review article contrast media viscosity versus osmolality...

Review ArticleContrast Media Viscosity versus Osmolality in Kidney InjuryLessons from Animal Studies

Erdmann Seeliger Diana C Lenhard and Pontus B Persson

Institute of Physiology and Center for Cardiovascular Research Charite-University Medicine Berlin Campus MitteHessische Straszlige 3-4 10115 Berlin Germany

Correspondence should be addressed to Erdmann Seeliger erdmannseeligercharitede

Received 18 October 2013 Accepted 29 December 2013 Published 23 February 2014

Academic Editor Richard Solomon

Copyright copy 2014 Erdmann Seeliger et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Iodinated contrastmedia (CM) can induce acute kidney injury (AKI) CMshare common iodine-related cytotoxic features but differconsiderably with regard to osmolality and viscosity Meta-analyses of clinical trials generally failed to reveal renal safety differencesofmodernCMwith regard to these physicochemical propertiesWhilemost trialsrsquo reliance on serumcreatinine as outcomemeasurecontributes to this lack of clinical evidence it largely relies on the nature of prospective clinical trials effective prophylaxis by amplehydration must be employed In everyday life patients are often not well hydrated here we lack clinical data However preclinicalstudies that directly measured glomerular filtration rate intrarenal perfusion and oxygenation and various markers of AKI haveshown that the viscosity of CM is of vast importance In the renal tubules CM become enriched as water is reabsorbed but CMare not In consequence tubular fluid viscosity increases exponentially This hinders glomerular filtration and tubular flow andthereby prolongs intrarenal retention of cytotoxic CM Renal cells become injured which triggers hypoperfusion and hypoxiafinally leading to AKI Comparisons between modern CM reveal that moderately elevated osmolality has a renoprotective effectin particular in the dehydrated state because it prevents excessive tubular fluid viscosity

1 Introduction

Iodinated X-ray contrast media (CM) are widely used indiagnostic and therapeutic procedures such as percutaneouscardiac and arterial interventions and contrast-enhancedcomputed tomography In general todayrsquos CM are very welltolerated However CM can cause acute kidney injury (AKI)in particular patients with preexisting renal impairmentendothelial dysfunction andor diabetes and patients whoare not sufficiently prehydrated are at risk As the num-bers of diagnostic and therapeutic procedures are steadilyincreasing CM-induced AKI (CIAKI) has become the thirdleading cause for iatrogenic AKI Fortunately CIAKI isa transient disorder in the majority of patients howeverCIAKI can also have severe consequences Patients withCIAKI suffer from an increased rate of in-hospital com-plications including an increased mortality rate and maybecome predisposed to long-term loss of kidney function[1ndash6]

All classes of CM share certain properties relevant forCIAKI such as some cytotoxicity However they vary con-siderably with regard to osmolality and viscosity and thereis a standing debate on which of these physicochemicalproperties determines renal safety One reason for this uncer-tainty is the lack of a clinical marker for AKI that would beboth reliable and practicable Meanwhile preclinical studieshave helped fill in gaps In particular animal experimentshave been instrumental in elucidating the pathophysiologicalmechanisms that rely on CM viscosity and osmolality Theoptimum physicochemical properties of CM to avoid CIAKIwill be the focus of this review

2 Why Preclinical Studies Could AnswerQuestions That Clinical Trials Could Not

CIAKI is broadly defined as a decrease in glomerular filtra-tion rate (GFR) within 2 to 3 days following the intravascular

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 358136 15 pageshttpdxdoiorg1011552014358136

2 BioMed Research International

administration of CM in the absence of an alternativeaetiology [7ndash9] For several reasons this definition is not anideal one [7ndash11] A decrease in GFR can per se not attest tokidney injury it rather indicates that one partial function ofthe kidney namely filtration is disturbed Second in clinicalpractice CIAKI is diagnosed by an increase in the surrogatemarker for GFR serum creatinine (SCrea) because directmeasurements of GFR by clearance methods require tediousurine collection Unfortunately SCrea is a poor marker ofGFR its sensitivity is very low with regard to both the degreeand the time course of GFR changes Due to the exponentialrelationship between SCrea and GFR SCrea is very insen-sitive in patients with preexisting normal GFR [3 7 10 12]Day-to-day variations in SCrea observed in patients in whomno cause for rapid GFR changes could be identified indicatethat SCrea is also insensitive at reduced preexisting GFR [1314] Moreover due to the kinetics of creatinine distributionamong the body fluid compartments SCrea is notoriouslyinsensitive to rapid GFR changes such as the immediateGFR drop induced by CM creatinine accumulationmay takedays before SCrea increase fulfils diagnostic criteria [7 10ndash12 15 16] Reflecting these drawbacks CIAKI is currentlydiagnosed when a certain absolute (eg 44 or 88 120583molL) orrelative (eg 25 or 50) increase in SCrea is observed within48 or 72 hours after CM whereby the optimum margins arestill under debate [3 8ndash11]This diagnostic delay poses severeproblems with regard to clinical practice the most obviousbeing that CIAKI will often go undetected in outpatients [17]

Besides the consequences for patient care the poorperformance of SCrea to reflect changes in GFR has greatlyhampered advances in knowledge The vast majority ofclinical trials have been relying on SCrea as the sole end pointOften the incidence of CIAKI cannot be compared amongtrials because of the different absolute or percentage marginsin SCrea increase andor the different timing and frequencyof post-CM SCrea measurements (eg 24 versus 72 hours)[8 10 18ndash21] Thus there is general agreement that manyimportant questions for example regarding the incidenceof CIAKI following contrast-enhanced CT regarding specificprophylactic strategies or comparisons among CM are notyet answered unequivocally because clinical trials with fewexceptions relied on SCrea as outcome measure [7 1017 21ndash28] Utilization of robust outcome measures such asrequirement of dialysis and if their reliability is convincinglyproven of new serum and urinary markers of renal injurywill certainly improve the power of evidence in future clinicaltrials [11 29 30]

Animal studies that made use of clearance methods todirectly measure GFR and that assessed various direct andindirect markers of renal injury and functions helped fill ingaps Thus experiments run under highly standardised con-ditions provided direct comparisons between classes of CMand between specific prophylactic strategies Moreover invitro and in vivo studies elucidated pathophysiological mech-anisms of CIAKI so that it became possible in recent yearsto shape a quite uniform scheme of CIAKI pathophysiology[7] Mechanisms underlying CIAKI include cytotoxic effectsparacrine factors that affect renal hemodynamics alteredrheological properties that perturb renal hemodynamics

and tubulodynamics and tissue hypoxia These mechanismsact in concert yet the individual mechanismsrsquo importancevaries with the classes of CM used with the subjectrsquoshydrationvolume status andmdashin patientsmdashwith the degreeof preexisting individual risk factors [7] One factor thathas a major impact on tubulodynamics is fluid viscosityFluid viscosity is a measure of the fluidrsquos resistance to flowdue to friction between neighboring parcels that are movedat different velocities In the context of CM the dynamicviscosity (usually given in millipascal second (mPa s)) andthe kinematic viscosity (usually given in square millimetreper second (mm2s)) are most relevant A fluidrsquos kinematicviscosity (which is typically measured by Ubbelohde-typeviscometers that make use of gravity to move the fluid withina tube) is converted to its dynamic viscosity by dividing it bythe fluidrsquos density The classes of CM vary considerably withregard to viscosity andosmolality and both high viscosity andhigh osmolality have been implicated to play pivotal roles inthe pathophysiology of CIAKI

3 Why the Current Labelling of CM ClassesRelies on Their Osmolalities

CM for intravascular use are tri-iodinated benzene deriva-tives Because their radio-opacity relies on iodine solutionswith high iodine concentration (usually 250ndash400mg ImLsolution) are requiredThis is achieved by highmolar concen-trations of benzene derivatives The molar concentration ofthe CM solution is a major determinant of both its osmolalityand its viscosity However whereas the osmolality of a givenCM solution increases only linearly with the molar concen-tration viscosity increases exponentially [31] The pioneerclass of CM comprised solutions of monomers (iothalamatediatrizoate) at high molar concentrations These compoundsare ionic which additionally increase the solutionsrsquo osmo-lalities so that their osmolalities are exceedingly high (sim1000ndash2500mosmolkgH

2O) as compared to blood plasma (sim

290mosmolkgH2O) [32]This class of CMwas termed high-

osmolar CM (HOCM) and was found to be associated with aconsiderable risk for CIAKI [1 32 33] As a consequence CMwith lower osmolalities were developed By forming eitherionic dimers (ioxaglate) or nonionic monomers (iopromideiopamidol iohexol ioversol iomeprol etc) osmolalities ofsim400ndash800mosmolkg H

2O were achieved [32] Although

their osmolalities are actually still higher than these ofplasma these compounds are referred to as low-osmolar CM(LOCM) The realisation that LOCM were associated witha marked lower CIAKI incidence than HOCM particularlyin at-risk patients had two consequences [32 33] FirstHOCM are virtually no longer in clinical use in WesternEurope and the USA Second the next goal in CM devel-opment seemed obvious further reduction in osmolality Bycreating nonionic dimeric compounds (iodixanol iotrolanand iosimenol) iso-osmolar CM (IOCM) were developed[32 33] Pure IOCM solutions are actually hypoosmolarelectrolytes are added to the clinically used solution to reachplasma osmolality [34]The low osmolality achieved with theIOCM came at the price of considerably increased viscosity

BioMed Research International 3

At comparable iodine concentration and thus comparableX-ray attenuation nonionic dimer IOCM have about twicethe viscosity of nonionic monomer LOCM [32 35] Thehigher viscosity of nonionic dimer IOCM probably relies onnumber of the compoundsrsquo features including the moleculesrsquoshape and the flexibility of the bridge between the twobenzene nuclei that may lead to their superposition [36ndash38]It must be noted however that viscosities of all CM classesare markedly higher than those of plasma ranging from 25-fold in HOCM to 11fold in IOCM [32] Both physicochemicalproperties of CM osmolality and viscosity have majorsimpact on CM handling in the renal tubules and thus theirpotential to harm

4 Why CM Become Concentrated inthe Kidney

CM administered intravascularly are considerably dilutedbefore they reach the kidney and more so upon intravenousadministration such as for contrast-enhanced CT than uponintraarterial administration such as for renovasography andleft ventriculographyThe different degree of dilution may bea main reason behind the apparent iv versus ia differencein CIAKI incidence [26ndash28] CM dilution en route to thekidney of course reduces their viscosity and osmolality(see schematic Figure 1 for factorsmechanisms that influencetubular fluid viscosity following CM administration) Like allother osmolytes small enough to pass the renal glomerularfilter CM are freely filtered so that their concentration inprimary urine equals that of the blood plasma enteringthe kidney Whereas a multitude of other small osmolytesare reabsorbed by specific tubular transport mechanismsthere are no such transporters for CM Because the vastmajority of the filtered water is reabsorbed along the lengthof the tubule and CM are not CM become considerablyconcentrated en route through the tubules This results ina progressive increase in tubular fluid osmolality and dueto the exponential concentration-viscosity relationship anoverproportional increase in tubular fluid viscosity Waterreabsorption along the tubules is driven by osmotic gradientsbetween the tubulesrsquo lumen and renal interstitial fluid Therenal medulla is unique in that its osmolality is higher thanthat of all other tissues In humans osmotic pressure achievesup to 600mosmolkg H

2O in the outer medulla in the

inner medulla and thus also in the long loops of Henleand the inner medullary collecting ducts it reaches up to1200mosmolkg H

2O

The quantitative effects of osmotic forces comparable tothose present in the different renal layers on water reabsorp-tion and thus on the concentrating of CM have recentlybeen illustrated by an in vitro dialysis study (Figure 2(a)) [34]Six CM solutions as marketedformulated for clinical usewere studied four LOCM and two IOCM with comparableiodine concentrations the viscosities of the IOCM solutionsare about twice those of LOCM solutions Dialysis of thesolutions at ambient osmotic pressure of 290mosmolkgH

2O

(ie isoosmotic to plasma) resulted in a decrease in theiodine concentration of LOCM but not IOCM solutions

Tubular fluidviscosity

CM dilutionen route tothe kidney Extrarenal

factors

Renal tubularfactors

CM propertiesCM viscosity

Dehydrationvolume contraction

Tubular water reabsorption

Tubular load of nonreabsorbable

osmolytes

CM osmolality

Vasopressinangiotensin II

+ +

+

+

+minus

Figure 1 Simplified scheme summarizing major factorsmecha-nisms that influence tubular fluid viscosity following CM adminis-tration For detailed explanations see text

as can be expected from the net water inflow into thesolutions that is driven by the LOCM solutionsrsquo higherosmolalities With increasing ambient osmotic pressureswater is progressively extracted from the solutions suchthat the iodine concentrations progressively increase Theiodine concentrations of IOCM exceeded those of LOCM oneach osmotic pressure step At ambient osmotic pressures of1000mosmolkgH

2O (ie comparable to the innermedulla)

iodine concentrations of LOCM solutions were somewhathigher than in the marketed solutions yet iodine concentra-tions of IOCM solutions were doubled as compared to theirmarketed solutions Owing to the exponential concentration-viscosity relationship this was accompanied by an increasein the viscosity of LOCM solutions yet the viscosity increaseof IOCM solutions was several times larger in fact it byfar exceeded the measuring range of the used viscometer(Figure 2(b)) [34]

5 Why the Hydration Status Impacts onTubular Fluid Viscosity

In line with these in vitro observations in vivo studies thatdirectly compared urine viscosities following LOCM versusIOCM administration in dogs and rats clearly demonstratedlarger increases in urine viscosities following IOCM [34 39ndash46] This was also confirmed by a small series of patients[44] In all these studies the subjects were well hydratedand presumably euvolaemic due to ample administrationof fluids It does not therefore surprise that in absoluteterms the increases in urine viscosity were rather smallThe degree of tubular water reabsorption depends on asubjectrsquos hydration and volume status (Figure 1) In subjectsthat are notwell hydrated andor hypovolaemic physiological


0

100

200

300

400

500

600

700

800

CA 290 400 500 700 1000

IopromideIohexolIoversol

IomeprolIodixanolIosimenol

Osmolality (mOsmkg H2O)

Iodi

ne (m

gIm

L)

(a)

CA 290 400 500 700 10000

50

100

150

200

250




Visc

osity

(mPa

lowasts)

≫200 ≫200

(b)

Figure 2 Changes of concentration and viscosity of solutions of six different contrast media (four LOCM depicted in blue iopromide 300iohexol 300 ioversol 300 and iomeprol 300 two IOCM depicted in red iodixanol 320 and iosimenol 350) caused by in vitro dialysis toemulate the renal tubular concentration process Iodine concentration (a) and viscosity (b) of the respective contrast agent solutions asmarketedformulated for clinical use (marked as CA) and after dialysis with PEG solutions with osmolalities of 290 400 500 700 and1000mosmkg H

2O Data are mean plusmn SEM Please note that the viscosity of both IOCM solutions after the dialysis at 700 and 1000mosmkg

H2O was so high that it even exceeded the upper measurement limit of the viscometer Redrawn from data in [34]

mechanisms that aim atwater andor volumepreservation aretriggered in particular activation of the renin-angiotensinsystem and of vasopressin [47ndash49] Angiotensin II and vaso-pressin augment tubular fluid reabsorption which furtherincreases the tubular concentration of CM and due tothe concentration-viscosity relationship overproportionallyincreases urine viscosity Accordingly dehydration andorvolume contraction are major individual risk factors forCIAKI hence the strong recommendation of prehydrationthat is embodied in clinical guidelines [8 9]

It must be noted that terms such as ldquovolume statusrdquoldquowell hydratedrdquo and ldquoeuvolaemiardquo are generally used in aqualitative rather than a quantitative sense Moreover termslike ldquohydrationrdquo ldquodehydratedrdquo and so forth are used through-out the literature on CIAKI including current guidelineswithout a clear distinction whether water or volume (isotonicfluid) is meant [1ndash9] For instance the term ldquodehydrationrdquoin its strict sense denotes a deficit of water with an ensuingincrease in osmolality (hypertonic dehydration) but is oftenused as a synonym for a deficit in isotonic volume (volumecontraction) The imprecise use of these terms may reflectthe fact that a quantitative assessment of a patientrsquos volumestatus is not easily achieved in clinical practice particularly inoutpatients and as long as the patient does not display clinicalsigns of a marked volume deficit is seldom performed Inaddition large portions of patients who undergo CM-relatedinterventions are at old age and therefore prune to suffer from(hypertonic) dehydration due to impaired sensation of thirst[2 50] Current guidelines recommend ldquohydrationrdquo either byisotonic NaCl or sodium bicarbonate by hypotonic 045NaCl solution or by water per os without requiring prior

quantitative assessment of the patientrsquos hydration and volumestatus [8 9] However irrespective of whether hydration isachieved by isotonic or hypotonic fluid or just by water peros the patientsrsquo kidneys will benefit from increased tubularflow

Despite the guidelinesrsquo strong recommendations a con-siderable portion of patients in everyday clinical practice isfor various reasons not sufficiently hydrated [24 51] Forethical reasons prospective clinical trials can of course onlybe performed according to protocols that include ample fluidadministration In order to fill in the gap in knowledgefreely drinking rats were studied that concentrated theirurine to an extent comparable to nonhydrated humans [39]As shown by Figure 3(a) injection of the IOCM iodixanol320mg ImL into the thoracic aorta led to a massive increasein urine viscosity whereas following the LOCM iopromide370mg ImL urine viscosity was only moderately elevatedMicropuncture studies in rats and functional MRI studiesin rats also found tubular fluid viscosity to be much higherfollowing IOCM than LOCM [43 52]

6 Why CM Osmolality Impacts onTubular Fluid Viscosity

The large difference observed between urine viscosities fol-lowing iodixanol versus iopromide (Figure 3(a)) cannot beexplained by the viscosity of the CM solutions alone forwhich the difference is much less (sim10 versus sim7mm2s)Here the difference in CM osmolalities plays a major role


0

10

20

30

40

Iopromide 370Iodixanol 320

1 2 3 4 5 6ControlSampling period

Urin

e visc

osity

(mm

2s

)

lowastlowastlowastlowastlowast

(a)

00

02

04

06

08

10



Urin

e flow

(mL10

min

)

lowast

lowast lowast lowast lowast

(b)


1 2 3 4 5 60

5

10

15

20

25

Deadspaceeffect

ControlSampling period

Glo

mer

ular

filtr

atio

n (m

L10

min

) lowastlowastlowast

(c)

Figure 3 Viscosity of urine samples urine flow rate and glomerular filtration rate (GFR measured by creatinine clearance) in rats before(control) and following contrast media administration (six 10min sampling periods) Iopromide 370mg Iper mL or iodixanol 320 mg ImLwas injected into the thoracic aorta as a bolus of 15mL Rats had access to drinking water prior to the experiment but were not hydrated byinfusions Data are mean plusmn SEM lowast119875 lt 005 iopromide versus iodixanol In all sample periods after contrast media injection urine viscositiesand urine flow rates were significantly higher than in the respective control sample In rats receiving iodixanol GFR was significantly lowerthan control GFR 10 to 40min after iodixanol injection whereas GFR remained unchanged in rats receiving iopromide Note that GFR valuesfor the first period following contrast media injection are not depicted as high creatinine clearance values obtained for this period do notrepresent actual increases in GFR but rely on the dead-space effect Redrawn from data in [39]

The more nonreabsorbable osmolytes the tubular fluid con-tains the smaller is the osmotic gradient between the tubulesrsquolumen and the interstitium that drives water reabsoptionTherefore nonreabsorbable CM all induce osmotic diuresisbut to different degrees the higher the osmolality of a givenCM the stronger is its diuretic effect (Figure 1) Thus theLOCM iopromide generates much more diuresis than theIOCM iodixanol and does thereby prevent amajor increasein urine viscosity even in animals that are not well hydrated(Figure 3(b)) [39]

The tubular osmotic force of iopromide is much greaterthan that of iodixanol for two reasons First the osmolalityof the iopromide 370mg ImL solution is more than twiceas high as that of the iodixanol 320mg ImL solution (770versus 290mosmolkg H

2O) Second because solutions of

pure iodixanol drug substance with 320mg ImL are hypo-osmolar (210mosmolkg H

2O) reabsorbable osmolytes are

added to the marketed solution to render it isoosmolar[40] As a portion of these osmolytes will be reabsorbedthe tubular osmotic force of iodixanol is further reduced


In accordance in another study in rats a solution ofthe pure iodixanol drug substance (320mg ImL) inducedless diuresis than the marketed solution [40] Moreoverin this study the effect of increasing the osmolality ofthe marketed iodixanol 320mg ImL solution by nonre-absorbable mannitol was tested Increasing the osmolal-ity of iodixanol solution to 610mosmolkg H

2O indeed

enhanced diuresis and thereby decreased urine viscosity[40] The finding that LOCM by virtue of their higherosmolality induce larger diuresis than IOCM has beenconfirmed by several preclinical studies including studiesin very well-hydrated rats [34 39 43ndash46] Taken togetherthe higher osmolality of LOCM as compared to IOCMbears the advantage of preventing excessive urine viscositylevels

7 Why High Tubular Fluid Viscosity ConveysDeleterious Effects

The fluid flow rate through a tube increases with thepressure gradient and decreases with the flow resistanceThe resistance increases proportionally to fluid viscosityit also increases with the tubersquos length and decreases withits radius (Poiseuillersquos law) Thus any increase in fluidviscosity will reduce the flow rate at a given pressure gra-dient The ensuing congestion in turn will increase theupstream pressure Considering the minute diameter andthe relatively great length of renal tubules it does not sur-prise that CM-induced high tubular fluid viscosity increasestubular pressure and may hinder glomerular filtration Infact early micropuncture studies in rats found that theIOCM iotrolan increased tubular pressure much more anddecreased single nephron GFR much more as comparedto the HOCM and LOCM studied [53 54] As shown byFigure 3(c) following injection of the IOCM iodixanolbut not the LOCM iopromide into the thoracic aorta ofrats a marked transient decrease in GFR is observed thatparallels the increase in urine viscosity [39] As expectedprehydration by saline or bicarbonate infusions blunted theincrease in tubular viscosity and thereby alleviated theiodixanol-induced decreases in GFR but did not prevent it[39 45]

It is possible thatmechanisms other than viscosity-relatedincrease in tubular pressure may contribute to lower GFRin a recent in vitro study in isolated mouse afferent andefferent glomerular arterioles perfused with electrolyte solu-tions that contained diluted iodixanol a small but significantvasoconstriction of afferent arterioles was found [55] Aswill be discussed below reduced blood perfusion and tissueoxygenation in particular medullary hypoperfusion andhypoxia are pivotal pathophysiological elements in CIAKIBecause afferent vasoconstriction does not only reduce per-fusion and GFR but at the same time also decreases oxygen-dependent tubular reabsorption it is unclear whether or notit contributes to renal injury In any case it must be notedthat a decrease in GFR following CM administration despitebeing the basis of clinical diagnosis is per se not proof of renal

injury The viscosity-induced increase in tubular pressurehowever may well contribute to medullary hypoperfusionand hypoxia in the face of the rather tough renal capsulecircular distension of the tubules must result in compressionof medullary vessels such as the vasa recta [53 56 57]Another effect of increased tubular fluid viscosity is thatincreased flow resistance markedly slows tubular flow [44]so that the intrarenal retention time of IOCM is much longerthan that of LOCM as shown in rats andminipigs [35 58 59]In the kidneys of renally impaired ZSF1 rats IOCM wereeven retained for 2 weeks [35] Recent comparisons in healthyrats among the marketed iopromide 300mg ImL solutionthe marketed iodixanol 320mg ImL solution and the above-mentionedmannitol-iodixanol 320mg ImL (610mosmolkgH2O) demonstrated that the higher the viscosity and the

lower the osmolality the longer is the intrarenal CM reten-tion (Figure 4) [40 58] As has been recognised in the1990s already [60] prolongation of retention is in partrelated to the induction of vacuoles in proximal tubu-lar cells (Figure 4) [40 58] Probably the worst effect ofthe viscosity-related intrarenal retention is the prolongedexposure of tubular epithelial cells to potentially cytotoxicCM

In vitro studies clearly demonstrated that CM of allclasses exert cytotoxic effects cultured cells of various typesincluding renal tubular epithelial and vascular endothelialcells present signs of cell damage oxidative stress andorapoptosis when exposed to CM [61ndash63] The cytotoxicityof CM may rely on iodine that can be released from CMby photolysis [38] Minute amounts of free iodine may behighly cytotoxic [64] Recent in vivo studies in rats assessedrenal injury following iv CM administration by studyingrenal tissue expression of several AKI biomarkers using real-time PCR (Figure 5) [35 40 58] Expressions of kidneyinjury molecule 1 (KIM-1 a marker of tubular injury mainlyproximal cells) [65] and of neutrophil gelatinase associatedlipocalin (NGAL here a marker of tubular injury mainly dis-tal cells) [66 67] were quantified 24 hours after CM injectionand those of plasminogen activator inhibitor-1 (PAI-1 heremainly amarker of injury to collecting duct cells) [68] 2 hoursafter CM injection Whereas administration of iopromide300mg ImL did not change renal KIM-1 and NGAL expres-sions iodixanol 320mg ImL resulted in sim3fold upregulationof NGAL and KIM-1 Iopromide induced a sim2fold upregula-tion and iodixanol asim74-fold upregulation in PAI-1 Injectionof the above-mentioned iodixanol solution with mannitol-induced elevation of osmolality markedly reduced the effectson these AKImarkers as compared to themarketed iodixanolsolution These results mirror the different retention timesthe higher the viscosity and the lower the osmolality thelonger are the cells exposed to CM and the more theyare injured The effect of viscosity-induced renal injury wasfurther demonstrated by histological immunofluorescenceanalysis of the incorporation of bromdesoxyuridine into cells(BrdU a marker of cell proliferation following injury) [69]48 hours after CM injection (Figure 6) [58] The numberof proliferating cells increased significantly more followingiodixanol versus iopromide


Saline

(a)

(b)

(c)

(d)

Iopromide Iodixanol

Iodixanolmannitol

24h pi

(a998400)

(b998400)

(c998400)

(d998400)

Figure 4 Exemplary computed tomographic (CT) scans to assess renal iodine retention and exemplary histological images (hematoxylin-eosin staining) to assess formation of vacuoles in proximal tubular cells both taken 24 hours after injection (24 h pi) of either saline (a)marketed iopromide 300mg ImL solution (b) iodixanol 320mg ImL solution with mannitol added to elevate the solutionrsquos osmolality (c)or marketed iodixanol 320mg ImL solution (d) CM were administered intravenously at a dose of 4 g Ikg of body mass CT scans showpredominantly cortical iodine retention 24 h pi for themarketed iodixanol solution less retention following the iodixanolmannitol solutionand virtually none following iopromide and saline Formation of vacuoles (arrows) in proximal tubular cells was prominent 24 h pi for themarketed iodixanol solution slightly less following the iodixanolmannitol solution and sparse after iopromide and saline Reprinted from[40]

8 Why High CM Viscosity Conveys MedullaryHypoperfusion and Hypoxia

Hypoxia in the renal medulla is a hallmark of CIAKI [1 733 70ndash73] Medullary hypoxia is part of a vicious circle thatentails cellular damage oxidative stress and vasoconstric-tion The outer medulla is especially vulnerable to hypoxiaoxygen requirements are high due to salt reabsorptionin Henlersquos thick ascending limbs while oxygen deliveryis sparse Oxygen supply to the medulla is low becauseof the small medullary fraction of total renal blood flow(lt10) and of arteriovenous oxygen shunt diffusion CMin the medulla affect the fragile balance between oxygendelivery and consumption by several mechanisms the mainmechanism being reduced blood perfusion [7 33 70ndash72]Constriction of preglomerular vessels although possiblycontributing to the CM-induced drop in GFR has small ifany impact on medullary oxygenation blood flow reductionin medullary vessels that emerge from efferent arterioles isusually accompanied by reduced solute reabsorption andthus reduced oxygen consumption Medullar hypoxia istherefore mainly caused by CM effects on the medullaryvessels themselves in particular on the long and narrow vasarecta

At least three CM effects possibly acting in concertcontribute to the increase in medullary vascular resistanceFirst as mentioned above viscosity-induced increase intubular pressure probably compresses the vasa recta [53 56]Second CM can constrict descending vasa recta (DVR) asDVR are lined by pericytes that are able to contract [74] In aseries of in vitro studies in isolated DVR obtained from ratsand human beings the effects of CM on vascular diameterand reactivity and on endothelial generation of nitric oxide(NO) and reactive oxygen species (ROS) were tested [75ndash77] In these studies DVR were perfused by crystalloidsolutions that contained CM in low concentrations so thatthe solutionsrsquo osmolalities and viscosities equaled those ofplasma CM of all classes caused similar degrees of DVRconstriction In addition the vasoconstrictive response toangiotensin II was enhanced by CM The concentration ofROS was increased which may rely on CM-induced damageof endothelial cells [77 78] Endothelial injury may alsoaccount for the impaired NO production by DVR observedin these studies [75] Under in vivo conditions vasomotionof DVR is subject to tubulovascular crosstalk [74] It is thusmost probable that signals from injured tubular epitheliumcontribute to DVR vasoconstriction On the other hand theimpaired endothelial NO generation of DVR could at least


KIM-1

0

50

100

150

200

250

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

(a)

NGAL

0

500

1000

1500

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

lowast

(b)

PAI-1

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

0

100

200

300

400

500

lowast

lowast

lowast

(c)

Figure 5 Renal tissue expression (mRNA levels as analysed by real-time PCR) of kidney injury molecule 1 (KIM-1) and of neutrophilgelatinase associated lipocalin (NGAL) as quantified 24 hours after injection and that of plasminogen activator inhibitor-1 (PAI-1) as quantified2 hours after injection of either saline marketed iopromide 300mg ImL solution marketed iodixanol 320mg ImL solution or iodixanol320mg ImL solution with mannitol added to elevate the solutionrsquos osmolality CMwere administered intravenously at a dose 4 g Ikg of bodymass Data are mean plusmn SEM lowast119875 lt 005 versus saline Data taken from [35 40 58]

in part be compensated for in vivo by hemoglobin-generatedNO hemoglobin reduces nitrite to NO in hypoxic areas suchthat NO and thus vasodilation are provided ldquoon demandrdquo[79 80]

The third CM effect that contributes to medullary hypop-erfusion and hypoxia again relies on viscosity namely onincreased blood viscosity This was demonstrated by a studyin rats that compared four solutions the IOCM iodixanolthe LOCM iopromide (both at 320mg ImL) mannitolsolution with equal osmolality as iopromide and dextran

500000 solutionwith equal viscosity as iodixanol [44] In thisstudy the solutions were injected into the thoracic aorta andlocal tissue perfusion and oxygen tension (pO

2) was moni-

tored by invasive techniques namely laser Doppler probesand fluorescence-quenching optodes Only the high viscoussolutions (iodixanol and dextran) resulted in long lastingmedullary hypoperfusion and thus in lower medullary pO

2

Because dextran 500000 is not filtered in the glomerulithe medullary hypoperfusion induced by this high viscoussolution cannot rely on high tubular fluid viscosity However


Saline

(a)

Iopromide 300

(b)

Iodixanol 320

(c)

BrdU incorporating cells

Prol

ifera

ting

cells

per

kid

ney

sect

ion

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

0

5000

10000

15000

(d)

Figure 6 Elevated proliferation rate of renal cells following CM administration as assessed by immunofluorescence analysis of theincorporation of bromdesoxyuridine (BrdU red staining) into proximal tubular cells (indicated by green staining of aquaporin-1 scale bar100120583m)TheBrdU incorporation timewas 46hours starting 2 h after iv injection of either saline (a) iopromide 300mg ImL (b) or iodixanol320mg ImL solution (c) CM doses were 4 g Ikg of bodymass Semiquantitative analysis of the BrdU-incorporated cells (d) Reprinted from[58]

events corresponding to the tubular concentration processtake place in the DVR as blood flows through the hypertonicenvironment of the medulla a portion of plasma water willleave these vessels towards the hypertonic interstitium Thiswill enrich CM within the vessels thus increasing bloodviscosity Both of the high osmolar solutionsmannitol and theLOCM iopromide did not affect medullary perfusion andpO2A recent study in rats that utilised the same monitoring

techniques corroborated the marked and prolonged (obser-vation time 60min after CM) medullary hypoperfusion andhypoxia following bolus injection of the IOCM iodixanolinto the thoracic aorta [80] Another study that assessedtissue perfusion by laser Doppler probes in rats directlycompared the effects of iv injection of the LOCM ioxaglatewith that of the IOCM iodixanol only iodixanol resultedin significant medullary hypoperfusion [81] A further studyin rats compared the effects of iv injection of the HOCMiothalamate with the IOCM iotrolan and found that outer

medullary hypoperfusion was pronounced by iotrolan versusiothalamate [82] In a study in dogs either the LOCMioxaglate or the IOCM iodixanol were injected into the renalartery and local tissue perfusion and pO

2were monitored by

laser Doppler probe and Clark-type electrodes respectivelyboth CM reduced medullary perfusion and pO

2 yet hypop-

erfusion and hypoxia lasted significantly longer followingiodixanol than ioxaglate [42] Using Clark-type electrodes inrats the IOCM iotrolan was found to decrease medullarypO2much more than the LOCM iopromide [83]The invasive pO

2-probes provide calibrated quantitative

measurements but cover only small tissue areas which isnot optimal because renal oxygenation displays considerablespatial heterogeneity [84ndash86] Magnetic resonance imaging(MRI) enables spatially resolved monitoring and bloodoxygen level-dependent (BOLD) MRI is increasingly usedto assess changes in kidney oxygenation as induced byvarious interventions [85] A recent BOLD study in ratsshowed a brief transient increase followed by a decrease in


Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300

Iodixanol 320Iopromide 300Saline

R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)

Figure 7 Time course of alterations in renal oxygenation as estimated by blood oxygen level-dependent (BOLD)MRI for the cortex and themedulla depicted as percentage changes (mean plusmn SEM) in 119877

2

lowast from baseline (100 dotted lines) Increase in 1198772

lowast above baseline signifiesreduced (blood) oxygenation that is hypoxia Intravenous injection of either saline iopromide 300mg ImL or iodixanol 320mg ImL wasdone at time 0 CM doses were 4 g Ikg of body mass Data taken from [40]

inner and outer medullary oxygenation upon bolus injectionof the IOCM iodixanol into the thoracic aorta [56] Astudy in rabbits found oxygenation in the outer stripe ofthe outer medulla unchanged but that in the inner stripedecreased following iv injection of the LOCM iopamidol[87] Direct comparisons between BOLD studies are impos-sible because BOLD is not quantitatively calibrated and thespecific MR protocols differ considerably among studies [8586] However using a cross-over design to enable directintraindividual comparison the effects of iv injection of theLOCM iopromide versus the IOCM iodixanol were studiedin pigs This BOLD study indicates that iodixanol impairsinner medullary but not outer medullary oxygenation whileiopromide did not impair oxygenation in both layers [88] Arecent study in rats also compared oxygenation changes fol-lowing iopromide versus iodixanol and foundbothmedullaryand cortical oxygenation decreased upon iv injection ofiodixanol but not iopromide (Figure 7) [40] Finally a studyin rats compared the effects of high viscosity versus highosmolality by use of the HOCM iothalamate and theIOCM iodixanol [89] Iodixanol dose dependently impairedmedullary oxygenation while iothalamate did not In orderto emulate endothelial dysfunction which is an importantindividual risk factor for CIAKI another group of rats wasexposed to inhibition of nitric oxide and prostaglandin beforeadministration of CM This pretreatment aggravated thedecrease in medullary oxygenation following iodixanol butalso rendered the rats receiving iothalamate susceptible forimpaired medullary oxygenation [89]

Taken together the bulk of evidence from animal studiesas presented here clearly indicates that LOCM are superiorto IOCM when it comes to renal adverse effects This is

due to both the lower viscosity and the higher osmolalityof LOCM The latter also becomes obvious from the resultsobtained with iodixanol solutions in which the osmolalitywas increased by addition of mannitol Considering theseclear-cut results two questions immediately come to mind

9 Why Excessive CM Osmolality May ConveyDeleterious Effects

When high CM osmolality indeed conveys beneficial effectswhy pioneer HOCM (osmolalities sim1000ndash2500mosmolkgH2O) were then associated with a greater CIAKI inci-

dence in at-risk patients than LOCM (osmolalities sim400ndash800mosmolkg H

2O) Here quantitative aspects of hyper-

osmolality play a pivotal role Adding a hyperosmolar solu-tion to normal tissue of course results in cell shrinkage yetthe cells of the area at risk for CIAKI the outer medulla areconstantly exposed to osmolalities of sim400ndash600mosmolkgH2O and the cells of the inner medulla to osmolalities up

to sim1200mosmolkg H2O Direct hyperosmolar injury of

cells can occur only if tubular fluid osmolality is in excessof ambient medullary osmolality Interestingly a correlationbetween CM osmolality and nephrotoxicity was observedfor CM with osmolalities gt800mosmolkg H

2O [1 32] It is

thus possible that HOCM solutions gt800mosmolkg H2O

become concentrated in tubules to such an excessive extentHowever to our knowledge this has never been shown inhuman beings

A number of additional explanations have been for-warded for the higher CIAKI incidence of HOCM versusLOCM Because HOCM and other high-osmolar solutions


can cause a distinct histological pattern with vacuoliza-tion of tubular cells (osmotic nephrosis) these alterationswere thought to rely on osmotic forces This explanationproved wrong the alterations are caused by pinocytosisand vacuolization was found even pronounced upon IOCM[40 60 90 91] Increased osmotic workload with ensuingincrease in tubular oxygen consumption may contribute toHOCM-inducedmedullary hypoxia furosemide that reducesoxygen-dependent tubular transport alleviated iothalamate-induced medullary hypoxia in rats [92] This mechanismdoes not seem to play a role in LOCM furosemide didnot improve medullary pO

2upon iopromide injection [93]

HOCM influence the shape and rigidity of erythrocytesmaking it more difficult for them to flow through thenarrow DVR which could also contribute to medullaryhypoperfusion [94] A video-microscopy study indicated thatHOCM but also LOCMand IOCMmay induce the so-calledsludge effects in vasa recta [95] Finally it must be noted thatseveral studies indicate that adverse effects of HOCM mayrely on their electric charge rather than their high osmolality[96]

10 How Preclinical Results Compare toThat of Clinical Studies

In the light of the evidence from preclinical studies it mayseem surprising that current meta-analyses of up to 36prospective randomised controlled clinical trials concludethat there is no significant difference in CIAKI incidencebetween LOCM and IOCM [97ndash99] Apart from the het-erogeneity of the trials included in the meta-analyses andthe poor sensitivity of SCrea (the end point used in thevast majority of trials) there is a most probable explanationvirtually all prospective clinical trials are performed accord-ing to protocols with ample fluid administration Becauseof the exponential concentration-viscosity relationship evenminor dilution will greatly reduce tubular fluid viscosity Theundesirable effects of high tubular fluid viscosity are likely tobe seen only in nonhydrated patients

In contrast to prospective clinical trials in everydayclinical practice many patients are not sufficiently hydrated[51] Such patients are certainly among the 57925 patientsincluded in a retrospective registry study on cardiac inter-ventions [100] In this study patients who received theIOCM iodixanol experienced clinically relevant renal failureincluding requirement of dialysis two to three times asoften as patients who received LOCM Likewise anotherregistry study in 58957 patients found CIAKI incidencesignificantly higher following the IOCM iodixanol versusLOCM (as assessed by SCrea by required dialysis and ahigher in-hospital mortality) [101] However in this latterstudy iodixanol was used more frequently in older patientswith more comorbidities and worse pre-CM renal functionand in propensity-matched models the differences did notreach statistical significance It is conceivable that patientswith higher risk scores received better hydration unfortu-nately the authors were unable to assess differences in fluid

administration [101] Taken together in patients who arenot sufficiently hydrated LOCM probably have an advantageover IOCM

11 Conclusions

This review of preclinical studies clearly indicates that therenal safety of modern CM varies dramatically with regardto their osmolality and viscosity High CM viscosity is akey element in the pathophysiology of CIAKI because thehyperosmolar environment of the renal medulla results inCM enrichment in both the tubules and the vasculatureThus fluid viscosity increases exponentially and flow throughmedullary tubules and vessels decreases Reducing the flowincreases the contact time of cytotoxic CM with the tubularepithelium and vascular endothelium This triggers a viciouscircle of cell injury medullary vasoconstriction and hypoxiaMoreover glomerular filtration declines due to congestion ofhighly viscous tubular fluid The viscosities of both LOCMand IOCM markedly exceed those of plasma yet the higherosmolalities of LOCM convey a renoprotective effect byvirtue of their greater tubular osmotic force LOCM cannotbe concentrated to the same extent as IOCM In consequencetubular fluid viscosity may not exceed a critical level Itmust be pointed out however that the preclinical studiesreported herewere performed in healthy animals In contrastclinical examinations and interventions that make use ofintravascularly applied CM and thus also clinical trials onCIAKI of course include patients who suffer from variouscomorbidities so that none of todayrsquos CM is without potentialclinical nephrotoxicity [102]

Conflict of Interests

Some of the authorsrsquo studies have in part been supportedby Bayer HealthCare This support was administered by theFaculty of Medicine (Charite-University Medicine Berlin)for which the investigators must adhere to the rules andguidelines of that faculty Diana C Lenhard had been anemployee of Bayer HealthCare she is now with the CharitePontus B Persson consults Bayer HealthCare as an expertfor renal damage He has received payment for lectures fromBayer HealthCare Bracco Imaging and Guerbet Pharma

Acknowledgments

The German Research Foundation (Deutsche Forschungsge-meinschaft) has been supporting some of the authorsrsquo studiesThe authors would like to thank Bert Flemming MD fordevising multiple innovative techniques and experiments toelucidate mechanisms of CIAKI and for continued insightfuldiscussionsThe authors also thankMechthild LadwigDVMKathleen Cantow DVM Karen Arakelyan MD AndreaGerhardt and Ariane Anger who obtained many of theresults presented here


References

[1] A D Calvin S Misra and A Pflueger ldquoContrast-inducedacute kidney injury and diabetic nephropathyrdquo Nature ReviewsNephrology vol 6 no 11 pp 679ndash688 2010

[2] SM Bagshaw and B F Culleton ldquoContrast-induced nephropa-thy epidemiology and preventionrdquoMinerva Cardioangiologicavol 54 no 1 pp 109ndash129 2006

[3] R Solomon and H L Dauerman ldquoContrast-induced acutekidney injuryrdquo Circulation vol 122 no 23 pp 2451ndash2455 2010

[4] M T James S M Samuel M A Manning et al ldquoContrast-induced acute kidney injury and risk of adverse clinical out-comes after coronary angiography a systematic review andmeta-analysisrdquo Circulation vol 6 pp 37ndash43 2013

[5] M M Waybill and P N Waybill ldquoContrast media-inducednephrotoxicity identification of patients at risk and algorithmsfor preventionrdquo Journal of Vascular and Interventional Radiol-ogy vol 12 no 1 pp 3ndash9 2001

[6] P A McCullough ldquoRadiocontrast-induced acute kidneyinjuryrdquo Nephron vol 109 no 4 pp 61ndash72 2008

[7] E Seeliger M Sendeski C S Rihal and P B PerssonldquoContrast-induced kidney injurymechanisms risk factors andpreventionrdquo European Heart Journal vol 33 pp 2007ndash20152012

[8] F Stacul A J van derMolen P Reimer et al ldquoContrast inducednephropathy updated ESUR contrast media safety committeeguidelinesrdquo European Radiology vol 21 no 12 pp 2527ndash25412011

[9] American College of Radiology ldquoCommittee on drugs andcontrast mediardquo ACR Manual on Contrast Media Version 92013

[10] R Solomon and A Segal ldquoDefining acute kidney injurywhat is the most appropriate metricrdquo Nature Clinical PracticeNephrology vol 4 no 4 pp 208ndash215 2008

[11] P A McCullough A D Shaw M Haase et al ldquoDiagnosis ofacute kidney injury using functional and injury biomarkersworkgroup statements from the tenth Acute Dialysis QualityInitiative Consensus Conferencerdquo Contributions to Nephrologyvol 182 pp 13ndash29 2013

[12] S S Waikar and J V Bonventre ldquoCreatinine kinetics andthe definition of acute kidney injuryrdquo Journal of the AmericanSociety of Nephrology vol 20 no 3 pp 672ndash679 2009

[13] R J Bruce A Djamali K Shinki S J Michel J P Fine andM A Pozniak ldquoBackground fluctuation of kidney functionversus contrast-induced nephrotoxicityrdquoThe American Journalof Roentgenology vol 192 no 3 pp 711ndash718 2009

[14] R W Katzberg and J H Newhouse ldquoIntravenous contrastmedium-induced nephrotoxicity is the medical risk really asgreat as we have come to believerdquo Radiology vol 256 no 1 pp21ndash28 2010

[15] D Russo R Minutolo B Cianciaruso B Memoli G Conteand L De Nicola ldquoEarly effects of contrast media on renalhemodynamics and tubular function in chronic renal failurerdquoJournal of the American Society of Nephrology vol 6 no 5 pp1451ndash1458 1995

[16] G L Bakris N A Lass and D Glock ldquoRenal hemodynamicsin radiocontrast medium-induced renal dysfunction a role fordopamine-1 receptorsrdquo Kidney International vol 56 no 1 pp206ndash210 1999

[17] S DWeisbord and P M Palevsky ldquoAcute kidney injury kidneyinjury after contrast media marker or mediatorrdquo NatureReviews Nephrology vol 6 no 11 pp 634ndash636 2010

[18] K J Harjai A Raizada C Shenoy et al ldquoA comparison ofcontemporary definitions of contrast nephropathy in patientsundergoing percutaneous coronary intervention and a proposalfor a novel nephropathy grading systemrdquoThe American Journalof Cardiology vol 101 no 6 pp 812ndash819 2008

[19] C Budano M Levis M DrsquoAmico et al ldquoImpact of contrast-induced acute kidney injury definition on clinical outcomesrdquoThe American Heart Journal vol 161 no 5 pp 963ndash971 2011

[20] J Li and R J Solomon ldquoCreatinine increases after intravenouscontrast administration incidence and impactrdquo InvestigativeRadiology vol 45 no 8 pp 471ndash476 2010

[21] D Reddan M Laville and V D Garovic ldquoContrast-inducednephropathy and its prevention what do we really know fromevidence-based findingsrdquo Journal of Nephrology vol 22 no 3pp 333ndash351 2009

[22] P A McCullough ldquoAcute kidney injury with iodinated con-trastrdquo Critical Care Medicine vol 36 supplement 4 pp S204ndashS211 2008

[23] S D Weisbord and P M Palevsky ldquoPrevention of contrast-induced nephropathy with volume expansionrdquo Clinical Journalof the American Society of Nephrology vol 3 no 1 pp 273ndash2802008

[24] M Fischereder ldquoUse of intravenous sodium bicarbonate mightincrease the risk of contrast nephropathyrdquo Nature ClinicalPractice Nephrology vol 4 no 6 pp 296ndash297 2008

[25] J T van Praet and A S de Vriese ldquoPrevention of contrast-induced nephropathy a critical reviewrdquo Current Opinion inNephrology and Hypertension vol 16 no 4 pp 336ndash347 2007

[26] J H Newhouse and A RoyChoudhury ldquoQuantitating contrastmedium-induced nephropathy controlling the controlsrdquo Radi-ology vol 267 pp 4ndash8 2013

[27] R J McDonald J S McDonald J P Bida et al ldquoIntravenouscontrast material-induced nephropathy causal or coincidentphenomenonrdquo Radiology vol 267 pp 106ndash118 2013

[28] M SDavenport S Khalatbari J RDillman RHCohan EMCaoili and J H Ellis ldquoContrast material-induced nephrotoxic-ity and intravenous low-osmolality iodinated contrastmaterialrdquoRadiology vol 267 pp 94ndash105 2013

[29] J Vanmassenhove R Vanholder E Nagler and B W VanldquoUrinary and serum biomarkers for the diagnosis of acutekidney injury an in-depth review of the literaturerdquo NephrologyDialysis Transplantation vol 28 pp 254ndash273 2013

[30] C Ronco F Stacul and P A McCullough ldquoSubclinical acutekidney injury (AKI) due to iodine-based contrast mediardquoEuropean Radiology vol 23 pp 319ndash323 2013

[31] U Speck ldquoX-ray contrast media physico-chemical propertiesrdquoin Textbook of Contrast Media P Dawson D O Cosgrove andR G Grainger Eds pp 35ndash46 Informa Health Care OxfordUK 1999

[32] N Pannu N Wiebe and M Tonelli ldquoProphylaxis strategiesfor contrast-induced nephropathyrdquo Journal of the AmericanMedical Association vol 295 no 23 pp 2765ndash2779 2006

[33] J Tumlin F Stacul A Adam et al ldquoPathophysiology ofcontrast-induced nephropathyrdquo The American Journal of Car-diology vol 98 no 6 pp 14ndash20 2006

[34] G Jost P Lengsfeld D C Lenhard H Pietsch J Hutter andMA Sieber ldquoViscosity of iodinated contrast agents during renalexcretionrdquoEuropean Journal of Radiology vol 80 no 2 pp 373ndash377 2011

[35] G Jost H Pietsch J Sommer et al ldquoRetention of iodine andexpression of biomarkers for renal damage in the kidney after


application of iodinated contrast media in ratsrdquo InvestigativeRadiology vol 44 no 2 pp 114ndash123 2009

[36] P Stratta M Quaglia A Airoldi and S Aime ldquoStructure-function relationships of iodinated contrast media and risk ofnephrotoxicityrdquo Current Medicinal Chemistry vol 19 no 5 pp736ndash743 2012

[37] K Dyvik K Dyrstad and A Tronstad ldquoRelationship betweenviscosity and determined injection pressure in angiographycatheters for common roentgen contrast mediardquoActa Radiolog-ica vol 399 pp 43ndash49 1995

[38] R Eloy C Corot and J Belleville ldquoContrast media for angiog-raphy physicochemical properties pharmacokinetics and bio-compatibilityrdquo Clinical Materials vol 7 no 2 pp 89ndash197 1991

[39] E Seeliger K Becker M Ladwig TWronski P B Persson andB Flemming ldquoUp to 50-fold increase in urine viscositywith iso-osmolar contrast media in the ratrdquoRadiology vol 256 no 2 pp406ndash414 2010

[40] D C Lenhard A L Frisk P Lengsfeld H Pietsch and GJost ldquoThe effect of iodinated contrast agent properties on renalkinetics and oxygenationrdquo Investigative Radiology vol 48 pp175ndash182 2013

[41] J Ueda T Furukawa K Higashino et al ldquoUrine viscosity afterinjections of iotrolan or iomeprolrdquoActa Radiologica vol 38 no6 pp 1079ndash1082 1997

[42] E Lancelot J M Idee C Lacledere R Santus and C CorotldquoEffects of two dimeric iodinated contrast media on renalmedullary blood perfusion and oxygenation in dogsrdquo Investiga-tive Radiology vol 37 no 7 pp 368ndash375 2002

[43] J Ueda A Nygren M Sjoquist E Jacobsson H R Ulfendahland Y Araki ldquoIodine concentrations in the rat kidney mea-sured by x-ray microanalysis comparison of concentrationsand viscosities in the proximal tubules and renal pelvis afterintravenous injections of contrast mediardquoActa Radiologica vol39 no 1 pp 90ndash95 1998

[44] E Seeliger B Flemming TWronski et al ldquoViscosity of contrastmedia perturbs renal hemodynamicsrdquo Journal of the AmericanSociety of Nephrology vol 18 no 11 pp 2912ndash2920 2007

[45] M Ladwig B Flemming E Seeliger L Sargsyan and P BPersson ldquoRenal effects of bicarbonate versus saline infusionfor iso-and lowosmolar contrast media in ratsrdquo InvestigativeRadiology vol 46 no 11 pp 672ndash677 2011

[46] E Seeliger M Ladwig L Sargsyan K Cantow P B Perssonand B Flemming ldquoProof of principle hydration by low-osmolar mannitol-glucose solution alleviates undesirable renaleffects of an iso-osmolar contrast medium in ratsrdquo InvestigativeRadiology vol 47 no 4 pp 240ndash246 2012

[47] T Berl and G L Robertson ldquoPathophysiology of watermetabolismrdquo in The Kidney B M Brenner Ed pp 866ndash924Saunders Philadelphia Pa USA 2000

[48] HW Reinhardt and E Seeliger ldquoToward an integrative conceptof control of total body sodiumrdquoNews in Physiological Sciencesvol 15 no 6 pp 319ndash325 2000

[49] E Seeliger T Lunenburg M Ladwig and H W ReinhardtldquoRole of the renin-angiotensin-aldosterone system for controlof arterial blood pressure following moderate deficit in totalbody sodium balance studies in freely moving dogsrdquo Clinicaland Experimental Pharmacology and Physiology vol 37 no 2pp e43ndashe51 2010

[50] W L Kenney and P Chiu ldquoInfluence of age on thirst and fluidintakerdquoMedicine and Science in Sports and Exercise vol 33 no9 pp 1524ndash1532 2001

[51] S D Weisbord M K Mor A L Resnick et al ldquoPreventionincidence and outcomes of contrast-induced acute kidneyinjuryrdquo Archives of Internal Medicine vol 168 no 12 pp 1325ndash1332 2008

[52] G Jost D C Lenhard M A Sieber P Lengsfeld J Hutterand H Pietsch ldquoChanges of renal water diffusion coefficientafter application of iodinated contrast agents effect of viscosityrdquoInvestigative Radiology vol 46 no 12 pp 796ndash800 2011

[53] J Ueda A Nygren P Hansell and H R Ulfendahl ldquoEffectof intravenous contrast media on proximal and distal tubularhydrostatic pressure in the rat kidneyrdquoActa Radiologica vol 34no 1 pp 83ndash87 1993

[54] J Ueda A Nygren P Hansell and U Erikson ldquoInfluenceof contrast media on single nephron glomerular filtrationrate in rat kidney a comparison between diatrizoate iohexolioxaglate and iotrolanrdquoActa Radiologica vol 33 no 6 pp 596ndash599 1992

[55] Z Z Liu V U Viegas A Perlewitz et al ldquoIodinated contrastmedia differentially affect afferent and efferent arteriolar toneand reactivity in mice a possible explanation for reducedglomerular filtration raterdquo Radiology vol 265 pp 762ndash7712012

[56] K Arakelyan K Cantow J Hentschel et al ldquoEarly effects ofan x-ray contrast medium on renal Tlowast

2T2MRI as compared

to short-term hyperoxia hypoxia and aortic occlusion in ratsrdquoActa Physiologica vol 208 pp 202ndash213 2013

[57] A A Khraibi and F G Knox ldquoEffect of renal decapsulationon renal interstitial hydrostatic pressure and natriuresisrdquo TheAmerican Journal of PhysiologymdashRegulatory Integrative andComparative Physiology vol 257 no 1 pp R44ndashR48 1989

[58] D C Lenhard H Pietsch M A Sieber et al ldquoThe osmolalityof nonionic iodinated contrast agents as an important factor forrenal safetyrdquo Investigative Radiology vol 47 pp 503ndash510 2012

[59] G Jost H Pietsch P Lengsfeld J Hutter andMA Sieber ldquoTheimpact of the viscosity and osmolality of iodine contrast agentson renal eliminationrdquo Investigative Radiology vol 45 no 5 pp255ndash261 2010

[60] M Dobrota C J Powell E Holtz A Wallin and H VikldquoBiochemical and morphological effects of contrast media onthe kidneyrdquo Acta Radiologica vol 399 pp 196ndash203 1995

[61] M C Heinrich M K Kuhlmann A Grgic M HeckmannB Kramann and M Uder ldquoCytotoxic effects of ionic high-osmolar nonionic monomeric and nonionic iso-osmolardimeric iodinated contrastmedia on renal tubular cells in vitrordquoRadiology vol 235 no 3 pp 843ndash849 2005

[62] M Wasaki J Sugimoto and K Shirota ldquoGlucose alters thesusceptibility of mesangial cells to contrast mediardquo InvestigativeRadiology vol 36 no 7 pp 355ndash362 2001

[63] I Hizoh and C Haller ldquoRadiocontrast-induced renal tubularcell apoptosis hypertonic versus oxidative stressrdquo InvestigativeRadiology vol 37 no 8 pp 428ndash434 2002

[64] N F Fanning B J Manning J Buckley and H P RedmondldquoIodinated contrast media induce neutrophil apoptosis throughamitochondrial and caspase mediated pathwayrdquo British Journalof Radiology vol 75 no 899 pp 861ndash873 2002

[65] A I Lim S C Tang K N Lai and J C Leung ldquoKidney injurymolecule-1more than just an injurymarker of tubular epithelialcellsrdquo Journal of Cellular Physiology vol 228 pp 917ndash924 2013

[66] M Haase A Haase-Fielitz R Bellomo and P R MertensldquoNeutrophil gelatinase-associated lipocalin as a marker of acuterenal diseaserdquo Current Opinion in Hematology vol 18 no 1 pp11ndash18 2011


[67] E Singer L Marko N Paragas et al ldquoNeutrophil gelatinase-associated lipocalin pathophysiology and clinical applicationsrdquoActa Physiologica vol 207 pp 663ndash672 2013

[68] H Ha E Y Oh and H B Lee ldquoThe role of plasminogenactivator inhibitor 1 in renal and cardiovascular diseasesrdquoNature Reviews Nephrology vol 5 no 4 pp 203ndash211 2009

[69] B L Cavanagh T Walker A Norazit and A C B MeedeniyaldquoThymidine analogues for tracking DNA synthesisrdquoMoleculesvol 16 no 9 pp 7980ndash7993 2011

[70] P B Persson P Hansell and P Liss ldquoPathophysiology ofcontrast medium-induced nephropathyrdquo Kidney Internationalvol 68 no 1 pp 14ndash22 2005

[71] R G Evans C Ince J A Joles et al ldquoHaemodynamic influenceson kidney oxygenation the clinical implications of integrativephysiologyrdquo Clinical and Experimental Pharmacology and Phys-iology vol 40 pp 106ndash122 2013

[72] S N Heyman S Rosen M Khamaisi J M Idee and CRosenberger ldquoReactive oxygen species and the pathogenesisof radiocontrast-induced nephropathyrdquo Investigative Radiologyvol 45 no 4 pp 188ndash195 2010

[73] M D Okusa B L Jaber P Doran et al ldquoPhysiologicalbiomarkers of acute kidney injury a conceptual approach toimproving outcomesrdquo Contributions to Nephrology vol 182 pp65ndash81 2013

[74] T M Kennedy-Lydon C Crawford S S Wildman and C MPeppiatt-Wildman ldquoRenal pericytes regulators of medullaryblood flowrdquo Acta Physiologica vol 207 pp 212ndash225 2013

[75] M Sendeski A Patzak T L Pallone C Cao A E Persson andP B Persson ldquoIodixanol constriction of medullary descendingvasa recta and risk for contrastmedium-induced nephropathyrdquoRadiology vol 251 no 3 pp 697ndash704 2009

[76] M Sendeski A Patzak and P B Persson ldquoConstriction of thevasa recta the vessels supplying the area at risk for acute kidneyinjury by four different iodinated contrast media evaluatingionic nonionic monomeric and dimeric agentsrdquo InvestigativeRadiology vol 45 no 8 pp 453ndash457 2010

[77] M M Sendeski P A Bondke Z Z Liu et al ldquoIodinatedcontrast media cause endothelial damage leading to vasocon-striction of human and rat vasa rectardquoThe American Journal ofPhysiologymdashRenal Physiology vol 303 pp F1592ndashF1598 2012

[78] G Aliev M E Obrenovich D Seyidova et al ldquoX-ray contrastmedia induce aortic endothelial damage which can be pre-vented with prior heparin treatmentrdquo Journal of SubmicroscopicCytology and Pathology vol 35 no 3 pp 253ndash266 2003

[79] M T Gladwin ldquoRole of the red blood cell in nitric oxide home-ostasis and hypoxic vasodilationrdquo Advances in ExperimentalMedicine and Biology vol 588 pp 189ndash205 2006

[80] E Seeliger K Cantow K Arakelyan M Ladwig P B Perssonand B Flemming ldquoLow-dose nitrite alleviates early effectsof an x-ray contrast medium on renal hemodynamics andoxygenation in ratsrdquo Investigative Radiology vol 49 no 2 pp70ndash77 2014

[81] E Lancelot J M Idee V Couturier V Vazin and C CorotldquoInfluence of the viscosity of iodixanol on medullary andcortical blood flow in the rat kidney a potential cause ofNephrotoxicityrdquo Journal of Applied Toxicology vol 19 pp 341ndash346 1999

[82] P Liss A Nygren and P Hansell ldquoHypoperfusion in the renalouter medulla after injection of contrast media in ratsrdquo ActaRadiologica vol 40 no 5 pp 521ndash527 1999

[83] P Liss A Nygren U Erikson andH R Ulfendahl ldquoInjection oflow and iso-osmolar contrastmediumdecreases oxygen tensionin the renal medullardquo Kidney International vol 53 no 3 pp698ndash702 1998

[84] H J Schurek ldquoMedullary hypoxia a key to understand acuterenal failurerdquo Klinische Wochenschrift vol 66 no 18 pp 828ndash835 1988

[85] A Pohlmann K Cantow J Hentschel et al ldquoLinking non-invasive parametric MRI with invasive physiological mea-surements (MR-PHYSIOL) towards a hybrid and integratedapproach for investigation of acute kidney injury in ratsrdquo ActaPhysiologica vol 207 pp 673ndash689 2012

[86] R G Evans B S Gardiner D W Smith and P M OrsquoConnorldquoMethods for studying the physiology of kidney oxygenationrdquoClinical and Experimental Pharmacology and Physiology vol 35no 12 pp 1405ndash1412 2008

[87] Y Zhang J Wang X Yang et al ldquoThe serial effect of iodinatedcontrast media on renal hemodynamics and oxygenation asevaluated by ASL and BOLDMRIrdquo Contrast Media and Molec-ular Imaging vol 7 pp 418ndash425 2012

[88] S Haneder J Augustin G Jost et al ldquoImpact of Iso-and low-osmolar iodinated contrast agents on BOLD and diffusionMRIin swine kidneysrdquo Investigative Radiology vol 47 no 5 pp 299ndash305 2012

[89] L P Li T Franklin H Du et al ldquoIntrarenal oxygenation byblood oxygenation level-dependent MRI in contrast nephropa-thy model effect of the viscosity and doserdquo Journal of MagneticResonance Imaging vol 36 pp 1162ndash1167 2012

[90] M Dickenmann T Oettl and M J Mihatsch ldquoOsmoticNephrosis acute kidney injury with accumulation of proximaltubular lysosomes due to administration of exogenous solutesrdquoThe American Journal of Kidney Diseases vol 51 no 3 pp 491ndash503 2008

[91] M C Heinrich ldquoOsmotic nephrosis and contrast mediardquo TheAmerican Journal of Kidney Diseases vol 52 no 3 p 629 2008

[92] S N Heyman M Brezis F H Epstein K Spokes P Silvaand S Rosen ldquoEarly renal medullary hypoxic injury fromradiocontrast and indomethacinrdquo Kidney International vol 40no 4 pp 632ndash642 1991

[93] P Liss A Nygren H R Ulfendahl and U Erikson ldquoEffectof furosemide or mannitol before injection of a non-ioniccontrast medium on intrarenal oxygen tensionrdquo Advances inExperimental Medicine and Biology vol 471 pp 353ndash359 1999

[94] S K Morcos P Dawson J D Pearson et al ldquoThe haemody-namic effects of iodinated water soluble radiographic contrastmedia a reviewrdquo European Journal of Radiology vol 29 no 1pp 31ndash46 1998

[95] P Liss A Nygren U Olsson H R Ulfendahl and U EriksonldquoEffects of contrast media and mannitol on renal medullaryblood flow and red cell aggregation in the rat kidneyrdquo KidneyInternational vol 49 no 5 pp 1268ndash1275 1996

[96] M R Rudnick S Goldfarb L Wexler et al ldquoNephrotoxicityof ionic and nonionic contrast media in 1196 patients arandomized trialrdquo Kidney International vol 47 no 1 pp 254ndash261 1995

[97] M Reed P Meier U U Tamhane K B Welch M Moscucciand H S Gurm ldquoThe relative renal safety of iodixanol com-paredwith low-osmolar contrastmedia Ameta-analysis of ran-domized controlled trialsrdquo JACC Cardiovascular Interventionsvol 2 no 7 pp 645ndash654 2009


[98] M C Heinrich L Haberle V Muller W Bautz and M UderldquoNephrotoxicity of iso-osmolar iodixanol compared with non-ionic low-osmolar contrastmediameta-analysis of randomizedcontrolled trialsrdquo Radiology vol 250 no 1 pp 68ndash86 2009

[99] AM From F J Al Badarin F S McDonald B J Bartholmai SS Cha and C S Rihal ldquoIodixanol versus low-osmolar contrastmedia for prevention of contrast induced nephropathy meta-analysis of randomized controlled trialsrdquoCirculation vol 3 no4 pp 351ndash358 2010

[100] P Liss P B Persson P Hansell and B Lagerqvist ldquoRenal failurein 57 925 patients undergoing coronary procedures using iso-osmolar or low-osmolar contrast mediardquo Kidney Internationalvol 70 no 10 pp 1811ndash1817 2006

[101] M C Reed M Moscucci D E Smith et al ldquoThe relative renalsafety of iodixanol and low-osmolar contrast media in patientsundergoing percutaneous coronary intervention Insights fromblue cross blue shield of Michigan cardiovascular consortium(BMC2)rdquo Journal of Invasive Cardiology vol 22 no 10 pp 467ndash472 2010

[102] H S Thomsen S K Morcos and B J Barrett ldquoContrast-induced nephropathy the wheel has turned 360 degreesrdquo ActaRadiologica vol 49 no 6 pp 646ndash657 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


administration of CM in the absence of an alternativeaetiology [7ndash9] For several reasons this definition is not anideal one [7ndash11] A decrease in GFR can per se not attest tokidney injury it rather indicates that one partial function ofthe kidney namely filtration is disturbed Second in clinicalpractice CIAKI is diagnosed by an increase in the surrogatemarker for GFR serum creatinine (SCrea) because directmeasurements of GFR by clearance methods require tediousurine collection Unfortunately SCrea is a poor marker ofGFR its sensitivity is very low with regard to both the degreeand the time course of GFR changes Due to the exponentialrelationship between SCrea and GFR SCrea is very insen-sitive in patients with preexisting normal GFR [3 7 10 12]Day-to-day variations in SCrea observed in patients in whomno cause for rapid GFR changes could be identified indicatethat SCrea is also insensitive at reduced preexisting GFR [1314] Moreover due to the kinetics of creatinine distributionamong the body fluid compartments SCrea is notoriouslyinsensitive to rapid GFR changes such as the immediateGFR drop induced by CM creatinine accumulationmay takedays before SCrea increase fulfils diagnostic criteria [7 10ndash12 15 16] Reflecting these drawbacks CIAKI is currentlydiagnosed when a certain absolute (eg 44 or 88 120583molL) orrelative (eg 25 or 50) increase in SCrea is observed within48 or 72 hours after CM whereby the optimum margins arestill under debate [3 8ndash11]This diagnostic delay poses severeproblems with regard to clinical practice the most obviousbeing that CIAKI will often go undetected in outpatients [17]

Besides the consequences for patient care the poorperformance of SCrea to reflect changes in GFR has greatlyhampered advances in knowledge The vast majority ofclinical trials have been relying on SCrea as the sole end pointOften the incidence of CIAKI cannot be compared amongtrials because of the different absolute or percentage marginsin SCrea increase andor the different timing and frequencyof post-CM SCrea measurements (eg 24 versus 72 hours)[8 10 18ndash21] Thus there is general agreement that manyimportant questions for example regarding the incidenceof CIAKI following contrast-enhanced CT regarding specificprophylactic strategies or comparisons among CM are notyet answered unequivocally because clinical trials with fewexceptions relied on SCrea as outcome measure [7 1017 21ndash28] Utilization of robust outcome measures such asrequirement of dialysis and if their reliability is convincinglyproven of new serum and urinary markers of renal injurywill certainly improve the power of evidence in future clinicaltrials [11 29 30]

Animal studies that made use of clearance methods todirectly measure GFR and that assessed various direct andindirect markers of renal injury and functions helped fill ingaps Thus experiments run under highly standardised con-ditions provided direct comparisons between classes of CMand between specific prophylactic strategies Moreover invitro and in vivo studies elucidated pathophysiological mech-anisms of CIAKI so that it became possible in recent yearsto shape a quite uniform scheme of CIAKI pathophysiology[7] Mechanisms underlying CIAKI include cytotoxic effectsparacrine factors that affect renal hemodynamics alteredrheological properties that perturb renal hemodynamics

and tubulodynamics and tissue hypoxia These mechanismsact in concert yet the individual mechanismsrsquo importancevaries with the classes of CM used with the subjectrsquoshydrationvolume status andmdashin patientsmdashwith the degreeof preexisting individual risk factors [7] One factor thathas a major impact on tubulodynamics is fluid viscosityFluid viscosity is a measure of the fluidrsquos resistance to flowdue to friction between neighboring parcels that are movedat different velocities In the context of CM the dynamicviscosity (usually given in millipascal second (mPa s)) andthe kinematic viscosity (usually given in square millimetreper second (mm2s)) are most relevant A fluidrsquos kinematicviscosity (which is typically measured by Ubbelohde-typeviscometers that make use of gravity to move the fluid withina tube) is converted to its dynamic viscosity by dividing it bythe fluidrsquos density The classes of CM vary considerably withregard to viscosity andosmolality and both high viscosity andhigh osmolality have been implicated to play pivotal roles inthe pathophysiology of CIAKI

3 Why the Current Labelling of CM ClassesRelies on Their Osmolalities

CM for intravascular use are tri-iodinated benzene deriva-tives Because their radio-opacity relies on iodine solutionswith high iodine concentration (usually 250ndash400mg ImLsolution) are requiredThis is achieved by highmolar concen-trations of benzene derivatives The molar concentration ofthe CM solution is a major determinant of both its osmolalityand its viscosity However whereas the osmolality of a givenCM solution increases only linearly with the molar concen-tration viscosity increases exponentially [31] The pioneerclass of CM comprised solutions of monomers (iothalamatediatrizoate) at high molar concentrations These compoundsare ionic which additionally increase the solutionsrsquo osmo-lalities so that their osmolalities are exceedingly high (sim1000ndash2500mosmolkgH

2O) as compared to blood plasma (sim

290mosmolkgH2O) [32]This class of CMwas termed high-

osmolar CM (HOCM) and was found to be associated with aconsiderable risk for CIAKI [1 32 33] As a consequence CMwith lower osmolalities were developed By forming eitherionic dimers (ioxaglate) or nonionic monomers (iopromideiopamidol iohexol ioversol iomeprol etc) osmolalities ofsim400ndash800mosmolkg H

2O were achieved [32] Although

their osmolalities are actually still higher than these ofplasma these compounds are referred to as low-osmolar CM(LOCM) The realisation that LOCM were associated witha marked lower CIAKI incidence than HOCM particularlyin at-risk patients had two consequences [32 33] FirstHOCM are virtually no longer in clinical use in WesternEurope and the USA Second the next goal in CM devel-opment seemed obvious further reduction in osmolality Bycreating nonionic dimeric compounds (iodixanol iotrolanand iosimenol) iso-osmolar CM (IOCM) were developed[32 33] Pure IOCM solutions are actually hypoosmolarelectrolytes are added to the clinically used solution to reachplasma osmolality [34]The low osmolality achieved with theIOCM came at the price of considerably increased viscosity







2O


2O




factors






osmolytes

CM osmolality


+ +

+

+

+minus








0

100

200

300

400

500

600

700

800

CA 290 400 500 700 1000




Iodi

ne (m

gIm

L)

(a)

CA 290 400 500 700 10000

50

100

150

200

250




Visc

osity

(mPa

lowasts)

≫200 ≫200

(b)











0

10

20

30

40



Urin

e visc

osity

(mm

2s

)


(a)

00

02

04

06

08

10



Urin

e flow

(mL10

min

)

lowast


(b)


1 2 3 4 5 60

5

10

15

20

25

Deadspaceeffect


Glo

mer

ular

filtr

atio

n (m

L10

min


(c)










2O indeed









Saline

(a)

(b)

(c)

(d)

Iopromide Iodixanol

Iodixanolmannitol

24h pi

(a998400)

(b998400)

(c998400)

(d998400)






KIM-1

0

50

100

150

200

250

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

(a)

NGAL

0

500

1000

1500

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

lowast

(b)

PAI-1

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

0

100

200

300

400

500

lowast

lowast

lowast

(c)





2) was moni-


2



Saline

(a)

Iopromide 300

(b)

Iodixanol 320

(c)


Prol

ifera

ting

cells

per

kid

ney

sect

ion

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

0

5000

10000

15000

(d)





2were monitored by


2 yet hypop-





Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300


R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)


2













2O [1 32] It is












11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






















2O


2O




factors






osmolytes

CM osmolality


+ +

+

+

+minus








0

100

200

300

400

500

600

700

800

CA 290 400 500 700 1000




Iodi

ne (m

gIm

L)

(a)

CA 290 400 500 700 10000

50

100

150

200

250




Visc

osity

(mPa

lowasts)

≫200 ≫200

(b)











0

10

20

30

40



Urin

e visc

osity

(mm

2s

)


(a)

00

02

04

06

08

10



Urin

e flow

(mL10

min

)

lowast


(b)


1 2 3 4 5 60

5

10

15

20

25

Deadspaceeffect


Glo

mer

ular

filtr

atio

n (m

L10

min


(c)










2O indeed









Saline

(a)

(b)

(c)

(d)

Iopromide Iodixanol

Iodixanolmannitol

24h pi

(a998400)

(b998400)

(c998400)

(d998400)






KIM-1

0

50

100

150

200

250

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

(a)

NGAL

0

500

1000

1500

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

lowast

(b)

PAI-1

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

0

100

200

300

400

500

lowast

lowast

lowast

(c)





2) was moni-


2



Saline

(a)

Iopromide 300

(b)

Iodixanol 320

(c)


Prol

ifera

ting

cells

per

kid

ney

sect

ion

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

0

5000

10000

15000

(d)





2were monitored by


2 yet hypop-





Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300


R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)


2













2O [1 32] It is












11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















0

100

200

300

400

500

600

700

800

CA 290 400 500 700 1000




Iodi

ne (m

gIm

L)

(a)

CA 290 400 500 700 10000

50

100

150

200

250




Visc

osity

(mPa

lowasts)

≫200 ≫200

(b)











0

10

20

30

40



Urin

e visc

osity

(mm

2s

)


(a)

00

02

04

06

08

10



Urin

e flow

(mL10

min

)

lowast


(b)


1 2 3 4 5 60

5

10

15

20

25

Deadspaceeffect


Glo

mer

ular

filtr

atio

n (m

L10

min


(c)










2O indeed









Saline

(a)

(b)

(c)

(d)

Iopromide Iodixanol

Iodixanolmannitol

24h pi

(a998400)

(b998400)

(c998400)

(d998400)






KIM-1

0

50

100

150

200

250

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

(a)

NGAL

0

500

1000

1500

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

lowast

(b)

PAI-1

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

0

100

200

300

400

500

lowast

lowast

lowast

(c)





2) was moni-


2



Saline

(a)

Iopromide 300

(b)

Iodixanol 320

(c)


Prol

ifera

ting

cells

per

kid

ney

sect

ion

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

0

5000

10000

15000

(d)





2were monitored by


2 yet hypop-





Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300


R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)


2













2O [1 32] It is












11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















0

10

20

30

40



Urin

e visc

osity

(mm

2s

)


(a)

00

02

04

06

08

10



Urin

e flow

(mL10

min

)

lowast


(b)


1 2 3 4 5 60

5

10

15

20

25

Deadspaceeffect


Glo

mer

ular

filtr

atio

n (m

L10

min


(c)










2O indeed









Saline

(a)

(b)

(c)

(d)

Iopromide Iodixanol

Iodixanolmannitol

24h pi

(a998400)

(b998400)

(c998400)

(d998400)






KIM-1

0

50

100

150

200

250

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

(a)

NGAL

0

500

1000

1500

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

lowast

(b)

PAI-1

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

0

100

200

300

400

500

lowast

lowast

lowast

(c)





2) was moni-


2



Saline

(a)

Iopromide 300

(b)

Iodixanol 320

(c)


Prol

ifera

ting

cells

per

kid

ney

sect

ion

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

0

5000

10000

15000

(d)





2were monitored by


2 yet hypop-





Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300


R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)


2













2O [1 32] It is












11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















2O indeed









Saline

(a)

(b)

(c)

(d)

Iopromide Iodixanol

Iodixanolmannitol

24h pi

(a998400)

(b998400)

(c998400)

(d998400)






KIM-1

0

50

100

150

200

250

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

(a)

NGAL

0

500

1000

1500

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

lowast

(b)

PAI-1

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

0

100

200

300

400

500

lowast

lowast

lowast

(c)





2) was moni-


2



Saline

(a)

Iopromide 300

(b)

Iodixanol 320

(c)


Prol

ifera

ting

cells

per

kid

ney

sect

ion

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

0

5000

10000

15000

(d)





2were monitored by


2 yet hypop-





Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300


R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)


2













2O [1 32] It is












11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Saline

(a)

(b)

(c)

(d)

Iopromide Iodixanol

Iodixanolmannitol

24h pi

(a998400)

(b998400)

(c998400)

(d998400)






KIM-1

0

50

100

150

200

250

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

(a)

NGAL

0

500

1000

1500

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

lowast

(b)

PAI-1

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

0

100

200

300

400

500

lowast

lowast

lowast

(c)





2) was moni-


2



Saline

(a)

Iopromide 300

(b)

Iodixanol 320

(c)


Prol

ifera

ting

cells

per

kid

ney

sect

ion

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

0

5000

10000

15000

(d)





2were monitored by


2 yet hypop-





Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300


R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)


2













2O [1 32] It is












11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















KIM-1

0

50

100

150

200

250

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

(a)

NGAL

0

500

1000

1500

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

lowast

lowast

(b)

PAI-1

mRN

A ex

pres

sion

(au

)

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

Iodi

xano

lman

nito

l

0

100

200

300

400

500

lowast

lowast

lowast

(c)





2) was moni-


2



Saline

(a)

Iopromide 300

(b)

Iodixanol 320

(c)


Prol

ifera

ting

cells

per

kid

ney

sect

ion

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

0

5000

10000

15000

(d)





2were monitored by


2 yet hypop-





Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300


R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)


2













2O [1 32] It is












11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Saline

(a)

Iopromide 300

(b)

Iodixanol 320

(c)


Prol

ifera

ting

cells

per

kid

ney

sect

ion

Salin

e

Iopr

omid

e 300

Iodi

xano

l 320

0

5000

10000

15000

(d)





2were monitored by


2 yet hypop-





Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300


R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)


2













2O [1 32] It is












11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Cortex

Time (min)0 20 40 60

6080

100120140160180200220240260280300


R2

lowastch

ange

s (

)

(a)

Medulla

0 20 40 60

6080

100120140160180200220240260280300


Time (min)

R2

lowastch

ange

s (

)

(b)


2













2O [1 32] It is












11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
























11 Conclusions




Acknowledgments



References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















References



























































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of







































2T2MRI as compared























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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