1. GRADE-ing Drug Combinations Associated with AKI
Sandra Kane-Gill, PharmD, MS, FCCM, FCCP
Associate Professor of Pharmacy, Critical Care Medicine, and Biomedical Informatics
Center for Critical Care Nephrology

2. Objectives
Describe the use of GRADE for evaluating the quality of evidence.
Summarize the literature on drug combinations.
Learn from the articles that are ranked as higher quality

3. Prevalence of Drug Associated Acute Kidney Injury (AKI)
5,143 patients in 20 ICUs
20% (74/355) associated with drugs
ICUs at 5 hospitals
25% (157/618) associated with drugs
26,269 critically ill patients in 54 hospitals in 23 countries
19% (328/1726) associated with drugs
3rd-5th
Bernieh lists as 2nd but not all ICU patients and sample very small.
Three hundred sixty patients with acute renal failure met the inclusion criteria (7% of ICU admissions); 217 patients were included at admission and 143 secondarily. Brivet CCM month evaluation- 3RD Place
Point prevalence study of 26,269 patients in 54 hospitals in 23 countries indicates drugs contribute to AKI in 19% of cases (n=1726)- Uchino, Kellum
Other factors septic shock, major surgery, cardiogenic shock, hypovolemia then drugs. - 5TH PLACE
Close to 80% of patients were on vasoactive drugs and mechanical ventilation at the time RRT was initiated. Silvester W Crit Care Med 2001
Mehta 31 months – Drugs top 4th with ishemic ATN, sepsis and hypotension, ahead-prospective observational cohort REMBER DOUBLE COUNTING OCCURRED for eval of 4th
AKI in hospital patients is about 5-7%
AKI in ICU patients jumps up to 20-50% with lower end in elective surg pts and higer in patients with sepsis. OTHER REF SAY AS LOW AS 6% (Mueller)
Approximately 6% proceed to CRRT
% that are drug
Drug induced AIN described to cause AKI in 3-10% (as high as 27% in select poplulations)- Parzella 2012
Drug induced AIN 4-15$ Mueller Crit Care Clin
16% of in hospital peds develop drug associated AKI- with 20-30% of ped patients having AKI after 5d aof AMG (Menon S, Goldstein 2014)
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. Nephrotoxin Use 182 drugs commonly prescribed in ICU
23% were known nephrotoxins
83,970 orders for the 182 drugs in 1 year
18,180 orders or 22% were for a nephrotoxin
Most Frequently Ordered Nephrotoxins
Frequency of Orders
Acetaminophen
2751
Aspirin
1935
Cefazolin
1083
Furoseminde
2085
Piperacillin/tazobactam
1258
Vancomycin
1890
Merged lists of top 100 drugs prescribed in 6 adult ICUs at the University of Michigan for a total of 182 drugs (including as needed) in 1 year 2004
23% or 41 of the 182 drugs
Nephrotoxic potential evaluated by reviewing MICROMEDEX
Drugs did not necessarily cross over between peds and adults
Taber SS et al. Crit Care Clin 2006;

5. Consequences of Drug Associated AKI
Patients with kidney injury in the ICU were 16-times more likely to have an adverse drug event
Rate of drug-induced AKI increased 2 fold ( )
70% of patients with drug associated AKI have evidence of residual kidney damage
Similar mortality rates and/or dialysis dependence to AKI of other etiologies
Prevention of Occurrence would be nice but prevention of progression is our likely intervention
70% of patients had evidence of residual kidney damage (reduced eGFR, hyperfiltration, proteinuria, or hypertension). F
Rate of drug-induced AKI resulting in hospitalzation increased 2 fold ( )- In England …. 10 year analysis of drug related hospital admissions in UK
Approximately 50% of patients with drug associated AKI may show permanent damage Grunfeld JP et al. In: Diseases of the Kidney (eds Schrier RW et al)
Recurrent AKI episodes have worse outcomes… not drug specific .. Harris DG et al. J Trauma Acute Care Surg 2014;76:1397
Kane-Gill SL et al. Crit Care Med 2012;40:823
Wu TY et al J R Soc Med 2010;103:239
Menon S et a. J Pediatr 2014;165:522
Mehta RL et al. Kid Int 2004;66:1613

6. Think about your list of known nephrotoxins…

7. Multivariable Regression Analyses for AKI Patients Compared to Non-AKI Patients by Age Strata

8. Drug Combinations: Risk for AKI
Development and refinement of a predictive AKI trigger with the goal of detection before injury, an ADE
Knowledge for alert
Patient receives 3 or more nephrotoxins on the same day
Patient received IV aminoglycosides for 3 ore more days in a row
Evidence of AKI by both relative and absolute criteria
SCr increased by ≥ 50% or SCr increased by 0.3mg/dL in 48h
Pharmacist managed-outside of workflow
Alert performance has neared 100% through an iterative process
BEFORE Injury occurred
Manual then automated
How did they determine Drug list
Kirkendall ES et al. Appl Clin Inform 2014;5:313

9. Questions
Are these drug combinations appropriate for the adult population?
What drug combinations create the greatest risk?
What is the evidence for different drug combinations?
The risk for drug associated AKI is real and the risk increases with combinations.

10. GRADE
GRADE criteria provide a systematic approach to review a body of literature through a quality of evidence assessment
2 Components:
Quality of evidence (VL, L, M, H)
Strength of recommendation (1, 2)
Factors deciding Quality of Evidence
Study limitations
Inconsistency in results
Plausible confounding
The criteria have been applied to numerous consensus guidelines evaluating large numbers of studies.
strength of a recommendation reflects the extent to which we can be confident that the desirable effects of an intervention outweigh the undesirable effects.
Guyatt GH et al. BMJ 2008;336:
Guayatt GH et al. BMJ 2008;2008:

11. Methods Medline and Embase from 1946 to September 2014
Inclusion: English language, full-text availability, at least one drug-combination reported
Excluded: contrast-induced nephrotoxicity, review articles
14 reviewers evaluated the relevant literature using the quality of evidence component of GRADE
Unique drug combinations were voted on by each reviewer
≥75% agreement required in order to assign a quality of evidence score

12. Results
Examples of the 74 drug-class combinations

13. Number of Drug-Class Combinations
Results
Quality of Evidence
Number of Drug-Class Combinations
Examples
Very Low
57 (76%)
Cyclosporine/Fluoroquinolone
Diuretic/ACE
Low
11 (14.7%)
Aminoglycoside/Cephalosporin
NSAID/ACE
Moderate
7 (9.3%)
NSAID/Diuretic/ACE
Statin/Macrolide
High
56 (75%) only had a single article to review
ACE= angiotensin converting enzyme inhibitor
NSAID= nonsteroidal anti-inflammatory
Statin= HMG-CoA reductase inhibitor

14. Hospitalization for AKI
Statin and Macrolide
Pharmacokinetic drug interaction
Population-based, retrospective cohort study
Continuous statin users, >65 y.o. (n=721,277)
Macrolide
Sample (n)
Inhibits CYP3A4
Hospitalization for AKI
Clarithromycin
72,954
Yes
347 (0.46%)
Erythromycin
3,267
Azithromycin
68,478 No
176 (0.26%)
3 articles with 1 large observational trial and 2 case reports
Number needed to harm 499; Adjusted relative risk 1.83
Increase statin blood concentrations
Followed 30-days post index (first day of coprescription
Used diagnostic codes = median absolute SCR of 98umol/L grerater than the most recent SCR before hospitalization
Also looked at hyperkalemia and all cause mortality
Patel AM et al. Ann Intern Med 2013;158:

15. Triple Whammy: NSAID, Diuretics, ACE inhibitor
Pharmacodynamic drug interaction
NSAID  prostaglandin synthesis, afferent arteriolar constriction
Compensatory efferent arteriolar dilation blocked by ACE inhibitor
Diuretic  renal blood flow
Retrospective cohort study with a nested case-control analysis
Case= first hospital admission for AKI (n=2,215)
Triple whammy
Use = 24.6% in case and 11% in control
Rate ratio (95% CI) = 1.31 ( )
Highest risk in 30 days after co-prescription and higher propensity for NSAIDs with a longer half-life
Six articles were evaluated – largely retrospective cohort trials and one prospective evaluation
NSAIDS lead to a decrease in prostaglandin synthesis creating afferent arteriolar constriction and the compensatory efferent arteriolar dilation in blocked by the use of ACE/ARB. Lastly, diuretics decrease renal blood flow which decreases renal perfusion, another compensatory mechanism.
Controls no AKI; matched 10:1
Refernce for LR was the double therapy of either ACE/Diuretic
Lapi F et al. BMJ 2013;346:e8525

16. Summary and Next Steps
Evidence for drug combinations and risk for AKI is lacking
Next Steps
More thoroughly test drug combinations (different combinations, larger set of patients)
Control for indication bias
Evaluate different patient populations
Goal: better manage nephrotoxins; prevent AKI and mitigate severity
indication bias; dosing; temporal sequence; peds and adults; ICU and non-Icu

17. Collaborators Ryan Rivosecchi John Kellum Raghavan Murugan
Mike Armahizer
Scott Bolesta
Mitch Buckley
Joe Dasta
Amy Dzeirba
Erin Frazeee
Heather Johnson
Cat Kim
Pam Smithburger
Adrian Wong