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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: [email protected]
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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).