HIV and Renal Disease

Transcription

1 HIV and Renal Disease THE MEDICAL MANAGEMENT OF HIV/AIDS DECEMBER 8, 2012 Disclosure: No conflicts of interest Disclaimer: This presentation may contain information on off-label or investigational uses of commercial products. MICHELLE M. ESTRELLA, MD, MHS DIVISION OF NEPHROLOGY JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE Objectives Kidney Disease in HIV-infected Persons Review the epidemiology of renal disease in the HIVinfected population Describe the spectrum of kidney diseases in HIV infection Discuss the work-up and management of kidney disease in HIV-infected individuals Discuss the potential impact of renal disease on HIV infection management Islam FM, et al. BMC Public Health 2012; 12:234. HIV-infected individuals at greater risk for: Acute kidney injury (AKI) Chronic kidney disease (CKD) 10-30% have albuminuria/ proteinuria % have estimated GFR<60 ml/min/1.73m 2 Szczech LA,et al. AIDS 2007;21: Fernando SK, et al. Am J Med Sci 2008;335: Jones CY, et al. Am J Kidney Dis 2008;51:

2 Spectrum of kidney diseases in HIV General Approach to Kidney Disease Screening and Monitoring HIVAN HIV-Mediated HIVICK Thrombotic microangiopathy Non-HIV Mediated Diabetic nephropathy Hypertensive nephrosclerosis Post-infectious GN Amyloidosis Drug Toxicities Acute interstitial nephritis Fanconi Syndrome (tenofovir, cidofovir, adefovir) Crystal neprophathy/ nephrolithiasis (indinavir, atazanavir) Screen all patients at HIV diagnosis for: Risk factors for kidney disease Kidney disease Monitor the following patients more closely Those with established kidney disease Those with kidney disease risk factors Those receiving potentially nephrotoxic drugs Frequency depends upon presence of risk factors and drug exposure Risk Factors for CKD in HIV-infected Individuals Recognition of Kidney Disease in HIV-infected Patients Traditional risk factors Older age Black race Family history of kidney disease Chronic medical conditions Diabetes Hypertension Cardiovascular/peripheral vascular disease Severe AKI Factors frequently found in HIV-infected persons Significant HIV viremia Hepatitis C co-infection Illicit drug use (esp. cocaine) Exposure to certain nephrotoxic drugs IDSA Guidelines Estimate GFR and proteinuria at first visit Further work-up or renal referral if: Estimated GFR <60 ml/min/1.73 m 2 Urine protein 1+ or greater Gupta SK, et al. Clin Infect Dis. 2005;40:

3 Estimating kidney function Estimating kidney function Do not rely on serum creatinine (SCr) alone to guess kidney function 24 yo black man 63 yo white man 63 yo white woman SCr (mg/dl) egfr (ml/min) > GFR Best overall index of kidney function Generally estimated using serum creatinine (SCr)-based equations which attempt to adjust for muscle mass Cockcroft-Gault MDRD Equation CKD-Epi Equation Drawbacks of SCr Insensitive to early declines in kidney function Misleading in patients with low/high muscle mass and poor nutritional status Caveats of Using GFR-Estimating Equations Assessing for Proteinuria Not validated in HIV-infected persons Tend to underestimate true GFR Less accurate at: GFR >60 ml/min Extremes of body weight Nephrotic proteinuria Old age Not accurate in: Pediatric patients AKI 24-hour urine collection is gold standard Urine protein: creatinine ratio Correlates w/ 24-hr collection More feasible Decreased accuracy in: Significant proteinuria AKI (esp. oliguric) Random urine: Protein mg/dl Creatinine mg/dl Levey AS, et al. Ann Intern Med. 2009:150: Ginsberg et al. NEJM 1983, 309:25 3

4 CKD Staging Reasonable triggers for renal consultation Stage Description GFR (ml/min) --- Increased risk 90 with risk factors 1 Kidney damaged but GFR normal 90 with proteinuria/ hematuria 2 Kidney damaged, GFR reduced Moderate CKD Severe CKD Kidney failure <15 or dialysis Rapid renal disease progression Uncertain etiology of renal disease Significant or worsening proteinuria Persistent/ recurrent electrolyte or acid-base disturbances of unclear etiology All patients with egfr <30 ml/min Severe or difficult-to-control hypertension Levey A. et al., Am J Kidney Dis. 2002; 39: S Case 1: 50 yo African American with AKI and proteinuria Differential Dx for Significant Proteinuria in HIV Infection PMH Untreated HIV infection CD4+ = 47 cell/mm 3 HIV RNA = 265,000 copies/ml Type 2 DM x 3 years Renal history Baseline SCr = 0.9 mg/dl 2 mos later SCr = 2.6 mg/dl UPCR = 1.78 g/g 3 weeks later SCr = 5.1 mg/dl UPCR > 8.0 g/g SCr, mg/dl HIV-Associated Nephropathy (HIVAN) Focal segmental glomerulosclerosis (FSGS) Idiopathic Drug-induced: Interferon, Lithium Post-Adaptive: Obesity, hypertension Minimal change Secondary causes: NSAIDs, Hematologic malignancies Membranous Nephropathy Secondary causes: Lupus, Solid tumor malignancies Amyloidosis Secondary causes: Chronic inflammatory diseases, recurrent infections Advanced diabetic nephropathy NEED RENAL BIOPSY TO MAKE DEFINITIVE DIAGNOSIS! 4

5 HIVAN HIVAN Pathogenesis Accounts for a decreasing proportion of kidney disease in HIV Exclusively in individuals of African descent Occurs in patients with significant HIV viremia Typically late HIV disease stage Rarely during acute HIV infection Characterized by: Nephrotic-range proteinuria Progressive renal function decline over weeks months Typically no edema Likely due to combination of host genetic susceptibility and HIV-infection Quaggin S. J Clin Invest 2009; 119: Gharavi A, et al. J Clin Invest 2009; 119: APOL1 Associated with Non-Diabetic Kidney Disease in African Americans including HIVAN APOL1 predicts underlying kidney disease in HIV Lesion 2 risk alleles (N=29) 1 risk allele (N=44) No risk allele (N=25) P- value FSGS 76% 23% 12% < HTN nephrosclerosis 10% 0 8% 0.03 DiabeFc nephropathy Immune- complex GN 10% 9% 28% % 47% 40% < Other 0 23% 4% < 0.01 Genovese G, et al. Science 2010;329: Leslie M. Science 2010;329:263. Abbrevia5ons: FSGS, focal segmental glomerulosclerosis; HTN, hypertension; GN, glomerulonephri5s Fine DM, et al. JASN 2012;23:

6 Treatment of HIVAN Case 2: 51 yo woman with rising SCr Initiate HAART immediately and never stop Empiric treatment if kidney biopsy not imminent Steroids early in course if severe Start at 1 mg/kg with a taper over 8-12 weeks ACE-inhibitors if tolerated Difficult to use in advanced disease TDF/FTC/LPV/RTV started in 07/2006 SCr at the time = 0.8 mg/dl (egfr = 88 ml/min) Clinical course Slow increase SCr over time Intermittent hypophosphatemia 04/2007 SCr = 1.3 mg/dl (egfr = 49 ml/min) Serum phosphate = 2.1 mg/dl Urinalysis: 2+ urine glucose, trace proteinuria Scialla J, et al. AIDS. 21; Tenofovir Nephrotoxicity Mechanism for TDF Nephrotoxicity Classically partial/ full Fanconi Syndrome Proteinuria (34% risk) Euglycemic glycosuria Hypokalemia Hypophosphatemia with phosphaturia Metabolic acidosis (type II RTA) Other clinical presentations Acute tubular necrosis GFR decline (33% for CKD) Osteomalacia Herlitz LC, et al. Kidney Int. 2010;78: Scherzer R, et al. AIDS 2012;26: Izzedine H, et al. Nature Rev Nephrol. 2009;5:

7 Proximal Tubular Disorder Features of 10 Patients with high FePhos FePhos (%) Serum Phos (mg/dl) Urine Gluc Time on drug (mos) Baseline SCr (mg/dl) SCr at drug d/c (mg/dl) GFR change (ml/min) > Unpublished data. Courtesy of DM Fine Risk Factors Tenofovir Nephrotoxicity CKD (contraindicated when egfr<70-80 ml/min) Co-administration with other nephrotoxic agents (e.g. atazanavir, lopinavir) Co-administration with ritonavir-boosted protease inhibitors Intravascular depletion Diagnosis based on laboratory data Mocroft A, et al. AIDS 2010;24: Goicoechea M, et al. J Infect Dis. 2008;197: Management Strategy for Patients on Tenofovir Monitor the following: Basic metabolic panel: particular attention to K+ and bicarb Urine dipstick UPCR in patient w/ established proteinuria Fractional excretion of phosphate if any other abnormalities Abnormal if: >10% when serum phosphate is low >20% when serum phosphate is normal Management Strategy for Patients on Tenofovir Issues of SCr on Stribild (elvitegravir/cobicistat/ emtricitabine/ tenofovir) In trials, cobicistat increased SCr independent of GFR Patients with increase in SCr >0.4 mg/dl from baseline should be closely monitored for renal safety In this setting, would check daily-weekly SCr D/c if ongoing increase as could be TDF-related AKI Discontinue TDF ASAP when renal abnormalities noted Reversible if caught early Kidney function does not always return to baseline Prevention by co-administration of probenecid? Wever K. et al. J Acquir Immune Defic Syn. 2010;55: Izzedine H. AIDS. 2010;24:

8 Other Drug Nephrotoxicities in HIV Case 3: 55 yo Caucasian woman with rising SCr ATN/tubular disorder Aminoglycosides, amphotericin B Cocaine Radiocontrast Crystalluria/Stones Indinavir, atazanavir, sulfadiazine, TMP/SMX Presentation varies: asymptomatic crystalluria, crystal nephropathy, flank pain w/ urinary tract obstruction Atherosclerotic vascular disease Tobacco Cocaine Past Medical History Longstanding controlled HIV infection HCV co-infection, Hypertension Baseline SCr of 1.4 mg/dl (egfr~42 ml/min) Previous renal bx (2/2008): Glomerulosclerosis, moderate tubulointerstitial scarring, moderate arterionephrosclerosis Recently re-initiated on furosemide for severe edema Meds: Furosemide, minoxidil, rabeprazole, metoprolol XL, losartan, vitamin D, efavirenz, lamivudine and zidovudine PE: Afebrile. BP = 140/ lower extremity edema. No rashes Labs at follow-up: Serum creatinine (SCr) = 2.0 mg/dl Urine protein-to-creatinine ratio (UPCR) = 5 g/g Kopp JB, et al. Ann Intern Med.1997;127: Case 3: Serum Creatinine Trend Renal Bx Etiology of AKI in HIV Infection Serum Creatinine, mg/dl Furosemide Furosemide AKI Events Number Diarrhea, Nausea, Vomiting, Dehydration (38%) Sepsis or Infection Cirrhosis Heart Failure Pancreatitis Adrenal Insufficiency Erythroderma 48 (46%) Acute Tubular Necrosis, Ischemic 22 Nephrotoxic Drugs Interstitial Nephritis Nephrotoxic Radiocontrast Thrombotic Thrombocytopenic Purpurahemolytic Uremic Syndrome 9 (7%) 11 (9%) Crystalluria Kidney Stones Gross Hematuria 11 Pre-renal Renal Obstructive Unknown Causes Franceschini N, et al. Kidney Int. 2005;67(4):

9 Case 3: Clinical Course Drug-Induced Acute Interstitial Nephritis (AIN) Renal biopsy findings: Acute interstitial nephritis Advanced tubulointerstitial fibrosis Furosemide discontinued Patient initiated on prednisone 60 mg/day Clinical Presentation SCr rise may be over several weeks on 1 st exposure More rapid rise (2-4 days) on 2 nd exposure Suggested by pyuria, eosinophilia/ eosinophiluria, fever, and rash... Absence of these findings does NOT rule out AIN Frequency of AIN Findings Management of AIN Methicillin Other Drugs Rossert J. Kidney Int. 60: Discontinue all potential culprits NSAIDs Antibiotics: penicillins, cephalosporins, ciprofloxacin, macrolides, isoniazid, ethambutol, rifampin, sulfonamides Diuretics: furosemide, thiazides Proton pump inhibitors ARTs: nevirapine, efavirenz, indinavir, atazanavir Oral steroids? Consider if no improvement by 3 rd -5 th day after drug discontinuation Typically prednisone mg/day, but duration dependent on response Gonzalez E. et al. Kidney Int. 2008;73:

10 General Approach to AKI Case 3: Clinical Course Consider usual non-hiv related causes first (eg. ATN, AIN, etc). Consider renal consultation sooner rather than later if: Worsening AKI despite treatment Accompanying electrolyte or acid/ base derangements Unclear etiology Adjust drug dosages for kidney function level If suspect HIVAN: Consider renal biopsy Initiate antiretrovirals ASAP If suspect drug-related toxicity Discontinue offending agent ASAP Consider steroids if due to AIN If etiology unclear, find alternatives to all neprotoxic drugs Renal Bx Management of Patients with CKD Management of Patients with CKD Management of HIV Disease Priority: suppress HIV viremia Selection of initial ART regimen Avoid drugs with nephrotoxic potential (tenofovir, atazanavir, indinavir) Adjust drug dosage based on egfr For ART-exposed individuals Changes in ART regimen depends on etiology of CKD & resistance panel Must be individualized Management of CKD progression Consider renal consultation if Etiology unclear egfr<30 ml/min Rapid or acute worsening of kidney function or proteinuria Manage CKD risk factors Control blood glucose in diabetics (goal HgbA1c<7%) If proteinuric: consider ACE-inhibitors/ ARBs Discontinue tobacco/ cocaine use Encourage weight loss if obese 10

11 Management of Patients with CKD Management of Patients with CKD Management of CKD-related Disorders Anemia: Work-up as with any other patient Target Hgb: g/dl Ensure patient iron-replete prior to initiating erythropoiesis stimulating agents (ESAs) ESAs contraindicated in patients with cancers Mineral and bone disorder Monitor serum calcium, phosphorus, 25-OH vit D, and intact PTH Target parameters: Serum calcium & phosphorus within normal; 25-OH vit D>30 ng/ml, ipth in high-normal Metabolic acidosis Target serum bicarbonate: meq/l Correction to 22 meq/l may slow CKD progression Kidney Disease Outcomes and Quality Initiative: Guideline for Anemia Kidney Disease Improving Global Outcomes: Guideline for CKD-Mineral and Bone Disorder de Brito-Ashurst et al. JASN 2009;20: Management of Patients with CKD Albuminuria and CKD Mortality Risk Cardioprotection CKD patients at high risk for cardiovascular disease Target BP: 130/80 Target Lipids: LDL<100 mg/dl, Triglyceride <200 mg/dl Choi AI, et al. Circulation.2010;121:

12 Case 4: 56 yo male with CKD and dyslipidemia Case 4: Clinical Course PMH: Hypertension CKD (egfr 45 ml/min) HIV treated with TDF/Emtricitabine, ritonavir, atazanavir Labs: SCr = 1.5 mg/dl LDL = 130 mg/dl Patient initiated on atorvastatin Two weeks later... Presents with AKI Creatine kinase = 80,000 IU/L What happened? Rhabdomyolysis Drug Interactions: Lipid Lowering Drugs and Protease Inhibitors Drug Culprits Raltegravir HMG CoA-reductase inhibitors Cocaine use Increased risk with Underlying liver disease Co-administration of protease inhibitors with HMG CoAreductase inhibitors or fibrates Izzedine H, et al. Nature Rev Nephrol. 2009;5:

13 Take Home Points THANK YOU! Screen initially and monitor for kidney disease Use egfr and UPCR Frequency depends on risk factors and existing kidney disease If AKI, Think of usual suspects If w/ significant proteinuria, r/o HIVAN Renal biopsy often needed to make diagnosis D/c nephrotoxic agents; don t forget to adjust med dosing If CKD, determine etiology then proceed with CKD management Selection of initial and subsequent ART regimens must balance between HIV control and kidney disease risk Derek Fine Mohamed Atta Greg Lucas Stephen Gange Lisa Jacobson Alison Abraham Michael Shlipak 13