stones Hamada et al. Clin Infect Dis, 2012

39. Cohort analysis of 1240 patients ATV/r (n=465) or other protease inhibitors (n=775) Renal stones developed in 31 patients on ATV/r (6.7%) and 4 patients (0.52%) on other PIs Risk was 10 times higher in ATV/r group Patients on ATV/r had lower eGFR Lower eGFR associated with renal stones ATV & Renal Stones: Hamada et al. Hamada et al. Clin Infect Dis, 2012

40. ATV & Renal Stones: Rockwood et al. • Event rate remained significantly higher in the ATV cohort after adjusting for prior ATV and IDV exposure • ATV/r patients who developed renal stones had significantly higher bilirubin levels vs. ATV/r patients who did not develop stones • At study baseline, 42% of ATV/r patients who developed renal stones had chronic renal impairment vs. 4.5% of ATV/r patients who did not develop stones Rockwood N, et al. 17e conférence annuelle de la BHIVA, Bournemouth, 2011, résumé O4.

41. Renal Impairment PI’s vs EFV *Adjusted for gender, age at start of HAART, ethnicity, baseline eGFR, baseline CD4 cell count, baseline viral load, HBsAg, prior exposure to TDF and IDV and total duration of TDF exposure Au cours des 12 premiers mois, 49 % des sujets ayant développé une insuffisance rénale s’étaient rétablis (TFGe > 60 ml/min/1,73 m2). Rockwood et al., J Antivir Antiretrovir 2012, 4:2 Rockwood N, et al. J Antivir Antiretrovir 2012;4:21-25.

42. ACTG 5202: CreatinineClearance Median Creatinine Clearance: ATV/r vs. EFV ** * p = 0,001 p/r at ATV/r ** p < 0,001 p/r at ATV/r * Week 48 Median Change in Calculated Creatinine from Baseline (mL/min) Week 96 ATV/r EFV ATV/r EFV +ABC/3TC +TDF/FTC n 338 287 377 330 360 327 394 352 Daar et al.Ann Intern Med, 2011

43. Chronic Kidney Disease & ARV Exposure Incidence of CKD with Each Additional Year of Exposure Mean follow up was 3.7 years N = 6,843 Adapté de Mocroft et al. AIDS, 2010

44. Cohort of 49,734 First analysis to focus on patients with normal renal function at baseline (n=22,603) eGFR > 90 ml/min/1.73m2 Followed to confirmed: eGFR < 70 ml/min/1.73m2 Or eGFR < 60 ml/min/1.73m2 Or last available eGFR ARVs & Renal Impairment: The D:A:D Cohort Ryom et al. Présentation d’affiche, CROI, 2012

45. N=22,603 4.5 year follow up 468 (2.1%) patients progressed to eGFR < 70 incidence rate 4.78/1000 patient years 131 (0.6%) patients progressed to CKD incidence rate 1.33/1000 patient years Equals an annual decline of at least 4-5 ml/min D:A:D Cohort: Results CKD=Chronic Kidney Disease Ryom et al. Présentation d’affiche, CROI, 2012

46. ARVs Exposure Rates of ceGFR <70 from eGFR > 90 (adjusted analysis) Ryom et al.Poster presentation, CROI, 2012

47. Canadian ObservationalCohort(CANOC) Collaboration Time to Impaired eGFR N = 965 Adapté de Hosein et al. Présentation d’affiche, IAS, 2011

48. EuroSIDAStudy: Risk for Chronic Kidney Disease • Analysis of patients with ≥ 3 creatinine measurements + body weight • 6,842 patients with 21,482 person-years of follow-up • Definition of CKD (eGFR by Cockcroft-Gault) • If baseline eGFR ≥60 mL/min/1.73 m2, fall to <60 • If baseline eGFR <60 mL/min/1.73 m2, fall by 25% • 225 (3.3%) progressed to CKD Cumulative Exposure to ARVs and Risk of CKD Risk factors for CKD on TDF: age, HTN, HCV, lower eGFR, lower CD4+ count Kirk O, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 107LB.

49. 86 127 67 143 20 21 31 23 34 19 20 35 18 25 11 29 55 21 67 48 Not Not Not Not 0-1 0-1 0-1 0-1 1-2 1-2 1-2 1-2 2-3 2-3 2-3 2-3 >3 >3 >3 >3 EuroSIDASTUDY: Crude Incidence Rate of CKD and Increasing Exposure to ARVs N with CKD 10 Tenofovir Indinavir Atazanavir Lopinavir/r 1 Incidence per 100 PYFU (95% CI) .01 started started started started CKD, confirmed (persisting for >3 months) decrease in eGFR ≤60 mL/min/1.73m2 if eGFR at baseline >60 mL/min/1.73m2 or confirmed 25% decrease in eGFR if baseline eGFR≤60 mL/min/1.73m2 Years of Exposure to ARV Kirk, CROI 2010; 107LB.

50. 1- Algorithm Nephropathy Advisory Committee on the clinical management of people living with HIV 2- HIV and Renal Health – Management tool National Development Committee – Supported by Janssen Algorithm