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  • WIHS 32% women had proteinuria (at least two non-consecutive >=+1) Arguably not population based!!!
  • The benefits of HAART and ARV monotherapy include delaying progression of renal disease within HIV+ patients. The specific risk factors that these agents target — increased HIV RNA levels and decreased CD4 cell counts were identified as significant in a study performed by Szczech and colleagues on 671 HIV+ women with proteinuria (  +1 on two consecutive dipstick exams) involved in the Women’s Interagency Health Study (WIHS). Of the 2057 women involved in WIHS, 32% (671) were proteinuric at initial evaluation. Biannual exams collected data including HIV RNA levels, CD4 cell count, blood pressure, and SCr and albumin levels. Renal failure was defined as a doubling of SCr from the last measurement obtained at the initial visit. As shown on the slide, five different risk factors were found to be significant predictors of renal failure following a multivariate Cox proportional hazards regression analysis: a CD4 count  200 cells/mm 3 vs  200 cells/mm 3 (hazard ratio [HR]: 3.57; P =0.001); a decrease in serum albumin of 1 mg/dL (HR: 3.33; P =0.0001); an HIV RNA level of  4000 copies/mL vs  4000 copies/mL (HR: 2.33; P =0.02); an increase in SCr of 1 mg/dL (HR: 1.67; P =0.0001); and an increase in systolic blood pressure of 1 mm Hg (HR: 1.02; P =0.002). From these findings, the researchers concluded that future therapies for renal disease in HIV+ patients should target suppression of HIV RNA and improvement in CD4 cell count. Szczech LA, Gange SJ, van der Horst C. Predictors of proteinuria and renal failure among women with HIV infection. Kidney Int . 2002;61:195-202.
  • HERS dataset 885 HIV infected women Definition of renal abnormality: creatinine > 1.4 and/or >2+ proteinuria either at baseline or developing during period of follow up.
  • Slide: Glomerular Filtration Rate Changes in Large Prospective Studies This slide lists comparative changes from baseline in glomerular filtration rate using both the Cockroft-Gault and the modification of diet in renal diseases (MDRD) methods for estimating glomerular filtration rate. Patients in these two studies were treatment-naïve and received tenofovir DF-containing regimens. These data demonstrate there are no clinically meaningful changes in glomerular filtration rate with efavirenz-based regimens containing tenofovir DF compared with either baseline values or with other efavirenz-based regimens containing either stavudine or zidovudine/lamivudine. 1-3 References Gallant JE, Staszewski S, Pozniak AL, Lu B, et al. Similar renal safety profile between tenofovir DF and stavudine using modification of diet in renal diseases and Cockroft-Gault estimation of glomerular filtration rate in antiretroviral-naïve patients through 144 weeks. Program and abstracts of the 45 th Interscience Conference on Antimicrobial Agents and Chemotherapy. December 16-19, 2005. Washington, DC. Abstract H-350. Pozniak AL, Gallant JE, DeJesus E, et al. Superior outcome for tenofovir DF and emtricitabine compared to fixed dose zidovudine/lamivudine in antiretroviral naïve HIV-infected patients. Program and abstracts of the 10 th European AIDS Clinical Society conference. November 17-20, 2005. Dublin, Ireland. Abstract PE7.3/14. Pozniak AL, Gallant JE, DeJesus E, et al. Superior outcome for tenofovir DF, emtricitabine and efavirenz compared to fixed dose zidovudine/lamivudine and efavirenz in antiretroviral naïve patients. Program and abstracts of the 3rd International AIDS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil. Abstract WeOa0202 .

Renal Disease in HIV: A Non-Nephrologist's Guide to Diagnosis ... Renal Disease in HIV: A Non-Nephrologist's Guide to Diagnosis ... Presentation Transcript

  • Renal Disease in HIV: A Non-Nephrologist’s Guide to Diagnosis and Management Frank J. Palella, Jr, MD Associate Professor of Medicine Northwestern University Feinberg School of Medicine The International AIDS Society–USA
  • Outline
    • Assessment of kidney disease
      • Measurement of renal function
      • Kidney disease markers: proteinuria/albuminuria
      • Chronic and acute renal disease
    • Epidemiology of HIV-related chronic and
    • acute kidney disease
      • HIV guidelines
    • Antiretroviral toxicities (tenofovir)
      • Monitoring recommendations
  • Measurement of Renal Function
    • Glomerular filtration rate (GFR)
      • Best measure for overall renal function
      • Renal clearance of a marker from plasma
      • Volume of plasma that can be cleared of that marker per unit of time
    • Ideal marker (endogenous or exogenous)
        • Constant production
        • Convenient and cheap
        • No protein-binding and freely filterable
        • No tubular secretion
        • No extrarenal metabolism
        • Accurate and reproducible
        • No interference from other compounds
        • Low interpatient and intrapatient coefficients of variation
  • Measurement of Renal Function
    • “ Gold Standards” – exogenous
      • Inulin
      • Radionuclide/Radiocontrast markers
        • 125 I-iothalamate, 51 Cr-labeled EDTA, 125m Tc-DTPA, Iohexol
        • Intrapersonal CV 5-7%
      • Pitfalls of exogenous infusions
        • Infusions (IV or SC)
        • Radioactivity, except for iohexol, (overall considered safe)
        • Time-consuming (between 2-24 hours)
        • Cost
        • Research tools
  • Measurement of Renal Function
    • Endogenous markers
      • Serum creatinine
        • Metabolic product of muscle-derived creatine and phosphocreatine
        • Production tied to muscle mass
          • Age, sex, extremes of BMI, disease states, amputations, chronic steroid use
        • Also tied to diet (heavy red meat eaters)
        • Cheap, easily measured, readily available
        • Freely filtered through glomerulus
  • Measurement of Renal Function
      • Secreted through proximal tubule
        • Inhibited by cimetidine, trimethoprim, dapsone (usually does not increase SCr over 2.0mg/dL)
        • Proportionally more important with reduced filtration
      • Large intrapersonal variation
      • (7-20%)
        • Minimum detectable change up to 0.2mg/dL
      • Poor intralaboratory calibration affecting higher GFR
        • Up to an additional 0.2mg/dL
      • Serum creatinine may not increase until up to 50% of GFR is reduced
    Krop, Arch Int Med, 1999. Coresh, AJKD, 2002. Levey, Ann Int Med, 1999.
  • Measurement of Renal Function
    • Creatinine clearance
      • 24-hour urine collection
      • Problems with complete collection
      • Suffers from tubular secretion issue
        • Not the same as GFR
        • Tends to overestimate GFR at ‘normal’ range
    • Renal function estimating equations
      • Avoids problems with timed collections
      • Attempts to correct for muscle mass using readily available clinical variables
  • Measurement of Renal Function
    • Cockcroft-Gault
    • CrCl (mL/min) = (140-age)(wt kg) x (0.85 if female)
    • 72 (Scr mg/dL)
    • 249 white, male (Canadian), hospitalized veterans
      • Retrospective review of those with two similar 24-hour urinary CrCl
      • 15% reduction for women based empirically on relative muscle masses
    • Renal drug-dosing based on this equation
  • Measurement of Renal Function
    • MDRD
      • Estimates GFR (mL/min/1.73m 2 )
      • Incorporates serum creatinine, age, sex, race (black vs. non-black), BUN, albumin (not weight)
      • Derived from 1070 subjects with kidney disease and validated in 558
      • 60% male, 88% white, 6% diabetic
      • Used for K/DOQI staging of CKD
    • Simplified MDRD
      • Serum creatinine, age, sex, race (not weight)
      • Remarkably similar results to full MDRD
      • Used extensively for epidemiology studies
  • Measurement of Renal Function
    • Pitfalls
      • All formulae derived primarily from patients with impaired renal function
      • All based on serum creatinine
        • May not be helpful in acute, early changes of renal function
        • May be inaccurate at extremes of weight
        • Lean body mass may improve estimates at
        • BMI <17kg/m 2 or >30kg/m 2
  • What is proteinuria and albuminuria?
    • Serum Protein
    • Albumin
    • Globulins
    Urine Protein Albumin >>> Globulins
    • Proteinuria/albuminuria strongly predictive of both renal and cardiovascular outcomes in the general population
  • Measurement of Renal Function
    • Proteinuria and/or albuminuria
      • Dipstick
        • Semiquantitative (0, trace, 1+, 2+, 3+, 4+)
        • Microscopic analysis (Hgb, WBC, RBC, casts)
      • ‘ Spot’ urine protein(albumin)/creatinine ratio
        • Just as good as 24-hour urine collection
        • Easy to get
        • Protein/creatinine > 220-300mg/gm
        • Albumin/creatinine
          • 30mg/gm (microalbuminuria)
          • >300mg/gm (macroalbuminuria/proteinuria)
  • Normal Renal Function
    • Serum creatinine in NHANES III
    • Men Women
    • Age Healthy All Healthy All
    • 20-39 1.14 1.09(1.33) 0.92 0.87(1.08)
    • 40-59 1.17 1.11(1.38) 0.95 0.90(1.14)
    • Best mean estimates for GFR are 130mL/min/1.73m 2 and 120mL/min/1.73m 2 in healthy young men and women, respectively
    • Wide variation (age, race, sex, diet)
    • Key point is complications (death, CV disease, ESRD, anemia, hyperPTH/calcium dysregulation) increase as a continuum with increasing serum creatinine – even with mild increases and especially when GFR falls below 60mL/min/1.73m 2
  • Chronic Kidney Disease K/DOQI. AJKD, 2002.
  • IDSA Guidelines
    • Estimating renal function
      • No systematic validation in HIV patients
      • Recommend Cockcroft-Gault for drug dosing
      • Recommend MDRD for staging
      • Both are used with caution in wasted patients
    Gupta, CID, 2005.
  • Spectrum of Renal Diseases in HIV Etiology Biopsy No biopsy Szczech, Kidney Int, 2003. HIVAN 45.9% (17 ) a 69.8% (30) a Membranoproliferative glomerulonephritis 10.8% (4) 4.7% (2) Diabetes mellitus 5.4% (2) 14.0% (6) Hypertension 5.4% (2) 4.7% (2) Amyloid 5.4% (2) 2.3% (1) Chronic focal glomerulonephritis 2.7% (1)   Focal segmental glomerulosclerosis 5.4% (2)   Membranous glomerulopathy 2.7% (1)   Nonspecific 2.7% (1)   No tissue obtained 8.1% (3)   Mesangial glomerulonephritis 5.4% (2)   Heroin abuse   2.3% (1) Nephrotoxic drugs   2.3% (1) Total 37 43 HIVAN is HIV-associated nephropathy a P = 0.03 (HIVAN vs. all others)
  • AIDS Nephropathy - ESRD
    • Between 1999-2003
      • 4218 new cases (1% of all new ESRD)
      • Median age 40
      • 70% men
        • No sex preference
      • 90% black
      • 3 rd leading cause of ESRD in blacks aged 20-64 (behind diabetes, HTN)
    USRDS, 2005.
  • Prognosis Depends on Histology
    • Retrospective study of biopsy-proven renal pathologies
      • 42 HIVAN, 47 non-HIVAN
      • Progression to ESRD faster in HIVAN
        • Other factors: use of ACE-I, CD4, hepatitis C, creatinine clearance at time of biopsy
    • Strong interaction between histology, viral load, and use of HAART
      • Achieving undetectable viral load did not impact renal progression in non-HIVAN
      • Use of HAART delayed progression in HIVAN, esp. with undetectable viral load; HR 0.24, P=0.03
      • Use of HAART did not impact renal progression in non-HIVAN; HR 3.29, P=0.06
    Szczech, Kidney Int, 2004.
  • Risk Factors for Proteinuria All p<0.0001 Szczech, Kidney Int, 2002. 14% with persistent dipstick proteinuria
  • Risk Factors for Development of Renal Failure 0 0.5 1 1.5 2 2.5 3 3.5 4 Hazard Ratio (HR) HIV RNA CD4 Count Systolic BP Albumin SCr ¦  ‡ * † (1.14–4.76) (1.007–1.03) (1.53–1.83) (1.72–7.14) (2.08–5.26) § 95% (CI) *P=0.02 (>4000 vs.  4000 copies/mL † P=0.001 (  200 vs. >200 cells/  L) ‡ P=0.002 (per increment of 1mmHg) §P=0.0001 (per decrement of 1mg/dL) ¦ P=0.0001 (per increment of 1mg/dL) Szczech, Kidney Int, 2002.
  • Epidemiology of Renal Disease in Africa
    • Prospectively enrolled, cross-sectional study of renal parameters in 373 ARV-naïve subjects
      • No known DM, HTN, renal disease
      • Mean age 35; 68% women, mean CD4 391
    • Renal function
      • Mean CrCl 90mL/min; mean MDRD 103mL/min/1.73m 2
      • 12% <60mL/min; 5% <50mL/min
      • Predictors of <60mL/min were lower HgB, wasting syndrome (proteinuria marginal significance)
    • Proteinuria  1+
      • Only 6%
      • Only predictor was history of TB
    • Implications for drug dosing in Africa (esp. for stavudine, tenofovir)
    Wools-Kaloustian, Nephrol Dial Transplant, 2007 (in press).
  • Proteinuria and CKD: Impact on Mortality (HERS Study) p- value: <0.0001 0.002 <0.0001 <0.0001 0.03 0.004 0.02 > 10K vs. <500 200-500 vs. <200 Gardner, JAIDS, 2003.
    • ≥ 2+ proteinuria
    • SCr > 1.4mg/dL
  • Acute Renal Failure
    • Consequences
      • Mortality
        • 20% overall mortality rate
        • 40-50% mortality for those with SCr > 3.0mg/dL or needing dialysis
        • If ambulatory, prognosis excellent
      • Mild ARF
        • Electrolyte abnormalities – cardiac arrhythmias and cellular enzyme dysfunction
        • Volume retention
        • Anemia
        • More a problem in those with underlying renal disease
        • Drug dosing adjustments
  •   Relative Hazard of Death Prior to the Widespread Use of HAART Sczcech, CID, 2004.
  • Predictors of Mortality Following HAART Sczcech, CID, 2004. 0.02 5.5 1.006, 1.06 1.03 Age (per year increase) 0.008 7.0 1.19, 3.27 1.97 History of hypertension 0.003 8.7 1.29, 3.57 2.15 Prior history of an AIDS defining illness <0.0001 15.5 1.49, 3.33 2.22 Albumin (per decrease in 1 mg/dL) <0.0001 18.3 1.19, 1.60 1.38 CD4 lymphocyte count (per 100 cell/ml decrease) 0.04 4.2 1.03, 3.85 1.96 Inverse creatinine (per decrease of 1 dL/mg) p-value 0.005 Chi 2 7.9 95% CI 1.25, 3.45 HR 2.07 Proteinuria
  • IDSA Guidelines: Screening Algorithm
    • Qualitative assessment for risk of kidney disease
    • Race
    • Family history of kidney disease
    • CD4 lymphocyte count
    • HIV RNA level
    • History of use of nephrotoxic medications
    • Comorbidities
      • Diabetes mellitus
      • Hypertension
      • Hepatitis 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 dipstick
    • creatinine clearance or glomerular filtration rate < 60 mL/min/1.73m 2
    No abnormal values
    • Evaluate proteinuria further with spot urine to protein creatinine
    • Renal ultrasound
    • Consider 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 Nephrotoxicity
    • Fanconi Syndrome
      • Generalized proximal renal tubule dysfunction
      • Hereditary or acquired (cancer vs drug)
      • Normal reabsorption of electrolytes and nutrients are impaired
      • Spillage of electrolytes and nutrients into the urine
      • Persistent, low-level ARF
      • Mortality and serious morbidity (dialysis) quite rare
      • Manifestations may reverse ( hyper kalemia, hyper phosphatemia) as glomerular filtration worsens
  • GFR Changes in Large Prospective Studies Gallant JE, et al. 45 th ICAAC. Washington, DC, 2005. Abstract H-350. Pozniak AL, et al. 10 th EACS. Dublin, 2005. Abstract PE7.3/14. Pozniak AL, et al. 3 rd IAS. Rio de Janeiro, 2005. Abstract WeOa0202. * P <0.05 versus baseline. † P <0.001 versus baseline. ‡ P =0.01 versus baseline. MDRD (mL/min/1.73m 2 ) Cockroft-Gault (mL/min) -0.7 † -0.4 ‡ 110 105 -1.3 +6.2 † 121 121 Tenofovir DF + FTC + EFV (n=257) Zidovudine/3TC + EFV (n=254) Study 934 (48 weeks) -2 +9* 113 114 +2 +7* 122 125 Tenofovir DF + 3TC + EFV (n=299) Stavudine + 3TC + EFV (n=301) Study 903 (144 weeks) Mean Change Baseline Mean Change Baseline
  • What about the real world?
    • Overall risk for TDF toxicity low
      • Retrospective database studies suggest low frequency of discontinuation for renal toxicity
        • 0.8% Jones, JAIDS, 2004.
        • 1.9% Karras, CID, 2003.
        • 7% (1.3% discontinued TDF) Harris, 2003 IAS.
        • 0.39% Moreno, JAIDS, 2006.
        • 1.6% Padilla AIDS Patient Care STDS, 2005.
        • 2/71 ARF cases Franceschini, KI, 2005
        • 0% Gallant, CID, 2005.
        • 1.8% Gupta, unpublished data.
      • Surveillance and recognition biases
      • Lack of a standard definition
  • Who gets this?
    • Risk factors
      • Lower weight Peyriere, JAIDS, 2004.
      • Lower baseline renal function (not just high serum creatinine) Harris, 11 th CROI, 2004.
      • Lower CD4 count Harris, 2003 IAS; Gallant, CID, 2005.
      • RTV-boosted PI or DDI concomitant use Zimmerman CID 2006
    • Not risk factors
      • Race, sex, age, previous adefovir use, duration of TDF use
  • Epidemiology and Outcomes of Tenofovir-Related Fanconi Syndrome
    • Retrospective review of the FDA Adverse Event Reporting System (AERS)
    • 164 cases reported from 2001-2006
      • Median age 45 (12-71)
      • Mostly men (78%)
    • Concomitant medications
      • PI (83%)
      • Boosted PI (74%)
      • DDI (43%)
      • DDI+Boosted PI (34%); DDI+LPV/RTV (22%)
    • Outcomes
      • Hospitalization (46%)
      • Fracture (2%), Dialysis (2%), Death (2%)
    Gupta, Submitted, 2007.
  • Gallant, CID, 2005.
  • Gallant, CID, 2005. Variable TDF group ( n = 344) NRTI group ( n = 314) P Serum creatinine level at start of treatment, mg/dL 0.8 (0.7, 1.0) 0.8 (0.7, 1.0) .56 CL Cr at start of treatment, mL/min 117 (95, 148) 118 (92, 177) .69 Treatment period, days 303 (169, 365) 336 (175, 365) .19 Maximum serum creatinine level, mg/dL 1.0 (0.8, 1.2) 0.9 (0.8, 1.1) .17 Absolute change in serum creatinine level, mg/dL +0.15 (+0.05, +0.30) +0.10 (0.0, +0.25) .01 Calculated minimum CL Cr , mL/min 98 (71, 125) 102 (79, 129) .43 Absolute change in CL Cr , mL/min -13.3 (-24.0, 0.0) -7.5 (-20.5, +6.5) .005 Percent change in CL Cr , % -10 (-22, 0) -6 (-17, +6) .007 Patients with decline in CL Cr , no. (%)       >50% decline 15 (4.4) 6 (1.9) .14 a
  • Possible Mechanisms
    • Increased exposure to tenofovir
      • Decreased renal clearance with LPV/RTV
        • Pop PK analysis Jullien, AAC, 2005.
          • Lower plasma TFV clearance associated with body weight/SCr, proximal tubulopathy, and LPV/RTV use
        • Direct TFV renal clearance analysis Kiser, CROI 2006.
          • TFV renal clearance lower in those also receiving LPV/RTV, but only when adjusted for baseline GFR
  • Possible Mechanisms
    • Increased didanosine exposure with TDF and mitochondrial toxicity in the kidney
      • Reduced kidney mitochondrial DNA in TDF-DDI subjects Cote, Antiviral Therapy 2006. Vidal AAC, 2006.
    • Genetic predisposition
      • hOAT1 SNP associated with lower TFV Km Bleasby, JPET, 2005.
      • SNPs in MRP2 and/or MRP 4 Izzedine, JID, 2006. Kiser, 7 th IWCP of HIV Therapy, 2006
  • What if I stop TDF?
    • Tubular abnormalities seem to resolve in all cases, but renal function may not come back to baseline in some patients (short follow-up period) Zimmerman, CID, 2006. Izzedine, AIDS, 2004.
    • Clinical significance of lower renal function (at relatively normal range) is unknown
  • IDSA Guidelines
    • With frequent use of TDF, most caregivers will see nephrotoxicity, including Fanconi Syndrome
    • TDF toxicity monitoring for high risk groups
      • GFR < 90mL/min/1.73m 2 at baseline
      • Concomitant nephrotoxic drugs
        • Adefovir, acyclovir, ganciclovir, cidofovir
        • Amphotericin, foscarnet
      • Comorbid diseases – diabetes, hypertension
      • Concomitant ritonavir-boosted PIs or DDI (???)
    Gupta, CID, 2005.
  • IDSA Guidelines
    • Biannual measurements
      • Renal function (GFR or CrCl, not just SCr )
      • Serum phosphorus
        • Newer data suggests this is not helpful Day, JAIDS, 2005. Jullien, AAC, 2005. Buchacz, HIV Medicine, 2006. Badiou, J Infect, 2006.
      • Urine analysis for protein and glucose
    • If abnormal?
      • Repeat and confirm!!!
      • Consider 24-hr urine collection for protein, glucose, potassium, phosphorus, calcium, bicarbonate
      • If nephrotoxicity/Fanconi Syndrome confirmed
        • Look for other offending drugs/conditions (myeloma??)
        • Consider stopping offending drugs, including TDF
      • If TDF stopped, get follow-up studies (SCr and urine analysis likely enough, but may want to do repeat 24-hr collection)