REVIEW Open Access

The 6R’s of drug induced nephrotoxicityLinda Awdishu1,2* and Ravindra L. Mehta2

Abstract

Drug induced kidney injury is a frequent adverse event which contributes to morbidity and increased healthcareutilization. Our current knowledge of drug induced kidney disease is limited due to varying definitions of kidneyinjury, incomplete assessment of concurrent risk factors and lack of long term outcome reporting. Electronicsurveillance presents a powerful tool to identify susceptible populations, improve recognition of events andprovide decision support on preventative strategies or early intervention in the case of injury. Research in thearea of biomarkers for detecting kidney injury and genetic predisposition for this adverse event will enhancedetection of injury, identify those susceptible to injury and likely mitigate risk. In this review we will present a 6Rframework to identify and mange drug induced kidney injury – risk, recognition, response, renal support,rehabilitation and research.

Keywords: Nephrotoxicity, Acute kidney injury, Drugs, Hypersensitivity, Adverse reaction, Tubular toxicity, Nephrolithiasis,Glomerular, Crystalluria

BackgroundDrug-induced nephrotoxicity is increasingly recognizedas a significant contributor to kidney disease includingacute kidney injury (AKI) and chronic kidney disease(CKD). Nephrotoxicity has a wide spectrum, reflectingdamage to different nephron segments based upon indi-vidual drug mechanisms. Both glomerular and tubularinjuries are recognized targets for drug toxicity and mayresult in acute or chronic functional changes. However,standard definitions of drug induced kidney disease(DIKD) are lacking, leading to challenges in recognitionand reporting. The clinical manifestations of DIKD oftengo unrecognized, particularly in the setting of short drugexposures. This poses challenges in assessing the inci-dence, severity and long-term consequences of DIKD.Our knowledge of the epidemiology of nephrotoxicity

focuses predominantly on drug induced AKI. Prospectivecohort studies of AKI have documented the frequency ofdrug-induced nephrotoxicity to be approximately 14-26%in adult populations [1–3]. Nephrotoxicity is a significantconcern in pediatrics with 16% of hospitalized AKIevents being attributable primarily to a drug [4]. Theepidemiology of tubular disorders is unclear as a standard

definition is lacking and many published reports docu-ment tubular dysfunction leading to AKI. This may under-estimate the true incidence of tubular disorders since onlycases associated with a change in serum creatinine (Scr)are recognized. However, frequent use of specific drugs,such as tenofovir, has led to greater attention to tubularinjuries with documented frequencies of 12–22% oftreated subjects in cohort studies [5, 6]. Glomerular in-jury is uncommon and most of the literature is limitedto case reports or case series. However, novel chemo-therapeutic agents are increasingly being associatedwith this form of toxicity [7]. Given these challenges inthe reported epidemiology and outcomes of DIKD, wepropose a novel framework to approach drug inducednephrotoxicity focused on Risk assessment, early Recogni-tion, targeted Response, timely Renal support and Re-habilitation coupled with Research (the 6R approach).

RiskTo evaluate the risk of nephrotoxicity, general questionscan be applied to each causal drug. What is the predict-able risk based on the known pharmacology of the drug?What is the known risk, contributing risk factors and thetypical timeline for injury? If the risks are known, how isthis information used clinically to predict the risk for anindividual patient (i.e. clinical risk scores for contrast

* Correspondence: lawdishu@ucsd.edu1UC San Diego Skaggs School of Pharmacy, San Diego, USA2UC San Diego School of Medicine, 9500 Gilman Dr, La Jolla, CA 92093, USA

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Awdishu and Mehta BMC Nephrology (2017) 18:124 DOI 10.1186/s12882-017-0536-3

nephropathy)? How is this information used to mitigatethe risk?Drug induced adverse events can be classified into two

categories: dose dependent and idiosyncratic reactions.This categorization is important to consider in the contextof drug induced kidney disease (DIKD) since the mecha-nisms for drug toxicity are different posing challenges inrisk assessment. Dose dependent reactions are predictablefrom the known pharmacology of the drug. For example,the risk of aminoglycoside induced nephrotoxicityincreases with higher trough drug concentrations andlonger duration of therapy [8]. Whereas, interstitialnephritis from proton pump inhibitors is an unpredictableidiosyncratic reaction, which is unlikely to be preventableor minimized.When assessing the known risk of DIKD, often this

information may be in the form of case reports, adverseevent reporting from clinical trials or post marketingsurveillance [9]. Prospective studies focused on determiningthe incidence of DIKD are few. Most studies are retro-spective and are focused largely on drugs with predictabletoxicities and therapeutic drug monitoring (TDM). Deter-mining the incidence of idiosyncratic reactions is difficultsince data is often limited to case reports. Some studies at-tempt to demonstrate an association using claims dataand diagnostic codes; however, the incidence of the AKI isvariable between cohorts and likely overstated [10–12]Most importantly, the definition of DIKD has not beenstandardized, making interpretation of the epidemiologychallenging. The information on drug specific DIKD riskis summarized in Table 1.Risk factors contributing to the development of DIKD

include patient specific factors, disease specific factors andprocess of care factors (Table 1). Common risk factors in-clude age, causal drug single and/or cumulative dose,underlying CKD and concurrent nephrotoxin exposures.In the case of hospitalized patients, our experience is thata retrospective evaluation of DIKD almost always revealsthe prescription of additional nephrotoxins concurrent tothe causal drug (i.e. ketorolac prescribed to a patient re-ceiving gentamicin and vancomycin). Minimizing theseexposures may mitigate the development of DIKD.Assessing kidney function is critical to the dosing of

drugs and mitigation of DIKD. An important patient spe-cific risk factor is low serum Scr values due to reducedmuscle mass, which may be age related or disease related(muscular dystrophy, spina bifida, etc.). This poses a chal-lenge to assessment of kidney function using estimatingequations. Pharmacists often “round” Scr values to an ar-bitrary threshold value in older patients or those with lowScr values to account for low muscle mass. This practiceis inaccurate and may lead to drug dosing errors in certainpopulations [13–16]. Currently, KDIGO guidelines ondrug dosing advocate using either Cockcroft Gault or

MDRD equation for drug dosing [17]. Since the drug in-formation from manufacturers submitted to the U.S. Foodand Drug Administration still utilizes the Cockcroft Gaultequation for estimates of kidney function and no pro-spective studies have been conducted on clinical outcomesof the various equations, we feel that either equation couldbe used in the absence of kidney disease.Published reports of DIKD have not consistently eval-

uated cases for the presence of common AKI risk fac-tors. Subsequently, risk factors specific to a causalagent have emerged but have not been validated in lar-ger studies and across multiple drugs. As an example,drug interactions have emerged as an important riskfactor for the development of AKI. Interactions leadingto increased concentrations of anti-hypertensive medi-cations, subsequent hypotension and AKI have been re-ported [18]. In a study by Gandhi and colleagues, therisk for hospitalization with AKI was compared in patientsreceiving a prescription for amlodipine and one of twomacrolide antimicrobials, clarithromycin or azithromycin.Clarithromycin is known to inhibit cytochrome P450 3A4isoenzyme, which is involved in the metabolism ofamlodipine, whereas azithromycin does not interact tothe same extent. The authors found co-prescription withclarithromycin was associated with an odds ratio [OR],1.98 [95% CI, 1.68–2.34] compared to co-prescriptionwith azithromycin [18].Identification of general DIKD risk factors is central to

the development of clinical risk scores for the predictionand minimization of risk. For example, the identificationof risk factors for contrast-induced nephropathy has ledto the development of risk scores and evaluation of pre-ventative treatments [19–23]. This has great applicabilityto the clinical setting, where an electronic medical rec-ord (EMR) can calculate the risk score and cardiologistsor radiologists can prescribe preventative measures.Additionally these risk scores may predict long-termoutcomes [24, 25].

RecognitionCurrently, there is no standard definition of DIKD andincidence of nephrotoxicity varies depending on thedefinition employed and the causal drug. The mostcommon drugs that cause DIKD include antibiotics, anti-rejection medications, antiviral agents, non-steroidal anti-inflammatory agents, anti-ulcer agents and chemotherapy.Most studies have defined nephrotoxicity as 0.5 mg/dL

or 50% rise in Scr over 24–72 h time frame and a mini-mum 24–48 h of drug exposure. However, these defini-tions pose challenges since a 50% increase in Scr may nothave high specificity for DIKD since the underlying dis-ease being treated as well as other AKI risk factors couldbe significant to the attribution of risk. In the setting offluctuating renal function or those patients receiving renal

Awdishu and Mehta BMC Nephrology (2017) 18:124 Page 2 of 12

Table

15R

Summaryby

CausalD

rug

Drug/Ph

enotype

Risk

Recogn

ition

Respon

seRenalsup

port

Rehabilitation

Patient

specific

Disease

specific

Processof

care

Aminog

lycoside

s[8,74–76]

AKI

Age

Diabe

tes

Volumede

pletion

Sepsis

Liverdysfun

ction

CKD

Hypokalem

iaHypom

agne

semia

Durationof

therapy

Type

ofam

inog

lycoside

Freq

uencyof

dosing

Elevated

trou

ghconcen

trations

>2m

cg/m

L[8,77]

Timingof

administration

Con

curren

tne

phrotoxins

(i.e.

vancom

ycin)[77]

Con

trast

administration

12.2%

forge

ntam

icin

inne

onates

[78]

11.5-60%

for

aminog

lycoside

sin

adults[8,74,77,79]

Prevention:

Oncedaily

dosing

[75]

Con

side

rusing

tobram

ycin

instead

ofge

ntam

icin

since

ithaslower

ratesof

neph

rotoxicity

[80,81]

Avoid

midnigh

tto

7am

administration

[76]

Nodifferencein

need

forrenal

supp

ortin

noge

ntam

icin

vs.

gentam

icin

treated

infection

endo

carditis,8vs.

6%respectively[82]

4.6%

mortalityina

coho

rtof

201critically

illpatients[8]

51%

recovery

with

in21

days

ofAMG

associated

AKI[77]

Coh

ortof

critically

illpatients,mortalityin

AKIvs.non

-AKIgrou

pwas

44.5vs.29.1%

,respectively.[74]

Acyclovir

Nep

hrolith

iasis/AKI

Older

children[83]

Obe

sity

[55,84,85]

Volumede

pletion

CKD

Rapidintraven

ous

administration

Dosede

pend

ent

Long

erdu

ratio

nof

therapy[83]

Leng

thof

hospital

stay

[83]

Con

comitant

neph

rotoxins

[86]

12-48%

crystal

neph

ropathywith

rapidintraven

ous

bolusadministration

0.27%

AKIfro

moral

acyclovir[87]

3.1-10.3%

children

develope

dAKIfro

mintraven

ousacyclovir

Prevention:

Hydratio

nSlow

intraven

ous

administration

Doseadjustmen

tforCKD

Treatm

ent:

Discontinuatio

nRehydration

Hem

odialysis

Calcine

urin

Inhibitors[88]

AKI/glomerular

Gen

eticvariatio

nsin

CYP3A

4,MDR1,A

CE,

TGF-β,

andCCR5

[89–93]

42%

inno

n-renalal-

lografts[88]

Redu

cedo

seCalcine

urin

minim

ization

Calcine

urin

replacem

entwith

mTorinhibitors

Cisplatin

[52,94]

AKI/tub

ular

Age

AfricanAmericans

CKD

Con

curren

tne

phrotoxins

58%

inpe

diatrics[52]

43.5%

inadults[94]

Minim

izeconcurrent

neph

rotoxin

expo

sure

49%

with

redu

ction

inGFR,71%

with

glucosuria,67%

with

proteinu

riaover

long

term

[95]

Colistin

[96]

AKI

Age

Obe

sity

48%

inoverweigh

tor

obesepatients[96]

Minim

izeconcurrent

neph

rotoxinexpo

sure

Con

side

ralternative

agen

ts

80%developedfailure

byRIFLEcatego

ry[96]

Nostatistically

sign

ificant

difference

inho

spitalo

r30

day

mortality[96]

Ifosfam

ide[97,98]

AKI/tub

ular

Age

CKD

Nep

hrectomy

Tumor

infiltrationin

kidn

ey

Cum

ulativedo

seMetho

dof

administration

50%

inpe

diatric

cancer

patients[97]

Minim

izeconcurrent

neph

rotoxinexpo

sure

Nodialysis

requ

iremen

t[98]

Noresolutio

nof

injury

[98]

Awdishu and Mehta BMC Nephrology (2017) 18:124 Page 3 of 12

Table

15R

Summaryby

CausalD

rug(Con

tinued)

Con

curren

tne

phrotoxins

(cisplatin,carbo

platin)

Lithium

Tubu

lar/

Glomerular

CKD

Durationof

therapy

11.6-15%

develop

AKI[99,100]

26.1%

develop

concen

trating

defect

[99]

Discontinuatio

nof

drug

78%

ofpatientswith

Scr≥2.5mg/dL

atbaselinerequ

ired

dialysis[101]

42.1%

develop

ESRD

[101]

Protease

Inhibitors

Atazanavir

Indinavir

Nep

hrolith

iasis/

AKI

Asymptom

atic

crystalluria

in20-67%

[102,103]

Nep

hrolith

iasisin

3%[103]

Preven

tion:

Patientsshou

lddrink

aminim

umof

1.5

L/dayof

water

topreven

tston

eform

ation

Perio

dicmon

itorin

gof

renalfun

ctionand

screen

ingforpyuria

durin

gthefirst

6mon

thsof

therapy

andbiannu

ally

Treatm

ent

Holdifpatient

develops

neph

rolithiasisun

tilrehydrated

[104]

Discontinue

thedrug

ifpatient

expe

riences

pyuria,A

KI,

hype

rten

sion

orrhabdo

myolysis[104]

Nodialysis

requ

iremen

ts21%

increasedrisk

ofCKD

[105]

12%

increasedrisk

ofCKD

[105]

Proton

Pump

Inhibitors

AKI

Age

>60

years[12]

Current

usershigh

erriskcomparedto

pastusers

Con

curren

tne

phrotoxins

(antibioticsor

diuretics)[10]

8-32

per100,000

person

-years

[11,12,106]

Discontinue

drug

Con

side

rcourse

ofsteroids

[107]

Nodialysis

requ

iremen

trepo

rted

Spon

taneou

srecovery

afterd

rugwith

draw

al[108]

Sulfametho

xazole/

trim

etho

prim

Non

eDM

HTN

CKD

[109]

Con

curren

tne

phrotoxins

Con

trastdye

11-22%

expe

rience

AKI[109,110]

Discontinue

drug

1%requ

ired

dialysis

Com

pleterecovery

with

in30

days

Teno

fovir

Tubu

lar

12-22%

with

proxim

altubu

larinjury

[5,6]

0.5%

expe

riencea

renalevent

[111]

0.3%

expe

riencerenal

failure

[111]

0.3-2%

fancon

isynd

rome[112]

Preven

tion:

Biannu

alscreen

ing

forproteinu

riaand

glycosuriawith

urinalysis,Scr,serum

phosph

atein

patientswith

eGFR

of<90

ml/m

in/

1.73

m2[104]

<2%

requ

iredialysis[113]

16%

increasedrisk

ofCKD

[105]

May

have

partialo

rcompleterecovery

with

inmon

thsto

ayear

Awdishu and Mehta BMC Nephrology (2017) 18:124 Page 4 of 12

Table

15R

Summaryby

CausalD

rug(Con

tinued)

Vancom

ycin

[29,37,114–124]

AKI

Age

Obe

sity

Sepsis

Hypoten

sion

CKD

Activecancers

Trou

ghconcen

trations

>15

ng/m

LDoses

greaterthan

4g/day

Durationof

therapy

Con

curren

tne

phrotoxins

(ACEI,

acyclovir,

aminog

lycoside

s,am

photericin,colistin

,pipe

racillin/

tazobactam

,vasopressoruse)

5-43%

[29,36,114–

116,118,119,125,

126]

Employ

therapeutic

drug

mon

itorin

gand

pharmacist

consultatio

n[41]

Maintaintrou

ghconcen

trations

to<15

ng/m

L[38]

Maintaindo

ses

<4g/day

Con

side

rsw

itching

toalternative

antib

ioticssuch

astelavancin

orlinezolid

[39,40]

Avoid

combinatio

nwith

pipe

racillin/

tazobactam

[119]

Minim

izeconcurrent

neph

rotoxin

expo

sure

Dialysis0–7.1%

[119,126]

Resolutio

n21–72.5%

[114,119,126]

Mortality45%

[126]

VEGFInhibitors

Glomerular

Doserelated[127]

21-63%

incide

nce

ofhype

rten

sion

[127]

Caserepo

rtsof

neph

ropathy.

Redu

cedo

seACEinhibitorsand

nitrates

totreat

proteinu

riaand

hype

rten

sion

Discontinue

drug

33%

resolutio

nof

injury

after

discon

tinuatio

nof

therapy[7]

Awdishu and Mehta BMC Nephrology (2017) 18:124 Page 5 of 12

replacement therapies, it is difficult to recognize DIKD.For example, if a critically ill patient develops AKI fromsepsis, it may be difficult to recognize whether an anti-biotic is causing additional injury to the susceptible kid-ney. Recognition is also complicated by the fact that themechanism of kidney injury and time period for onset ofinjury varies by drug and some drugs cause injury by morethan one mechanism. For instance, NSAIDS can result inAKI due to hemodynamic changes or acute interstitialnephritis (AIN), or nephrotic range proteinuria fromglomerular injury.In order to improve the recognition of DIKD in the

literature, we convened an expert panel to developconsensus-based definitions [26]. We propose that DIKDpresents in one of four phenotypes: AKI, glomerular dis-order, tubular disorder, or nephrolithiasis/crystalluria[26]. The clinical presentation of each phenotype isbased on primary and secondary criteria. We suggestthat at least one primary criterion must be met for alldrugs suspected of causing DIKD [26]. For each pheno-type definition, the following critical elements from theBradford-Hill causal criteria must be met:

1. The drug exposure must be at least 24 h precedingthe event.

2. There should be biological plausibility for the causaldrug, based on known mechanism of drug effect;metabolism and immunogenicity.

3. Complete data (including but not limited toco-morbidities, additional nephrotoxic exposures,exposure to contrast agents, surgical procedures,blood pressure, urine output) surrounding theperiod of drug exposure is required to accountfor concomitant risks and exposures to othernephrotoxic agents.

4. The strength of the relationship between theattributable drug and phenotype should be basedon drug exposure duration, extent of primary andsecondary criteria met and the time course ofthe injury.

In defining the time course for DIKD, it is importantto consider consensus definitions for AKI, acute kidneydisease and CKD. Acute kidney injury develops in 7 daysor less, injury beyond 7 days but less than 90 days re-flects acute kidney disease and beyond 90 days CKD[27]. Using the KDIGO definitions, the development ofDIKD can similarly be divided into acute (1–7 days),sub-acute (8–90 days) and chronic (>90 days) post drugexposure [26]. This approach permits classification andtracking of injuries for duration and outcomes. Based onthis conceptual model, for each phenotype, thresholdscould be established to detect DIKD, define its severityand ascertain recovery.

The reference Scr used for defining DIKD should asclose as possible to the event to meet the definition ofAKI but may not always be available as in the case ofambulatory care exposures. In this scenario, we recom-mend using the lowest Scr within 90 days of the eventas the reference Scr. It is recognized that CKD is an im-portant risk factor for the development of DIKD. Under-lying kidney disease impacts the recognition of DIKD.We recommend using a Scr value greater than 90 daysfrom the DIKD event to define the presence of CKD.These standard definitions will become increasingly

important when designing tools within the EMR toscreen for DIKD. Such screening tools have been success-ful at identifying AKI and guiding the physician on theneed for nephrology consultation [28]. Pharmacovigilenceprograms can identify patients who have been exposed tonephrotoxic medications and develop AKI with highserum drug concentrations [29]. Additionally, theseelectronic screening tools can be customized. At riskpatients, such as those receiving multiple nephrotoxinsor prolonged nephrotoxin exposures, can be targeted.Identification of such patients can prompt interventionssuch as intensified Scr monitoring and improve the re-covery of DIKD [30]. However, electronic screening andidentification cannot establish causality. These tools arelimited due to the complex interplay of risk factor as-sessment, concurrent multi-drug exposures, lack ofTDM, comorbid conditions and lack of kidney damagebiomarkers. It is important that DIKD cases are adjudi-cated for causality and an attribution of risk is esti-mated for each contributing drug or risk factor. In thecase of vancomycin, a pharmaco-vigilence programidentified 32% of patients exposed to vancomycin withhigh trough concentrations and AKI [29]. However,when the cases were adjudicated, only 8.4% of AKIcases were attributed to vancomycin toxicity [29]. Attri-bution of risk from each potential risk factor or fromeach causal drug in the case of multi-drug injury is diffi-cult since these assessments are based on the individualpatient presentation and might reflect a substantial degreeof subjectivity depending on the adjudicator’s knowledgeof DIKD and AKI epidemiology. We recommend whenevaluating cases of DIKD, the consulting nephrologistdocument their causality assessment in the medical recordincluding a percent attribution assigned to each causaldrug with an overall likelihood to cause the DIKD, as wellas a percent attribution for each of the identified concur-rent AKI risk factors. Adverse event causality scoring toolsexist for general adverse events as well as drug inducedliver and skin injury (Naranjo, Rucam, Liverpool), how-ever, these tools have not been evaluated for the causalityscoring of DIKD. Previous genomic studies of druginduced liver and skin injury have employed adjudicationof cases by unbiased hepatologists or immunologists/

Awdishu and Mehta BMC Nephrology (2017) 18:124 Page 6 of 12

dermatologists, respectively [31, 32]. Often, published casereports lack the evaluation of causality using these scoringsystems or adjudication. As the body of knowledge sur-rounding DIKD increases, we recommend employingthese scoring tools in addition to adjudication of cases bya secondary nephrologist when publishing case reports orseries.

ResponseTreatment of nephrotoxicity is dependent on the pheno-type, severity of the injury and the underlying conditionfor which the medication was prescribed. The decisionto stop or reduce the dose of the offending drug requiresa careful consideration of the risk versus benefit. In TypeA reactions, dose reduction may be sufficient to mitigatethe injury (e.g. vancomycin or gentamicin). However,stage 2 AKI often warrants drug discontinuation. In thesetting of vancomycin DIKD, a critical appraisal of othertherapeutic options and dose minimization is warranted.National guidelines on the use of vancomycin have rec-ommended higher target trough concentrations to obtaina high area under the curve (AUC) to minimum inhibitoryconcentration (MIC) ratio [33, 34]. However, the level ofevidence for this recommendation was grade IIIb (limitedevidence) [34]. With the widespread adoption of thisrecommendation [35], the rate of nephrotoxicity has in-creased. Meta-analysis conducted found the incidence ofnephrotoxicity to be between 5-43% and target troughconcentrations > 15 ng/mL to have a 2.67 odds ratio forthe development of nephrotoxicity [36]. A more recentstudy of 1430 patients receiving vancomycin providessupport for the association between concentrations andduration of therapy with risk of nephrotoxicity [37]. Posthoc analysis of prospective studies have examined theneed for higher targets and demonstrated equivocal orlower cure rates with trough concentrations above15 ng/mL for the treatment of staphylococcus aureusnosocomial acquired pneumonia [38, 39]. Additionally,these studies have demonstrated that alternative treat-ments such as linezolid or telavancin could be considered[39, 40]. Based on these studies, we believe that DIKDfrom higher vancomycin trough concentrations is a realconcern. However, prospective studies designed toevaluate the benefits and risks of high therapeutic con-centrations need to be done. Type B DIKD, which isidiosyncratic, will require discontinuation of the offendingdrug and careful observation. Severe injuries or type Breactions often require longer periods of time to improveand may not completely resolve.When DIKD has been identified, the patient should be

monitored carefully including daily assessment of Scrand urine output as changes in kidney function may leadto further injury or lack of clinical cure for infections.Concurrent risk factors for kidney injury should be

addressed such as but not limited to hypotension, hyper-glycemia, anemia, minimization of nephrotoxins or druginteractions, which may contribute to the injury. Doseadjustments for kidney function should be made forother medications the patient is receiving. In some cases,timed urine collections for CLcr determination may bewarranted to assist in the determination of renal functionfor the purpose of dosage adjustment. Where available,TDM should be employed and continued even after drugdiscontinuation in cases where supra-therapeutic concen-trations are documented during the injury. Pharmacistconsultation improves the achievement of target concen-trations and improves clinical cure rates [41]. Additionally,documentation of the event is imperative to prevent futureinjuries from subsequent exposures. Patients should beinformed of the event to empower them to inform otherhealthcare providers of their susceptibility to the drug.Often, the sub-phenotype is difficult to distinguish from

laboratory parameters (i.e. ATN vs. AIN) and kidney bi-opsy information can guide treatment decisions. Severalstudies have demonstrated the importance of kidney biop-sies for classifying the type of injury and establishing thecausal drug in the setting of nephrotoxicity. Zaidan andcolleagues published a series of 222 kidney biopsies fromHIV infected patients, 59 cases demonstrated tubulopathyor interstitial nephritis with 52.5% attributable to a drug[42]. Tenofovir was identified as the most common culpritof tubular damage in this series whereas infections anddysimmune syndromes accounted for the majority ofinterstitial nephritis cases [42]. Xie and colleagues pub-lished a case series of kidney injury from clindamycin, apreviously unrecognized adverse event [43]. Biopsy resultsdocumented the majority of cases with AIN (75%) andremainder with ATN (25%) [43]. Chu and colleaguesdemonstrated that only 79.2% of patients with biopsyproven acute tubular necrosis met the clinical criteriafor AKI [44]. Most patients had a slower increase in Scrthan current KDIGO definitions [44]. Kidney biopsy in-formation in addition to careful consideration of thetemporal and causal relationship to drugs can provide amore accurate diagnosis of DIKD. Additionally, DIKDis often caused by multiple drugs and determining causal-ity can be difficult. Even with kidney biopsy data, it may bedifficult to determine exact causality for multi-drug in-jury. Sequential discontinuation of suspected causaldrugs and subsequent re-challenge may assist in causalityassessment.

Renal SupportThe need for renal support to treat DIKD is low (Table 1).The use of renal replacement therapy for DIKD is two-fold, firstly, dialysis can be utilized to remove the offendingdrug and minimize ongoing damage; additionally, dialysiscan be utilized to support renal function to allow recovery.

Awdishu and Mehta BMC Nephrology (2017) 18:124 Page 7 of 12

The decision to start renal replacement therapy is acomplex one and generally reserved for severe injuriesor cases in which the drug toxicity may be mitigatedthrough removal by dialysis (example: vancomycin [45],aminoglycosides [46]).Drug removal by dialysis is dependent on the charac-

teristic of the drug including molecular weight, proteinbinding, volume of distribution and operational charac-teristics of the dialysis treatment include type of mem-brane, blood and dialysate flow rates and duration oftherapy [47].When starting renal support therapy, it is critical to

consider the potential for errors in drug dosing and ex-posures. Renal clearance is determined by the dialysisprescription for drug dosing. However, in the critically illpopulation, gaps in dialysis delivery are frequent (e.g.filter clotting, time off treatment for procedures) andcurrent prediction equations do not account for thesesituations. When possible, TDM should be employed.The decision to stop renal support is challenging andgenerally based on changes in pre-dialysis Scr values,urine output, fluid status and acidosis. These transitionsfrom AKI with no renal support to dialysis therapies toresolution of injury are time periods with increased sus-ceptibility to drug dosing errors. During recovery, totalrenal clearance should be estimated by quantifying in-trinsic kidney function in addition to the dialysis therapyfor drug dosing. Urinary creatinine clearance determin-ation, despite its limitations [48, 49], may assist in the esti-mation of intrinsic kidney function. During resolution,drug clearance estimated from TDM may be used in theassessment of kidney function. For example, the clearanceof aminoglycosides and vancomycin correlate well withcreatinine clearance [50, 51]. Estimation of clearance ofthese drugs by TDM may assist the clinician in dosingother drugs that are not monitored (e.g. cephalosporins,quinolones).

RehabilitationMost cases of nephrotoxicity are acute, non-oliguric andresolve with discontinuation of the causal drug (e.g. amino-glycosides) (Table 1). However, for some drugs, mixedpatterns of injury may complicate the assessment ofrecovery. In the case of cisplatin, glomerular filtrationdecline tends to be reversible whereas tubular dysfunc-tion may persist [52]. Clinical issues to consider includefollow-up in specialized AKI ambulatory clinics and repeatassessment of kidney function to ascertain reversibilityand delayed recovery, reporting of the adverse event tothe U.S. Food and Drug Administration (https://www.ac-cessdata.fda.gov/scripts/medwatch) [53], documentationof the adverse effect in the allergy section of the EMR,limiting re-exposures to the causal drug and appropriatelyusing information from past exposures (i.e. TDM) to limit

future adverse events. For example, TDM software can beused to determine appropriate initial dosing for antibioticsbased on population based pharmacokinetic parameters.However, if a patient has experienced AKI from anantibiotic in the past and the information is relativelyrecent, the past pharmacokinetic parameters estimatesfor that particular patient should be used to guide futureempiric dosing recommendations. Therapeutic drugmonitoring may prevent nephrotoxicity and result in costavoidance [54, 55].

ResearchResearch in the epidemiology of DIKD has been limited.The lack of consensus definitions has led to variability inthe incidence of DIKD. Acute kidney injury is multifac-torial and risk factors for AKI have been identified fordifferent populations. Risk factors for DIKD vary bydrug; however, it is very likely that we can determinecommon risk factors that identify vulnerable popula-tions, such as older age or history of CKD. Establishingcausality is challenging in DIKD; it requires attributionof risk to not only the suspect drug but also the relativecontribution from each concurrent risk factor. Newlyidentified DIKD is often published as case reports orcase series. In such reports, the attribution of risk fromconcurrent risk factors is lacking. Clinical trials and FDAsurveillance programs provide some information, butpost-marketing surveillance is voluntary and requiresclinicians to identify the association of an AKI eventwith a drug. As accepted definitions of AKI are imple-mented in research and AKI awareness increases, theidentification and outcomes of DIKD will be better char-acterized. The use of EMRs and decision support toolswill facilitate electronic surveillance of DIKD, identifyingthe event and risk factors and directing clinicians ontreatment options. However, more research is requiredin the area of causality assessment, risk score calculationand adjudication of cases. Electronic surveillance aloneprovides an initial step in case identification, however,without causality assessment, these tools lack validityand will lose their effectiveness in clinical practice.Often, histologic confirmation of drug toxicity is lacking.

The decision to biopsy a patient is a risk/benefit assess-ment and central is the question of whether a biopsy willchange patient management? The majority of cliniciansopt to discontinue a suspect drug rather than biopsy.However, given the lack of validated tools for causalityassessment, we feel that biopsy information from casesseries of drug toxicity will contribute significantly tothis area of research. As our body of knowledge increases;risk score calculators, causality assessment tools coupledwith information on outcomes of DIKD can lead to thedevelopment of predictive analytics which may identify in-dividuals at risk of nephrotoxicity from a drug. Population

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based studies provide a large sample and aid in the identi-fication of rare or previously unrecognized events such asantipsychotic associated AKI [56] or drug interactions thatlead to drug toxicity and AKI [18].Translational research models of drug-induced nephro-

toxicity identifying pharmacokinetic parameters, drugtransporters and kidney injury biomarkers have been de-veloped but there are no prospective studies validatingthese models [57–61]. Molecular characterization of drugtoxicity using proteomics and microarrays will furtherdelineate mechanisms for kidney injury and pathwaysfor repair [62–65]. Ongoing research in the area of bio-markers to earlier detect damage in drug toxicity willfacilitate prevention of functional changes [66–70].Importantly, research on the preventative strategies

and response to nephrotoxicity is limited. Although,TDM and pharmacokinetic analysis improves achieve-ment of target concentrations, vulnerable populations donot have the same pharmacokinetic parameters as generalpopulation based estimates. For example, there is limitedinformation on pharmacokinetic parameters for specificnephrotoxic drugs in CKD or heart failure putting thesepopulations at risk. Additionally, TDM is not uniformacross the United States. There is a need for increasedpharmacokinetic studies on vulnerable populations, aswell as studies on target drug concentrations linked to pa-tient outcomes. The emergence of increased vancomycinnephrotoxicity is a case example of widespread applicationof consensus-based recommendations on higher drugconcentrations with a lack of strong evidence for patientoutcomes across various types of infections.Consensus guidelines on drug dosing in AKI provide

practical recommendations and should be considered fordosing other drugs that patient is concurrently takingduring a nephrotoxic insult [17]. However, research ondrug dosing in AKI is limited. More information is neededon kidney function estimation in AKI, the impact of tubu-lar function and metabolism of drugs during AKI andpharmacokinetic changes in AKI [71–73]. Enhancing thisresearch will translate to the mitigation of additional riskand in turn enhanced recovery from a nephrotoxic event.The field of AKI and DIKD research is rapidly evolving

with the development of large international registries ofpatients with AKI and DIKD. This presents tremendousopportunities for trainees with an interest in kidney diseaseto collaborate with other disciplines on research that willenhance our body of knowledge in these important areas.

ConclusionsIn conclusion, we provide a 6R framework for DIKD thatallows clinicians to apply what is known about DIKDand more importantly to recognize the unknown andlimitations of our current clinical care.

AbbreviationsAIN: Acute interstitial nephritis; AKI: Acute kidney injury; ATN: Acute tubularnecrosis; AUC: Area under the curve; CKD: Chronic kidney disease; CLcr: Clearancecreatinine; DIKD: Drug induced kidney injury; EMR: Electronic medical record;KDIGO: Kidney disease improvement global outcomes; MIC: Minimum inhibitoryconcentration; NSAIDs: Non-steroidal anti-inflammatory drugs; Scr: Serumcreatinine; TDM: Therapeutic drug monitoring

AcknowledgementsNot applicable.

FundingNot applicable.

Availability of data and materialsNot applicable.

Authors’ contributionsLA conducted the literature search and drafted the manuscript. RM draftedthe manuscript. Both authors read and approved the final manuscript.

Authors’ informationDr. Linda Awdishu is an Associate Clinical Professor of Pharmacy and Medicine.Dr. Ravindra Mehta is a Professor of Clinical Medicine and the Vice Chair forResearch in the Department of Medicine. Drs. Awdishu and Mehta areconducting an international, multicenter study examining the genomicrisk factors for the development of drug induced kidney disease.

Competing interestsL. Awdishu and R. Mehta have received grant funding from the InternationalSerious Adverse Events Consortium.

Consent for publicationNot applicable.

Ethics approval and consent to participateNot applicable.

Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in publishedmaps and institutional affiliations.

Received: 16 June 2016 Accepted: 25 March 2017

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