Nephrotoxic Burden and Consequences Associated with Drug Induced AKI (D-AKI)

Transcription

1 Nephrotoxic Burden and Consequences Associated with Drug Induced AKI (D-AKI) Sandra Kane-Gill, PharmD, MSc, FCCM, FCCP Associate Professor, University of Pittsburgh Critical Care Medication Safety Pharmacist, UPMC

2 OBJECTIVES Support the importance of nephrotoxic burden as a risk for AKI. Explain the negative consequences attributable to D-AKI. Disclosures: None

3 PREVALENCE OF DRUG ASSOCIATED ACUTE KIDNEY INJURY (D-AKI) IN THE ICU 5,143 patients in 20 ICUs 20% (74/355) associated with drugs ICUs at 5 hospitals 3 rd -5 th 25% (157/618) associated with drugs 26,269 critically ill patients in 54 hospitals in 23 countries 19% (328/1726) associated with drugs Brivet FG et al. Crit Care Med 1996;24:192; Mehta RL et al. Kid International 2004;66: ; Uchino S et al. JAMA 2005;294:

4 RISK FACTORS FOR AKI/D-AKI Description Susceptibilities Exposures Drug-specific Exposure Risk Factors for Critically Ill Age, black race, female,history of diabetes, history of hypertension, previous AKI episode, elevated baseline serum creatinine Nephtoroxin administration, trauma, burn, circulatory shock, sepsis, high risk surgery, hypotension, fluid overload Nephrotoxin treatment duration, cumulative dose, total daily dose, pharmacokinetic and pharmacodynamic drug interactions, nephrotoxic burden Kane-Gill SL, Goldstein SL. Crit Care Clin 2015;31:675 Cotner SE et al. AAC 2017;61:e00871 Cartin-Ceba R et al. Crit Care Res Pract 2012; article ID Ostermann M et al. Crit Care Med 2018: ahead of print Concomitant nephrotoxin administration was an independent predictor of AKI 53% greater odds of developing AKI for every nephrotoxic drug received (OR 1.53; CI ) Significant association between cumulative number of exposures and risk of AKI (p = 0.02) but no association between the each type of exposure and AKI (p = 0.22)

5 NEPHROTOXIC BURDEN IS A CONCERN

6 ADVANCE OUR THINKING BEYOND SINGLE NEPHROTOXINS: DRUG COMBINATIONS Evidence for drug class combinations associated with AKI Completed a formal GRADE process for quality of evidence assessment 76 unique drug combinations 74% very low quality of evidence (D) 16% low quality of evidence (C) 10% moderate quality of evidence (B) 0% high quality of evidence (A) Rivosecchi RM et al. Ann Pharmacother 2016;50:

7 DRUG COMBINATIONS: MODERATE QUALITY OF EVIDENCE Drug Class 1 Drug Class II Mechanism NSAIDs Diuretic pharmacodynamic effect with a decrease in prostaglandin synthesis by NSAIDs causing afferent vasoconstriction and a decrease in effective blood volume by diuretics NSAIDs Diuretic plus reninangiotensin aldosterone system triple whammy cumulative pharmacodynamic effect of each drug - exacerbated by the efferent arteriolar vasodilation caused by the RAAS Statins Macrolide increased serum statin concentrations as a result of inhibition of the cytochrome 450 (CYP450) enzyme system by macrolides Calcium channel blockers Statins Piperacillin/tazobactam Clarithromycin Calcium channel blockers Vancomycin CYP3A4 inhibition of clarithromycin, leading to elevated concentrations of calcium channel blockers leads to global hypotension, affecting the kidney results in ischemic renal injury resulting in AKI drug-drug interaction between certain calcium channel blockers inhibiting CYP3A4 metabolism of statins metabolized through this pathway decreased vancomycin clearance caused by piperacillin/tazobactam potentially leading to a greater degree of vancomycin exposure Rivosecchi RM et al. Ann Pharmacother 2016;50:

8 Vancomycin- AKI VANCOMYCIN AND PIPERACILLIN/TAZOBACTAM ASSOCIATED AKI Renal tubular ischemia following oxidative effects on proximal renal tubule cells- reports of ATN> AIN Relative risk 2.45 (95% CI ) compared to nonglycopeptide antibiotics with moderate level of evidence Piperacillin/tazobactam- AKI Similar rates of AKI for piperacillin/tazobactam compared to ampicillin/sulbactam was 9.5% vs. 8.9%, respectively. Pooled percentages indicate odds of AKI for piperacillin/tazobactam monotherapy > vancomycin monotherapy (Luther 2018) Acute interstitial nephritis (AIN)- characterized by inflammatory infiltrate localizing in renal interstitium Ray AS et al. CJASN 2016;11:2132 Bamgbola O et al. Ther Adv Endocriol Metabl 2016;7:136 D Hoore et al. J Nephrol 2015;28:709 Panwar et al. Am J Med Sci 2013;345:396

9 META-ANALYSES SUMMARY: VANCOMYCIN PLUS PIPERACILLIN/TAZOBACTAM Population Hammond et al # of studies OR (95% CI) Luther et al (adults) # of studies OR (95% CI) Giuliano CA et al (adults) # of studies OR (95% CI) All studies (2-4.8) ( ) Adults ( ) Children 3 5.3( ) V + β lactam** 6 3.6( ) 4 3.0( ) V + Cefepime or carbapenem 4 7.1( ) ( ) V alone ** 3 3.2( ) 18 (5) 3.4 ( ) ( ) PT alone ( ) Good Quality 8 2.4( ) 5 3.0( ) Fair/Poor ( ) Critically ill 4 3.8( ) ( ) Non-ICU 7 2.4( )

10 WHY? Piperacillin/tazobactam Similar rate of AKI for piperacillin/tazobactam compared to ampicillin/sulbactam was 9.5% vs 8.9%, respectively (Rutter 2017); however addition of vancomycin was 18% vs 10% for the combinations. Longer renal recovery rate than other beta-lactams (Jensen 2012) Additive effect of acute interstitial nephritis from piperacillin/tazobactam plus direct cellular necrosis from vancomycin (Hammond 2017) Contrary opinion Longer renal recovery rate compared other beta-lactams but when piperacillin/tazobactam is discontinued SCr resolves (Jensen 2012) pip/tazo competitively inhibits organic anion transport system causing psuedo-nephrotoxicity (Farkas 2016) Need to Answer- Severity/Dialysis? Dialysis rate in piperacillin/tazobactam 19% and comparator groups 38% (p = 0.277) (Hammond 2016)

11 CONSEQUENCES OF D-AKI

12 D-AKI CONSEQUENCES PEDIATRIC, NON-ICU PATIENTS Variable Baseline egfr (ml/min/1.73m2) egfr at 6 months (ml/min/1.73m2) Up/C ratio at 6 months, mg/mg AKI due to Nephrotoxin (n=77) No AKI P Value Hypertension 37.7% sign of CKD < % of patients with drug associated AKI have evidence (reduced egfr, hyperfiltration, proteinuria, or hypertension) of residual kidney damage Menon S et al. J Pediatr 2014;165:522

13 D-AKI CONSEQUENCES 60% 50% 40% 30% Acute Tubular Necrosis (ATN) Nephrotoxicity 20% 10% ATN + Nephrotoxicity 0% In-Hospital Mortality In-Hospital Mortality and/or Dialysis Dependence Other Etiologies Similar, slightly better, mortality rates and/or dialysis dependence compare to AKI of other etiologies Mehta RL et al. Kid Int 2004;66:1613

14 TRANSITIONING FROM ACUTE KIDNEY INJURY TO CHRONIC KIDNEY DISEASE Patients with AKI have a substantial risk of progressing to CKD About 30% of patients who have AKI progress to CKD Dialysis dependence for AKI survivors is 40% Chawla LS et al. Nat Rev Nephrol 2017;13:241. AKI- acute kidney injury AKD- acute kidney disease CKD- chronic kidney disease

15 COLISTIN-AKI TO CKD Up to 40% of patients receiving Purpose Predictors of CKD in survivors of multi-drug resistant infections with colistin-associated AKI Methods Retrospective cohort of pts. with colistin-associated AKI (n=72) compared to controls (n=58), matched by age, sex, diabetes, vancomycin use and baseline kidney fxn Outcome caspase-mediated apoptosis, inducible nitric oxide synthesase (inos), caspase 1, and calpain 1 are involved in the pathogenesis of colistin-associated nephropathy Development of CKD after 6 months of follow-up Ozkan G et al. AAC 2013;57:3463 Meraz-Munoz A et al. J Crit Care 2017;44:244 Results CKD in 75% of colistin group compared to 27% controls; Predictors- colistin exposure (OR 8.9) and age (OR 1.04)

16 COST OF AKI Admission to 1-yr for Hospitalized Adults Total Cost Incremenatal Cose Total Costs Incremental Costs Admissions for Hospitalized Adults from Recovered Not Recovered Collister D et al. Clin J Am Soc Nephrol 2017: 12:1733 Recovery or 90 days to 1-year

17 MONITORING BEYOND INITIAL ONSET OF D-AKI IS NEEDED TO PREVENT CHRONIC COMPLICATIONS

18 FOLLOW UP IS POOR Guidelines recommend follow up within 3 months of acute kidney injury episode Medicare Population High Risk for Progression to CKD 13% saw a nephrologist 75% saw a primary care physician 12% no follow up 25% saw a nephrologist 75% not with a nephrologist Silver SA, Siew ED. Adv Chronic Kidney Dis. 2017;24(4): Saran R, et al. Am J Kidney Dis. 2016;67(3 Suppl 1):Svii, S1-305.

19 FOLLOW UP IS POOR Guidelines recommend follow up within 3 months of acute kidney injury episode Medicare Population High Risk for Progression to CKD 13% saw a nephrologist 75% saw a primary care physician 12% no follow up 25% saw a nephrologist 75% not with a nephrologist Only 60% had a creatinine checked Silver SA, Siew ED. Adv Chronic Kidney Dis. 2017;24(4): Saran R, et al. Am J Kidney Dis. 2016;67(3 Suppl 1):Svii, S1-305.

20 BUT FOLLOW UP CAN IMPROVE OUTCOMES! All-cause mortality was lower in patients with early nephrology follow-up compared with those without (8.4 compared with 10.6 per 100-patient years, hazard ratio 0.76 (95% CI: )) Harel Z et al. Kidney Int2013;83:901

21 PUBLIC KNOWLEDGE 1 in 2 people know their kidneys make urine 1 in 8 thought kidneys processed medications Most drugs and or their metabolites are eliminated by the kidney at least 75% 2 in 10 are aware that they experienced an episode of AKI in the hospital This is a public concern and needs to be improved. Further problem: 68% had not heard of AKI

22 BEGINS WITH HEALTH LITERACY ABOUT MEDICATIONS Patients with low health literacy have difficulty taking prescription medications Medication errors are linked to a patient's understanding of the indication, dosage schedule, proper administration, and potential adverse effects 2 in 10 patients take a drug like ibuprofen after an acute kidney injury episode Lipworth L, et al. BMC Nephrol. 2016;17(1):189. AHRQ PSNet and Wolf MS et al. Patient Educ Couns 2007;67:293.

23 MEDICATION MANAGEMENT APPROACH FOR AKD

24 FOCUS AT HOSPITAL DISCHARGE AND BEYOND Discussion with patient at hospital discharge about AKI and medications Medications Which to avoid Consider appropriate dosing Verbal discussion and written information Encourage consultation with a pharmacist about medications after their hospital stay Encourage follow with a physician and conversation about AKI after their hospital stay Kane-Gill SL et al. Hosp. Pharm 2017;52:663 Ostermann M et al. Br J Clin Pharmacol 2018;84:396

25 PROVIDE A MOBILE APPLICATION FOR PATIENT USE: MYKIDNEY Allows patient to enter laboratory values From hospital and over time Allows patient to enter medications Provides caution signals for medications Provides some education about AKI Can be used as a tool to communicate with the physician during a follow up visit

26 Silver SA et al. Can J Kidney Health Dis 2015;2:36 WALLET CARD

27 SUMMARY Advanced thinking requires consideration of nephrotoxic burden as a cause of AKI Piperacillin/tazobactam results in increased serum creatinine however the contribution to AKI in combination with vancomycin is still unclear Similar, slightly better, mortality rates and/or dialysis dependence for D-AKI compared to AKI from other etiologies AKI transition to CKD concerning so post-aki monitoring, education and medication management is important.