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NDTeditorial

Title:RenalFanconisyndrome:takingaproximallookatthenephron

Enriko D Klootwijk, Markus Reichold, Robert J Unwin, Robert Kleta, Richard

Warth,DetlefBockenhauer

Correspondenceto:

ProfessorRobertKleta,MD,PhD,FASN,FACMGPotterChairofNephrologyUniversityCollegeLondonRoyalFreeHospital/MedicalSchoolRowlandHillStreet,LondonNW32PF,UnitedKingdomphone: +44-20-73177554fax: +44-20-74726476email: r.kleta@ucl.ac.uk

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Summary

Renal Fanconi Syndrome (RFS) refers to the generalised dysfunction of the

proximaltubule(PT)[1].Initsisolatedform,RFSonlyaffectsthePT,butnotthe

other nephron segments. The study of isolated RFS can thus provide specific

insights into the function of the PT. In a recent paper, Klootwijk et al.,

investigated one such form of isolated RFS and revealed the underlying

molecular basis [2]. The affected family had been described previously,

demonstrating the typical features of RFS, such as low-molecular weight

proteinuria, aminoaciduria, glycosuria and phosphaturia with consequent

rickets; yet, importantly, patients had no evidence of impaired glomerular

filtration [3]. Inheritance was consistent with an autosomal dominant mode.

Klootwijk et al. discovered a surprising explanation: a heterozygousmissense

mutation causing partial mistargeting of the peroxisomal enzyme EHHADH to

themitochondria.Notably,diseasecausingwasnottheabsenceoftheenzymein

theperoxisome,butitsinterferencewithmitochondrialfunction.Thediscovery

of this novel disease mechanism not only confirmed the importance of

mitochondrial function for PT transport, but also demonstrated the critical

dependenceofPTonfattyacidmetabolismforenergygeneration.

Thereview:

Proximaltubule:functionandphysiology

Inanaverageadult,thekidneys(glomeruli)generateapproximately150litresof

filtrate per day, of which about 99% is reabsorbed by the tubules, yielding a

urine volume of 1-2 litres (Figure 1) [4]. The vastmajority of the glomerular

filtrate is reabsorbed by the PT, the “workhorse” of tubular segments. Insight

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into the contributions of the individual nephron segments has been mainly

providedbymicropunctureexperiments,wheremicropipettesareinsertedinto

different segments of the nephron to measure flow and obtain samples for

analysis.Thistechniquehasanimportantlimitation,however,inthatonlythose

segmentsthatareclosetothesurfaceofthekidneyareaccessibleforpuncture.

Thus,thelastaccessiblesiteinPTistheendoftheproximalconvoluteandthe

nextaccessible sitedownstream is thebeginningof thedistal convolute [5]. In

between these two sites is the straight descending PT (the pars recta or S3

segment)andtheloopofHenleanditisimpossibletoaccuratelydeterminethe

individual contributions of these segments.Whilst the function of all nephron

segments including those not accessible by the micropuncture technique has

been studied using the technique of isolated tubule perfusion, quantitative

information with respect to relative transport activity in vivo is difficult to

extrapolate[6].

Inanycase,thePTnotonlyreabsorbsthevastmajorityoffiltrateintermsofsalt

andwater, but also is the sole site of reabsorption formany valuable solutes,

such as amino- and organic acids, filtered proteins, glucose and phosphate. In

quantitative terms,without a functional PT,wewould lose approximately 120

litres of water per day, plus solutes, including about 18 mol of sodium (the

equivalent of roughly 1 kg of cooking salt) andmore than 100 g of sugar. In

addition, all the filtered amino acidswouldbe lost, deficiency ofwhich canbe

associatedwithspecificdiseases[7],aswellasallfilteredphosphate,resultingin

hypophosphataemic rickets. In short: the PT is important for our survival! In

addition, it becomes evident from those numbers that RFS refers to an

impairmentofPTfunction,ratherthanacompleteabsenceoffunction.

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The enormous reabsorptive capacity is provided by a whole orchestra of

specialisedapical,basolateralandparacellularpermeabilitiesanddrivenbythe

electrochemicalgradientgeneratedbythebasolateralNa+-K+-ATPase(seeFigure

2). Not surprisingly, the PT has a high energy demand to keep the transport

going,whichmayexplain,whyitisalsothenephronsegmentmostsusceptibleto

ischaemicdamage[8].UnderstandingPTfunctionthuswillnotonlyelucidatethe

pathophysiology of the rare RFS, butmay also provide insights into themore

commonproblemofacutekidneyinjury[9].

RFS:thehistory

Ricketsandalbuminuriasecondarytokidneydiseasewasfirstdescribedin1881

but attributed to be a “disorder of adolescence” [10]. It was the Swiss

paediatricianGuidoFanconi,whofirstdescribedtheconceptthatdefectiverenal

proximal tubule reabsorption of solutes might contribute to “non-nephrotic

glycosuric dwarfing with hypophosphataemic rickets in early childhood” [11].

Fanconi’sfirstcasepresentedattheageof3monthswithricketsandrecurrent

fevers. She had glycosuria and albuminuria and progressed to terminal renal

failureby5yearsofageandsubsequentlydied.Atautopsytherenaltubulecells

appeared filledwith crystals,whichwere thought tobe cystine. In subsequent

reports,Debré,deToniandFanconialldescribedseriesofchildrenwithrickets,

glycosuriaandalbuminuria[12-14].Inacknowledgmentofthispioneeringwork,

RFS is also referred to as Fanconi-Debré-de Toni syndrome, but in clinical

practice most people use the shorter name. The presentation, course and

outcomeof the childrendescribed in these earlydescriptions variedmarkedly

and this concurswith our clinical experiencenow. It reflects thatRFS is not a

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uniform entity, but a diagnosis of proximal tubular dysfunction, which can be

due to a variety of different causes. RFS can be isolated, such as in the family

investigatedbyKlootwijketal.,orinthecontextofmultiorgandisorders,suchas

nephropathic cystinosis or mitochondrial cytopathies; it can be congenital or

acquired, transient or permanent, associated with progression to end-stage

kidneydisease(ESKD)orwithstableglomerularfiltration[15-17].Moreover,it

can differ in the extent and severity of tubular dysfunction. Severe and

generalised PT dysfunction is seen in nephropathic cystinosis, whilst some

patientswithe.g.DentdiseaseorLowesyndromehavewastingoflow-molecular

weight proteins and calcium, yet without clinically significant disturbance of

phosphateandbicarbonatetransport[18].Indeed,thereissomedebateatwhat

point proximal tubular dysfunction can be called RFS [1]. There seems to be

agreement that several individual PT functions have to be compromised and

isolated renal tubular aminoacidurias (e.g., cystinuria or Hartnup disorder)

would not be labelled as renal Fanconi syndrome. Dissecting the various

pathways involved in these individual diseases of course contributes to our

understandingofPTfunction.

RFS:theinheritance

ThereareseveralgeneticformsofRFS,themajorityofwhichareassociatedwith

multisystem disorders (Table 1). In general, the disease mechanism for these

disorderscanbecategorisedaseithera)accumulationofatoxicmetabolite(e.g.

cystinosis, tyrosinaemia, galactosaemia, Fanconi-Bickel, congenital fructose

intolerance and Wilson’s disease), b) disruption of energy provision (e.g.

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mitochondrial cytopathies) or c) disruption of endocytosis and intracellular

transport(e.g.Lowesyndrome,DentdiseaseandARCsyndrome).

Recently, RFS was described in some patients with MODY1 (“maturity-onset

diabetesoftheyoung”type1)[19].Interestingly,thisrenalphenotypewasseen

onlyinpatientswithaspecificheterozygousmutation,R76WinHNF4A,whereas

thosepatientswithothermutationsinHNF4Asufferedfrompancreaticbetacell

dysfunctiononly. SinceHNF4A is a transcription factor, this finding suggests a

specific effect of the R76W mutation on transcription of certain genes in the

kidney,butwhichonesexactlyareaffectedisunknown.

Ofspecialinterestare,ofcourse,theformsofisolatedRFS,asthesemayprovide

the most specific insight into PT function. Three genetic forms have been

described(Table1):FanconiRenotubularSyndrome(FRTS)types1-3.Thefirst

onewaspublishedalreadyin2001,includinglinkagetoalocusonchromosome

15,yetidentificationoftheunderlyinggeneisyetawaited[20].Ofnote,FRTS1is

also associated with progressive chronic kidney disease (CKD). Thus,

identificationoftheunderlyingproblemmayalsoelucidateamechanismofCKD

progression.OtherfamilieswithasimilarphenotypeofRFSandprogressiveCKD

inheritedinanautosomaldominantfashionhadbeendescribedpreviously[21-

23],suggestingthatthismaybeaslightlymorecommonformoftheseotherwise

veryrarediseases.

FRTS2hassofarbeendescribedonlyin2siblings.Aninitialclinicaldescription

was provided in 1988 [24], revealing a phenotype dominated by phosphate

wastingandricketsdespiteelevatedlevelsof1,25OHvitaminDwithassociated

disturbances of some, but not all PT transport pathways, as e.g. renal tubular

acidosiswasnotpresent,raisingagainthequestionofwhatconstitutesRFS[1].

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In2010,anunderlyingmutationwasreportedinformofahomozygousin-frame

21bpduplicationinSLC34A1,encodingthephosphatetransporterNaPi-IIa[25].

In vitro studies demonstrated significant loss-of-function of the mutant

transporter.ThefindingofSLC34A1mutationsinRFShasbeensurprising,given

thatmutationsinSLC34A3,encodinganotherrenalphosphatetransporterNaPi-

IIc, cause hereditary hypophosphataemic rickets with hypercalciuria [26]. No

furtherpatientswithRFSandrecessivemutationsinSLC34A1havesofarbeen

reported. The genetic finding, however, is consistent with the clinical

observation of phosphate wasting and rickets being the key clinical

abnormalitiesinthesetwosiblingsandthatthephenotypecouldbeameliorated

byphosphatesupplementation.Theunderlyingmechanismmaybeintracellular

phosphatedepletionwithconsequentinsufficientATPgeneration.Abnormalities

in an unrelated proximal transport pathway has been observed in mice with

hypophosphataemicrickets[27]andglycosuriaisindeedacommonobservation

in patients with hypophosphataemic rickets in our own clinical practice.

However, other indicators of PT dysfunction, such as low-molecular weight

proteinuriaarenormalinthesepatients(unpublishedownobservations).

FRTS3 is the formof isolatedRFS thatwas investigatedbyour laboratoryand

reportedbyKlootwijketal.[2].Westudiedthefivegenerationfamilydescribed

by Tolaymat et al. [3]. Reassessment of the clinical phenotype confirmed the

original observations made by Tolaymat et al.. Moreover, it demonstrated

normal age-appropriate GFR in all affected family members, including the by

then74-yearoldmatriarch.Thisaloneprovidedvaluable insights: the life-long

loss of water and solutes, including about 1g/d of filtered proteins does not

appeartobeacriticalriskfactorforthedevelopmentofCKD.

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With respect to revealing the underlying genetic cause we first performed

linkageanalysis,whichidentifiedasinglelocusonchromosome3.Sequencingof

allknowngeneswithinthislocusrevealedaheterozygousmissensemutationin

a gene called EHHADH that segregated with the disease. EHHADH encodes a

bifunctionalenzyme involved inperoxisomal fattyacidmetabolism(alsocalled

L-PBEforL-peroxisomalbifunctionalenzyme).TheidentificationofEHHADHas

theunderlyinggenewasinitiallysurprising:thepatientsdidnothaveaclinical

phenotype consistent with a peroxisomal disorder, which typically comprises

severeCNSinvolvement[28].Moreover,thefunctionofEhhadhinmiceappears

to be at least partially redundant, as knock-outmice do not have an apparent

abnormalphenotype,except forsomechanges in lipidmetabolitesafter fasting

[29].Theyonlydeveloparelevantclinicalphenotype,whentherelatedenzyme

D-PBEisalsodeleted[30,31].Sohowdoesaheterozygotemissensemutationin

agenecausedisease,whenweknowthatcompleteloss-of-functioncaneasilybe

tolerated(atleastinmice)?Thesolutiontothisconundrumcamecloserwiththe

realisationthattheidentifiedmutation(c.7G>A,p.E3K)introducedadenovoN-

terminal mitochondrial targeting motif and indeed, subsequent cell-biological

studiesconfirmedamitochondriallocalisationofthemutatedenzyme.Couldthe

mutant enzyme perhaps impair the function of the erroneously targeted

organelle, the mitochondria? To address this question, we performed

respirometry in proximal tubular cells expressing either wild type or mutant

EHHADH, which indeed demonstrated a significantly decreased capacity for

oxidativephosphorylationinthemutantcellscomparedtowildtype,compatible

with a defect in ATP production. Thus, we concluded that mistargeting of

EHHADH led to a dominant negative effect on mitochondrial function,

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presumably by interferencewith themitochondrial trifunctional enzyme. This

enzyme is amultimeric protein involved inmitochondrial fatty acid oxidation

andhasahighdegreeofhomology toEHHADH,so thaterroneousassemblyof

mutant mislocalised EHHADH into this enzyme may occur. Subsequent co-

immunoprecipitation experiments confirmed an association ofmutant but not

wild typeEHHADHwith twosubunitsof the trifunctionalenzyme,HADHAand

HADHB.

This dominant negative effect of mistargeting constitutes a previously

unrecognised disease mechanism. Mistargeting of a peroxisomal enzyme to

mitochondriahadbeendescribedasadiseasemechanismwithaspecificvariant

in AGXT, causing primary hyperoxaluria [32]. However, in this recessive

disorder, it is theabsenceofperoxisomalAGXTactivity that isdiseasecausing

ratherthaninterferencewithmitochondrialfunction,asseeninFRTS3.

A key question, however, remained: why did the affected patients develop an

isolated renal phenotype,when the enzyme is also expressed in other tissues?

Shouldnotageneralisedmitochondrialphenotypebepresent?

Energypoliticsoftheproximaltubule

Theexplanationforthisconundrummayhaveseveralcomponents.Onerelates

to the magnitude of the observed impairment in mitochondrial function: the

capacity for oxidative phosphorylation was reduced by approximately 25%;

whilethiswassignificant,itmaybedisease-causing(i.e.relevant)onlyinthose

tissueswithahighmetabolicdemand,suchasthePT.Yetaprobablymuchmore

important component is aunique featureofPT fuel consumption: thePTdoes

not utilise glucose, but is dependent on fatty acidmetabolism [33]! This may

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reflectanevolutionarydevelopmenttomaximiseglucoseprovisiontothebrain,

in thatall filteredglucose is returned into thebloodstream.However, itmakes

thePTuniquelysusceptibletodisturbancesinfattyacidmetabolism,consistent

withthephenotypeofFRTS3.

Futureresearchquestions

The discovery of new disease genes and mechanisms often generate more

questionsthananswers.Whilsttheclinicalandgeneticdataareclear,theprecise

natureofthemechanismrequiresfurtherinvestigations:

Is there biochemical evidence for disturbed fatty acid metabolism? Obtaining

thesedatafromthepatientswouldlikelybedifficult,asplasmalevelsreflectthe

overall metabolism, rather than the specific metabolites generated in PT.

However,thequestioncouldbeaddressedinthecellculturesystemdeveloped

in our lab. Alternatively, cell lines could be established from proximal tubular

cellsshedintheurine,asdescribedinotherdisorders[34].PTcellsasmodelto

studythesequestionsneedtobedifferentiatedasonlythenglucosemetabolism

reflectsthesituationofthePTinvivo.ThisisnotthecaseformanyPTcelllines,

especiallynotiftheyarenotdifferentiatedonpermeablesupports.

Given the insight provided by the investigation of FRTS3, a key question is, of

course, the nature of the disease mechanism in another form of RFS, FRTS1.

WhatistheunderlyinggeneandhowdoesitcauseRFSandCKD?

Last,butnotleast:whatlessonsfromthestudyofrarediseasecanbetranslated

tobenefit the treatmentofcommondisease?RFTS3clearlyhashighlightedthe

importance of fatty acid metabolism for PT function. Could this be used

therapeutically,e.g.inthepreventionortreatmentofacutekidneyinjury(AKI)?

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Thereissomeevidencethatitmight:Increasedlevelsofcertainfreefattyacids

havebeenassociatedwith increasedgraft survival in renal transplantpatients

[35]. The fatty acid binding protein L-FABP, functions of which include the

promotionoffattyacidmetabolism,hasbeenidentifiednotonlyasabiomarker,

butalsoasaprotectivefactorinAKI(reviewedin[36]).

Thus,thejourneyofdiscoveryisongoing!

Acknowledgements:

Funding was kindly provided by the David and Elaine Potter Charitable

Foundation(toRK),StPeter’sTrustforKidney,Bladder&ProstateResearch(to

DB,RK), theLoweSyndromeTrust (toDB,RJU,RK), theEuropeanUnion, FP7

(grant agreement 2012-305608 “European Consortium for High-Throughput

Research in Rare KidneyDiseases (EURenOmics)” to DB, RJU, RK), and by the

DeutscheForschungsgemeinschaft(SFB699toMR,RW).

Transparencydeclarations:

Nonetodeclare.

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References

1. KletaR.FanconiornotFanconi?Lowesyndromerevisited.ClinJAmSocNephrol2008;3(5):1244-1245

2. Klootwijk ED, Reichold M, Helip-Wooley A, et al. Mistargeting ofperoxisomalEHHADHand inherited renal Fanconi's syndrome.NEngl JMed2014;370(2):129-138

3. TolaymatA, SakarcanA,NeibergerR. Idiopathic Fanconi syndrome in afamily.PartI.Clinicalaspects.JAmSocNephrol1992;2(8):1310-1317

4. Kleta R, Bockenhauer D. Bartter syndromes and other salt-losingtubulopathies.Nephron.Physiology2006;104(2):p73-80

5. BockenhauerD, CruwysM,KletaR, etal. Antenatal Bartter's syndrome:why is this not a lethal condition? QJM : monthly journal of theAssociationofPhysicians2008;101(12):927-942

6. Pohl M, Shan Q, Petsch T, et al. Short-Term Functional Adaptation ofAquaporin-1SurfaceExpressionintheProximalTubule,aComponentofGlomerulotubularBalance.JAmSocNephrol2014,inpress

7. Camargo SM, Bockenhauer D, Kleta R. Aminoacidurias: Clinical andmolecularaspects.KidneyInt2008;73(8):918-925

8. AshworthSL,MolitorisBA.Pathophysiologyandfunctionalsignificanceofapical membrane disruption during ischemia. Curr Opin NephrolHypertens1999;8(4):449-458

9. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet2012;380(9843):756-766

10. LucasRC.OnaFormofLateRicketsassociatedwithAlbuminuria,RicketsofAdolescence.Lancet1883:993-994

11. FanconiG.DienichtdiabetischenGlykosurienundHyperglykaemiendesaelterenKindes.JahrbuchfuerKinderheilkunde1931;133:257-300

12. de Toni G. Remarks on the Relationship between Renal Rickets (RenalDwarfism)andRenalDiabetes.ActaPediatrica1933;16:479-484

13. Debre R, Marie J, Cleret F, et al. Rachitisme tardif coexistant avec uneNephrite chronique et une Glycosurie. Archive deMedicine des Enfants1934;37:597-606

14. Fanconi G. Der nephrotisch-glykosurische Zwergwuchs mithypophosphataemischer Rachitis. Deutsche MedizinischeWochenschrift1936;62:1169-1171

15. Kleta R, Blair SC, Bernardini I, et al. Keratopathy of multiple myelomamasquerading as corneal crystals of ocular cystinosis. Mayo Clin Proc2004;79(3):410-412

16. Magnano L, Fernandez de Larrea C, CibeiraMT, etal. Acquired Fanconisyndromesecondary tomonoclonalgammopathies:acaseseries fromasinglecenter.ClinLymphomaMyelomaLeuk2013;13(5):614-618

17. Sirac C, Bridoux F, Essig M, et al. Toward understanding renal Fanconisyndrome: stepby stepadvances throughexperimentalmodels.ContribNephrol2011;169:247-261

18. Bockenhauer D, Bokenkamp A, van't Hoff W, et al. Renal phenotype inLoweSyndrome:aselectiveproximaltubulardysfunction.ClinicaljournaloftheAmericanSocietyofNephrology:CJASN2008;3(5):1430-1436

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19. HamiltonAJ,BinghamC,McDonaldTJ,etal.TheHNF4AR76Wmutationcauses atypical dominant Fanconi syndrome in addition to a beta cellphenotype.JMedGenet2014;51(3):165-169

20. Lichter-Konecki U, Broman KW, Blau EB, et al. Genetic and physicalmappingofthelocusforautosomaldominantrenalFanconisyndrome,onchromosome15q15.3.AmJHumGenet2001;68(1):264-268

21. Luder J, SheldonW. A familial tubular absorption defect of glucose andaminoacids.ArchDisChild1955;30(150):160-164

22. Sheldon W, Luder J, Webb B. A Familial Tubular Absorption Defect ofGlucoseandAminoAcids.ArchDisChild1961;36(185):90-95

23. WenSF,FriedmanAL,OberleyTD.Twocase studies froma familywithprimaryFanconisyndrome.AmJKidneyDis1989;13(3):240-246

24. TiederM,ArieR,ModaiD,etal.Elevatedserum1,25-dihydroxyvitaminDconcentrationsinsiblingswithprimaryFanconi'ssyndrome.NEnglJMed1988;319(13):845-849

25. MagenD,BergerL,CoadyMJ,etal.Aloss-of-functionmutationinNaPi-IIaandrenalFanconi'ssyndrome.NEnglJMed2010;362(12):1102-1109

26. Bergwitz C, Roslin NM, Tieder M, et al. SLC34A3 mutations in patientswithhereditaryhypophosphatemic ricketswithhypercalciuriapredictakeyroleforthesodium-phosphatecotransporterNaPi-IIcinmaintainingphosphatehomeostasis.AmJHumGenet2006;78(2):179-192

27. Muhlbauer RC, Fleisch H. Abnormal renal glucose handling in X-linkedhypophosphataemicmice.ClinSci(Lond)1991;80(1):71-76

28. Fujiki Y, Yagita Y, Matsuzaki T. Peroxisome biogenesis disorders:molecular basis for impaired peroxisomal membrane assembly: inmetabolicfunctionsandbiogenesisofperoxisomesinhealthanddisease.BiochimBiophysActa2012;1822(9):1337-1342

29. Houten SM, Denis S, Argmann CA, et al. Peroxisomal L-bifunctionalenzyme (Ehhadh) is essential for the production of medium-chaindicarboxylicacids.JLipidRes2012;53(7):1296-1303

30. Fan CY, Pan J, Usuda N, et al. Steatohepatitis, spontaneous peroxisomeproliferationandlivertumorsinmicelackingperoxisomalfattyacyl-CoAoxidase. Implications for peroxisome proliferator-activated receptoralphanaturalligandmetabolism.JBiolChem1998;273(25):15639-15645

31. Jia Y, Qi C, Zhang Z, et al. Overexpression of peroxisome proliferator-activated receptor-alpha (PPARalpha)-regulated genes in liver in theabsence of peroxisomeproliferation inmice deficient in both L- andD-forms of enoyl-CoA hydratase/dehydrogenase enzymes of peroxisomalbeta-oxidationsystem.JBiolChem2003;278(47):47232-47239

32. DanpureCJ.Variableperoxisomalandmitochondrialtargetingofalanine:glyoxylate aminotransferase in mammalian evolution and disease.Bioessays1997;19(4):317-326

33. BalabanRS,MandelLJ.Metabolicsubstrateutilizationbyrabbitproximaltubule.AnNADHfluorescencestudy.AmJPhysiol1988;254(3Pt2):F407-416

34. LaubeGF,ShahV,StewartVC,etal.Glutathionedepletionandincreasedapoptosisrateinhumancystinoticproximaltubularcells.PediatrNephrol2006;21(4):503-509

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35. Baker AC, de Mattos A, Watkins S, et al. Pretransplant free fatty acids(FFA) and allograft survival in renal transplantation. J Surg Res2010;164(2):182-187

36. AlgeJL,ArthurJM.BiomarkersofAKI:AReviewofMechanisticRelevanceandPotentialTherapeuticImplications.ClinJAmSocNephrol2014

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Table1:GeneticformsofRFS

Systemicdisorders

Gene OMIM Disorder AssociatedFeatures

GALT 230400 Galactosemia Liver dysfunction, jaundice,encephalopathy,sepsis

Multiplenuclear andmitochondrialDNAvariants

multiple

Mitochondrialcytopathies

Usually multisystemdysfunction (brain, muscle,liver,heart)

FAH 276700 Tyrosinemia Poor growth, hepaticenlargement and dysfunction,livercancer

ALDOB 229600 CongenitalFructoseIntolerance

Rapid onset after fructoseingestion, vomiting,hypoglycemia,hepatomegaly

CTNS 219800 Cystinosis Poorgrowth,vomiting,rickets±corneal cystine crystals, kidneyfailure

GLUT2 227810 Fanconi Bickelsyndrome

Failuretothrive,hepatomegaly,hypoglycemia,rickets

OCRL 309000 Lowe’ssyndrome

Males (X-linked), cataracts,hypotonia,developmentaldelay

CLCN5,OCRL 300009,300555

Dent disease I,II

Males (X-linked),hypercalciuria,nephrocalcinosis

ATP7B 277900 Wilson’sdisease

Hepatic & neurological disease,Kayser-Fleischerrings

VPS33B,VIPAR 208085,613404

ARCsyndrome Arthrogryposis, plateletabnormalities,cholestasis

HNF4A 125850 MODY1 neonatal hyperinsulinism,Maturity-onset of diabetes inthe young, mutation R76WshowsRFS

IsolatedRFS

? 134600 FRTS1 glomerularkidneyfailure

SLC34A1 613388 FRTS2 phosphaturiadominating

EHHADH 615605 FRTS3 nokidneyfailure

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Table2:Keypoints

• FRTS3iscausedbyamutationinEHHADH

• Discoveryofanoveldiseasemechanism:adominantnegativeeffectfrom

intracellularmistargetingofthemutatedenzyme

• Life long dysfunction of PT including the loss of about 1g/d of filtered

proteinsalonedoesnotcausechronickidneydisease

• The proximal tubule is dependent on fatty acid metabolism for energy

generation

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Figure 1: Genetic renal tubular diseases caused by failure of sodiumreabsorptioninindividualnephronsegments

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Figure 2: Simplified schematic of renal proximal tubular cell with keytransepithelialtransportsystems(note,Cl-andHCO3--transportsystemshavebeenomitted).