Dr. Patrice Junod Clinique médicale l’Actuel

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

Program Development Principle Content Development Anita Rachlis
Ali Zahirieh David Fletcher Content Contributors 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

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.

Faculty Disclosures Abbvie Gilead Janssen Merck ViiV

Objectives 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

Background: HIV and the Kydney
6

Renal Disease in HIV Positive Patients
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 Objective: Highlight the fact that kidney disease is prevalent in the aging HIV positive population. Transition: How does this compare to the general (non-HIV positive) population? 1 Gupta SK, et al. Clinical Infectious Disease 2005;40: Gupta SK, et al. Clinical Nephrology 2004;61:1-6. 7

Kidney Disease in HIV Positive Patients
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 Objective: Causation of kidney disease in HIV positive patients is multi-factorial Transition: There are many risk factors associated with CKD Wyatt CM. AJM 2007;120: 8

Risk Factors for Kidney Disease in the HIV Positive Population
Ethnicity Age Family History CKD Risk HIV Hyper- tension Diabetes, HTN, Hep C and HIV are listed as "modifiable", not because they are curable per se, but can be controlled. Nephrotoxic medication Diabetes = Modifiable = Nonmodifiable Hepatitis C Gupta SK, et al. Clinical Infectious Disease 2005;40: 9

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

Allergic Interstitial Nephritis Thrombotic Microangiopathy
Medications and Renal Disease Prerenal Tubular Injury Allergic Interstitial Nephritis Thrombotic Microangiopathy Obstructive ACE-I ARBs Direct Renin Inhibitors Amphotericin NSAIDS Cyclosporine Diuretics Interferon Cidofovir Adefovir Tenofovir Didanosine Lamivudine Stavudine Aminoglycosides Cocaine Foscarnet Pentamidine Ketamin Abacavir Indinavir Ritonavir Atazanavir Acyclovir Cephalosporins Penicillins Ciprofloxacin TMP/SMX Rifampin NSAIDs Proton Pump Inhibitors Valacyclovir Sulfadiazine There are also many medications used in the treatment of HIV and its co-morbidities that may have potentially harmful effects on the kidneys. Reference: Guo X, Nzerue C. How to prevent, recognize, and treat drug-induced nephrotoxicity. Cleve Clin J Med 2002;69: TMP/SMX: trimethoprim and sulfamethoxazole Adapted from: Guo X, Nzerue C. Cleve Clin J Med 2002;69: 11

HIV & The Kidney: Summary
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

Classification of CKD Stage Description I
GFR (mL/min/1.73m2) I Urinary and/or Structural Abnormality > 89 II 60 - 89 IIIa Mild GFR decline 45 - 59 IIIb Moderate GFR decline 30 - 44 IV Severe GFR decline 15 - 29 V Kidney Failure < 15 ESRD Requiring Renal Replacement Therapy Levey A. KI 2010;80: 17.

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

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

Renal Function Measurement
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 Krop JS, et al. Arch Intern Med 1999;159: Coresh J, et al. Am J Kidney Dis 2002;39:

Serum Creatinine 110 μmol/L

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

Cockcroft-Gault Equation
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

MDRD Equation MDRD GFR (mL/min/1.73m2) = 175 x [serum creatinine(µmol/L)/88.4] x (Age) 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

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

Quantifying Proteinuria
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

Practical Point 15 mmol of creatinine/day 10 mmol of creatinine/day
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)

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

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

Ernst M, Moser M. N Engl J Med 2009;361:2153-2164.
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:

“What Are You Looking For?”
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

F-A Dauchy et al. Kidney International 2011;80:302-309.
Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy 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 F-A Dauchy et al. Kidney International 2011;80:

F-A Dauchy et al. Kidney International 2011;80:302-309.
Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy 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 F-A Dauchy et al. Kidney International 2011;80:

Guidelines 33

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: 34 34

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 Objective: That physicians follow guidelines to screen and monitor patients appropriately for kidney disease Transition: On to the lipodystrophy section Gupta SK, et al. Clinical Infectious Disease 2005;40: 35

DHHS Recommendations Table 3. Laboratory Monitoring Schedule for Patients Before and After Initiation of Antiretroviral Therapy Entry info care Follow-up before ART ART Initiation or modification Follow-up 2-8 weeks post-ART initiation or modification Every 3-6 months Every 6 months Every 12 months Treatment failure Clinically indicated ALT, AST, T bilirubin  Every 6-12 months CBC with differential If on ZDV Fasting lipid profile If normal annually Consider 4-8 weeks after starting new ART regimen that affects lipids If abnormal at last measurement Fasting glucose or hemoglobin A1C Urinalysis If on TDF Pregnancy test If startting EFV 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

Emerging Evidence Kidney Stones Chronic Kidney Disease (CKD)

Hamada et al. Clin Infect Dis, 2012
Renal Stones 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 Hamada et al. Clin Infect Dis, 2012

Hamada et al. Clin Infect Dis, 2012
ATV & Renal Stones: Hamada et al. 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 Other PIs were: FPV n=45; FPV/r n=93; LPV/r n=546; DRV/r n=91 Hamada et al. Clin Infect Dis, 2012 39

EFV / DRV / LPV combined cohort (n=4,449)
ATV & Renal Stones: Rockwood et al. ATV (n = 1,206) EFV / DRV / LPV combined cohort (n=4,449) p value No. of patients with kidney stones 24 Prevalence of kidney stones per 1,000 patients (95% CI) 20 (13 - 30) 5.4 (3.2 – 7.6) < 0.001 Event rate per 1,000 pt-yrs of exposure, n (95% CI) 7.3 (4.7 - 10.8) 1.9 (1.2 - 2.8) 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. 40

Renal Impairment PI’s vs EFV
Hazard ratio* (95% CI) p value LPV/r 1.69 (1.1 - 2.6) 0.017 ATV/r 1.52 (1.14 - 2.03) 0.004 DRV/r 1.31 (0.94 à 1.81) 0.108 EFV 1.00 *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: 41

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

Chronic Kidney Disease & ARV Exposure
Incidence of CKD with Each Additional Year of Exposure Medication Annual Increased Risk Atazanavir + Tenofovir 41 % Atazanavir 22 % Tenofovir 16 % Indinavir 11 % Lopinavir/r 8 % Mean follow up was 3.7 years N = 6,843 Adapté de Mocroft et al. AIDS, 2010

ARVs & Renal Impairment: The D:A:D Cohort
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 Ryom et al. Présentation d’affiche, CROI, 2012

Ryom et al. Présentation d’affiche, CROI, 2012
D:A:D Cohort: Results 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 CKD=Chronic Kidney Disease Ryom et al. Présentation d’affiche, CROI, 2012

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

Canadian Observational Cohort (CANOC) Collaboration
Time to Impaired eGFR Medication Adjusted Hazard Ratio (95% CI) P Value Non PI 1.00 Tenofovir 1.16 0.177 Lopinavir 1.32 0.024 Atazanavir 1.46 < 0.001 N = 965 Adapté de Hosein et al. Présentation d’affiche, IAS, 2011

EuroSIDA Study: 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 Univariable Multivariable IRR/year 95% CI P-value Tenofovir 1.32 <0.0001 1.16 Indinavir 1.18 1.12 Atazanavir 1.48 1.21 0.0003 Lopinavir/r 1.15 1.08 0.030 Background: Renal impairment in HIV+ persons might be caused by traditional and HIV-related factors; impact of longer-term exposure to specific ART remains poorly elucidated. Methods: HIV+ persons with ≥3 serum creatinine measurements and corresponding body weight measurements from 2004 onwards were included. Chronic kidney disease (CKD) was defined as either confirmed measurements ≥3 months apart, estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73 m2 for persons with eGFR >60 at baseline; or confirmed 25% decline in eGFR for persons with eGFR ≤60 at baseline, using the Cockcroft-Gault formula. Poisson regression was used to determine factors (including ART) associated with chronic kidney disease. Results: During 21,482 person-years of follow-up (median 3.7 [IQR 2.8 to 5.7]) in 6843 persons, 225 (3.3%) progressed to chronic kidney disease, incidence 1.1/100 person-years of follow-up (95%CI 0.9 to 1.2). Using the first definition, 203 patients (90.2%) developed chronic kidney disease, and 150 of these progressed with >10 mL/min/1.73 m2 decline in eGFR. The incidence of CDK increased from 0.7/100 person-years of follow-up (0.5 to 0.8) in persons never exposed to tenofovir (TDF) to 2.4 (1.7 to 3.0) with ≥4 years exposure; for indinavir (IDV), corresponding figures were 0.6 (0.5 to 0.7) and 1.9 (1.4 to 2.3), for atazanavir (ATV) 0.8 (0.7 to 1.0) and 3.9 (2.2 to 5.5), and for lopinavir (LPV) 0.9 (0.7 to 1.1) and 1.8 (1.3 to 2.3). Increasing cumulative exposure of TDF, IDV, ATV, and LPV were associated with a significantly increased rate of CDK(see the table), whereas use of other ART was not. Consistent results were observed in a range of sensitivity analyses and when using the modification of diet in renal disease (MDRD) formulae for eGFR, although of marginal statistical significance for LPV. Among 1558 persons who started TDF, older age, hypertension, hepatitis C co-infection, lower baseline eGFR, and CD4 count were independently associated with increased risk of chronic kidney disease, as was cumulative exposure to TDF, LPV, and ATV. Conclusions: In this non-randomized, but well-described, large cohort, increasing exposure to TDF was associated with a higher risk of CDK independently of other ART and traditional CKD risk factors. The risk was cumulative for TDF exposure within a follow-up period of 3 to 4 years. The increase in risk of CKD was also true for IDV and ATV, likely reflecting high renal excretion rates for these particular protease inhibitors, while the results for LPV were less clear. Persons who start TDF with a low eGFR and with traditional risk factors for CKD were at greatest 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, Abst. 107LB. 48 48

Incidence per 100 PYFU (95% CI) Years of Exposure to ARV
EuroSIDA STUDY: Crude Incidence Rate of CKD and Increasing Exposure to ARVs Incidence per 100 PYFU (95% CI) Years of Exposure to ARV N with CKD Not 0-1 1-2 2-3 >3 started 86 21 34 29 55 67 31 35 25 127 20 19 11 48 143 23 18 Tenofovir Indinavir Atazanavir Lopinavir/r 10 1 .01 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 Kirk, CROI 2010; 107LB.

Algorithm 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

PERIODIC HEALTH EXAMINATION OF ADULTS LIVING WITH HIV (HUMAN IMMUNODEFICIENCY VIRUS)
− Nephropathy − Advisory Committee on the Clinical Management of Persons Living with HIV

Untreated HIV+ patients
Screening for Kidney Problems Advisory Committee on the Clinical Management of Persons Living with HIV Screening schedule based on risk factors for kidney disease (EACS 2011) Untreated HIV+ patients Treated HIV+ patients Without TDF With TDF Assessment of risk factors for CKD* Annual 6–12 months Urinalysis or urine dipstick 6 months if GFR < 60 3-6 months eGFR 6-12 months Phosphorus As needed Optional * Risk factors for CKD: Diabetes, hypertension, CVD, viral hepatitis, concomitant nephrotoxic drugs, family history of CKD, black African ethnicity

GFR using CKD-EPI or MDRD
> 60 and < 90 cc/min < 60 cc/min* < 30 cc/min* Increase in Cr > 20% for > 3 months** Glucose+ Protein+ HypoPO4 ACR and MAU CaPO4 Renal ultrasound Repeat CKD-EPI or MDRD calculation Refer to algorithms (next pages) Refer to proteinuria algorithm (next page) Referral to nephrologist or internist GFR < 90 GFR > 90 Follow up every 3 months Regular follow-up * If GFR < 50 cc/min: consider adjusting the dose of certain ARV and concomitant medications ** Test for tubulopathy if GFR declines > 10 cc/min while on tenofovir

> 60 and < 90 cc/min Increase in Cr > 20% for > 3 months** Repeat CKD-EPI or MDRD calculation Refer to algorithms (next pages) GFR < 90 Glucose+ Protein+ HypoPO4 GFR > 90 Regular follow-up Follow up every 3 months GFR using CKD-EPI or MDRD * If GFR < 50 cc/min: consider adjusting the dose of certain ARV and concomitant medications ** Test for tubulopathy if GFR declines > 10 cc/min while on tenofovir

> 60 and < 90 cc/min < 60 cc/min* < 30 cc/min* Increase in Cr > 20% for > 3 months** Glucose+ Protein+ HypoPO4 ACR and MAU CaPO4 Renal ultrasound Repeat CKD-EPI or MDRD calculation Refer to algorithms (next pages) Refer to proteinuria algorithm (next page) Referral to nephrologist or internist GFR < 90 GFR > 90 Follow up every 3 months Regular follow-up * If GFR < 50 cc/min: consider adjusting the dose of certain ARV and concomitant medications ** Test for tubulopathy if GFR declines > 10 cc/min while on tenofovir

ACR and MAU Refer to proteinuria algorithm (next page) Referral to nephrologist or internist < 60 cc/min* < 30 cc/min* CaPO4 Renal ultrasound * If GFR < 50 cc/min: consider adjusting the dose of certain ARV and concomitant medications ** Test for tubulopathy if GFR declines > 10 cc/min while on tenofovir

Urinalysis or urine dipstick
Glucose > 0 Glycosuri a DB + DB – DB follow-up Fasting glucose + Rule out diabetes Repeat 1x Referral to nephrologist or internist ACR ≤ 0.05 g/mmol and MAU < 2.1 mg/mmol Normal - Renal ultrasound - Ascertain the risk factors - Referral to nephrologist or internist, or to urologist for isolated hematuria Protein ≥ 1 + or 0.25 g/L Repeat at next appt. Protein < 1+ or g/L Protein ≥ 1+ or g/L ACR and MAU ACR > 0.05 g/mmol or MAU > 2.1 mg/mmol hematuria (> 2 RBC/HPF)

Glucose > 0 Protein ≥ 1 + or 0.25 g/L Fasting glucose + Rule out diabetes Repeat at next appt. Glycosuri a DB + Glycosuri a DB – Protein ≥ 1+ or g/L Protein < 1+ or g/L DB follow-up Repeat 1x ACR and MAU Normal ACR > 0.05 g/mmol or MAU > 2.1 mg/mmol hematuria (> 2 RBC/HPF) ACR ≤ 0.05 g/mmol and MAU < 2.1 mg/mmol Glycosuri a DB – - Renal ultrasound - Ascertain the risk factors - Referral to nephrologist or internist, or to urologist for isolated hematuria Normal Referral to nephrologist or internist

Urinalysis or urine dipstick Referral to nephrologist or internist
Glucose > 0 Glycosuri a DB + DB – DB follow-up Fasting glucose + Rule out diabetes Repeat 1x Referral to nephrologist or internist

Glucose > 0 Protein ≥ 1 + or 0.25 g/L Fasting glucose + Rule out diabetes Repeat at next appt. Glycosuri a DB + Glycosuri a DB – Protein ≥ 1+ or g/L Protein < 1+ or g/L DB follow-up Repeat 1x ACR and MAU Normal ACR > 0.05 g/mmol or MAU > 2.1 mg/mmol hematuria (> 2 RBC/HPF) ACR ≤ 0.05 g/mmol and MAU < 2.1 mg/mmol Glycosuri a DB – - Renal ultrasound - Ascertain the risk factors - Referral to nephrologist or internist, or to urologist for isolated hematuria Normal Referral to nephrologist or internist

ACR ≤ 0.05 g/mmol and MAU < 2.1 mg/mmol Normal - Renal ultrasound - Ascertain the risk factors - Referral to nephrologist or internist, or to urologist for isolated hematuria Protein ≥ 1 + or 0.25 g/L Repeat at next appt. Protein < 1+ or g/L Protein ≥ 1+ or g/L ACR and MAU ACR > 0.05 g/mmol or MAU > 2.1 mg/mmol hematuria (> 2 RBC/HPF)

Repeat and if < normal levels Referral to nephrologist
Serum phosphorus < normal levels Repeat and if < normal levels PTH assay 25-OH Vit D Albumin- corrected Ca < 50: deficiency < 75: insufficiency > 75 Vit D Rx Normal Abnorma l Referral to nephrologist or internist Urinary fractional excretion of phosphorus if available (if > 20% or > 10% and hypophosphatemia: referral to a specialist Abnormal 0.65 – normal level 0.32 – mmol/L < 0.32 mmol/L Repeat in 3 months Repeat in 1 month Treat immediately Referral to nephrologist

Serum phosphorus 0.65 – normal level Repeat in 3 months < normal levels 0.32 – mmol/L Repeat in 1 month Urinary fractional excretion of phosphorus if available (if > 20% or > 10% and hypophosphatemia: referral to a specialist Repeat and if < normal levels < 0.32 mmol/L Treat immediately Referral to nephrologist 25-OH Vit D PTH assay Albumin- corrected Ca < 50: deficiency < 75: insufficiency > 75 Abnorma l Normal Abnormal Normal Vit D Rx Normal Referral to nephrologist or internist Referral to nephrologist or internist

Serum phosphorus < normal levels Repeat and if < normal levels Urinary fractional excretion of phosphorus if available (if > 20% or > 10% and hypophosphatemia: referral to a specialist 0.65 – normal level 0.32 – mmol/L < 0.32 mmol/L Repeat in 3 months Repeat in 1 month Treat immediately Referral to nephrologist

Serum phosphorus 0.65 – normal level Repeat in 3 months < normal levels 0.32 – mmol/L Repeat in 1 month Urinary fractional excretion of phosphorus if available (if > 20% or > 10% and hypophosphatemia: referral to a specialist Repeat and if < normal levels < 0.32 mmol/L Treat immediately Referral to nephrologist 25-OH Vit D PTH assay Albumin- corrected Ca < 50: deficiency < 75: insufficiency > 75 Abnorma l Normal Abnormal Normal Vit D Rx Normal Referral to nephrologist or internist Referral to nephrologist or internist

Repeat and if < normal levels
Serum phosphorus < normal levels Repeat and if < normal levels PTH assay 25-OH Vit D Albumin- corrected Ca < 50: deficiency < 75: insufficiency > 75 Vit D Rx Normal Abnorma l Referral to nephrologist or internist Urinary fractional excretion of phosphorus if available (if > 20% or > 10% and hypophosphatemia: referral to a specialist Abnormal

Algorithm

Aging Woman with longstanding HIV and multiple comorbidities
Case Study Aging Woman with longstanding HIV and multiple comorbidities Dr. Gord Arbess 73

Background Information
62 year old woman From Jamaica HIV + since 1996, heterosexual transmission Nadir CD4 108, VL > 500,000 Intermittent adherence Multiple ARV Regimens due to intolerance/resistance (AZT, 3TC, ddI, d4T, Nelfinavir, Amprenavir, LPV, EFV, Indinavir, Tenofovir, RTV) Hx ABC/3TC HSR

Multiple Co-Morbidities
Obese Hypertension NIDDM (Gastroparesis-intermittent vomiting) Sleep Apnea-CPAP Angina? Severe Osteoarthritis Knees Hypothyroid Hyperlipidemia Major Depression

HIV Medications Present HIV Regimen started June 2012
Darunavir 800 mg/d Ritonavir 100 mg/d Raltegravir 400 mg bid Etravirine 400 mg/d

Other Medications Lisinopril Atorvastatin Ibuprofen Metformin Cipralex
Zofran Eltroxin

Routine Bloodwork You notice Serum Cr is 158 (eGFR 48) on routine BW in August 2012

What Would You Do? 79 Review medications Switch ARV regimen Ultrasound
Albumin/Cr or Protein/Cr ratio Refer to nephrologist Check for STI/UTI – if negative, do urine cytology 79

ACR and MAU Refer to proteinuria algorithm (next page) Referral to nephrologist or internist < 60 cc/min* < 30 cc/min* CaPO4 Renal ultrasound * If GFR < 50 cc/min: consider adjusting the dose of certain ARV and concomitant medications ** Test for tubulopathy if GFR declines > 10 cc/min while on tenofovir

Algorithm

Investigations to assess Renal Function
Urinalysis ACR Serum Cr (eGFR) Electrolytes, Bicarb, albumin Urine for Protein, Cr Renal Ultrasound Other? Biopsy?

Results VL < 40 CD 4 843 Hgb 108 BS 7.3 Hga1c 0.061 ACR 1.1
Trace Protein, no blood, no glucose, White cells/hpf, occ red cells/hpf, hyaline casts with some cells Spot urine 0.1 g/L protein, 7.8 mmol/L Cr Cr range (eGFR range) over number of years Normal electrolytes, normal albumin, normal Bicarb Normal renal Ultrasound (small-sized kidneys)

What Would You Do? 84 Review medications Switch ARV regimen Ultrasound
Albumin/Cr or Protein/Cr ratio Refer to nephrologist Check for STI/UTI – if negative, do urine cytology 84

Glucose > 0 Glycosuri a DB + DB – DB follow-up Fasting glucose + Rule out diabetes Repeat 1x Referral to nephrologist or internist ACR ≤ 0.05 g/mmol and MAU < 2.1 mg/mmol Normal - Renal ultrasound - Ascertain the risk factors - Referral to nephrologist or internist, or to urologist for isolated hematuria Protein ≥ 1 + or 0.25 g/L Repeat at next appt. Protein < 1+ or g/L Protein ≥ 1+ or g/L ACR and MAU ACR > 0.05 g/mmol or MAU > 2.1 mg/mmol hematuria (> 2 RBC/HPF)

Algorithm

What do you think could be accounting for Cr elevation?
Review medications Switch ARV regimen Ultrasound Albumin/Cr or Protein/Cr ratio Refer to nephrologist Check for STI/UTI – if negative, do urine cytology 87

Etiology HIVAN? IgA Nephropathy? Medication-related? Hypertension?
NIDDM? Pre-renal component/volume contraction? Other?

How would you manage this patient?
Review medications Switch ARV regimen Ultrasound Albumin/Cr or Protein/Cr ratio Refer to nephrologist Check for STI/UTI – if negative, do urine cytology 89

Management Options? Do you d/c metformin? Do you d/c NSAIDs?
Do you d/c statin? Do you Need to dose Adjust ARVs? Should you Change ARVs? Do you Hold Ace Inhibitor? Do you ensure BP/BS well controlled? Do Nothing? Ask audience what they would have done differently based on what they have learned from this CHE Program 90

Follow Up BP well controlled Hga1c 0.062, therefore Metformin stopped
Asked not to take any NSAIDS ARV regimen continued at same doses Continued same dose of statin, ACEi Cr monitored closely in range of (eGFR range)

Dr. Patrice Junod Clinique médicale l’Actuel

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Dr. Patrice Junod Clinique médicale l’Actuel

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