renal disease in hiv: a non-nephrologist's guide to diagnosis

Renal Disease in HIV: A Non-Renal Disease in HIV: A Non-Nephrologist’s Guide to Nephrologist’s Guide to

Diagnosis and ManagementDiagnosis and Management

Frank J. Palella, Jr, MDFrank J. Palella, Jr, MDAssociate Professor of MedicineAssociate Professor of Medicine

Northwestern UniversityNorthwestern UniversityFeinberg School of MedicineFeinberg School of Medicine

The International AIDS Society–USA

OutlineOutlineAssessment of kidney diseaseAssessment of kidney disease– Measurement of renal functionMeasurement of renal function– Kidney disease markers: proteinuria/albuminuriaKidney disease markers: proteinuria/albuminuria– Chronic and acute renal diseaseChronic and acute renal disease

Epidemiology of HIV-related chronic and Epidemiology of HIV-related chronic and acute kidney diseaseacute kidney disease– HIV guidelinesHIV guidelines

Antiretroviral toxicities (tenofovir)Antiretroviral toxicities (tenofovir)– Monitoring recommendationsMonitoring recommendations

Measurement of Renal FunctionMeasurement of Renal FunctionGlomerular filtration rate (GFR)Glomerular filtration rate (GFR)– Best measure for overall renal functionBest measure for overall renal function– Renal clearance of a marker from plasmaRenal clearance of a marker from plasma– Volume of plasma that can be cleared of that marker Volume of plasma that can be cleared of that marker

per unit of timeper unit of time

Ideal marker (endogenous or exogenous)Ideal marker (endogenous or exogenous)Constant productionConstant productionConvenient and cheapConvenient and cheapNo protein-binding and freely filterableNo protein-binding and freely filterableNo tubular secretionNo tubular secretionNo extrarenal metabolismNo extrarenal metabolismAccurate and reproducibleAccurate and reproducibleNo interference from other compoundsNo interference from other compoundsLow interpatient and intrapatient coefficients of Low interpatient and intrapatient coefficients of variationvariation

Measurement of Renal FunctionMeasurement of Renal Function““Gold Standards” – exogenousGold Standards” – exogenous– InulinInulin– Radionuclide/Radiocontrast markersRadionuclide/Radiocontrast markers

125125I-iothalamate, I-iothalamate, 5151Cr-labeled EDTA, Cr-labeled EDTA, 125m125mTc-DTPA, Tc-DTPA, IohexolIohexolIntrapersonal CV 5-7%Intrapersonal CV 5-7%

– Pitfalls of exogenous infusionsPitfalls of exogenous infusionsInfusions (IV or SC)Infusions (IV or SC)Radioactivity, except for iohexol, (overall Radioactivity, except for iohexol, (overall considered safe)considered safe)Time-consuming (between 2-24 hours)Time-consuming (between 2-24 hours)CostCostResearch toolsResearch tools

Measurement of Renal FunctionMeasurement of Renal Function

Endogenous markersEndogenous markers– Serum creatinineSerum creatinine

Metabolic product of muscle-derived creatine Metabolic product of muscle-derived creatine and phosphocreatineand phosphocreatine

Production tied to muscle massProduction tied to muscle mass– Age, sex, extremes of BMI, disease states, Age, sex, extremes of BMI, disease states,

amputations, chronic steroid useamputations, chronic steroid use

Also tied to diet (heavy red meat eaters)Also tied to diet (heavy red meat eaters)

Cheap, easily measured, readily availableCheap, easily measured, readily available

Freely filtered through glomerulusFreely filtered through glomerulus

Measurement of Renal FunctionMeasurement of Renal Function– Secreted through proximal tubuleSecreted through proximal tubule

Inhibited by cimetidine, Inhibited by cimetidine, trimethoprim, dapsone (usually trimethoprim, dapsone (usually does not increase SCr over does not increase SCr over 2.0mg/dL)2.0mg/dL)Proportionally more important Proportionally more important with reduced filtrationwith reduced filtration

– Large intrapersonal variation Large intrapersonal variation (7-20%)(7-20%)

Minimum detectable change up Minimum detectable change up to 0.2mg/dL to 0.2mg/dL

– Poor intralaboratory calibration Poor intralaboratory calibration affecting higher GFRaffecting higher GFR

Up to an additional 0.2mg/dLUp to an additional 0.2mg/dL– Serum creatinine may not Serum creatinine may not

increase until up to 50% of GFR increase until up to 50% of GFR is reducedis reduced

Krop, Arch Int Med, 1999. Coresh, AJKD, 2002. Levey, Ann Int Med, 1999.Krop, Arch Int Med, 1999. Coresh, AJKD, 2002. Levey, Ann Int Med, 1999.

Measurement of Renal FunctionMeasurement of Renal FunctionCreatinine clearanceCreatinine clearance– 24-hour urine collection24-hour urine collection– Problems with complete collection Problems with complete collection – Suffers from tubular secretion issueSuffers from tubular secretion issue

Not the same as GFRNot the same as GFR

Tends to overestimate GFR at ‘normal’ rangeTends to overestimate GFR at ‘normal’ range

Renal function estimating equations Renal function estimating equations – Avoids problems with timed collectionsAvoids problems with timed collections– Attempts to correct for muscle mass using Attempts to correct for muscle mass using

readily available clinical variablesreadily available clinical variables

Measurement of Renal FunctionMeasurement of Renal FunctionCockcroft-GaultCockcroft-GaultCrCl (mL/min) = CrCl (mL/min) = (140-age)(wt kg) x (0.85 if female)(140-age)(wt kg) x (0.85 if female)

72 (Scr mg/dL)72 (Scr mg/dL)

249 white, male (Canadian), hospitalized 249 white, male (Canadian), hospitalized veteransveterans– Retrospective review of those with two similar Retrospective review of those with two similar

24-hour urinary CrCl24-hour urinary CrCl– 15% reduction for women based empirically 15% reduction for women based empirically

on relative muscle masseson relative muscle masses

Renal drug-dosing based on this equationRenal drug-dosing based on this equation

Measurement of Renal FunctionMeasurement of Renal FunctionMDRDMDRD– Estimates GFR (mL/min/1.73mEstimates GFR (mL/min/1.73m22))– Incorporates serum creatinine, age, sex, race (black Incorporates serum creatinine, age, sex, race (black

vs. non-black), BUN, albumin (not weight)vs. non-black), BUN, albumin (not weight)– Derived from 1070 subjects with kidney disease and Derived from 1070 subjects with kidney disease and

validated in 558validated in 558– 60% male, 88% white, 6% diabetic60% male, 88% white, 6% diabetic– Used for K/DOQI staging of CKDUsed for K/DOQI staging of CKD

Simplified MDRD Simplified MDRD – Serum creatinine, age, sex, race (not weight)Serum creatinine, age, sex, race (not weight)– Remarkably similar results to full MDRDRemarkably similar results to full MDRD– Used extensively for epidemiology studiesUsed extensively for epidemiology studies

Measurement of Renal FunctionMeasurement of Renal FunctionPitfallsPitfalls– All formulae derived primarily from patients All formulae derived primarily from patients

with impaired renal functionwith impaired renal function– All based on serum creatinineAll based on serum creatinine

May not be helpful in acute, early changes of renal May not be helpful in acute, early changes of renal functionfunction

May be inaccurate at extremes of weightMay be inaccurate at extremes of weight

Lean body mass may improve estimates at Lean body mass may improve estimates at

BMI <17kg/mBMI <17kg/m22 or >30kg/m or >30kg/m22

What is proteinuria and albuminuria?What is proteinuria and albuminuria?

Serum Protein

• Albumin

• Globulins

Urine Protein

Albumin >>>

Globulins

• Proteinuria/albuminuria strongly Proteinuria/albuminuria strongly predictive of both renal and predictive of both renal and cardiovascular outcomes in the cardiovascular outcomes in the general populationgeneral population

Measurement of Renal FunctionMeasurement of Renal Function

Proteinuria and/or albuminuriaProteinuria and/or albuminuria– DipstickDipstick

Semiquantitative (0, trace, 1+, 2+, 3+, 4+)Semiquantitative (0, trace, 1+, 2+, 3+, 4+)Microscopic analysis (Hgb, WBC, RBC, casts)Microscopic analysis (Hgb, WBC, RBC, casts)

– ‘‘Spot’ urine protein(albumin)/creatinine ratioSpot’ urine protein(albumin)/creatinine ratioJust as good as 24-hour urine collectionJust as good as 24-hour urine collectionEasy to getEasy to getProtein/creatinine > 220-300mg/gmProtein/creatinine > 220-300mg/gmAlbumin/creatinine Albumin/creatinine

– 30mg/gm (microalbuminuria)30mg/gm (microalbuminuria)– >300mg/gm (macroalbuminuria/proteinuria)>300mg/gm (macroalbuminuria/proteinuria)

Normal Renal FunctionNormal Renal FunctionSerum creatinine in NHANES III Serum creatinine in NHANES III

MenMen Women WomenAgeAge Healthy AllHealthy All Healthy Healthy All All

20-3920-39 1.141.14 1.09(1.33) 1.09(1.33) 0.92 0.92 0.87(1.08) 0.87(1.08)

40-5940-59 1.171.17 1.11(1.38)1.11(1.38) 0.95 0.95 0.90(1.14) 0.90(1.14)

Best mean estimates for GFR are 130mL/min/1.73mBest mean estimates for GFR are 130mL/min/1.73m22 and and 120mL/min/1.73m120mL/min/1.73m22 in healthy young men and women, in healthy young men and women, respectivelyrespectivelyWide variation (age, race, sex, diet)Wide variation (age, race, sex, diet)Key point is complications (death, CV disease, ESRD, Key point is complications (death, CV disease, ESRD, anemia, hyperPTH/calcium dysregulation) increase as a anemia, hyperPTH/calcium dysregulation) increase as a continuum with increasing serum creatinine – even with continuum with increasing serum creatinine – even with mild increases and especially when GFR falls below mild increases and especially when GFR falls below 60mL/min/1.73m60mL/min/1.73m22

Chronic Kidney DiseaseChronic Kidney Disease

K/DOQI. AJKD, 2002.K/DOQI. AJKD, 2002.

IDSA GuidelinesIDSA Guidelines

Estimating renal functionEstimating renal function– No systematic validation in HIV patientsNo systematic validation in HIV patients– Recommend Cockcroft-Gault for drug dosingRecommend Cockcroft-Gault for drug dosing– Recommend MDRD for stagingRecommend MDRD for staging– Both are used with caution in wasted patientsBoth are used with caution in wasted patients

Gupta, CID, 2005.Gupta, CID, 2005.

HIVANHIVAN 45.9% (1745.9% (17)) a 69.8% (30)69.8% (30) a

Membranoproliferative glomerulonephritisMembranoproliferative glomerulonephritis 10.8% (4)10.8% (4) 4.7% (2)4.7% (2)

Diabetes mellitusDiabetes mellitus 5.4% (2)5.4% (2) 14.0% (6)14.0% (6)

HypertensionHypertension 5.4% (2)5.4% (2) 4.7% (2)4.7% (2)

AmyloidAmyloid 5.4% (2)5.4% (2) 2.3% (1)2.3% (1)

Chronic focal glomerulonephritisChronic focal glomerulonephritis 2.7% (1)2.7% (1)

Focal segmental glomerulosclerosisFocal segmental glomerulosclerosis 5.4% (2)5.4% (2)

Membranous glomerulopathyMembranous glomerulopathy 2.7% (1)2.7% (1)

NonspecificNonspecific 2.7% (1)2.7% (1)

No tissue obtainedNo tissue obtained 8.1% (3)8.1% (3)

Mesangial glomerulonephritisMesangial glomerulonephritis 5.4% (2)5.4% (2)

Heroin abuseHeroin abuse 2.3% (1)2.3% (1)

Nephrotoxic drugsNephrotoxic drugs 2.3% (1)2.3% (1)

TotalTotal 3737 4343

HIVAN is HIV-associated nephropathyHIVAN is HIV-associated nephropathyaa P = 0.03 (HIVAN vs. all others) P = 0.03 (HIVAN vs. all others)

Spectrum of Renal Diseases in HIVSpectrum of Renal Diseases in HIV

EtiologyEtiology BiopsyBiopsy No biopsyNo biopsy

Szczech, Kidney Int, 2003.Szczech, Kidney Int, 2003.

AIDS Nephropathy - ESRDAIDS Nephropathy - ESRD

Between 1999-2003 Between 1999-2003 – 4218 new cases (1% of all new ESRD)4218 new cases (1% of all new ESRD)– Median age 40Median age 40– 70% men70% men

No sex preferenceNo sex preference

– 90% black90% black– 33rdrd leading cause of ESRD in leading cause of ESRD in blacks aged blacks aged

20-6420-64 (behind diabetes, HTN) (behind diabetes, HTN)

USRDS, 2005.USRDS, 2005.

Prognosis Depends on HistologyPrognosis Depends on HistologyRetrospective study of biopsy-proven renal Retrospective study of biopsy-proven renal pathologiespathologies– 42 HIVAN, 47 non-HIVAN42 HIVAN, 47 non-HIVAN– Progression to ESRD faster in HIVANProgression to ESRD faster in HIVAN

Other factors: use of ACE-I, CD4, hepatitis C, creatinine Other factors: use of ACE-I, CD4, hepatitis C, creatinine clearance at time of biopsyclearance at time of biopsy

Strong interaction between histology, viral load, Strong interaction between histology, viral load, and use of HAARTand use of HAART– Achieving undetectable viral load did not impact renal Achieving undetectable viral load did not impact renal

progression in non-HIVANprogression in non-HIVAN– Use of HAART delayed progression in HIVAN, esp. Use of HAART delayed progression in HIVAN, esp.

with undetectable viral load; HR 0.24, P=0.03with undetectable viral load; HR 0.24, P=0.03– Use of HAART did not impact renal progression in Use of HAART did not impact renal progression in

non-HIVAN; HR 3.29, non-HIVAN; HR 3.29, P=0.06P=0.06

Szczech, Kidney Int, 2004.Szczech, Kidney Int, 2004.

Risk Factors for ProteinuriaRisk Factors for Proteinuria

11.11.21.31.41.51.61.71.81.9

2

Log HIV RNA CD4 <200cells/ml

Race (blackvs. other)

Hepatitis Cantibody

All p<0.0001All p<0.0001Szczech, Kidney Int, 2002.Szczech, Kidney Int, 2002.

14% with persistent dipstick proteinuria14% with persistent dipstick proteinuria

Risk Factors for Development of Renal FailureRisk Factors for Development of Renal Failure

0

0.5

1

1.5

2

2.5

3

3.5

4

Haz

ard

Rat

io (

HR

)

HIV RNA CD4 Count Systolic BP Albumin SCr

¦ ¦ ¦ ¦

‡‡

****

††

(1.14–4.76)(1.14–4.76) (1.007–1.03)(1.007–1.03) (1.53–1.83)(1.53–1.83)(1.72–7.14)(1.72–7.14) (2.08–5.26)(2.08–5.26)

§§

95% (CI)95% (CI)

*P=0.02 (>4000 vs. *P=0.02 (>4000 vs. 4000 copies/mL4000 copies/mL††P=0.001 (P=0.001 (200 vs. >200 cells/200 vs. >200 cells/L)L)‡‡P=0.002 (per increment of 1mmHg)P=0.002 (per increment of 1mmHg)§P=0.0001 (per decrement of 1mg/dL)§P=0.0001 (per decrement of 1mg/dL)¦ P=0.0001 (per increment of 1mg/dL)¦ P=0.0001 (per increment of 1mg/dL) Szczech, Kidney Int, 2002.Szczech, Kidney Int, 2002.

Epidemiology of Renal Disease in AfricaEpidemiology of Renal Disease in AfricaProspectively enrolled, cross-sectional study of renal Prospectively enrolled, cross-sectional study of renal parameters in 373 ARV-naïve subjectsparameters in 373 ARV-naïve subjects– No known DM, HTN, renal diseaseNo known DM, HTN, renal disease– Mean age 35; 68% women, mean CD4 391 Mean age 35; 68% women, mean CD4 391

Renal functionRenal function– Mean CrCl 90mL/min; mean MDRD 103mL/min/1.73mMean CrCl 90mL/min; mean MDRD 103mL/min/1.73m22

– 12% <60mL/min; 5% <50mL/min12% <60mL/min; 5% <50mL/min– Predictors of <60mL/min were lower HgB, wasting syndrome Predictors of <60mL/min were lower HgB, wasting syndrome

(proteinuria marginal significance)(proteinuria marginal significance)

Proteinuria Proteinuria 1+1+– Only 6%Only 6%– Only predictor was history of TBOnly predictor was history of TB

Implications for drug dosing in Africa (esp. for stavudine, Implications for drug dosing in Africa (esp. for stavudine, tenofovir)tenofovir)

Wools-Kaloustian, Nephrol Dial Transplant, 2007 (in press). Wools-Kaloustian, Nephrol Dial Transplant, 2007 (in press).

Proteinuria and CKD: Proteinuria and CKD: Impact on Mortality (HERS Study)Impact on Mortality (HERS Study)

00.5

11.5

22.5

33.5

44.5

ClinicalAIDS

HIV RNA CD4count

Renalabn.

DM Htn Hep C

p- value: <0.0001 0.002 <0.0001 <0.0001 0.03 0.004 0.02p- value: <0.0001 0.002 <0.0001 <0.0001 0.03 0.004 0.02

> 10K vs. <500> 10K vs. <500

200-500 vs. 200-500 vs. <200<200

Gardner, JAIDS, 2003.Gardner, JAIDS, 2003.

• ≥ 2+ proteinuria

• SCr > 1.4mg/dL

Acute Renal FailureAcute Renal FailureConsequencesConsequences– MortalityMortality

20% overall mortality rate20% overall mortality rate

40-50% mortality for those with SCr > 3.0mg/dL or needing 40-50% mortality for those with SCr > 3.0mg/dL or needing dialysisdialysis

If ambulatory, prognosis excellentIf ambulatory, prognosis excellent

– Mild ARFMild ARFElectrolyte abnormalities – cardiac arrhythmias and cellular Electrolyte abnormalities – cardiac arrhythmias and cellular enzyme dysfunctionenzyme dysfunction

Volume retentionVolume retention

AnemiaAnemia

More a problem in those with underlying renal diseaseMore a problem in those with underlying renal disease

Drug dosing adjustmentsDrug dosing adjustments

Relative Hazard of Death Prior to the Relative Hazard of Death Prior to the Widespread Use of HAARTWidespread Use of HAART

Sczcech, CID, 2004.Sczcech, CID, 2004.

Predictors of Mortality Following HAARTPredictors of Mortality Following HAART

ProteinuriaProteinuriaHRHR2.072.07

95% CI95% CI1.25, 3.451.25, 3.45

ChiChi22

7.97.9p-valuep-value0.0050.005

Inverse creatinine Inverse creatinine (per decrease of 1 dL/mg)(per decrease of 1 dL/mg)

1.961.96 1.03, 3.851.03, 3.85 4.24.2 0.040.04

CD4 lymphocyte count CD4 lymphocyte count (per 100 cell/ml decrease)(per 100 cell/ml decrease)

1.381.38 1.19, 1.601.19, 1.60 18.318.3 <0.0001<0.0001

Albumin Albumin (per decrease in 1 mg/dL)(per decrease in 1 mg/dL)

2.222.22 1.49, 3.331.49, 3.33 15.515.5 <0.0001<0.0001

Prior history of an AIDS defining Prior history of an AIDS defining illnessillness

2.152.15 1.29, 3.571.29, 3.57 8.78.7 0.0030.003

History of hypertension History of hypertension 1.971.97 1.19, 3.271.19, 3.27 7.07.0 0.0080.008

Age (per year increase)Age (per year increase) 1.031.03 1.006, 1.061.006, 1.06 5.55.5 0.020.02

Sczcech, CID, 2004.Sczcech, CID, 2004.

IDSA Guidelines: Screening AlgorithmIDSA Guidelines: Screening AlgorithmQualitative assessment for risk of kidney disease•RaceFamily history of kidney diseaseCD4 lymphocyte countHIV RNA levelHistory of use of nephrotoxic medicationsComorbidities

oDiabetes mellitus oHypertension oHepatitis C infection

Screening studies for patients at increased risk:• Urine analysis (for proteinuria) Serum creatinine (estimate creatinine clearance or glomerular filtration rate using appropriate formula)

Abnormal values•> +1 proteinuria by dipstickcreatinine clearance or glomerular filtration rate < 60 mL/min/1.73m2

No abnormal values

Evaluate proteinuria further with spot urine to protein creatinineRenal ultrasoundConsider referral to a nephrologist for further evaluation and potentially biopsy

Groups at risk for kidney disease related to HIV infection should be reassessed periodically (e.g. yearly)

Groups 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

Tenofovir and NephrotoxicityTenofovir and NephrotoxicityFanconi SyndromeFanconi Syndrome– Generalized proximal renal tubule dysfunctionGeneralized proximal renal tubule dysfunction– Hereditary or acquired (cancer vs drug)Hereditary or acquired (cancer vs drug)– Normal reabsorption of electrolytes and nutrients are Normal reabsorption of electrolytes and nutrients are

impairedimpaired– Spillage of electrolytes and nutrients into the urineSpillage of electrolytes and nutrients into the urine– Persistent, low-level ARFPersistent, low-level ARF– Mortality and serious morbidity (dialysis) quite rareMortality and serious morbidity (dialysis) quite rare– Manifestations may reverse (Manifestations may reverse (hyperhyperkalemia, kalemia,

hyperhyperphosphatemia) as glomerular filtration worsensphosphatemia) as glomerular filtration worsens

GFR Changes in Large Prospective StudiesGFR Changes in Large Prospective Studies

Cockroft-GaultCockroft-Gault(mL/min)(mL/min)

MDRDMDRD(mL/min/1.73m(mL/min/1.73m22))

BaselineBaselineMean Mean

ChangeChange BaselineBaselineMean Mean

ChangeChange

Study 903 Study 903 (144 weeks)(144 weeks)

Tenofovir DF + 3TC + EFV Tenofovir DF + 3TC + EFV (n=299)(n=299)

Stavudine + 3TC + EFV Stavudine + 3TC + EFV (n=301)(n=301)

122122125125

+2+2+7*+7*

113113114114

-2-2+9*+9*

Study 934 Study 934 (48 weeks)(48 weeks)

Tenofovir DF + FTC + EFV Tenofovir DF + FTC + EFV (n=257)(n=257)

Zidovudine/3TC + EFV Zidovudine/3TC + EFV (n=254)(n=254)

121121121121

-1.3-1.3+6.2+6.2††

110110105105

-0.7-0.7††

-0.4-0.4‡‡

Gallant JE, et al. 45th ICAAC. Washington, DC, 2005. Abstract H-350.Pozniak AL, et al. 10th EACS. Dublin, 2005. Abstract PE7.3/14.

Pozniak AL, et al. 3rd IAS. Rio de Janeiro, 2005. Abstract WeOa0202.

**PP<0.05 versus baseline.<0.05 versus baseline.††PP<0.001 versus baseline.<0.001 versus baseline.‡‡PP=0.01 versus baseline.=0.01 versus baseline.

What about the real world?What about the real world?

Overall risk for TDF toxicity lowOverall risk for TDF toxicity low– Retrospective database studies suggest low Retrospective database studies suggest low

frequency of frequency of discontinuation discontinuation for renal toxicityfor renal toxicity0.8%0.8% Jones, JAIDS, 2004.Jones, JAIDS, 2004.

1.9% 1.9% Karras, CID, 2003.Karras, CID, 2003.

7% (1.3% discontinued TDF) 7% (1.3% discontinued TDF) Harris, 2003 IAS.Harris, 2003 IAS.

0.39% 0.39% Moreno, JAIDS, 2006.Moreno, JAIDS, 2006.

1.6% Padilla 1.6% Padilla AIDS Patient Care STDS, 2005.AIDS Patient Care STDS, 2005.

2/71 ARF cases 2/71 ARF cases Franceschini, KI, 2005Franceschini, KI, 2005

0% 0% Gallant, CID, 2005.Gallant, CID, 2005.

1.8% 1.8% Gupta, unpublished data.Gupta, unpublished data.

– Surveillance and recognition biasesSurveillance and recognition biases– Lack of a standard definitionLack of a standard definition

Who gets this?Who gets this?Risk factors Risk factors – Lower weight Lower weight Peyriere, JAIDS, 2004.Peyriere, JAIDS, 2004.

– Lower baseline renal function (not just Lower baseline renal function (not just high serum creatinine) high serum creatinine) Harris, 11Harris, 11thth CROI, 2004. CROI, 2004.

– Lower CD4 count Lower CD4 count Harris, 2003 IAS; Gallant, CID, 2005.Harris, 2003 IAS; Gallant, CID, 2005.

– RTV-boosted PI or DDI concomitant use RTV-boosted PI or DDI concomitant use Zimmerman CID 2006Zimmerman CID 2006

Not risk factorsNot risk factors– Race, sex, age, previous adefovir use, Race, sex, age, previous adefovir use,

duration of TDF useduration of TDF use

Epidemiology and Outcomes of Epidemiology and Outcomes of Tenofovir-Related Fanconi SyndromeTenofovir-Related Fanconi Syndrome

Retrospective review of the FDA Adverse Event Retrospective review of the FDA Adverse Event Reporting System (AERS)Reporting System (AERS)

164 cases reported from 2001-2006164 cases reported from 2001-2006– Median age 45 (12-71)Median age 45 (12-71)– Mostly men (78%)Mostly men (78%)

Concomitant medicationsConcomitant medications– PI (83%)PI (83%)– Boosted PI (74%)Boosted PI (74%)– DDI (43%)DDI (43%)– DDI+Boosted PI (34%); DDI+LPV/RTV (22%)DDI+Boosted PI (34%); DDI+LPV/RTV (22%)

OutcomesOutcomes– Hospitalization (46%)Hospitalization (46%)– Fracture (2%), Dialysis (2%), Death (2%)Fracture (2%), Dialysis (2%), Death (2%)

Gupta, Submitted, 2007.Gupta, Submitted, 2007.

Gallant, CID, 2005.Gallant, CID, 2005.

VariableVariableTDF groupTDF group

((nn = 344) = 344)NRTI groupNRTI group

((nn = 314) = 314) PP

Serum creatinine level at start of treatment, mg/dLSerum creatinine level at start of treatment, mg/dL0.8 (0.7, 1.0)0.8 (0.7, 1.0) 0.8 (0.7, 1.0)0.8 (0.7, 1.0)

.56.56

CLCLCrCr at start of treatment, mL/min at start of treatment, mL/min117 (95, 148)117 (95, 148) 118 (92, 177)118 (92, 177)

.69.69

Treatment period, daysTreatment period, days303 (169, 365)303 (169, 365) 336 (175, 365)336 (175, 365)

.19.19

Maximum serum creatinine level, mg/dLMaximum serum creatinine level, mg/dL1.0 (0.8, 1.2)1.0 (0.8, 1.2) 0.9 (0.8, 1.1)0.9 (0.8, 1.1)

.17.17

Absolute change in serum creatinine level, mg/dLAbsolute change in serum creatinine level, mg/dL+0.15 (+0.05, +0.30)+0.15 (+0.05, +0.30) +0.10 (0.0, +0.25)+0.10 (0.0, +0.25)

.01.01

Calculated minimum CLCalculated minimum CLCrCr, mL/min, mL/min98 (71, 125)98 (71, 125) 102 (79, 129)102 (79, 129)

.43.43

Absolute change in CLAbsolute change in CLCrCr, mL/min, mL/min-13.3 (-24.0, 0.0)-13.3 (-24.0, 0.0) -7.5 (-20.5, +6.5)-7.5 (-20.5, +6.5)

.005.005

Percent change in CLPercent change in CLCrCr, %, %-10 (-22, 0)-10 (-22, 0) -6 (-17, +6)-6 (-17, +6)

.007.007

Patients with decline in CLPatients with decline in CLCrCr, no. (%), no. (%)

>50% decline>50% decline15 (4.4)15 (4.4) 6 (1.9)6 (1.9)

.14.14a

Gallant, CID, 2005.Gallant, CID, 2005.

Possible MechanismsPossible Mechanisms

Increased exposure to tenofovirIncreased exposure to tenofovir– Decreased renal clearance with LPV/RTVDecreased renal clearance with LPV/RTV

Pop PK analysis Pop PK analysis Jullien, AAC, 2005.Jullien, AAC, 2005.

– Lower plasma TFV clearance associated with body Lower plasma TFV clearance associated with body weight/SCr, proximal tubulopathy, and LPV/RTV useweight/SCr, proximal tubulopathy, and LPV/RTV use

Direct TFV renal clearance analysis Direct TFV renal clearance analysis Kiser, CROI 2006.Kiser, CROI 2006.

– TFV renal clearance lower in those also receiving TFV renal clearance lower in those also receiving LPV/RTV, but only when adjusted for baseline GFRLPV/RTV, but only when adjusted for baseline GFR

Possible MechanismsPossible Mechanisms

Increased didanosine exposure with TDF Increased didanosine exposure with TDF and mitochondrial toxicity in the kidneyand mitochondrial toxicity in the kidney– Reduced kidney mitochondrial DNA in TDF-Reduced kidney mitochondrial DNA in TDF-

DDI subjects DDI subjects Cote, Antiviral Therapy 2006. Vidal AAC, 2006.Cote, Antiviral Therapy 2006. Vidal AAC, 2006.

Genetic predispositionGenetic predisposition– hOAT1 SNP associated with lower TFV Km hOAT1 SNP associated with lower TFV Km

Bleasby, JPET, 2005.Bleasby, JPET, 2005.

– SNPs in MRP2 and/or MRP 4 SNPs in MRP2 and/or MRP 4 Izzedine, JID, 2006. Kiser, 7Izzedine, JID, 2006. Kiser, 7 thth

IWCP of HIV Therapy, 2006IWCP of HIV Therapy, 2006

What if I stop TDF?What if I stop TDF?

Tubular abnormalities seem to resolve in Tubular abnormalities seem to resolve in all cases, but renal function may not come all cases, but renal function may not come back to baseline in some patients (short back to baseline in some patients (short follow-up period) follow-up period) Zimmerman, CID, 2006. Izzedine, AIDS, 2004.Zimmerman, CID, 2006. Izzedine, AIDS, 2004.

Clinical significance of lower renal function Clinical significance of lower renal function (at relatively normal range) is unknown(at relatively normal range) is unknown

IDSA GuidelinesIDSA GuidelinesWith frequent use of TDF, most caregivers With frequent use of TDF, most caregivers will see nephrotoxicity, including Fanconi will see nephrotoxicity, including Fanconi SyndromeSyndrome

TDF TDF toxicity monitoringtoxicity monitoring for high risk groups for high risk groups– GFR < 90mL/min/1.73mGFR < 90mL/min/1.73m2 2 at baselineat baseline– Concomitant nephrotoxic drugsConcomitant nephrotoxic drugs

Adefovir, acyclovir, ganciclovir, cidofovirAdefovir, acyclovir, ganciclovir, cidofovir

Amphotericin, foscarnetAmphotericin, foscarnet

– Comorbid diseases – diabetes, hypertensionComorbid diseases – diabetes, hypertension– Concomitant ritonavir-boosted PIs or DDI (???)Concomitant ritonavir-boosted PIs or DDI (???)

Gupta, CID, 2005.Gupta, CID, 2005.

IDSA GuidelinesIDSA GuidelinesBiannual measurementsBiannual measurements– Renal function (GFR or CrCl, Renal function (GFR or CrCl, not just SCrnot just SCr))– Serum phosphorusSerum phosphorus

Newer data suggests this is not helpful Newer data suggests this is not helpful Day, JAIDS, 2005. Jullien, AAC, 2005. Day, JAIDS, 2005. Jullien, AAC, 2005. Buchacz, HIV Medicine, 2006. Badiou, J Infect, 2006.Buchacz, HIV Medicine, 2006. Badiou, J Infect, 2006.

– Urine analysis for protein and glucoseUrine analysis for protein and glucose

If abnormal?If abnormal?– Repeat and confirm!!!Repeat and confirm!!!– Consider 24-hr urine collection for protein, glucose, potassium, Consider 24-hr urine collection for protein, glucose, potassium,

phosphorus, calcium, bicarbonatephosphorus, calcium, bicarbonate– If nephrotoxicity/Fanconi Syndrome confirmedIf nephrotoxicity/Fanconi Syndrome confirmed

Look for other offending drugs/conditions (myeloma??)Look for other offending drugs/conditions (myeloma??)

Consider stopping offending drugs, including TDFConsider stopping offending drugs, including TDF

– If TDF stopped, get follow-up studies (SCr and urine analysis likely If TDF stopped, get follow-up studies (SCr and urine analysis likely enough, but may want to do repeat 24-hr collection)enough, but may want to do repeat 24-hr collection)

renal disease in hiv: a non-nephrologist's guide to diagnosis

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