evidence report: risk of renal stone formation · 2017-05-15 · risk of renal stone formation...

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EvidenceReport:RiskofRenalStoneFormationHumanResearchProgramExplorationMedicalCapabilitiesElementApprovedforPublicRelease:May15,2017NationalAeronauticsandSpaceAdministrationLyndonB.JohnsonSpaceCenterHouston,Texas

Risk of Renal Stone Formation

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CURRENTCONTRIBUTINGAUTHORS:JeanD.Sibonga NASAJohnsonSpaceCenter,Houston,TXRobertPietrzyk KBRwyle,Houston,TX

PREVIOUSCONTRIBUTINGAUTHORS:Jeffrey.A.Jones,M.D.,M.S. BaylorCollegeofMedicine,Houston,TXJosephE.Zerwekh,Ph.D. UniversityofTexasSouthwesternMedicalCenter,Dallas,TXClaritaV.Odvina,M.D. UniversityofTexasSouthwesternMedicalCenter,Dallas,TX


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TABLEOFCONTENTS

I. PRDRISKTITLE:RISKOFRENALSTONEFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 II. EXECUTIVESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

III. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 IV. EVIDENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

A. SpaceflightEvidence ......................................................................................................... 7

1.HistoricalDatafromSkylab ........................................................................................ 72. Short-durationspaceflightmissionsontheSpaceShuttle ......................................... 8

3.Long-durationduringtheShuttle-MirMissions ....................................................... 12

4. InternationalSpaceStation ....................................................................................... 12B. Ground-BasedEvidence .................................................................................................. 13

V. COMPUTER-BASEDSIMULATIONINFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 VI. RISKINCONTEXTOFEXPLORATIONMISSIONSCENARIOS . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

VII.MINIMIZINGTHERISKOFSTONEFORMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

A. Countermeasures ............................................................................................................ 17B. RenalStoneRiskAssessment ......................................................................................... 18

C. In-flightPrevention ......................................................................................................... 19

D. In-flightDiagnosisandMonitoring ................................................................................ 19VIII. GAPS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

IX. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 X. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

XI. TEAM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

XII. LISTOFACRONYMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26


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I. PRDRISKTITLE:RISKOFRENALSTONEFORMATIONDescription:Kidneystoneformationandpassagehasthepotentialtogreatlyimpactmissionsuccessandcrewmemberhealthforlong-durationmissions.Alterationsinhydrationstate(relativedehydration),spaceflight-inducedchangesinurinebiochemistry(urinesuper-saturation),andbonemetabolism(increasedcalciumexcretion)duringexposuretomicrogravitymayincreasetheriskofkidneystoneformation.Itisunclearwhatmitigationstrategieswouldbethemosteffectiveinaddressingthisrisk.

II. EXECUTIVESUMMARYTheformationofrenalstonesposesanin-flighthealthriskofhighseverity,notonlybecauseoftheimpactofrenalcoliconhumanperformancebutalsobecauseofcomplicationsthatcouldpotentiallyleadtocrewevacuation,suchashematuria,infection,hydronephrosis,andsepsis.Evidenceforriskfactorscomesfromurineanalysesofcrewmembers,documentingchangestotheurinaryenvironmentthatareconducivetoincreasedsaturationofstone-formingsalts,whicharethedrivingforcefornucleationandgrowthofastonenidus.Further,renalstoneshavebeendocumentedinastronautsafterreturntoEarthandinonecosmonautduringflight.Biochemicalanalysisofurinespecimenshasprovidedindicationofhypercalciuriaandhyperuricemia,reducedurinevolumes,andincreasedurinesaturationofcalciumoxalateandcalciumphosphate.Amajorcontributortotheriskforrenalstoneformationisboneatrophywithincreasedturnoveroftheboneminerals.DietaryandfluidintakesalsoplaymajorrolesintheriskbecauseoftheinfluenceonurinepH(moreacidic)andonvolume(decreased).Historically,specificassessmentsonurinesamplesfromsomeSkylabcrewmembersindicatedthatcalciumexcretionincreasedearlyinflight,notablebyday10offlight,andalmostexceededtheupperthresholdfornormalexcretion(300mg/dayinmales).Othercrewmemberdatadocumentedreducedintakeoffluidandreducedintakeofpotassium,phosphorus,magnesium,andcitrate(aninhibitorofcalciumstoneformation)inthediet.Hence,datafrombothshort-durationandlong-durationmissionsindicatethatspacetravelinducesriskfactorsforrenalstoneformationthatcontinuetopersistafterflight;thisriskhasbeendocumentedbyreportedkidneystonesincrewmembers.

III. INTRODUCTIONNephrolithiasisistheconditionmarkedbythedevelopmentofrenalstones.Renalstonesareaggregatesofcrystalsthatareformedinurinethatissupersaturatedintermsofitssaltcomponents.Hypercalciuria,acharacteristicoftheskeletaladaptationtospace,contributestotheincreasedsupersaturationofurine,withelevationsofcalciumphosphateorcalciumoxalate.However,whetherarenalstoneformsinsupersaturatedurinedependsuponotherriskfactors.Thepresenceoftheseaggregatesintherenalcollectionorexcretionsystemcanpotentiallyresultinstoneformation,renalcolic,hematuria,infectionorsepsis,andcanobstructurineflowtocausehydronephrosis.Arenalstoneformedduringaspaceflightmissioncouldcauseacuteillnesswithcrewmemberfunctionalimpairment,negativemissionimpact,orevensignificantmorbidityormortalityfortheafflictedcrewmember.


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Todate,therehasbeenonereportedepisodeofnephrolithiasisduringspaceflight,whereacosmonautexperiencedseverelowerabdominalpainthatspontaneouslyresolved,laterattributedtorenalcolic(Lebedev1990).AprevioussurveyofrenalstonesinUSastronautshasrevealedatotalof14episodesofkidneystones(Pietrzyketal.2007);someoftheseepisodesoccurredinthepre-flightperiod(n=5)withthebalance(n=9)havingoccurredinthepost-flightphase.Thetimeperiodfortheonsetofsymptomaticstoneformationfollowingreturnrangedfrom9-120monthsafterlanding.Sixoftheninepost-flightepisodeshadoccurredafter1994,correspondingwiththeextensionofSpaceShuttlemissionlengthto12daysduration.Atotalof12astronautshaveexperiencednephrolithiasis,withtwoastronautsreportingmultipleepisodes;bothmale(n=10)andfemale(n=2)astronautshavebeenafflicted.

Giventheseverityoftheriskforrenalstoneformation,itisimportanttocharacterizethespaceflightconditionsthatpromotenephrolithiasisinordertotakeappropriatestepstomitigatethisrisk.Theprimaryriskfactorsforrenalstoneformationinspacearetheincreasedexcretionofcalciumduetoboneatrophyandlowerurineoutputassociatedwiththemicrogravityenvironment.Othercontributingriskfactorsincludedehydration,diet(highsodium,highanimalproteins),lowurinarycitrate,genetics,andenvironmentalderangements(forexample,alterationsinambienttemperatures).Thesefactorscancontributetoincreasedurinarysupersaturationofsalts,lowurinepH,andreducedurinevolumes,whichareallfavorableconditionsforcrystallization.

Renalstonescomeindifferenttypes,includingcalciumoxalate,uricacid,struvite,cysteine,andbrushite(calciumphosphate)stones.Theformationofaspecificstone-typedependsuponthepresenceofparticularriskfactors.Themostcommonrenalstone,andamaincomponentinstonesofmixedcomposition,iscalciumoxalate.Thisstonetypeiscommonlycausedbytreatablemetabolicdisordersofhypercalciuriaandisassociatedwithmultiplesimultaneousstoneformationorstonerecurrence,inducingpainwithbothpassageandobstruction(Figure1).Similartocalciumoxalatestones,uricacidstonesinducethesameadverseeffectsbutoccuratdecreasedincidence,responsibleforonly5%ofrenalstones.Uricacidstonesarealsotranslucentand,unliketheotherstones,cannotbedistinguishedbyradiographicimaging.Struvitestonesaregeneratedbyinfectionsofurease-containingmicroorganismsthatarecapableofhydrolyzingtheureainurinetocarbondioxideandammonia.WhenurinepHexceeds7.2,struvitestonesmayform,andtheresultingobstructioncanfilltherenalcollectionsystemanderodeintotherenaltissue.Treatmentisbysurgicalremovalunlessstonesizeis<2cmwherelithotripsycanbeappliedtofragmentthestone.Unlikeotherrenalstones,cystinestoneshaveasingleetiology,hereditarycystinuria;withthiscondition,stoneformationbeginsinchildhood,andstonesmaygrowlargeenoughtofilltherenalcollectionsystem.Finally,brushiteisthenameforacalciumphosphatestone,theformationofwhichispromotedbyhighurinepHandsupersaturationofurinewiththecalciumphosphatesalt.JustasonEarth,itismorecosteffectivetopreventstoneformationduringaspaceflightmissionthanitistotreatacrewmember(ParksandCoe1996).Thus,understandingtheetiologyfortheformationofspecificstonetypesandidentifyingwhichstonesaremorelikelytobeformedduringspaceflightmissionswilldirecttheapplicationofappropriatecountermeasuresfornephrolithiasis.


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Figure1.Microphotographsofacalcium-containingrenalstones

Diagnosingnephrolithiasisisnotasdifficultasdistinguishingthetypeofrenalstone.Itmaybepossibletodelineatestonesbyphysicalfeatures.Oxalate,cystineandstruvitestoneshavedistinctiveappearances(mimickingstars,wax-likeeggs,andtreeroots,respectively),butfinaldiagnosisrequiresrecoveryofthestoneitself,whichisnotalwayspossible.Laboratoryevaluationscanbeusedtodetermineriskfactorsforstoneformationbaseduponsaturationlevelsofcalcium,oxalate,anduricacidmeasuredin24-hoururinespecimens.However,assessmentofpH,urinevolumes,urinecitratelevels(aninhibitorofstoneformation),creatininelevels(amarkerofoptimalrenalfunction),andserumcalciumlevelscanprovideevidenceofwhetherconditionsareconducivetostoneformation.Ifhypercalcemiaisdetected,thenassayofparathyroidhormonecanbeusedtodiagnosetheexistenceofametabolicdisorderthatmaybeatfault.

Additionally,ifconditionsthatfavorincreasedurinesaturationandstoneformationaredetected,countermeasureapproaches,specificforstonetype,canbeimplemented.Forexample,treatinghypercalciuria(>300mg/dayinmales,>250mg/dayinfemales)requiresidentifyingandaddressingthecauseofincreasedurinarycalcium.Pharmacologicalagents,suchasthiazidediuretics,ordietaryadjustmentscansuppressboneatrophyorpromoterenalcalciumreabsorption.Avoidingfoodshighinoxalate(nuts,pepper,chocolate,rhubarb,spinach,darkgreenvegetables,fruits)anddietshighinfatwillreducehyperoxaluria(>75-150mg/day).AtJohnsonSpaceCenter,<45mg/dayofurineoxalateisconsideredintherangeofdecreasedriskandanythingover45mg/daypromptsconsiderationofincreasedrisk.Reducingtheingestionofpurine-containingfoods,suchasmostmeats,willsuppresshyperuricosuria.IngestinganoralalkalisuchaspotassiumcitratewillsuppresscalciumoxalatecrystallizationbyraisingurinepHandprovideaninhibitorofcrystalaggregationandgrowthbybindingthecalciumiontoformthesolublecalciumcitrate.Increasingfluidintaketoincreaseurinevolumecandilutetheurinaryriskfactorstobringthesefactorsundertheupperlimitofmetastabilityforsolubilityofthestone-formingsalts(Whitsonetal.2001b).Evenpersonshomozygousforcystinuria(andthereforeathighriskofcysteine-stoneformation)candiluteouttheconcentrationofcystinebyhighfluidintake,therebyreducingtheirpersonalriskforstone.Unfortunately,giventheconstraintsofmissionoperations,theindiscriminateapplicationofallthesecountermeasureswouldnotbeaneffectiveapproachtoriskmanagement.Instead,thefullunderstandingoftheriskfactorsincurredduringmissionsinspaceandknowledgeofthe


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incidenceofrenalstonetypesiswarrantedinordertomakejudiciousselectionofprophylacticapproaches.

Recentmedicalresearchhashighlightedanadditiveeffectofpotassiumcitratebeyondtheriskofstoneformation.Onestudydemonstratedapositiveassociationbetweentheingestionofpotassiumcitrateandincreasedbonedensity(Paketal.2002).Potassiumcitratemayalsopreventbonelossbyprovidinganalkaliload,avertingthebone-resorbingeffectofsodiumchlorideexcess(Sellmeyeretal.2002).Thereisalsoevidencethatpotassiumcitratecanreducebonelossinpostmenopausalwomen,asrevealedbydecreasesinboneresorptionbiomarkers,possiblybycounteractingthedeleteriouseffectofacidemia(Marangellaetal.2004).Potassiumcitratealsoimprovescalciumbalanceamongpatientswithdistalrenaltubularacidosis,bothbyincreasingintestinalcalciumabsorptionandbymitigatingcalciumexcretion(Premingeretal.1987).

Thisreportwillhighlighttheriskforrenalstoneformationinspacebyoutliningthecharacterizationofriskfactorsasdeterminedincrewmembersaftershort-durationspaceflightmissionsaboardtheSpaceShuttle.Publishedflightdatadocumentsomeoftheenvironmentalanddietarycontributorstorenalstoneformation,includinghighanimalproteinintakeandhighacidload.Asmentionedabove,riskfactorsforstoneformationduringspaceflightincludeincreasedcalciumexcretionduetonetboneresorptionandlowurinevolume.Thus,theriskforrenalstoneformationisintimatelylinkedtohypercalciuriainducedbytheunbalancedboneresorptionduringtheuncoupledboneremodelinginspace.

IV. EVIDENCEA. SpaceflightEvidenceTheresultsfromspecimensobtainedfromcrewmemberswhohaveflowninspacedetailthebiochemicalandenvironmentalriskfactorsassociatedwiththeriskforrenalstoneformationduringandafterspaceflight.Datasourcesaredescribedbelow.

1. HistoricalDatafromSkylabSpecificassessmentsinsomeSkylabcrewmembersindicatedthatcalciumexcretionincreasedearlyinflight,notablebyday10offlight,andalmostexceededtheupperthresholdfornormalexcretion(300mg/dayinmales)insomecrewmembersduringSkylabmissions(Figure2).


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Figure2.CalciumbalanceduringandafterSkylabmissions.AdaptedfromRambautandJohnston(1979)

2. Short-durationspaceflightmissionsontheSpaceShuttle

RetrospectiveanalysisofurinarydatafromU.S.SpaceShuttlecrewmemberswasconductedin24-hoururinespecimenscollected10dayspre-launch(~L-10day)andimmediatelypost-landing.Analysisconsistedofurinecharacteristicsassociatedwithrenalstoneformationandrelativesupersaturationofstone-formingconstituents.Allpre-andpost-flightdatafromSpaceShuttlecrewmembersaretabulatedbelow(Tables1-3).Table1.MeanValuesforUrinaryBiochemicalParametersinCrewmembersafterShort-DurationSpaceflight

Parameter Pre-flight(n=332)

Post-flight(n=329)

Pvalue NormalReferenceValues*

TotalVolume(L/d) 2.1±0.06 2.0±0.06 NS 2-2.5<1L/d 13.0% 13.1% -<1-2L/d 38.9% 46.2% ->2Ld 48.2% 40.7% -Oxalate(mg/d) 38±0.9 37±0.9 NS 0-45Calcium(mg/d) 183±5.3 234±6 <0.05 <300M<250FpH 6.05±0.02 5.79±0.03 <0.05 4.5-8.0Citrate(mg/d)714±16 629±18 <0.05 >320Magnesium(mg/d) 116.0±2.5 99.0±2.2 NS 75-120

ValuesareMean±SEM;L/d–litersperday.Pre-flighturinescollected10daysbeforelaunchandpost-flighturinescollectedonlandingfollowingmissionsof<16days.*JohnsonSpaceCenterClinicalLaboratoryandJohnsonSpaceCenterCellularandBiomedicalLaboratory.Table2.MeanValuesforRelativeSaturationofStone-FormingSaltsinUrinefromCrewmembersduringShort-DurationSpaceflight

Parameter

Pre-flightn=332

Post-flightn=329

Pvalue

NormalReferenceValue

CalciumOxalate 1.53±0.06 2.26±0.07 <0.05 <2.0Brushite 1.25±0.06 1.00±0.06 <0.05 <2.0Sodiumurate 2.41±0.11 1.42±0.07 <0.05 <2.0Struvite 3.05±0.83 3.69±2.21 NS <75.0uricH+ 1.69±0.08 2.27±0.09 <0.05 <2.0


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ValuesareMean±SEM.Therelativeurinarysupersaturationsareunitlessratiosdeterminedfromtheactivityproductofthevariousconcentrationsoftheurinarychemicalcompositionandrepresentthesaturationofthestone-formingsaltsandtheconcentrationoftheundissociateduricacid.Thesupersaturationdataareexpressedrelativetothevaluesfromnormalnon-stoneformingsubjectsandindicatethestateofurinarysupersaturation,afundamentalrequirementforstoneformation.Urinarysupersaturationvalues<2.0indicateadecreasedriskforcalciumoxalate,brushite,sodiumurateanduricacidstoneformation.Values<75.0reflectadecreasedriskforstruvitestones.

Table3.PrevalenceofBiochemicalAbnormalitiesinUrineinAstronautsBeforeandFollowingShort-DurationSpaceflight

Abnormality Pre-flight Post-flight

Hypercalciuria(>250mg/d) 20.8%38.9%Hypocitraturia(<320mg/d) 6.9% 14.6%Hypomagnesuria(<60mg/d) 6.0%15.8%Urinarysupersaturation(>2.0) Calciumoxalate 25.6% 46.2%UricAcid 32.8% 48.6%Brushite 19.3% 13.1%Sodiumurate 44.9% 25.8%

Table4.UrinaryTractStoneEventsintheAstronautCorps(asofmid-2016)

Time #ofEvents

Comments

Prefight 5 Beforeflight,nopreviousflightexperienceR+0to90days 1 R+90to180days* 3 R+180to270days* 1 R+270to360days* 2 Inter-flight 4 Greaterthan360dayspost-flight,butflewagainR>360days(Active) 2 Greaterthan360daysandneverflewagainPostNASACareer 19 Total 37

AllU.S.Astronauts(n=357).Totalnumberofcrewmembersreportingevents=37.*Nocasesinthisintervalreportedpre-flightevents.R+:numberofdayspost-flight.PostNASACareer=eventoccurredfollowingretirementfromactiveastronautduty.InaseriesofinvestigationsledbyPeggyWhitson,Ph.D,environmentalandbiochemicalriskfactorsforrenalstoneformationwereextensivelycharacterizedforbothshort-andlonger-durationmissions.Itwasfirstreportedthatanincreasedriskofcalciumoxalateanduricacidstoneformationwasevidentimmediatelyafterspaceflight,concurrentwiththehypercalciuriaandhypocitraturiaquantifiedafterreturn(Whitsonetal.1993).Furtherinvestigation,whichincludedanalysisofurinecollectedduringflight,revealedthatmanyofthecontributingfactorstorenalstoneformationassociatedwithspaceflightwererelatedtonutrition,urinarypH,andvolumeoutput(Whitsonetal.1997).Inaddition,biochemicalanalysisofurinespecimensobtainedduringlongerSpaceShuttlemissionsprovidedatemporalreflectionoftherisk,indicatingthattheincreasedriskforrenalstoneformationoccursrapidlyduringspaceflight,continuesthroughoutthemission,andpersistsfollowinglanding(Whitsonetal.1999).In-flightevidencefromSpaceShuttlemissionsassociatedurinarysupersaturationanddecreasedurineexcretionwithreducedfluidintake;further,increasingthevolumeofurineoutputeffectivelyreducedtheurine


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supersaturationrisk(Whitsonetal.2001b).However,theuseofthisapproachasanin-flightcountermeasuremaynotaddressallriskfactorsduringaspaceflightmission.Figure3a(pre-flight)and3b(post-flight)displaystherelativeriskofstoneformationinarepresentativecrewmemberofaSpaceShuttleflight.Notethattheincreasedpost-flightriskforstoneformation(Figure3b)correspondedwithalargerexcretionofcalciumandareductioninpH(metabolicfactors),withareductionintotalurinevolumeandincreasedlevelsofsulfate(hydrationanddietaryfactors),andwithgreaterurinesaturationforstone-formingsalts(sodiumurate,calciumoxalate,brushite,anduricacidstones).

Figure3aRepresentativepre-flightrenalstoneriskprofiledeterminedinasinglecrewmemberbeforeashort-durationflight(i.e.SpaceShuttle).Bluebarsrepresentdecreasedrisk,redbarsrepresentincreasedrisk.


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Figure3b.Representativepost-flightrenalstoneriskprofiledeterminedinthesamecrewmemberimmediatelyfollowingashort-durationflight(i.e.,SpaceShuttle).Bluebarsrepresentdecreasedrisk,redbarsrepresentincreasedrisk.

Aspresentedinthe2008EvidenceReportontheRiskofRenalStoneFormation(Sibongaetal.2008),aretrospectivechartreviewforstoneformationinU.S.astronautsidentifiedfourteencasesofrenalstoneformationoccurringintwelvedifferentastronauts,withnineofthoseepisodesoccurringinthepost-flightperiod(n=7astronauts).Inadditiontoonein-flightstoneformationinacosmonaut,oneadditionalcosmonauthasbeenidentifiedasformingmultipleurinarycalculi(J.A.Jones;personalcommunication).Oftherenalstonesrecoveredfromastronautspre-andpost-flight,4stoneswereofcalciumoxalate,1stonewasofuricacid,1stonewasofmixedcomponents,and9wereofunknowncomposition.Whilesomeofthesecrewmembersappearedtohaveahistoryorpredispositionforstoneformationpriortospaceflight,uniquehabitabilityissuescommontospaceflightandmissionoperationsmayexacerbatetheriskforrenalstoneformation.Theseissuesincludefoodstability,preservationoffoodusinghighsodiumcontent,dehydration,boneatrophy,quantityofonboardwatersupplies,andlimitednutritionalchoices.Itmaybepossibletoreducethisriskbycorrectingoperationalissues;however,dependinguponthedurationofaspecificmission,itmayalsobeprudenttoformulatecriteriaforexcludingpersonswithpre-existingriskfactorstoreducethepotentialimpacttomissionobjectives.


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3. Long-durationduringtheShuttle-MirMissions

TheresultsfromaninvestigationofelevenastronautsandcosmonautswhoflewontheMirspacestationprovidedevidenceoftheriskforstoneformationduringlong-durationmissions(Whitsonetal.2001a).Datafrommissionsrangingfrom129-208dayssuggestedspaceflightandthereturntoEarthhaveacuteeffectsontheurinarybiochemistrythatmayfavorincreasedcrystallizationintheurine.Changespreviouslyobservedduringshort-durationSpaceShuttleflightsincludedarapidincreaseinthesupersaturationofthestone-formingsaltsintheurineearlyduringtheflightthatcontinuedthroughlandingday.However,thestone-formingpotentialintheurinewasdifferentduringandafterspaceflight.Duringflight,anincreasedriskoccurredforbothcalciumoxalateandcalciumphosphatestones.Immediatelyafterflight,however,theriskwasgreaterforcalciumoxalateanduricacidstonedevelopment,whichcouldbeattributedtolowurinevolumesanddecreasedurinarypH.Intheselong-durationcrewmembers,therewasa47%decreaseinurinevolumeearlyduringthemissions(beforeflightday30)anda39%lowerurineoutputlateinthemission(aftermissionday60).Urinarycalciumlevelsduringthepre-flightperiodrangedfrom159mg/dayto316mg/day,andduringflighttherangewas129mg/dayto435mg/day.Duringflight,7ofthe11crewmembersdemonstratedhigherin-flighturinarycalciumvaluesascomparedtotheirrespectivepre-flightlevels,and5ofthese11crewmembersexhibitedcalciumexcretiongreaterthan250mg/day.Datafromtheselong-durationmissionssuggestedasimilartrend,aswithshort-durationmissions,showingincreasedriskforcalciumphosphatestoneformationoccurringearlyinflight.Thesedatasuggestedthattheearlyphase(<30days)ofspaceflightmaygenerateconditionsinwhichtheriskofstoneformationwasgreaterthanduringthelaterphasesofthemission.Thesedataareconsistentwiththeshort-durationSpaceShuttledatainwhichbothcalciumoxalateandcalciumphosphateriskincreased.

4. InternationalSpaceStation

Finally,aflightexperiment(96-E057)performedduringlong-durationmissions(“Renalstoneriskduringspaceflight:AssessmentandCountermeasureEvaluation,”PrimaryInvestigatorP.Whitson)iscollectingdatafromcrewmembersofInternationalSpaceStation(ISS)missions(Whitson2009).Theaimoftheexperimentistoevaluatethein-flightefficacyofpotassiumcitrateasamitigatorofnephrolithiasis(particularlyofstonescomposedofcalciumsalts)duringlong-durationspaceflight.Potassiumcitrateisaknowntherapyfortheformationofcalciumoxalate,calciumphosphate,anduricacidcontainingstonesbecauseoftheformationofthesolublecalciumcitratecomplex.Riskfactorsarealsoalleviatedbythealkalizationofurineandbythereductionofphysiologicalacid/baseratioasinducedbypotassiumandthemetabolismofcitratetocarbonate.Inthisdouble-blindstudy,crewmembersubjectsonExpeditions3-6,8,and11-14consumedtwotablets,eitherplaceboor20mEqpotassiumcitrate,withtheirlastdailymealfromL-3toR+14days(3dayspre-launchto14daysafterreturn).Twenty-fourhoururinespecimenswerecollectedthreetimesduringflight:early(<35daysintoflight),middle(between36-120daysofflight),andlatemission(within30daysofundockingforreturn).Theurinarybiochemistrywasanalysedandtheurinarysupersaturationlevelswerecalculatedafterreturn.Alldiet,fluid,exerciseandmedicationswereloggedfor48hbeforeandduringtheurinecollection


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timetoassessanypotentialimpactfromenvironmentalfactors.Inadditiontoevaluatingtheefficacyofpotassiumcitratetominimizetheriskofstoneformation,theresultsofthisexperimentdescribedtherenalstoneformingpotentialincrewmembersasafunctionoftimeinspaceaswellasthestoneformingpotentialduringthepost-flightperiod.Resultsofthisinvestigationwerebrieflydescribedaboveandrecentlypublished(Whitsonetal.2009).Asaresultoftheknowledgegainedinthisstudy,potassiumcitrateasaprophylacticcountermeasurehadbeenapprovedfortransitiontomedicaloperationsbytheOfficeoftheChiefHealthandMedicalOfficer.

Possiblesideeffectsofpotassiumcitratesupplementation,althoughuncommon,includeminorgastrointestinalcomplaints(forexample,abdominaldiscomfort,vomiting,diarrhea,ornausea)andhyperkalemia,whichmayoccurinsubjectswithrenaldisease,potassium-sparingdiureticingestion,oracutedehydration.Uppergastrointestinalmucosallesions,includingerosionsandulcerations,havebeenreportedinassociationwithoralpotassiumsupplementation;however,studiesincludingplacebocontrolshavereportedmixedresultswithnodemonstratedcorrelationbetweensuchlesionsandsymptomaticcomplaintsoroccultbleeding.Theriskofseverecomplications,suchassmallbowelulceration,stenosis,orgastrointestinalperforationisestimatedatlessthan1per100,000patient-yearsbasedonspontaneousadversereactionreports(Gonzalezetal.1998).Theserisksmaybeminimizedbyprovidingslow-releasewaxmatrixtablets,ingestingthedosewithmeals,ingestingthetabletwholewithoutchewing,crushing,orsucking,limitingadditionalsaltintake,andencouraginghighfluidintake.Thisagenthasbeenusedprophylacticallyduringspaceflightinknownstone-formingastronautswhohavereceivedamedicalwaiverforshort-durationmissions;theefficacyofpotassiumcitratesupplementationhasbeendemonstratedinspaceflightcrews,asdescribedabove.Todate,potassiumcitrateremainsoneoftheonlyNASA-validatedandapprovedoperationalcountermeasuresforspaceflight.

Recentmedicalresearchhashighlightedanadditiveeffectofpotassiumcitratebeyondtheriskofstoneformation,showingapositiveassociationbetweentheingestionofpotassiumcitrateandincreasedbonedensity(Paketal.2002).Potassiumcitratemayalsopreventbonelossbyprovidinganalkaliload,avertingtheboneresorbingeffectofsodiumchlorideexcess(Sellmeyeretal.2002;Marangellaetal.2004).Potassiumcitratehasalsobeenshowntoreducebonelossinpostmenopausalwomen,asrevealedbydecreasesinboneresorptionbiomarkers,possiblybycounteractingthedeleteriouseffectofacademia.Inhibitingboneresorptionassociatedwithmicrogravityshouldalsodiminishtheriskofrenalstoneformation.Intheory,thiscouldalsobeaccomplishedbyphysicalloading(forexample,viaexercisecountermeasures)orbytheuseofotherpharmaceuticalagents,suchasbisphosphonates.

B. Ground-BasedEvidence

Similartopotassiumcitrate,potassium-magnesiumcitrateisalsounderclinicalstudyandmaysoonbeapprovedasanadditionalsupplementforinhibitionofstoneformation(PakandFuller1986;Pak1994;Whalleyetal.1996).Potassium-magnesiumcitratewasevaluatedasacountermeasureforrenalstonesinaflightanalogexperiment(Zerwekhetal.2007).Adouble-blind,placebo-controlledstudywasconductedinnormocalciuric


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humantestsubjectsskeletallyunloadedbyfiveweeksofprolongedbedrestasananalogforspaceflight.Two24hurinecollectionswereobtainedtoevaluaterenalstoneriskparametersandtherelativesaturationofcalciumoxalate,brushite,andundissociateduricacid.CirculatingparathyroidhormoneandvitaminDmetabolitesweremeasuredinserumsamples.Asexpected,bedrestimmediatelyinducedhypercalciuriabyanincreaseof50mg/dayinbothgroups.Subjectstreatedwithpotassium-magnesiumcitratedisplayedreductionsintherelativesaturationofcalciumoxalateandintheconcentrationofundissociateduricacidcomparedtoplacebo.ParathyroidhormoneandvitaminDmetaboliteswerereducedinbothgroups,withnostatisticaldifferencebetweengroupsinthedecrements.ThestudyauthorsconcludedthatpotassiummagnesiumcitrateisaneffectiveinhibitorofrenalstoneformationasindicatedbythereducedurinesaturationofcalciumoxalateandconcentrationofundissociateduricacidbythecitratechelationofcalciumandthealkalizationofpH,respectively(Zerwekhetal.2007).

V. COMPUTER-BASEDSIMULATIONINFORMATIONAPopulationBalanceEquationmodelwasdevelopedatNASAGlennResearchCenterfortheIntegratedMedicalModel(IMM)asatooltopredictasteadystatedistributionofrenalcalculisize(calciumoxalatecrystals)throughstagesofnucleation,growthandagglomerationasitmovesinthekidneywhileinmicrogravity(KassemiandThompson2016a).TheIMMisaMonteCarlosimulationmodelthatexplorestheeventspaceformedicalconcernsduringagivenreferencemission(Gilkeyetal.2012).Here,thePopulationBalanceEquationmodelbuildsoffoftheIMMcapabilitiesbyinputtingdatafromthebiochemicalprofileofastronautsforpredictionsregardingtheefficacyandinfluenceofdietarycountermeasures,suchaspyrophosphate,citratesupplementation,andhydration,onrenalstoneformation(KassemiandThompson2016b).ThemodelpredictionssuggestedthatsomemitigationbenefitisachievedbyincreasingcitratelevelsfromaverageEarth-basedlevels,butpreventingdeclinesincitratelevels(i.e.,maintainingnormalurinevalues)duringspaceflightisaseffective,ifnotmoreacritical,mitigationstrategy.Inaddition,pyrophosphatehasthepotentialofshiftingthemaximumcrystalaggregatetoamuchsmallersizestone,presumablyonethatissafer,andlesssymptomatic,topass(KassemiandThompson2016b).Finally,theriskforrenalstonedevelopmentincreaseswhenurinaryvolumedropsbelow1.5liters/day;therefore,aneffectivehydrationcountermeasureshouldbesufficienttoproduce2.5-3liters/dayofurinevolume(KassemiandThompson2016b).

VI. RISKINCONTEXTOFEXPLORATIONMISSIONSCENARIOSBecauseofthelimitationsofin-flightmedicalcapabilities,nephrolithiasisduringspaceflightcouldcauseanacuteillnesswithseverefunctionalimpairment,negativemissionimpact,orevensignificantmorbidityormortalityfortheafflictedcrewmember.Thereforeitisacriticalrequirementtohaveavalidatedcountermeasuretopreventrenalstoneformationpriortoexplorationmissions.Countermeasuresrelatedtospaceandplanetaryhabitabilityareimportant;withrespecttonephrolithiasis,thismayincludedietaryrestrictionstoreduceriskfactors,improvedfoodscience,andsufficienthydration.Aspreviouslymentioned,theprimaryriskfactorfortheformationofcalciumrenalstonesinspaceisthehypercalcuriainducedbyboneatrophyandlowurinaryoutput.Increasingfluidintakeandtherebyincreasingurinevolumecanprovidefavorablechangesinthe


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urinarysupersaturationofthestone-formingsalts.However,increasedurinevolumealonedoesnotaddresstheunderlyingphysiologicalprocessesthatmayexacerbatethein-flightstoneriskincludinghypercalciuria,hypocitraturia,anddecreasedurinarypH.Operationalconstraints,includingsuppliesofonboardwaterandthebusycrewworkloads,maylimitthebenefitsofhydrationtominimizetheriskofstoneformation.Optimalcountermeasuresfortheriskcouldmitigatemultipleriskfactorsrangingfromboneatrophytothesupersaturationofurine.Ideally,acountermeasureforboneatrophycouldalsomitigatetheriskforrenalstoneformation.Researchprioritiesrelatedtounderstandingthetimecourseofbonelossandtheinfluenceofmechanicalloading,frompost-landingactivitiesaswellasfractionalgravity,onplanetarysurfacesarerelevanttotheriskforrenalstoneformationduringexplorationmissions(Sibonga2008).Specificscenariosforexplorationmissionsaredefinedaccordingtothedurationoftimeinspace;givenmissionduration,location,andtimeintransit,eachmissionprofilemaydictatesignificantdifferencesintherelativeriskofrenalstoneformationaswellastheneedforvariedmitigationstrategiestoaddresssuchrisk(Table4).

Table4.DefinitionofExplorationMissionDurations.DurationLength

MissionLocation

TransittimetoLocation(days)

LengthofStay(days)

TransittimebackToEarth(days)

Short Moon 3 8 3Long Moon 5 170 5Short Mars 162 40 162Long Mars 189 540 189

ProbabilityEstimationforRenalStoneEventIntheabsenceofspaceflightincidenceofrenalstonesintheU.S.astronautpopulation,theIMMdatabaseandmodelingtoolhasbeenusedtoprojectanestimationofthelikelihoodofstoneoccurrenceaswellastheoutcomeofvarioustreatmentstrategies.EstimateincidenceratesweregeneratedbyBayesianmethods,usingdatafromNASA’sLifetimeSurveillanceofAstronautHealth(LSAH)andpopulationdatafromtheCentersforDiseaseControl(CDC)(LitwinandSaigal2012).Duetothislowoccurrence,Bayesianmethodsweredeemednecessaryinordertobetterpredictprobabilityestimatesforincidenceratesofthismedicalevent.TheBayesianprocessallowsresearcherstomakeinferencestodeterminetheprobabilitythatahypothesisistrue,conditionalonallavailableevidence.InformationfromthesesourceswascombinedusingaBayesianupdateapproachtoestimatetheaveragerateofstoneformation.Bymakinganaveragerateassumption,aPoissonprobabilitydistributionwasassumedtogoverntheprobabilityofstoneformation.Thismodelusedonlydatapertainingtostoneoccurrence,notdatarelatedtobloodorurinechemistry.FromtheCDC,asof2004,theincidenceofrenalstonesinmaleswas1-3eventsper1000personsperyearand0.6-1eventsper1000personsperyearinfemales.Forthisspaceflightanalysis,genderdifferenceswerenotconsideredsincethevastmajorityofastronautsweremale;theresultantaverageincidencerateofrenalstoneswas0.0018peryear.Alongwithtrackingcurrentandformerastronauts,theLSAHmaintainsanastronautcontrolpopulationdatabaseprimarilymadeupofNASAJohnsonSpaceCenter


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personnel.Thesedataareofinterestasrenalstoneincidenceisgeographicallydependent,duetofactorsincludingdietaryhabits,lifestyle,andsimilar;inclusionoftheanalogcohortallowsforgeographicaldiscrepanciestobeaccountedforbythemodel.Of927participants,therewere74occurrencesofrenalstonesover17740.8person-years,yieldinganincidencerateof0.0042eventsperperson-yearforthisground-basedcomparisonpopulation(Pietrzyketal.2007).Therehavebeenanumberofrenalstoneoccurrencesintheastronautpopulation,primarilyfollowingshort-durationflightsasnotedabove.Atthetimethatthismodelwasdeveloped,fromapopulationof332astronautstherewere14occurrencesover5434.5person-years,yieldinganincidencerateof0.0026eventsperperson-year(Pietrzyketal.2007).Ofnote,thisrateaccountsforalloccurrences,includingrepeatoccurrences(twoknownintheastronautpopulation).Approximately40%oftheincidencesoccurredwithin30monthsofreturn-to-Earth,andtheremainderoccurredafter66monthspost-return.Theskewedtimelineforstonedevelopmentmaynegatetheassumptionofanaverageratefortheentireperiodofinterest,decreasingthefidelityofthemodel.Thetotalnumberofperson-yearsreportedincludesthetimeframeforbothin-flightandpost-flightdata.Thisprocessreturnedanestimateoftherateofrenalstoneformationintheastronautpopulation(mostrepresentativeofpost-flightrates),allowingforcomparisontothegeneralpopulationandtheLSAHcontrolpopulation.ThisratecanbeusedastheinputratetoaPoissondistributionprobabilitymodeltoestimatetheprobabilityofrenalstoneoccurrence.Themodelpredictsameanincidencerateofrenalstoneformationamongastronautsof0.00365±0.000375eventsperperson-year.ApplyingthisprobabilitytothevariousproposedNASAmissions,theIMMestimatedriskofrenalstoneformationforanindividualastronautasof2015iscalculatedandshowninTable5.Table5.Probabilityofarenalstoneeventduringspaceflightmissions.

MissionProbabilityperpersonyearofoneormoreinonecrewmember

AnyEvent BestCase WorstCase

LunarSortie(21day) 0.0002(0.02%) 0.0001(0.01%) 0.0001(0.01%)

ISS(6month) 0.0018(0.18%) 0.0011(0.11%) 0.0007(0.07%)

Mars(3years) 0.019(1.90%) 0.0066(0.66%) 0.0043(0.43%)BestCaseScenario–arenalstonethatrespondstoconservativetreatment(analgesics,hydration)WorstCaseScenario–arenalstonethatrequiresadvancedmedicalintervention

Theseriskpredictionsshouldbeconsideredverylimitedinthattheyassumeanaverageoccurrencerateofrenalstones,irrespectiveofthestonetypeorenvironmentalconditions.Additionally,theinclusionofrepeatedoccurrencescouldinfluencethepredictedrateofincidences,asitisknownthattheoccurrenceofonestoneincreasesthelikelihoodofsubsequentstones.However,itislikelyareasonablerepresentationoftherateofstoneformationgiventheoccurrencedataavailableandgiventheassumptionsmadeduringconstructionoftheestimate.Futuremodelswillincludethesedatatoimprovetheestimateoftherateofoccurrenceintheastronautcorps.Moreaccurateestimatescanbemadewithfurtheranalysisoftheperiodsofrenalstoneoccurrenceinpost-flightnephrolithiasiscases


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andtheurinaryandserumchemistryvaluesthatpertaintostoneformation.Thecurrentmodeldatawillserveasthebaselineforfutureestimatesthatutilizesuchbiochemicalstoneforming/inhibitingparameters.VII.MINIMIZINGTHERISKOFSTONEFORMATIONA. CountermeasuresNephrolithiasishasbeenidentifiedbytheIMMasoneoftheleadingmedicalconditionsthatwouldleadtoevacuationofacrewmemberduringaspacemission.However,evacuationduringanexploration-classmissiontothemoonorMarswillbechallenging,ifatallpossible.Therefore,preventivemedicineapproachesarenecessaryinordertolowerthelikelihoodandseverityofin-flightrenalstoneoccurrence.Dietarymodificationandpromisingpharmacologictreatmentsmaybeusedtoreducethepotentialriskofrenalstoneformation.Dietslowinoxalatecontentandanimalproteinsmaybeadvised.Someoftheinhibitorsubstancesarebeingconsideredforhigherriskspaceflightcrewmembers.Potassiumcitrate,asdescribedabove,isusedclinicallytominimizethedevelopmentofcrystalsandthegrowthofrenalstones.Mostorallyadministeredcitrateismetabolizedtoproduceanalkaliload.AdministrationoforalcitrateincreasesboththeurinarycitrateandpH.Thecitratecomplexeswithcalcium,decreasingionactivity,and,thus,theurinarysupersaturationandcrystallizationofcalciumoxalateandbrushite.TheincreaseinurinarypHdecreasescalciumionactivitybyincreasingcalciumcomplexationtodissociatedanions;itsimultaneouslyincreasestheionizationofuricacidtothemoresolubleurateion,leadingtofeweruricacidstones.

Bisphosphonatesareaclassofdrugswithdemonstratedefficacyintreatingelderlypatientswithosteoporosisbyinhibitingthelossofbone.Theseagentscouldpotentiallypreventthebonelossobservedinastronautsandtherebymitigateoravertstoneformation,promotingresorptivehypercalciuria.Oneextended(90-day)terrestrialbed-reststudydemonstrateddecreasedurinarycalciumexcretion,alongsidedecreasedsupersaturationofcalciumoxalateandcalciumphosphate,insubjectsreceivingpamidronate(abisphosphonate)ascomparedtocontrols;therewasaconcomitanttrendtowardsdecreasedstoneformationinthepamidronategroup(Okadaetal.2008).Morerecently,ajointstudyconductedbyNASAandtheJapaneseAerospaceExplorationAgencyevaluatedtheuseofalendronate,incombinationwithresistiveexercises,foritsabilitytodecreaseboneresorptionandurinarycalciumexcretioninISSastronauts.Thealendronategroupdemonstratedatrendtowardsreducedurinarycalciumexcretionthroughflightday60,and,further,maintainedurinarycalciumatpre-flightlevelsthroughoutthe6-monthISSmission(LeBlancetal.2013).Incontrasttothis,subjectsparticipatinginresistiveexercisesalonedemonstratedasignificant(50%)increaseinurinarycalciumexcretionduringtheearlyphasesofflight;urinarycalciumlevelswerecomparabletopre-flightlevelsimmediatelypost-flightandat1-yearfollow-up(LeBlancetal.2014).Thecombinationofbisphosphonatesandaresistiveexerciseregimenappearstoimprovebonehealthanddecreaseurinarycalciumexcretion,andthusmayreducetheriskofstoneformationduringandpossiblyafterlong-durationspaceflight.


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B. RenalStoneRiskAssessmentU.S.crewmembersareassessedwiththerenalstoneriskprofile(MissionPharmacal,UniversityofTexasSouthwestLaboratories,(MissionPharmacal2016)),graphicallyplottedforeachindividual.Althoughtheurinaryriskprofiledoesnotdirectlypredicttheformationofrenalstones,itillustratestotheflightsurgeonandcrewmemberthecurrenturinechemistryenvironment(RyallandMarshall1983;Paketal.1985;Grasesetal.1997;Pak1997).Figures3aand3bshowexamplegraphsoftheurinaryanalysisperformed.Thegraphicprovidesaconvenientandeasilyinterpretableriskprofileunderstoodbyflightsurgeonsandcrewmembers.Inourretrospectivereviewofcasesandthepost-flightrenalstoneriskindex(RSRI)assessment,wefounda93%correlationbetweenknownstone-formersandahighRSRI.Allbutonecasewerefoundtohavesignificanturinarybiochemicalabnormalitiesinthestoneriskprofile;theoneoutlyingcasehadminorabnormalities.Thereweresomefalsepositivesinprospectivecases,confoundedbyurinecollectionbiases,buttherewerenofalsenegatives.

Theriskprofile,consideredinconjunctionwiththelifestyleanddietaryhabitsoftheindividual,canbeavaluablemonitoringandeducationtool(Riversetal.2000).Individualswhoareatanincreasedriskorhavepreviouslyformedrenalstonescanbefollowed,patientcompliancecanbeassessed,andtheeffectivenessofmedicaltreatmentcanbedeterminedwiththisprofile.Therenalstoneriskprofilehasprovenvalueintheclinicalsettingasatoolforclassifyingpatientsaccordingtotheetiologyoftheformationoftheirrenalstones(Paketal.1985;Yagisawaetal.1998;Lifshitzetal.1999).Further,therelativelylowcostoftherenalstoneriskprofilemakesthisacost-effectivemethodology,andmaymitigateboththeriskofdevelopingastonein-flightandthepotentialmissionimpactifnephrolithiasisoccurs.Clinicalandresearchexperiencehasshownthatmonitoringtheurinaryenvironmentandestimatingtheriskforrenalstonedevelopmentcanleadtosignificantlyimprovedcontrolofstonediseasewhenthisinformationisusedtoguidemedicaltherapy(MorganandPearle2016),andtheneedforsurgicalinterventionandstoneremovalcanbedramaticallyreducedbyaneffectiveprophylacticprogram.Studieshaveconcludedthat,forterrestrialstone-formers,thereproducibilityofurinarystoneriskfactoranalysesissatisfactoryinrepeaturinesamplesandasinglestoneriskanalysisissufficientforasimplifiedmedicalevaluationofurolithiasis(Paketal.2001).Theaccuracyofmeasuringurinarystonepromoter-andinhibitor-substancesisimprovedbyincludingmatrixcomponents,uroproteins,uromucoid,andglycosaminoglycansintheanalysis(Batinićetal.2000).Otherlaboratoryanalysesforurinarystonesincludebloodureanitrogen,serumelectrolytes,creatinine,calcium,uricacid,andphosphorous.AsappliedtotheU.S.spaceprogram,thishealthcaremonitoringprogrammayprovideseveraldistinctadvantages.Crewmemberswithanincreasedbaselineriskpriortospaceflightwillfurtherincreasetheirriskofstoneformationwhenexposedtothemicrogravityenvironmentandtheresultantboneloss,hypercalciuria,increasedurinarysodium,anddecreasedurinaryoutput.TheRSRIevaluationmayidentifytheriskpriortoflight,helptoidentifyappropriatemedicalintervention,andreducethepotentialriskbefore,during,andafterspaceflight.InimplementingthescheduleofRSRImeasurementwith24hurinecollection,itwasdeterminedthatallastronautsshouldhaveanannualassessmentdedicatedtostoneriskfactoridentification.SpaceShuttlecrewmemberswith


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significantriskfactorsorhistoryofpreviouscalculialsohadpre-flightevaluationsforstones.Currently,thisassessmentisperformedannuallyaswellaspost-flight,duringthecomprehensivemedicalexamination,performedtwiceat3and30daysafterreturninallcrews.Pre-flightandpost-flightrenalstoneriskprofilescontinuetobeconductedasamedicalrequirementforallISScrewmembers.Additionalresearchstudiesarecurrentlycollectingurinesamplesforbiochemicalanalysestoidentifychangesintheurinarybiochemistrythatpotentiallyincreasetheriskofstoneformation.Togetherthesedatawillprovideanindicatoroftheimpactofdietaryfactors,hydrationstatus,andmicrogravityexposureforstonedevelopment.Theurinarybiochemicaldataarefurtheremployedtoimprovethemodellingofstoneformationriskandthepotentialtoenhancethepredictivepowerofthesemodels.C. In-flightPreventionDuringamission,crewmembersfollowproceduresthatpreventthegrowthofstones.Inparticular,takingoralfluidsinamountssufficienttomaintainadequatehydrationisencouraged.Ifanastronautissufferingfromseverespacemotionsicknessearlyinflight,intravenousfluidsmaybeconsideredtoguardagainstdehydration;todate,thisinterventionhasnotbeenrequired.Inadditiontohydration,sodiumconsumptionshouldbelimitedduringflight.Aspreviouslynoted,potassiumcitrateorpotassium-magnesiumcitratemaybeusefulcountermeasurestostoneformationincertainhigh-riskindividuals.

D. In-flightDiagnosisandMonitoringUltrasoundimagingtechnologyisavailabletothecrewsontheISS.Ifsymptomssuggestingnephrolithiasisoccurinflight,spaceflightcrewscantakespecificstepstorespondandmitigatefurtherrisk,includingtheuseofsonographicimaging.Theonboardcrewmedicalofficer,withguidancefromgroundmedicalspecialists,isabletomonitoranaffectedcrewmember’svitalsigns,hydrationstatus,andclinicalappearance,andmayperformanultrasoundexamwithreal-timeguidancefromgroundcontrollers.Guidedultrasoundexaminationshavebeenperformedmanytimesforinvestigationalpurposesandshowntoprovideadequatediagnosticimagery(Sargsyanetal.2005;Jonesetal.2009).Theanatomiccontentandfidelityoftheimagescapturedinthesestudieswereexcellentandsufficientforclinicaldecisionmaking,comparabletoimagingobtainedunderterrestrialconditions.Inthecaseofanacuterenalstoneevent,imagecharacterizationwouldallowforstonelocalizationandestimationofsize,datathatcouldprovecriticaltomedicaldecision-making.


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Figure4.Ultrasoundimageshowingcapabilitytodetectarenalstonelessthan3mm.

For example, ultrasound may be used to show visible calculi in the ureteropelvic

junction or renal pelvis, and can further identify unilateral distension of the collectingsystemfromeitherhydronephrosisorhydroureterifadequatetimehaspassedtoallowfordistention to occur. Ultrasound may also show loss of the ureteral jet in the bladderipsilateraltothesideofpain,furthersupportingaclinicaldiagnosisofnephrolithiasis.

VIII. GAPSThefollowingsectionraisesrelevantimplementationissuesandknowledgegapsassociatedwithmitigatingrenalstoneformationinthecontextofthecurrentexplorationmissionscenariosandtheoperationalconstraintsofpower,mass,volume,timeandexpense.Atthetimeofwriting,7researchknowledgegapshavebeenidentifiedthataredirectlyrelatedtotheRiskofRenalStoneFormation.Theseare:

• B5-Whatisthecurrentstateofknowledgeregardingrenalstoneformationdueto spaceflight?

• N13-Canrenalstoneriskbedecreasedusingnutritionalcountermeasures?

• B6-Whatarethecontributingfactorsotherthanlossofbonemineraldensity?

• B7-Isitnecessarytoincreasecrewfluidintakeand,ifpossible,towhatextentwillitmitigatestoneformation?

• B8-Dopharmaceuticalsworkeffectivelyinspaceflighttopreventrenalstones?

• B9-Whatisthefrequencyofpost-flightstoneformation;theincidenceandtypesofstones;andthetimecourseofstoneformation?Howdoesstoneformationcorrelatewithfoodintakeandhydrationstatus?

• B16-Caninhibitorsofstoneformationbesufficientlyprovidedthroughdietarysources?


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CurrentStatusofGapKnowledge

Medicalrecordsarereviewedforindividualcrewmemberstoidentifyrenalstonesevents.ThedatabaseofstoneeventsispresentedannuallytotheJSCHumanSystemsRiskBoard(HSRB)characterizingthenumberofeventsandtimeoftheevent.Toassesstheriskofstoneformationduetospaceflight,postflightultrasoundwasbeguninFebruary2016.Theimagingisscheduledtooccurwithin30daysofthecrewmember’slanding.Atthistime58ultrasoundexamshavebeencompletedon49crewmembersincluding2preflightand4postflight.ThereviewoftheseimagesisinmedicalreviewwithasummaryoftheresultstobepresentedtotheHSRB.Thepostflightultrasoundswillprovideinitialevidenceforin-flightrenalstoneformation.PreflightandpostflightrenalstoneriskprofilescontinuetobeconductedasamedicalrequirementonallISScrewmembers.Additionalresearchstudiesarecollectingurinesamplesforbiochemicalanalysesidentifyingchangesintheurinarybiochemistrypotentiallyincreasingtheriskofstoneformation.Togetherthesedatawillprovideanindicatoroftheimpactofdietaryfactors,hydrationstatusandmicrogravityexposureforstonedevelopment.Theurinarybiochemicaldataarealsobeingemployedtoimprovethemodellingofstoneformationandthepotentialtoenhancethepredictivepowerofthesemodels.IX. CONCLUSIONSNASA’sstrategicgoalsareforahumanpresenceforexploration-classmissions,whichincludethegoalsofreturningtothemoonandlandingonMars.Withtheseobjectives,explorationcrewmemberswillexperienceextendedexposuretotheuniqueenvironmentsofspaceandtheadaptiveeffectsofhumanphysiologytomicrogravity,partialgravity,andtotheoperationalconstraintsandlimitationsofspacehabitation.TheadaptiveeffectsofspacetravelonhumanphysiologyresultinalteredurinarychemicalcompositionthatoccursbothduringspaceflightandafterreturntoEarth,resultinginknownriskfactorsfortheformationofrenalstones.Asof2016,37knownsymptomaticmedicaleventsconsistentwithurinarycalculihavebeenexperiencedbyU.S.astronauts.Althoughpreviousstoneformersareathighrisktoformnewstones,itisnotpossibletopredictwhichcrewmemberswillformrenalstonesdenovoonEarthorduringspacemissions.Thus,effortsshouldcontinuetodefinetheriskofrenalstoneformationinspacewithcountermeasuresfocusedonthepreventionofstoneformation.


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XI. TEAMJeanD.Sibonga,Ph.D.,BoneDisciplineLead,HumanResearchProgram,NASAJohnson

SpaceCenter.Biochemistry;Iliaccrestbonehistomorphometry;PreclinicalResearchinBoneCellBiologyandPhysiology,AnimalModelsofOsteoporosis.

RobertA.Pietrzyk,M.S.,Co-Investigator:RenalStoneRiskAssessment;ProjectScientist,

ISSMedicalProject.HumanPhysiologyandBiochemistry;KBRWyle;Houston,TX.Consultant&ContributingAuthor.

PREVIOUSCONTRIBUTINGAUTHORS:Jeffrey.A.Jones,M.D.,M.S.,FACS,FACPM-FormerNASAFlightSurgeon,LeadExploration

MedicalOperations,SpaceMedicineDivision,JSC;AdjunctProfessorBaylorCollegeofMedicine;CaptainUSNavyReserves,SeniorMedicalOfficer,MarineAirGroup41Medical.Consultant.

JosephE.Zerwekh,Ph.D.,Professor,DepartmentofInternalMedicineandtheCenterfor

MineralMetabolismandClinicalResearch,UniversityofTexasSouthwesternMedicalCenter,Dallas,TXConsultant

ClaritaV.Odvina,M.D.,AssociateProfessorofMedicine,DivisionofMineralMetabolism,UTSouthwesternMedicalCenterFormerappointment.Consultant.

XII. LISTOFACRONYMSCDC CenterforDiseaseControlIMM IntegratedMedicalModelISS InternationalSpaceStationLSAH LifetimeSurveillanceofAstronautHealthRSRI RenalStoneriskIndex

evidence report: risk of renal stone formation · 2017-05-15 · risk of renal stone formation...

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