Drug Induced/Associated AKI

Sandra Kane-Gill, PharmD, MSc, FCCM, FCCP

Professor, University of Pittsburgh, School of Pharmacy
Faculty, Program for Critical Care Nephrology, Department of
Critical Care Medicine
Immediate Past President, Society of Critical Care Medicine
 • Grant funding from the National Institute of Diabetes and
Digestive and Kidney Diseases R01DK121730
and U01DK130010, the National Center for
Complementary and Integrative Health U54AT008909 and
Disclosure/Conflict the Jewish Healthcare Foundation.

of Interest(s)
• Hold an executive position in the Society of Critical Care
Medicine.
Objectives

1 2 3 4
Discuss the taxonomy Organize D-AKI by State the deleterious Review a patient case
for kidney related mechanisms of injury risk modifiers than can for causality
diseases and disorders into contemporary influence movement assessment
– drug classification that aligns between categories
induced/associated AKI with the proposed
classification for AKI
What existing definitions and functional
criteria for AKI would you use to detect
drug related KD?
 Definition/Description of Drug Related Kidney
Diseases and Disorders
Author (Year) Guidelines Referenced for Definition of D-AKI
Definitions
Ye (2022) RIFLE - risk, injury, failure, "The RIFLE criteria, which are based on the highest serum creatinine value
loss, end-stage kidney observed during polymyxin B therapy and compared with the baseline, were
disease used to evaluate whether the patients had developed renal injury and the
severity of nephrotoxicity."
Wang (2020) Clinical practice guideline "The diagnosis of drug-induced kidney injury was based on the 2016 clinical
for drug-induced kidney guidelines in Japan."
injury in Japan 2016
Oda (2020) AKIN "...an increase in SCr level >0.3 mg/dL or >50% in at least two consecutive
measurements during vancomycin therapy."
Yamamoto (2019) KDIGO (CKD) "The following categories were included in the definition of RAS inhibitor–
related kidney injury: (a) RAS inhibitor–related eGFR decline of greater than
or equal to 30% defined as an eGFR decline that recovered by greater than or
equal to 30% within 3 months of discontinuation of the RAS inhibitor and (b)
RAS inhibitor–related hyperkalemia of greater than or equal to 6.0 mEq/L
defined as a potassium level greater than or equal to 6.0 mEq/L that
normalized after discontinuation of the RAS inhibitor."
 Definition/Description of Drug Related Kidney
Diseases and Disorders
Author (Year) Guidelines Referenced for Definition of D-AKI
Definitions
Ye (2022) RIFLE - risk, injury, failure, "The RIFLE criteria, which are based on the highest serum creatinine value
loss, end-stage kidney observed during polymyxin B therapy and compared with the baseline, were
disease used to evaluate whether the patients had developed renal injury and the
severity of nephrotoxicity."
Wang (2020) Clinical practice guideline "The diagnosis of drug-induced kidney injury was based on the 2016 clinical
for drug-induced kidney guidelines in Japan."
injury in Japan 2016
Oda (2020) AKIN "...an increase in SCr level >0.3 mg/dL or >50% in at least two consecutive
measurements during vancomycin therapy."
Yamamoto (2019) KDIGO (CKD) "The following categories were included in the definition of RAS inhibitor–
related kidney injury: (a) RAS inhibitor–related eGFR decline of greater than
or equal to 30% defined as an eGFR decline that recovered by greater than or
equal to 30% within 3 months of discontinuation of the RAS inhibitor and (b)
RAS inhibitor–related hyperkalemia of greater than or equal to 6.0 mEq/L
defined as a potassium level greater than or equal to 6.0 mEq/L that
normalized after discontinuation of the RAS inhibitor."
 Temporal Sequence- Drug Related Kidney
Diseases and Disorders

Author (Year) Guidelines Referenced for Temporal Sequence

Definitions
Ye (2022) RIFLE - risk, injury, failure, loss, end- During polymyxin B therapy
stage kidney disease
Wang (2020) Clinical practice guideline for drug- A drug exposure history within 3 month of AKI
induced kidney injury in Japan 2016
Oda (2020) AKIN During vancomycin therapy

Yamamoto (2019) KDIGO (CKD) Within 3 months of discontinuation of the RAS

inhibitor
What is acute kidney disease (AKD)?
 Kidney Diseases and Disorders (KD)
abnormalities in kidney structure and function, with implications for health

AKI AKD CKD

Duration Within 7 days </= 3 months >3 months

Definition a subgroup of AKD, defined by
abnormalities in kidney function
over 6 hours to 1 week with
duration <3 months
Functional Criteria Increase in Scr by >50% within 7
days,
OR Increase within 2 days,
OR Oliguria for >4 hours
Structural Criteria Not defined
abnormalities in kidney structure and abnormalities in kidney
function for <3 months, with implications structure and function, with
for health, which may precede CKD or may implications health, with
be superimposed on CKD, with duration <3 duration >3 months
months
AKI, GFR <60 ml/min/1.73m2
OR GFR<60 mL/min/1.73m2,
OR Decrease in GFR by >35% times
baseline,
OR Increase in SCr by >50% times baseline
Marker of kidney damage (albuminuria, Marker of kidney damage
hematuria, or pyuria are most common) (albuminuria is most common)

Levy AS. Nephron 2022;146:302–305

 Kidney Diseases and Disorders (KD)
abnormalities in kidney structure and function, with implications for health

AKI AKD CKD

Duration Within 7 days </= 3 months >3 months

Definition a subgroup of AKD, defined by
abnormalities in kidney function
over 6 hours to 1 week with
duration <3 months
Functional Criteria Increase in Scr by >50% within 7
days,
OR Increase within 2 days,
OR Oliguria for >4 hours
Structural Criteria Not defined
abnormalities in kidney structure and abnormalities in kidney
function for <3 months, with implications structure and function, with
for health, which may precede CKD or may implications health, with
be superimposed on CKD, with duration <3 duration >3 months
months
AKI, GFR <60 ml/min/1.73m2
OR GFR<60 mL/min/1.73m2,
OR Decrease in GFR by >35% times
baseline,
OR Increase in SCr by >50% times baseline
Marker of kidney damage (albuminuria, Marker of kidney damage
hematuria, or pyuria are most common) (albuminuria is most common)

Levy AS. Nephron 2022;146:302–305

Drug related kidney disease or disorder (DKD)
An AKI, AKD or CKD event that is determined to be associated or induced by
a nephrotoxic drug.

Induced vs Associated
Drug Associated AKI Drug Induced AKI

No definite or conclusive data

that a drug is causing the AKI Definite or conclusive drug
event but… causality (beyond association)

It is being administered at the At minimum the SCr was

time of the index SCr
stable before the drug
administration
OR after the AKI event began

AND could be causal or

contributing to the AKI
Serum Creatinine Trend

Example - KD
1.5
1.3 1.3 1.3
1.4 1.4 Do you think this is:
1.2 1.2
1 1 1
1.1 a. AKI
0.9 0.9 0.9
b. AKD
c. CKD
d. None of the above

DAY 1 DAY 2 DAY 3 DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY DAY DAY DAY DAY
10 11 12 13 14
Serum Creatinine
Serum Creatinine Trend

Example - KD
1.5
1.3 1.3 1.3
1.4 1.4 Do you think this is:
1.2 1.2
1 1 1
1.1 a. AKI
0.9 0.9 0.9
b. AKD without AKI
c. CKD
d. None of the above

DAY 1 DAY 2 DAY 3 DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY DAY DAY DAY DAY
10 11 12 13 14
Serum Creatinine
Serum Creatinine Trend

Example - KD

1.4 1.4
1.5 Do you think this is:
1.3 1.3 1.3
1.1
1.2 1.2 a. Drug related KD
0.9 0.9 0.9
1 1 1
b. Drug induced AKI
c. Drug associated AKI
d. Drug induced AKD
e. Drug associated AKD
DAY 1 DAY 2 DAY 3 DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY DAY DAY DAY DAY f. Not drug related
10 11 12 13 14
Serum Creatinine

Drug = vancomycin
Serum Creatinine Trend

Example - KD

1.4 1.4
1.5
Do you think this is:
1.3 1.3 1.3
1.1
1.2 1.2 a. Drug related KD
0.9 0.9 0.9
1 1 1
b. Drug induced AKI
c. Drug associated AKI
d. Drug induced AKD without AKI
e. Drug associated AKD
DAY 1 DAY 2 DAY 3 DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY DAY DAY DAY DAY f. Not drug related
10 11 12 13 14
Serum Creatinine

Drugs = vancomycin
Serum Creatinine Trend

Example - KD

1.4 1.4
1.5
Do you think this (ibuprofen) is:
1.3 1.3 1.3
1.1
1.2 1.2 a. Drug related KD
0.9 0.9 0.9
1 1 1
b. Drug induced AKI
c. Drug associated AKI
d. Drug induced AKD
e. Drug associated AKD
DAY 1 DAY 2 DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY DAY DAY DAY DAY DAY f. Not drug related
10 11 12 13 14 14
* Patient could have more than one event if
Serum Creatinine
drug started after an ongoing event

Drugs = vancomycin, Day 2

Plus Ibuprofen started on Day 6
Serum Creatinine Trend

Example - KD

1.4 1.4
1.5 Do you think this (ibuprofen) is:
1.2 1.2
1.3 1.3 1.3
a. Drug induced AKI
1.1
0.9 0.9 0.9
1 1 1 b. Drug associated AKI
c. Drug induced AKD
d. Drug associated AKD without AKI
e. Not drug related
DAY 1 DAY 2 DAY 3 DAY 3 DAY 4 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY DAY DAY DAY DAY
10 11 12 13 14
Serum Creatinine

Drugs = vancomycin Day 2

Plus Ibuprofen started on Day 6
 Need for Contemporary Classification
• AKI
• Heterogeneous syndrome
• 8-23% of hospitalized patients

Consistency
• Up to 65% of critically ill patients

• Drug Induced/Associated AKI (D-AKI)

• Hospital admission
• 22% of adults & 34% of children
• 30% of critically ill patients
• In-hospital mortality and/or dialysis similar regardless of etiology

• D-AKI subset of AKI so classification should be

consistent
Pavkov ME et al. MMWR Morb Mortal Wkly Rep. 2018;67:289-293.
Hoste EA et al. Intensive Care Med 2015;1411–1423.
Brivet FG et al. Crit Care Med 1996;24:192;
Mehta RL et al. Kid International 2004;66:1613
Uchino S et al. JAMA 2005;294:813-818.
 Rethinking AKI Classification
Biomarker negative Biomarker positive
No increase in SCr or No increase in SCr or
PRE decrease in UO decrease in UO
Resolution AKI Stage 1S
INTRA
Redefining
AKI Staging

POST
Biomarker negative Biomarker positive
Increase in SCr or Increase in SCr or
decrease in UO decrease in UO
AKI Stage 1A, 2A, 3A AKI Stage 1B, 2B, 3B
ADQI= Acute Disease Quality Initiative
SCr = serum creatinine
UO = urine output Ostermann M et al. JAMA Network Open. 2020;3(10):e2019209
 Classifying Drugs Associated with AKI
(-) Injury (+) Injury
Marker(s) Marker(s)

Neither Dysfunction or Injury Without

(-) Functional
Marker(s)
Injury Dysfunction

Classification
(+) Functional
Marker(s) Dysfunction Without
Dysfunction and Injury
Injury
Deleterious Risk Modifiers
Intervention to Mitigate Risk Ostermann M et al. Kidney Int 2020;98:294
 Classifying Drugs Associated with AKI
(-) Injury (+) Injury
Marker(s) Marker(s)

Neither Dysfunction or Injury Without

(-) Functional
Marker(s)
Injury Dysfunction
Susceptibility/exposures factors

Classification
(+) Functional
Marker(s) Dysfunction Without
Dysfunction and Injury
Injury
Deleterious Risk Modifiers
Intervention to Mitigate Risk Ostermann M et al. Kidney Int 2020;98:294
 Susceptibilities and Exposures for AKI

Susceptibilities Exposures/Deleterious Risk Modifiers

• Dehydration or volume depletion • Sepsis
• Advanced age • Critical illness
• Female gender • Circulatory shock
• Black race • Burns
• Chronic kidney disease • Trauma
• Chronic diseases (heart, lung, liver) • Cardiac surgery
• Diabetes mellitus • Major non-cardiac surgery
• Cancer • Nephrotoxic drugs
• Anemia • Radiocontrast agents
• Poisonous plants and animals

Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for AKI 2012
 Classifying Drugs Associated with AKI
Drugs Associated (-) Injury (+) Injury
with PseudoAKI Marker(s) Marker(s)

Neither Dysfunction or Injury Without

(-) Functional
Marker(s)
Injury Dysfunction
susceptibility factors

Classification
(+) Functional
Marker(s) Dysfunction Without
Dysfunction and Injury
Injury
Deleterious Risk Modifiers
Intervention to Mitigate Risk Ostermann M et al. Kidney Int 2020;98:294
Ostermann M et al. Crit Care 2016;20:299
 Classifying Drugs Associated with AKI
(-) Injury (+) Injury
Marker(s) Marker(s)

Neither Dysfunction Injury Without

(-) Functional
Marker(s) or Injury Dysfunction
susceptibility factors

Classification
(+) Functional
Marker(s)
Dysfunction Without
Dysfunction and Injury
Injury
Includes drugs that impact kidney
function through systematic
hypoperfusion and/or Deleterious Risk Modifiers
intraglomerular hemodynamic effects
(ex. angiotensin converting enzyme
inhibitor (ACEi) and angiotensin II Intervention to Mitigate Risk
receptor blockers (ARB) Ostermann M et al. Kidney Int 2020;98:294
 Classifying Drugs Associated with AKI Includes drugs that
cause injury through
various mechanisms,
including tubular cell
(+) Injury injury triggered by
(-) Injury filtered toxins, tubular
Marker(s) Marker(s)
obstruction, allergic
reactions

Neither Dysfunction or Injury Without

(-) Functional
Marker(s)
Injury Dysfunction
susceptibility factors

Classification
(+) Functional
Marker(s) Dysfunction Without
Dysfunction and Injury
Injury
Deleterious Risk Modifiers

Ostermann M et al. Kidney Int 2020;98:294 Intervention to Mitigate Risk

Further Classifying Injury without Dysfunction
Acute Tubular Necrosis
Aminoglycosides, Amphotericin,
AKI Vancomycin, NSAIDs

Nephrotoxic, Allergic, Mixed

Acute Interstitial Nephritis

Injury without Dysfunction

Penicillins, Cephalosporins, PPIs

Tubular Dysfunction
Cisplatin, Ifosfamide, Tenofovir
Renal tubular acidosis, Diabetes
Insipidus

Lupus Like
Hydralazine

Glomerular Disorder
Membranous
NSAIDS

Nephrolithiasis Acyclovir, SMX/TMP, Indinavir,

Atazanavir
Tubular Obstruction
Mehta R et al. Kidney Int 2015;88:226
 Further Classifying Injury without Dysfunction:
PPI= proton pump inhibitor
NSAIDs= nonsteroidal anti-inflammatory drug
Mechanism Explained Perazella A. CJASN 17; 2022.
doi: https://doi.org/10.2215/CJN.11290821
SMX/TMP = Sulfamethoxazole/Trimethoprim`
Acute Tubular Necrosis 0-20% occurrence; others 5%-43%
Aminoglycosides, Amphotericin, - increase mitochondrial stress, releasing cytochrome-
AKI Vancomycin, NSAIDs c and activating the caspase pathway, resulting in
cellular stress and apoptosis
Nephrotoxic, Allergic, Mixed - vancomycin casts, which are non-crystalline
Acute Interstitial Nephritis
Injury without Dysfunction

vancomycin aggregates with uromodulin, may

Penicillins, Cephalosporins, PPIs contribute to AKI by obstructing tubular lumens
(below)

Tubular Dysfunction
Cisplatin, Ifosfamide, Tenofovir 43-58% of adult and peds, respectively
Renal tubular acidosis, Diabetes
Insipidus Cisplatin is metabolized to a reactive thiol
resulting in tubular toxicity
Lupus Like
Hydralazine

Glomerular Disorder
Membranous
NSAIDS
Crystalline induced AKI (rapid, bolus dose)

Nephrolithiasis Acyclovir, SMX/TMP, Indinavir, SMX/TMP – acute interstitial nephritis (above)

Atazanavir SMX - crystalline nephropathy
Tubular Obstruction
 Classifying Drugs Associated with AKI
(-) Injury (+) Injury
Marker(s) Marker(s)

Neither Dysfunction or Injury Without

(-) Functional
Marker(s)
Injury Dysfunction
susceptibility factors

Classification
(+) Functional
Marker(s) Dysfunction Without
Dysfunction and Injury
Injury
Nonsteroidal
Deleterious Risk Modifiers Anti-inflammatory
Intervention to Mitigate Risk Drugs (NSAIDS)
Ostermann M et al. Kid Inter 2020;98:294
CASE FOR CONSIDERATION
 Patient Case

Sasaki TJ et al. International Journal of Surgery Case Reports 20 (2016) 63–67

Is this drug induced?
Perform a causality assessment
Hill’s Criteria for Causality
Criteria
Strength of association

Consistency of findings

Specificity

Temporality

Biological gradient • Dose response relationship

Plausibility (mechanism) • Other causes

Coherence

Experiment

Analogy

Reversibility
 Causality Assessment for SD
• Consistency
• 20-30% of patients undergoing treatment

• Temporality
• Occurs 3 to 5 days after its administration and may occur
even after a single exposure
• SD: On day 5, SDs serum creatinine level increased to 7.83
mg/ml

• Biological Gradient
• Dose-dependent and can occur acutely at doses greater
than 60 mg/m2 per cycle2 or cumulatively with doses
greater than 300 mg/m
• SD: 80 mg/m2 cisplatin on day 1
Sasaki TJ et al. International Journal of Surgery Case Reports 20 (2016) 63–67
Plausibility – • Cisplatin accumulates in the renal tubule
• Primarily S3 segment of the proximal tubule
Mechanism • Lesser but still involves the loop of Henle and distal
tubules
• Leads to toxicity
• DNA damage
• Mitochondrial dysfunction
• Endoplasmic reticulum stress
• Activation of the apoptotic pathways
• Formation of reactive oxygen species
• Inflammation via tubular necrosis
• + injury in the kidney vasculature
 Specificity – Other Causes
• Pre-renal
Hemodynamic • Nausea, vomiting,
diarrhea
Risk of AKI after cancer diagnosis • Third spacing (HRS)

• Thrombotic
microangiopathy
Injury due to • Direct infiltration of
First Year 18% Cancer glomeruli or interstitium
• Obstructive
nephropathy

First 5 Years 27%

• Chemotherapy
• Immunotherapy
Treatment
Related Injury • HSC Transplant
• Nephrectomy
• Radiation

40% of patients who are critically ill require KRT

Injury due to • Hyepercalcemia
Metabolic
Complications • Tumor Lysis Syndrome
Patient Case –
Strength/Effect Size
• On day 5, SDs serum creatinine level increased
from 0.98 mg/ml to 7.83 mg/ml
• Diagnosed with grade 4 acute renal failure
based on the Common Terminology Criteria for
Adverse Events (CTC-AE ver. 3.0),
• Chemotherapy was stopped, and the patient
was administered hemodialysis without delay.

Sasaki T et al. PMID: 26851395

What biomarkers do you want to
consider specific to cisplatin?
Coherence

Cisplatin-associated AKI is characterized by electrolyte wasting and/or polyuria

with or without a serum creatinine increase
 Analogy- • Second generation platins
• Carboplatin
Other agents? • Nedaplatin

• Third generation
• Oxaliplatin

• Tubular epithelial injury via

intracellular accumulation
Reversibility
 Patient Case
• SD’s renal function was expected to recover
after discontinuing the offending agent, but
after 2 months of hemodialysis did not.
• Resumed treatment of his esophageal cancer
while continuing hemodialysis

• “mostly reversible”
• GFR was still 30% below baseline at 2 years

Sasaki TJ et al. International Journal of Surgery Case Reports 20 (2016) 63–67

Apply Causality Tool: Naranjo
 Instruments • Austin Bradford-Hill Criteria for Causal Association
(1965)

Available for ADR • General Assessment Tools

• Seidl (1965)

Causality
• Karch (1977)
• Kramer (1979)

Assessment
• Venulet (1980)
• Naranjo (1981)
• Jones (1982)
• Australian (1984)
• French Method of Causality Assessment (1984)
• Liverpool (2011)

• Disease Specific Instruments

• RUCAM (1990)- Drug-induced liver injury
• Eland (1999) - Pancreatitis

Taofkat B et al. Drug Safety 2008;31(1):21-37.

 Naranjoʼs ADR Causality Algorithm

Questions Yes No Don’t Know

1. Previous conclusive reports on this reaction? +1 0 0
2. Event appear after the drug was administered? +2 -1 0
3. Improve when drug d/ced or antagonist given ? +1 0 0
4. Reaction reappear when drug is readministered? +2 -1 0
5. Alternative causes for the reaction? -1 +2 0
6. Reaction reappear when placebo was given? -1 +1 0
7. Drug detected in blood in toxic concentration? +1 0 0
8. Rxn more severe when dose ­, or less when ¯ed? +1 0 0
9. Similar rxn to previous exposure to similar drugs? +1 0 0
10. Adverse event confirmed by objective evidence? +1 0 0

TOTAL SCORE Scores -Doubtful < 0; Possible 1-4; Probable 5-8; Definite > 9

Naranjo CA, et al. J Clin Pharmacol 1992;10:897-904

Lanctot KL, et al. Clin Pharmacol Ther 1995;6:692-8
Nephrotoxin Stewardship
 Interventions/Strategies to Mitigate Risk:
Nephrotoxin (and renal dosing) Stewardship
• “Nephrotoxin stewardship is a set of coordinated patient care
management strategies for safe medication use, ensuring kidney
health and avoiding unnecessary costs to improve the use of
nephrotoxins, renally eliminated drugs and kidney disease treatments
with the goal of enhancing patient outcomes.”
• Goals of enhancing patient outcomes through nephrotoxin stewardship are:
• Safe medication use is appropriate drug dosing (avoid overdosing or underdosing) and
preventing/ameliorating adverse drug events.
• Ensuring kidney health by preventing AKI, AKI to CKD transition (known as acute kidney
disease) or worsening of AKI or CKD.
• Avoiding unnecessary costs means implementing efficiently coordinated patient care
strategies and choosing tests and treatments wisely.

Kane-Gill SL. Crit Care Clinics 2021; 37:303

 Goal #1 Medication Safety:
Appropriate drug dosing, prevention
and ameliorating adverse drug events
 Standardization of Renally Famotidine
Nizatidine
Am Geriatric Society
Beers 2015
Eliminated Drugs Fondaparinux
Cimetidine
Enoxaparin
• Approximately 19-67% of orders are dosed Levetiracetam
excessively in kidney disease Pregabalin
Dabigatran Probenecid
• 2/3 of older patients receive inappropriately Rivaroxaban
Edoxaban
Triamterene
Ranitidine
Lithium
high doses Duloxetine
Apixiban
Gabapentin
Dapagliflozin Spironolactone
• Too many drugs to expect a clinician to maintain Empagliflozin
Colchicine

knowledge of the full array Amantadine

Canagliflozin Acyclovir
Rimantidine
Baclofen Valacyclovir
• Concordance between different Cotriamazole Memantine
Digoxin
pharmacotherapy information sources regarding Ciprofloxacin
Chlorpropamide
Fibrates Glyburide
dosing Nitrofurantoin Propoxyphene
Metformin
• Update list annually Levofloxacin
Hanlon JT et al.
JAGS 2009
Taji L et al.
Ann Pharmcother 2020
 Drug Dosing During Recovery
• Single center, observational, 3-months
• 396 patient, 0.5mg/dL change in SCr during a
rolling 48-hour period, received nephrotoxin or
Preventable renally eliminated drug
• 170 (43%) had a potential ADE, ADE, therapeutic
failure (TF) or potential TF
Events - • Potential TFs
Therapeutic • 33 occurred in 29 patients
• 85% from antibiotics
Failures • 40% significant; 36% serious; 24% life-
threatening
• TF = 1 and was fatal

Cox ZL et al. CJASN 2013;8:1070-78

 Medication Safety Summary:
Plan for coordinated patient care strategies

Nephrotoxin Stewardship Actions Associated with Goals to Enhance Patient Outcomes

Safe medication use: nephrotoxins,
renally eliminated drugs and kidney
disease treatments
Renally eliminated drugs
Medication Safety (preventing medication errors and ADEs)
Standardize a minimum list of renally adjusted drugs to target for
surveillance
Recommendations for/or verification of initial and maintenance dose
Check dosing when changes (improve or decline) in kidney function with
use estimates
(i.e. Cockcroft Gault; CKD-EPI 2021; kinetic eGFR for unstable SCr)
Therapeutic monitoring for non-nephrotoxic drugs (i.e. digoxin)
Monitoring for adverse drug events (ADEs) and therapeutic failures
Goal #2 Ensuring Kidney Health:
Preventing AKI, AKI to CKD
transition or worsening of CKD
 Nephrotoxin
Minimum List of Committee Reviews
Meds

Nephrotoxins to Target for Finalize List- Repeat Propose New

Surveillance Annually Medications

Sample of List for the Collaborative (n=57)

Acyclovir Celecoxib Diatrizoate

sodium
Amikacin Cidofovir Enalapril

Ampho Cisplatin Enalaprilat Discussion of Remove

Liposomal Evidence Medications
Ampho B Cyclosporine Foscarnet

Aspirin Colistiethate Ganciclovir

Captorpril Deferasirox Gentamicin

Carboplatin Diatrizoate Ibuprofen Assign Evidence Classify Medications

meglumine
Grade Based on (include all same
Literature class meds)

Goswami E et al. AJHP 2019;76:1869

 Various Nephrotoxin Drug Lists
Ambisome,
Cefotaxime,
Ceftazidime,
Cefuroxime,
Cyclosporine, Dapsone,
Enalaprilat, Ifosfamide,
Iopamidol, Mesalamine,
Nafcillin, Piperacillin/
Tazobactam,
FOLLOWERS Piperacillin,
Sirolimus, Sulfasalazine,
Ticarcillin/Clavulanic,
Topiramate, Valacyclovir,
Valganciclovir,
Vancomycin,
Zonisamide
Goldstein S, et al. PMID: 27217196.
Kirkendall E, et al. PMID: 25024752.
Arias Pou P, et al. PMID: 31157093.
Adefovir, Amiloride,
Atenolol, Canrenoate,
Celecoxib, Chlorthalidone,
Ciclosporin, Dextran,
Acyclovir, Amikacin, Diazoxide, Diclofenac,
Dihydroergotamine,
Amphotericin B, Captopril,
Carboplatin, Cidofovir, Cisplatin, Diltiazem, Furosemide,
Colistimethate, Enalapril, Foscarnet, Gadobenate, Gadobutrol,
Gadodiamide, HCTZ, IVIG,
Gadopentetate, Gadoxetate
disodium, Ganciclovir, Gentamicin, Indapamide, Indinavir,
FOLLOWERS Indomethacin, Interferon,
LIKES
Ibuprofen, Iodixanol, Iohexol,
Iobitridol, Iomeprol, Irbesartan,
Ioversol, Ketorolac, Lisinopril,
Lithium, Methotrexate, Tacrolimus, Losartan, Mannitol,
Meloxicam, Methyldopa,
Tobramycin
Minoxidil, Mitomycin,
Naproxen, Nicardipine,
Nifedipine, Parecoxib,
Pentamidine, Spironolactone,
Sulindac, Torsemide,
Verapamil
52
 Number Nephrotoxins is a Struggle
Study
Hsu EH et al. J Pediatr Pharmacol Ther
2019;24:416–420
Cotner SE et al. AAC 2017;61:e00871
Slater MB et al. Pediatr Drugs
2017;19:59-67
Cartin-Ceba R et al. Crit Care Res Pract
2012; 691013
Additional Odds of AKI with Each Nephrotoxin
Each additional nephrotoxin increased the risk of AKI by 40% (adjusted OR, 1.40;
95% CI, 1.06–1.85; p = 0.019)
Concomitant nephrotoxin administration was an independent predictor of AKI
occurrence
Patients with AKI were more likely to be exposed to at least one nephrotoxic
medication (88% cases vs. 74% controls; <0.001) and risk increased as the
number of nephrotoxic medications increased (OR 1.3; CI 1.2-1.4)
53% greater odds of developing AKI
for every nephrotoxic drug received
(OR 1.53; CI 1.09-2.14)
 Nephrotoxic Burden
Nephrotoxin burden is the cumulative or aggregate exposure to nephrotoxins, with
consideration to nephrotoxin potential for each drug, evaluated at a given time or within a
reasonable time frame depending on the elimination half-life of the drug

Duration of drug • Need cumulative assessment over

exposure time

Nephrotoxic
• Requires a weighting scheme for
potential (NxP) of each individual drug
the drug

Kane-Gill S, et al, PMID: 33752857.

 Nephrotoxic Injury Negated by Just-In-Time Action (NINJA)
Development and refinement of a predictive AKI CDSS focused on nephrotoxic burden with the goal of
reducing AKI severity
Evidence of AKI: pediatric RIFLE criteria; no urine output

Knowledge for the Alert Results

(Pharmacist Managed)
• 1-yr: 42% reduction in days of AKI/100 days of
• ≥3 nephrotoxins on the same day exposure
• 3-yrs sustained: 31% AKI intensity decrease &
• IV aminoglycoside for ≥ 3 days
64% reduction in AKI
• Vancomycin for ≥ 3 days
• 9 centers: 0.4 episodes per 1000 patient days
reduction in AKI (24%) & 9% reduction in AKI
rates per exposure (absolute)

Goldstein S, et al, PMID: 23940245. Kirkendall E, et al. PMID: 25024752. Goldstein S, et al, PMID: 27217196. Goldstein S, et al, PMID: 31980139.
 Hypervigilance and Early Detection:
Use of a Stress Biomarker for Early Warning
Similar to NINJA: A predictive AKI trigger with the goal of reducing AKI severity
Adults? ICU patients?
• Monitor serum creatinine regularly
• Change serum creatinine to [TIMP-2]*[IGFBP7] monitoring

Pharmacists evaluate Pharmacists order

Alert
alert biomarker test
≥3 nephrotoxins [TIMP-2]•[IGFBP7]
-repeat, patient and inform Pharmacists aid in
already has AKI physician interpretation and
makes medication
management
recommendations

QI- AKI severity ,

days of AKI and AKI
incidence

Kane-Gill S, et al, PMID: 33752857.

 Kidney Health Summary:
Plan for coordinated patient care strategies
Nephrotoxin Stewardship Actions Associated with Goals to Enhance Patient Outcomes
Safe medication use: nephrotoxins, renally Prevention of AKI/ Worsening of Kidney Function
eliminated drugs and kidney disease
treatments
Nephrotoxins Standardize a minimum list of nephrotoxins to target for surveillance
Prevention or worsening Standardize D-AKI definitions for transparency and consistency
Therapeutic monitoring of nephrotoxic drugs (i.e. aminoglycosides and vancomycin)
Monitor pharmacokinetic & pharmacodynamic drug-drug interactions – potential
nephrotoxicity
Nephrotoxin burden assessment with the addition of each new nephrotoxin starting at >/= 3
Evaluate functional biomarkers - appropriate initial and maintenance drug dosing
Evaluate damage biomarkers - risk of AKI before nephrotoxin administration
Transition of care protocol for patients with de novo AKI (especially if at risk for CKD) or CKD
at risk for ESKD
Kidney treatments (when available) Use implementation strategies to ensure adoption of treatment is applied

Kane-Gill SL. Crit Care Clinics 2022 PMID: 33752857. Grey= discussed
 Nephrotoxin Stewardship Summary

Multiple management strategies can

be used for coordinated patient care
that include safe medication use,
ensuring kidney health and avoiding
unnecessary costs.