Can Dietary Modification Alleviate the Burden of CKD?

29 Pages·2017·0.87 MB·English

nutrients
Review
Stirring the Pot: Can Dietary Modification Alleviate
the Burden of CKD?
MatthewSnelson1,*,†,RachelE.Clarke1,2,† andMelindaT.Coughlan1,3,*
1 Glycation,NutritionandMetabolismLaboratory,BakerIDIHeartandDiabetesInstitute,Melbourne3004,
Australia;[email protected]
2 DepartmentofPhysiology,MonashUniversity,Clayton3800,Australia
3 DepartmentofDiabetes,CentralClinicalSchool,MonashUniversity,
AlfredMedicalResearchandEducationPrecinct,Melbourne3004,Australia
* Correspondence:[email protected](M.S.);[email protected](M.T.C.);
Tel.:[phone](M.T.C.)
† Theseauthorscontributedequallytothiswork.
Received:23January2017;Accepted:6March2017;Published:11March2017
Abstract: Dietisoneofthelargestmodifiableriskfactorsforchronickidneydisease(CKD)-related
deathanddisability. CKDislargelyaprogressivedisease;however,itisincreasinglyappreciated
that hallmarks of chronic kidney disease such as albuminuria can regress over time. The factors
drivingalbuminuriaresolutionremainelusive. SincealbuminuriaisastrongriskfactorforGFR
loss,modifiablelifestylefactorsthatleadtoanimprovementinalbuminuriawouldlikelyreduce
theburdenofCKDinhigh-riskindividuals,suchaspatientswithdiabetes. Dietarytherapysuchas
proteinandsodiumrestrictionhashistoricallybeenusedinthemanagementofCKD.Evidenceis
emergingtoindicatethatothernutrientsmayinfluencekidneyhealth,eitherthroughmetabolicor
haemodynamicpathwaysorviathemodificationofguthomeostasis. Thisreviewfocusesontherole
ofdietinthepathogenesisandprogressionofCKDanddiscussesthelatestfindingsrelatedtothe
mechanismsofdiet-inducedkidneydisease. Itispossiblethatoptimizingdietqualityorrestricting
dietary intake could be harnessed as an adjunct therapy for CKD prevention or progression in
susceptibleindividuals,therebyreducingtheburdenofCKD.
Keywords: advancedglycationendproducts;albuminuria;diet;chronickidneydisease;diabetes;
cardiovasculardisease;inflammation
1. Introduction
Chronic kidney disease (CKD) is a broad term given to a range of disorders characterised by
impairedkidneystructureandfunction[1]. Chronicconditionssuchasdiabetes,obesity,hypertension
or cardiovascular disease can lead to the development of CKD; however, it can also occur in the
absenceofdiseaseduetoaging,exposuretotoxinsorinfection[1]. Thecurrentdiagnosticcriterion
for CKD is a glomerular filtration rate (GFR) of <60 mL/min per 1.73 m2 or a urinary albumin to
creatinineratioof>30mg/g[2]. Basedonthisdefinition,CKDisestimatedtoaffectmorethan10%of
theglobalpopulation[3]. AGFRof<60mL/minper1.73m2isassociatedwithanincreasedriskof
cardiovasculardisease(CVD)mortalityandall-causemortality[4]. Giventheseobservations,CKDis
poisedtobecomeamajorburdentohealthcaresystemsglobally,particularlyaspopulationscontinue
toage.
Thekidneyplaysacentralroleinmaintaininghomeostasisinthebody,andisoftenthetarget
organofinflammatory,metabolicandsystemicvasculardisorders[5]. Nutritionanddietarypatterns
areimplicatedinthedevelopmentofchronicmetabolicdiseases,andaremodifiablefactorsthatcan
beutilisedtopreventorslowtheprogressionofCKD.ThemodernWesterndiet,composedoffoods
Nutrients2017,9,265;doi:10.3390/nu9030265 www.mdpi.com/journal/nutrients
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that are high in fat, protein, sugar and sodium and low in fibre, is considered to be a key driver
behindthecurrentepidemicofchronicdiseases[6,7]. Incomparison, balanceddietsconsistingof
moderatefatandhighinwholegraincarbohydratesareassociatedwithreducedriskofdiseaseand
improvedmortality[7]. DietarytherapyhashistoricallybeenusedinthemanagementofCKDand
guidelinesexistsurroundingtheintakeofproteinandsodiumforpatientswithCKD[8]. Adherence
tocurrentdietaryguidelinescanreducetheincidence,orslowtheprogressionofCKDandimprove
mortality[9]. Evidenceisemergingtosuggestthattherearemanyothernutrientsthatcanpotentially
influencekidneyhealtheitherthroughmetabolicorhaemodynamiceffects,orviathemodificationof
guthomeostasisincludingchangestogutmicrobiota. Thepurposeofthisreviewistosummarisethe
keyrecommendationstodate,andtoprovideanoverviewofrecentliteraturepertainingtopotential
novelmodifiabledietarycomponentsthatmaybeusefulinthetreatmentofCKD.
2. Protein
DietaryproteinrestrictionhasbeenrecommendedforindividualswithCKDfordecades. Early
experimentalevidenceinanumberofrodentmodelsofkidneydisease,includingmodelsofdiabetic
nephropathyandspontaneouslyhypertensiverats,consistentlydemonstratedthatlowproteindiets
amelioratetheprogressionofglomerulardysfunction[10,11]. Evidencethatproteinrestrictionwas
beneficialinimprovingalbuminuriainpatientswithkidneydiseasewasfirstdescribedin1986[11,12].
CurrentrecommendationsforproteinintakeinindividualswithCKDstages1–4is0.8g/kgbody
weight, and avoidance of high protein intake (>1.3 g/kg/day) [13]. The key benefits of protein
restriction are primarily thought to arise from the amelioration of proteinuria and it has been
proposed that an even lower protein intake of 0.6–0.8 g/kg bodyweight in patients with CKD
stages3–5maybedesirable[11,14]. Furtherdietaryproteinreduction,usingaverylowproteindiet
supplementedwithketoanaloguesofessentialaminoacids(0.35g/kg/day)hasbeenshowntoreduce
bloodpressureinCKDpatients[15,16]. Otherfactorsthatoccurduetoexcessproteinmetabolism,
such as increased GFR [17], metabolic acidosis [11] and oxidative stress [18], are also thought to
contributetokidneydamageassociatedwithhighproteinintake[11].Despitesubstantialexperimental
evidence to indicate that dietary protein restriction prevents the development of proteinuria and
renal fibrosis [19–21], many clinical studies in humans have failed to find the same level of renal
protection [11,22–24]. The Modification of Diet in Renal Disease (MDRM) study found that a low
proteindiet(0.58gprotein/kg/day)didnotsignificantlyimproveglomerularfiltrationrateinCKD
patientswhencomparedtoastandardproteindiet(1.3g/kg/day)atatwo-yearfollow-up[24]. This
islikelybecauseoftheextremedifferencesinproteincontentusedinexperimentaldiets,butmayalso
beduetotheeffectofotherfactorsassociatedwithproteinfoods,suchasenergy,water,sodiumand
phosphorous,thatmayaffectkidneyfunction[11]. Proteinenergywastingisamajorcomplicationof
kidneydisease[25],particularlyinlaterstages. Along-termfollow-upofpatientsfromtheMDRM
studyfoundthatassignmenttoaverylowproteindietsupplementedwithamixtureofessentialketo
acidsandaminoacids(0.28gprotein+0.28ketoandaminoacids/kg/day)wasassociatedwitha
significantlygreaterriskofdeathcomparedtoalowproteindiet(0.58g/kg/day)[26]. Thoughit
wasnotclearwhetherthisfindingmaybeduetothereducedmeanenergyintakethatoccurredwith
theverylow-proteindiet,orthepossibletoxicityoftheketoacidsandaminoacidssupplement[26].
Consequently,effectivestrategiestoimproveGFRorreduceproteinuriawithoutjeopardisingprotein
balanceareahighpriorityinadvancingCKDtreatment.
2.1. ProteinSourceandMetabolicAcidosis
Growingevidencesuggeststhatthesourceofprotein(plantoranimal)maybemoreimportant
thanthequantityofproteinconsumed(Figure1). Onereasonforthisisthetendencyforexcessmeat
intaketodisrupttheacid-basebalance. MetabolicacidosisisacommonoccurrenceinCKDpatients
andresultsinlowcirculatingbicarbonate—ariskfactorfortheprogressionofnephropathy[27,28]
and is associated with increased mortality [29]. Protein from animal sources is composed of
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sulphur-containingaminoacidswhich,whenoxidized,generatesulphate,anon-metabolizableanion
that contributes to total body acid load [30]. Protein from plant sources contains higher levels of
glutamate,ananionicaminoacidthatuponmetabolismconsumeshydrogenionstoremainneutral,
thereby reducing acidity levels [30]. Plant foods are also generally higher in anionic potassium
salts, which also result in the consumption of hydrogen ions upon metabolism and reduction in
acidload[30]. Inresponsetoanincreaseinacidloadthekidneyadaptsbyincreasingammonium
Nutrients 2017, 9, 265  3 of 28 
ionexcretioninordertoexpelexcesshydrogenions,thereforeincreasingthedemandforammonia
anion that contributes to total body acid load [30]. Protein from plant sources contains higher levels 
production[30]. Thisstimulatesthebreakdownofglutamineandotheraminoacidspromotingprotein
of glutamate, an anionic amino acid that upon metabolism consumes hydrogen ions to remain 
catabolismandmusclewasting[31]whilealsoleadingtorenalhypertrophy[32]. Metabolicacidosis
neutral, thereby reducing acidity levels [30]. Plant foods are also generally higher in anionic 
alsoprompoottaesssipurmo tseailnts,m wuhsicchle awlsoa srteisnuglt viina tthhee caocntsiuvmaptitoionn ooff thhyedAroTgPen- dioenpse nudpoenn tmuebtaibqouliistmin -apnrdo teasome
system[3r3e]d.uIcntiorne sipn oancisde lotaoda [3h0i]g. hIn arcesidpolnosae dto, tahne inkcirdeanseey ina alsciod ulonadd etrhge okeidsnfeuyn acdtaioptnsa blyc ihnacrnegaseisngin  cluding
promotionamomfgonloiumme riounl aerxchryetpioenr fiinl torardtieor ntoa enxdperle enxaclesvsa hsyoddriolgaetino ino,nfse, athtuerreefosrtey ipniccraealsoinfge athrley ddemiaabnedt ickidney
for ammonia production [30]. This stimulates the breakdown of glutamine and other amino acids 
disease[30]. ResultsoftheChronicRenalInsufficiencyCohortStudysuggestthatconsumptionofa
promoting protein catabolism and muscle wasting [31] while also leading to renal hypertrophy [32]. 
greaterproportionofproteinfromplantsourcesisassociatedwithhigherbicarbonatelevelsaswellas
Metabolic acidosis also promotes protein muscle wasting via the activation of the ATP‐dependent 
animprovuebdiqupihtino‐spprohtoearosoumseb asylastnemce [i3n3]p. aItni ernestspownsiteh toC Ka Dhig[3h4 a].ciTdr ilaoalsd,i nthheu kmidanneys ianlsvoe sutnigdaertginoges theeffect
ofplantsfouuncrtcioenpalr octheainngevse irnsculusdainngi mpraolmsootuiornc eopf rgolotemienrualraer lhiympietrefidlt,rabtiuont saondfa rresnualg gveassotdtihlaatitonin, creasing
features typical of early diabetic kidney disease [30]. Results of the Chronic Renal Insufficiency 
theproportionofdietaryproteinfromplantfoodsimproveskidneyhealth. Alongitudinalcontrolled
Cohort Study suggest that consumption of a greater proportion of protein from plant sources is 
trial in patients with diabetic nephropathy reported that replacing proteins from animal sources
associated with higher bicarbonate levels as well as an improved phosphorous balance in patients 
withsoywpirtoht CeKinDi [m34p].r Torviaelsd inp hruomteainnsu inrivaesatingdatiungri tnhae reyffeccrte oaf tpilnainnt esoausrcwe perloltaeisn mvearsrukse arnsimofalc saorudrcieo vascular
disease[3p5ro].teAin naoret hliemritsetdu, dbuyt isno fhaer asultghgyesat dthualt tisncfroeuasnindg tthhea tpirnoptaorkteiono fofv deigeteatrayb pleropterino tferoinm, pinladnte pendent
oftotalpfroootdesi niminprtoavkees kreiddnueyc ehdeagltlho. mA elornugliaturdfiinltarl actoinotnrolrlaedte t,rirael nina plaptileanstms waitflho dwiabaentidc niemphprroopvatehdy albumin
reported that replacing proteins from animal sources with soy protein improved proteinuria and 
clearancecomparedtoanimalprotein[36]. Arecentstudycomparedtheeffectofaverylowprotein
urinary creatinine as well as markers of cardiovascular disease [35]. Another study in healthy adults 
vegetariandiet(0.3g/kg/day)supplementedwithketoanolougestoastandardmixed-sourcelow
found that intake of vegetable protein, independent of total protein intake reduced glomerular 
proteindfiielttra(0ti.o6n gra/tek,g r/endaal ypl)aosmnaC flKowD apndro igmrpersosvieodn a[lb3u7m].inA ctleaanra1n8ce- mcoomnptahrefdo ltolo awni-muapl psriogtneiinfi [c3a6n].t lyfewer
patientsfrAo mretchenet vsetruydylo wcomprpoatreeidn  vtheeg eetfafercita nofd iae tvgerroyu  plowre qpuroirteeidn revnegaeltraeripanla cdeimet e(n0t.3t hge/rkagp/dya,yo)r  reached
supplemented with ketoanolouges to a standard mixed‐source low protein diet (0.6 g/kg/day) on 
the primary end-point of >50% reduction in GFR [37]. A study in CKD patients with dual RAAS
CKD progression [37]. At an 18‐month follow‐up significantly fewer patients from the very low 
blockade,notedthathighserumphosphatelevelsattenuatedtheantiproteinuriceffectofaverylow
protein vegetarian diet group required renal replacement therapy, or reached the primary end‐point 
proteindioeft >w50i%th rekdeutcotaionna ilno uGgFRes [3[17]6. ]A, asntuddya nini mCKaDlp praotiteenints swoiuthr cdeusalc RoAnAtaSi nblmocokardeeb, inooatevda itlhaabt lheigphh osphate,
which nosterounmly pihnocsrpehaastee sletvoetlsa labttoenduyataedc idthele avnetlisprboutetiniusriacl seoffeuctn dofe ras tvoeoryd ltoowb peroateuinr edmieitc wtoitxhi n that is
associatedkewtoiatnhalaolul-gceas u[s1e6],m aonrdt aalniitmya(ld pisrcoutesins esdoubrecelos wco)n[t3ai2n] .mAorve ebriyoalvoawilapblreo tpehionspvheagtee,t awrhiaicnh dnioett hasalso
only increases total body acid levels but is also understood to be a uremic toxin that is associated 
beennotedtoreducemetabolicacidosisinacohortofCKDpatients[38]. Fruitandvegetablesare
with all‐cause mortality (discussed below) [32]. A very low protein vegetarian diet has also been 
sourcesofdietaryalkaliandinterventionstoincreasefruitandvegetablesinCKDpopulationshave
noted to reduce metabolic acidosis in a cohort of CKD patients [38]. Fruit and vegetables are sources 
beenshowof nditeotariny carlkeaalsi eanpdl ainstmeraveCntOio2nsl etov einlcsre[3as9e, 4fr0u]i,t iannddi cvaegtievtaebloefs ainm CeKliDo rpaotpioulnatoiofnms heatvaeb boeleinc acidosis.
Takentogsehtohwenr ,toth inecerevaisde epnlacsemsau CgOg2e lsetvseltsh [a3t9,i4n0c],r ienadsicinatgivteh oef apmroelpioorrattiioonn oof fmpeltaabnotl-ibc aacsieddospisr. oTtaekienn intakein
together, the evidence suggests that increasing the proportion of plant‐based protein intake in 
patientswithCKDmayimproverenaloutcomes,providedthereisanadequatequantityofproteinto
patients with CKD may improve renal outcomes, provided there is an adequate quantity of protein 
preventproteinenergywasting.
to prevent protein energy wasting. 

Figure 1. Mechanisms of dietary factors impact on chronic kidney disease. n‐3 PUFAs = Omega 3 
Figure1. Mechanismsofdietaryfactorsimpactonchronickidneydisease. n-3PUFAs=Omega3
Polyunsaturated Fatty Acids. CRP = C‐Reactive Protein. MCP‐1 = Monocyte Chemoattractant Protein‐1. 
PolyunsaturatedFattyAcids.CRP=C-ReactiveProtein.MCP-1=MonocyteChemoattractantProtein-1.
Nutrients2017,9,265 4of29
2.2. ProteinFermentationbytheColonicMicrobiota
Themicrobialmetabolismofproteinalsoproducesanumberofmetabolitesthatmaynegatively
affect the kidneys. The fermentation of protein in the colon results in the production of indoxyl
sulphate and p-cresylsulphate (the conjugated form of p-cresol), which are known nephrotoxic
compounds [41]. Circulating indoxyl sulphate can increase oxidative stress in the renal tubular
cellsandtheglomeruli[42].Also,invitroindoxylsulphatehasbeenobservedtoactivateinflammatory
pathwaysresultinginanincreaseintheexpressionofmonocytechemoattractantprotein-1(MCP-1)and
intracellularadhesionmolecule-1(ICAM-1)[43]. P-cresylsulphatehassimilarlybeenlinkedtoCKD
andCVDmortality,althoughthemechanismisnotaswelldefined[44,45]. Interestingly,ithasbeen
notedthatvegetarianshavelowerlevelsofthesenephrotoxiccompoundscomparedwithomnivores,
in bothhealthy [46] andCKDpopulations [47]. Vegetarians tendto havehigher fibre intakes[46],
whichcouldbemetabolizedbythecolonicmicrobiotainsteadofaminoacids,leadingtoareductionin
indoxylsulphateandp-cresylsulphate. Thisprovidesanothermechanismtoexplainwhyvegetarian
protein sources appear less detrimental than animal protein sources. Furthermore, carnitine and
lecithinpresentinredmeataremetabolizedbythemicrobiotatoformtrimethylamine-N-oxide[48],
whichhasbeenlinkedtocardiovascularevents. Theinteractionbetweenanimalsourcesofproteinand
gutbacteriainCKDwarrantsfurtherinvestigation. Determininganoptimumproteintofibreratio
couldallowforappropriateproteinintaketopreventproteinenergywasting,withoutadverseeffects
onrenaloutcomes.
3. DietaryFibre/NonDigestibleCarbohydrates
Dietaryfibrewasconsideredasatreatmentforchronicrenalfailuremorethan30yearsago,where
itwasfoundtoreduceplasmaurea[49]. Sincethen,interesthasextendedtoavarietyofnon-digestible
carbohydratesfortheirabilitiestoimpactmarkersofCKD.Non-digestiblecarbohydratesareresistant
tohydrolysisbyhumandigestiveenzymes,areabletopassthroughthegastrointestinaltractintothe
largeintestineandincludedietaryfibres,non-starchpolysaccharides,β-linkedoligosaccharidesand
resistantstarch[13].
HumanStudies—Intervention
Chronickidneydiseaseresultsinastateofchroniclow-gradeinflammation,withincreasesseenin
pro-inflammatorymarkerssuchasinterleukin6(IL-6)andC-reactiveprotein(CRP),whichcontributes
toworsenedmortalityoutcomesinthispopulation[50]. Epidemiologicalsurveydataindicatedan
inverse association between dietary fibre intake and the inflammatory marker CRP and mortality
inpatientswithCKD[51]. Suchepidemiologicaldatashouldbeinterpretedwithcaution,however,
asthereissomeuncertaintyaboutwhetherdietaryfibreperseisbeneficialorwhetherothernutrients,
includingantioxidantcompoundsthatarepresentinfibre-richfoods,actinabeneficialmanner[52].
Interventionsthathavefocusedonincreasingtotaldietaryfibreintakeinpatientswithpre-dialysis
CKDhavereportedreductionsinserumcreatininelevels[53]andplasmap-cresol[54]. Afour-week
studyinwhichpatientswithchronicrenalfailureconsumed50gramsperdayofacaciagum,ahighly
fermentablefibre,ledtoameanreductioninplasmaureaof12%[55]. Supplementationwithacacia
gum for three months led to decreases in serum urea, creatinine and phosphate by 31%, 10% and
22%,respectively[56]. Arecentmeta-analysisofhumantrialsfoundthatdietarysupplementation
with fermentable fibres was associated with a reduction in serum urea and creatinine in patients
with stage 3–5 CKD (pre-dialysis only); however, it should be noted that most of the trials (86%)
thatwerereviewedwereconsideredtobeofalowquality[57]. Recently,severalshorttermstudies
havebeenundertakenusingnondigestiblecarbohydratesinpatientsreceivingdialysis. Afour-week
Belgian study in haemodialysis patients showed that plasma p-cresylsulphate decreased by 20%
whensupplementedwitholigofructose-enrichedinulin[58]. Thisresulthasbeenechoedinasimilar
studythatcombinedgalacto-oligosaccharideswithprobiotics[59]. Whilstneitherofthesestudies
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showedareductioninindoxylsulphate,arecentsix-weekdietaryinterventionwithresistantstarchin
haemodialysispatientsledtoameanreductionofplasmaindoxylsulphateandp-cresylsulfateby29%
and28%,respectively[60]. Whilstthesestudiesshowanimprovementinthelevelsofuremictoxins,
thishasyettobetranslatedintohardclinicaloutcomessuchasCVDeventsandmortality.
Current Australian guidelines recommend that patients with early CKD consume a diet rich
indietaryfibre; however,thisrecommendationwasgiventhelowestevidencegradingscore(2D),
indicating that this is a weak recommendation based upon very low-quality evidence [61]. Other
guidelinesforthemanagementofCKDmakenomentiontotheroleofnon-digestiblecarbohydrates[8],
whichsomecommentatorsfeelshouldberectifiedonthebasisofemergingevidence[52]. Dietary
fibreintakeisabout20%–30%lowerinhaemodialysispatientscomparedtocontrolsubjects[62,63],
withdialysispatientsconsumingapproximately11(±6)g/daydietaryfibre,significantlylessthanthe
recommendationof25g/day[64]. Thesedatasuggestthatnon-digestiblecarbohydratesareeffective
atimprovingbiochemistrymarkersinhaemodialysispatients,andthatdietaryinterventionsinvolving
thesecompoundsmaybeparticularlyrelevantgiventhelowintakesseeninthispopulation.
Theuseofnon-digestiblecarbohydratesforthetreatmentofCKDisanemergingfieldandithas
beennotedthatthereisapaucityofstudiesrelatedtoclinicaloutcomes[65]. Theuseofdietaryfibre
supplementationisasimple,non-invasiveoptionthatdoesnotnegativelyimpactpatients’qualityof
life[66],althoughsomeprebioticcompoundshavebeennotedtohaveminornegativegastrointestinal
effectswhenconsumedathighdoses[67].
4. Sodium
High dietary sodium intake is a risk factor for hypertension, which is understood to be both
a cause and a consequence of CKD [68]. Hypertension promotes glomerular hyper-filtration and
proteinuriaandthereforeincreasestherateofprogressionofCKD[8,69]. Highbloodpressurecan
leadtovascularremodellinginthekidney,whichisthoughttobethecauseofsubsequenttubular
atrophy, glomerulosclerosis and reduced filtration surface area [69]. These structural changes in
the kidney, whether they initially occur due to hypertension or by other factors such as diabetes,
impair the excretion of sodium [70]. Therefore, high dietary sodium intake in CKD can worsen
existing hypertension, or result in the development of salt-sensitive hypertension [68]. Current
guidelinesforsodiumintakeforindividualswithCKDstages1–4arelessthan2000mgperday[13].
Theserecommendationsarebasedontheresultsofalargesystematicreviewofexperimentaland
non-experimental studies, which, despite varying quality and heterogeneity of included studies,
consistently show that high sodium intake is associated with kidney tissue injury and worsening
albuminuria [71]. Salt restriction in patients with moderate to severe CKD has been shown to
significantlyreducebloodpressure,albuminuriaandproteinuria[72]. Thedegreeofimprovement
inthesemarkerswassignificantlygreaterinpatientswithCKDthanwithout,supportingtheidea
thatpatientswithCKDareparticularlysalt-sensitive[72]. Interestingly,restrictingdietarysodium
intakeinpatientswithCKDonangiotensinconvertingenzyme(ACE)inhibitorswasmoreeffective
thandualblockadeoftherenin-angiotensin-aldosteronesystem(ACEinhibitorplusanaldosterone
receptor blockade) in reducing blood pressure and proteinuria [73]. This trial, although possibly
underpoweredforabloodpressurestudy,highlightstheimportanceofCKDpatientsaccomplishing
sodiumrestrictionwhilebeingtreatedwithACEinhibitorstobestimproverenalmarkers.
5. Potassium
In addition to the direct benefits of reducing dietary sodium intake on blood pressure and
proteinuria,reducingconsumptionofhighsodiumfoodsgenerallyincreasestheamountofpotassium
inthediet[74].Potassiumisunderstoodtobeantihypertensiveandmayabolishsodiumsensitivity[74].
An improved sodium to potassium ratio may be one reason why the Dietary Approaches to Stop
Hypertension(DASH)diet,whichcontainstwicethepotassiumofastandardwesterndiet,iseffective
inreducingbloodpressure[74]. TheDASHdiethasnotbeenwidelyassessedinpatientswithCKD
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duetothehighprotein,potassium,calciumandphosphorouscontent[75]. Inpatientswithsevere
CKD, such as those on dialysis, impaired potassium excretion leads to hyperkalaemia, which is
associated with higher all-cause mortality [76]. For this reason intake of potassium is restricted
in these patients. However, during earlier stages of CKD a diet high in potassium, such as a
diet rich in fruits and vegetables, may slow progression to later stages through lowering blood
pressure[74]. AsmallretrospectivestudyfoundthattheDASHdietwasstilleffectiveinindividuals
withreducedkidneyfunctionatbaseline[75]. LargerstudiesarerequiredbeforetheDASHdietcanbe
recommendedtoCKDpatients. However,itislikelythatthebenefitsofplant-baseddietsnaturally
highinpotassiumandfibreandlowinacidogenicproteinsandmineralswouldoutweighthepotential
riskofdevelopinghyperkalaemiainearlyCKD.Inagroupofstage4CKDpatients,selectedtobeat
lowriskforhyperkalaemia,treatingmetabolicacidosiswithbase-producingvegetableswaseffective
in improving metabolic acidosis and reducing kidney injury [40]. Larger long-term trials in CKD
patientsinvestigatingplant-baseddietsonrenalbiomarkersandclinicaloutcomesarewarrantedon
thebasisofthepositivefindingstodate.
6. VitaminD
The kidneys play an important role in the metabolism of vitamin D into its active form,
from vitamin D precursors which are obtained either through the diet or from conversion of
7-dehydrocholesterolintheskinbyUVlight. Theseprecursorsareconvertedinthelivertocalcidiol
(25 hydroxy vitamin D), which is further converted into the active form of vitamin D, calcitriol
(1,25-dihydroxyvitaminD3)inthemitochondriaoftheproximalconvolutedtubulesofthekidney,
byanenzymecalledrenal1-αhydroxylase. Askidneyfunctiondeclinesthereisadirectdecrease
in the synthesis of calcitriol [77]. Calcitriol suppresses the release of parathyroid hormone (PTH);
however, in CKD this mechanism is blunted due to decreased production of calcitriol, leading to
over-release of parathyroid hormone in a condition called secondary hyperparathyroidism. This
secondary hyperparathyroidism can lead to alterations in bone turnover and metabolism and the
developmentofrenalosteodystrophy[78]. VitaminDdeficiencyandsecondaryhyperparathyroidism
arerecognisedtobecomplicationsassociatedwithchronickidneydisease[61].
6.1. LowVitaminD,CKDandAssociationwithMortality
Cardiovascular disease is a significant contributor to mortality in patients with renal disease,
withsuddencardiacdeathaccountingfor20%–30%ofdeathsindialysispatients[79]. Haemodialysis
patientswithaseverevitaminDdeficiency(≤25nmol/Lof25(OH)D)haveathreefoldhigherrisk
of sudden cardiac death compared with those with vitamin D levels greater than 75 nmol/L [80].
A meta-analysis of data from observational studies showed that, for each 25 nmol/L increase in
serumlevelsof25(OH)Dtherewasasignificantdecreaseintherelativerisk(RR=0.86,CI:0.81–0.92)
of mortality [81]. Altered vitamin D levels and subsequent hyperparathyroidism can contribute
to the formation of extracellular insoluble calcium phosphate and subsequent calcification of the
vasculature[78].CoronaryarterycalcificationhasbeenreportedinpatientswithCKD[82],andcalcium
phosphatelevelshavebeenshowntocorrelatewithincreasedmortalityriskinHDpatients[83]. Low
plasma25(OH)Disalsoassociatedwithahigherriskofdevelopingincreasedalbuminuria,particularly
inindividualswithhighsodiumintake[84]. ThusitisthoughtthatcorrectingvitaminDlevelsmay
reducePTHlevels,correctalterationsinboneturnoverandcalciummetabolism,andsubsequently
reducemortalityintheCKDpopulation.
6.2. VitaminDSupplementationandParathyroidHormone
NewervitaminDanalogues,suchasparicalcitol,playanimportantroleinCKDastheyappearto
havebettersuppressionofparathyroidhormoneandpossiblylessofacalcaemiceffectcomparedto
othervitaminDsterolforms[85]. Severalstudieshaveshownthatparicalcitolsupplementationin
CKDpatientswasassociatedwithadecreaseinPTHlevels[86–88]. ThestudybyAlborzietal. did
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notfindanychangeinPTHlevels,whichmaybeduetoitsshorterdurationofonemonth[89]. Data
frombothobservationalstudiesandRCTsshowedthatvitaminDsupplementationimproveslevels
ofparathyroidhormoneinbothpre-dialysisanddialysis-requiringpatients[90]. Whilstitmaybe
effectiveinloweringparathyroidhormonelevels,someconcernhasbeenraisedoverthepotentialrisk
thatparicalcitolmayexacerbatevascularcalcification[91].
6.3. VitaminDSupplementationandProteinuria
Reduction of residual proteinuria is associated with reductions in serum creatinine levels,
progression to end-stage renal disease and mortality [92]. Several studies have shown that oral
supplementationwiththevitaminDanalogparicalcitoliseffectiveatreducingproteinuriainstage
2–4 CKD patients [87–89,93]. Furthermore, oral paricalcitol therapy achieves these reductions in
proteinuria without an increase in adverse events [77]. A meta-analysis of trials in CKD patients
showedthatsupplementationwithvitaminDwasassociatedwithameanreductioninproteinuriaof
16%,whichwasareductionseeninadditiontotheeffectseenbyRASblockade[94]. WhilstvitaminD
supplementationdoesreduceproteinuria,thisisnotassociatedwithchangesinothermarkersofrenal
functions,suchasGFR,anddoesnotappeartoaltertheriskofpre-dialysisCKDpatientsprogressing
todialysis[85,91]. Thislackofaneffectonclinicaloutcomesisperplexing,astrialsthathaveused
RASblockerstoreduceproteinuriatoasimilarextentwereassociatedwithimprovementsinGFRand
reducedprogressiontoESRD[92,95,96]. Apossibleexplanationmaybeinsufficientstudyduration;
inthemeta-analysisbyXuetal. 12studiesassessedvitaminDsupplementationandGFR,ofwhich
sevenhadaninterventionthatlastedforsixmonthsorless;threestudiesranfor12months,whilstthe
remainingstudieshaddurationsof18and24months,respectively.
6.4. VitaminDSupplementationandClinicalOutcomes—Mortality
WhilstvitaminDsupplementationhasbeenshowntoalterbiochemicalparametersofpatients
with CKD, the effect on morbidity and mortality outcomes in this patient group is less clear.
A meta-analysis of observational studies showed that patients with CKD receiving vitamin D
supplementation had a reduction in risk of all-cause mortality and cardiovascular mortality [97].
However,arecentmeta-analysisthatlookedspecificallyatRCTsthatassessedtheeffectofvitaminD
supplementationonall-causeandcardiovascularmortalityinCKDpatientsfoundnoevidencethat
supplementationaffectedmortalityoutcomes[98]. Ofthepatientsinthismeta-analysis,abouttwo
thirdswerefollowedupforlessthanayear,andithasbeensuggestedthatthismaybeinsufficient
follow-up time to capture CVD events, which are a major contributor to mortality in the CKD
population[99].
ManystudiesassessingtheefficacyofvitaminDinCKDpatientsutilisebiochemicaloutcomes,
suchasparathyroidlevelsorproteinuria,ratherthanclinicalendpointssuchasprogressiontoESRD
ormortality[77]. Arecentumbrellareviewfoundthattherewasalackofconvincingevidencefor
vitaminDsupplementationacrossarangeofhealthoutcomes,includingchronickidneydisease[100].
CurrentAustralianguidelinesrecommendvitaminDsupplementationinthosewithearlychronic
kidneydiseaseandsecondaryhyperparathyroidismthoughadmitsevidencedoesnotexisttosupport
thatthisleadstoimprovementinpatient-leveloutcomes[61]. ThuswhilstvitaminDmayeffectively
alterbiochemicalparameters, larger, longerrandomisedcontroltrialsareurgentlyrequiredtosee
whetherthesetranslateintomeaningfulpatient-centredoutcomes.
7. Phosphorus
The kidneys play a major role in phosphorus homeostasis with the glomeruli filtering
between3700and6100mgofphosphorusperday,although75%–85%ofthisisreabsorbed,primarily
throughtheproximaltubules,resultinginnetexcretionofbetween600and1500mgofphosphorus
perday[101]. Askidneyfunctiondeclines,thereisadecreaseinthenumberoffunctioningnephrons
and subsequent decrease in phosphorus excretion [102]. As renal function decreases to less than
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80% of normal, phosphorus absorption can exceed the rate of clearance by the kidneys, and a
subsequent rise in serum phosphate levels is seen [61,103]. Phosphate anions can combine with
extracellular cationic calcium to form insoluble calcium phosphate and subsequent calcification
can occur, particularly in the cardiovascular system [78]. Hyperphosphataemia is associated with
vascular calcification [104], increased cardiovascular disease risk [105] and increased mortality in
both predialytic CKD patients [106–108] and patients receiving dialysis [109–111]. Furthermore
severalstudieshaveshownthatelevatedphosphatelevelsareassociatedwithafasterrateofrenal
diseaseprogressioninCKDpatients[112–115]andhealthysubjectswithnormalrenalfunction[116].
Maintainingnormalphosphatelevelsorminimizinghyperphosphataemiaisseenasacrucialstepto
limitmortalityinCKDpatients.
7.1. DietarySourcesofOrganicPhosphorus
Phosphorousmaybepresentinthedietasorganicorinorganicphosphate. Protein-richfoods
suchaslegumes,meat,poultry,fish,eggsanddairyproductsarethemainsourcesoforganicphosphate
andthereisacorrelationbetweendietaryintakesofproteinandphosphorous[117];however,ahigh
protein(andhighphosphorus)dietdoesnotalwaystranslatetoincreasedserumphosphatelevels[118].
The bioavailability of organic phosphate varies depending on the food source with plant sources
havingalimitedbioavailabilityduetothephosphorousbeingpresentlargelyasphytate. Humans
(andothermonogastricanimals)lacktheenzymephytaseandthuscannotdigestphytate,although
somedegradationmayoccurviatheintestinalmicrobiota[119]. Dairyproductshaveabout30%–60%
bioavailability,andthehighestbioavailabilityoforganicphosphate,inmeatproducts,maybeashigh
as80%[102]. Thisdifferenceinphosphorusbioavailabilitybetweenmeatandplantproteinsources,
maypartiallyexplainthebenefitsofconsumingagreaterproportionofproteinfromplantssources,
asdescribedabove. Phosphateabsorptionislinearlyrelatedtophosphateintake,withbioavailability
being the major determining factor in phosphate uptake from the diet [120]. Thus, for organic
phosphate,foodchoicescanmakeasignificantdifferenceintheamountofphosphatethatisabsorbed
fromthediet.
7.2. DietarySourcesofInorganicPhosphorous
Phosphorous may be added to foods in the form of inorganic additives, which are typically
used to improve taste, texture, shelf life or processing time [121]. These additives are primarily
inorganic phosphate salts that require no enzymatic digestion and dissociate rapidly in the low
pHenvironmentofthestomach;thusinorganicphosphateadditiveshaveahighbioavailabilityof
90%–100%[102]. Phosphoricacid,whichispresentincoladrinks,hasabioavailabilityof100%[121].
Inorganic phosphate additives are found in many processed foods including frozen meals, snack
bars,Frenchfries,spreadablecheeses,instantfoodproductsandbeveragessuchassodas,flavoured
water,juicesandsportdrinks[122]. ThephosphorouscontentinatypicalWesterndiethasincreased
substantiallyduringthepastfewdecades[123]andinmanycountriesdietaryphosphorusexceedsthe
recommendeddailyallowance[124]. ArecentAustralianstudyfoundthatphosphateadditiveswere
presentin44%ofthemostcommonlypurchasedgroceryfoods,andwereparticularlyprevalentin
smallgoods(96%),bakeryproducts(93%)andfrozenmeals(75%)[125]. Inorganicphosphateisreadily
absorbedandhasbecomehighlyprevalentinthefoodsupplyduetotheriseofconveniencefoodsand
beverages,andisasignificantcontributortodietaryphosphateloadinatypicalWesterndiet.
7.3. ReducingDietaryPhosphorusandSerumPhosphateLevels
Given the deleterious effects of hyperphosphataemia and the rising phosphate content of
foods, several studies have addressed reducing dietary phosphorus to reduce serum phosphate
levels. Onesmallstudyfoundthatreplacingnaturalproteinsourceswithalowphosphorusprotein
concentratecanreduceserumlevelsofphosphateandparathyroidhormone[126]. Arandomised
controlled trial using dietary education to limit intake of foods containing phosphate additives
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led to a reduction in serum phosphate levels of 0.6 mg/dL (95% CI: 0.1–1.0 mg/dL), a decrease
that, the authors state, corresponds with a 5%–15% reduction in relative mortality risk, based on
findingsfromobservationalstudies[127]. Dietaryreductionofphosphatecanreduceserumlevels;
however, whether this translates to clinical benefits is not clear as limitation of dietary phosphate
mayexcessivelylimitothernutrients—particularlyprotein,whichoftencorrelateswithphosphorous
intake. Alargeretrospectivecohortstudythatconsidered30,000haemodialysispatientsfoundthat
therelationshipbetweenserumphosphatelevelsandmortalityisaJ-shapedcurveandthatthose
patients who had high phosphate levels and high protein intake had lower mortality compared
to those patients with high phosphate levels and low protein intake [128]. Dialysis patients on
a phosphate-restricted diet have greater mortality than those without phosphate restriction [129],
and it has been suggested that excessive phosphate restriction may be associated with decreased
dietaryproteinintakeandsubsequentproteinenergymalnutrition,whichleadstoincreasedriskof
mortality[130]. Theconclusionbornfromthesestudiesisthathaemodialysispatientsshouldaimto
minimizephosphorousintakewhilstnotcompromisingtheadequacyofproteinintake.
7.4. PhosphatetoProteinRatio
Thishasledtorecommendationsforusingaratiobetweenthephosphatecontentandprotein
content to identify foods that will provide adequate protein whilst properly controlling dietary
phosphate[122]. Anobservationalprospectivefiveyearstudyfoundthathaemodialysispatientswith
higherdietaryphosphate:proteinratiohadincreasedmortality,evenafterserumphosphatelevels
werecontrolledfor[117]. Eggwhitehasoneofthelowestphosphate:proteinratios[102]whilstmany
processed foods and beverages are high in phosphate with low protein. One study compared the
phosphate:proteinratioinmeatproductspreparedwithandwithoutphosphateadditivesfoundthat
therewasa60%increaseinthephosphate:proteinratiointhoseproductscontainingadditives[131].
Previousstudieshaveshownthatphosphateadditivestomeatandpoultryproductscanleadtoa
nearlydoublingofthephosphorouscontentoftheseproducts[132]. Worryinglywhethermeatshave
beenenhancedwithinorganicphosphateadditives,ortowhatlevel,maynotbeeasilydetermined
fromthenutritioninformationpanel.
WhilstmanystudieshaveshownanassociationbetweenserumphosphatelevelsandriskofCVD
deathinCKDpatients,ithasbeennotedthatthereisadearthofrandomisedcontrolledtrialswith
aninterventionthatmodifiesdietaryphosphateandassessesmortalityasanoutcome[123]. Whilst
thisevidencemaybelackingformortalityoutcomes,thecurrentguidelinesrecommendmaintaining
serumphosphatewithinanormalrangeforCKDstages3–5anddialysispatients,bydietaryrestriction
andtheuseofphosphatebinders[14],withinsufficientevidenceforrecommendingdietaryphosphate
restrictionforearlyCKDpatients(stages1–3)[61]. Thecurrentevidencesuggeststhatlimitingfoods
that have a high phosphate:protein ratio (such as spreadable cheeses and egg yolk) and avoiding
inorganic phosphate additives (such as those in cola) may improve outcomes for CKD patients.
Treatinghyperphosphataemiabylimitingtheintakeofprotein-richfoodsmaycontributetomortality
inCKDpatients.
8. Omega-3PolyunsaturatedFattyAcids(n-3PUFAs)
In the general population fish intake is associated with a reduction in all-cause mortality,
whichhasbeenattributedtothehighcontentofn-3polyunsaturatedfattyacids(n-3PUFAs)[133].
The anti-inflammatory, anti-hyperlipidaemic and antihypertensive effects of n-3 PUFAs are well
established in the general population [134]; however, there is less conclusive evidence for those
patientswithCKD.Inparticular,thereisadearthofconclusivestudieswithinCKDpopulationswith
regardstomortality[135,136].
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8.1. n-3PUFAsandTriglycerideLevels
Lipid abnormalities may be a common contributing factor to cardiovascular mortality in
end-stage renal disease, with elevated triglyceride levels being the major lipid alteration [136].
A 2009 meta-analysis of trials in hyperlipidaemic patients without renal impairment showed that
n-3 PUFA supplementation has a clinically significant dose-dependent reduction of triglycerides
levels [137]. In CKD patients, several studies have found an 8–12-week intervention with daily
eicosapentaenoicacid(EPA)anddocosahexaenoicacid(DHA)supplementationresultedindecreases
in triglycerides [138–145]. Furthermore several studies have shown that these interventions can
improveHDLlevels[139,140,146,147]. Theevidencefromthesetrialssuggeststhatdailyn-3PUFA
supplementationiseffectiveatamelioratingdyslipidaemiainCKDpatients.
However,notallstudieshaveconfirmedthiseffect. Afour-weekcrossoverstudywherepatients
received960mg/dayEPAand620mg/dayDHAfoundnoeffectonserumcholesterolortriglyceride
levels[148]. Donnellyetal. conductedafour-weekcrossoverstudywith3.6g/dayn-3PUFAandsaw
anon-significantdecreaseintriglycerides,thoughtherewasnowashoutperiodbetweentreatments,
whichmayhaveledtoacarryovereffectthatmayhavemaskedtheresultinthegroupthatreceived
thetreatmentbeforeplacebo[149]. Athree-monthstudyfoundthatsupplementationwith4g/day
fishoiltendedtodecreaseserumtriglycerides;however,thisfailedtoachievestatisticalsignificance
(p=0.07)[150]. Longerstudieshavecastadditionaldoubtontheefficacyofn-3PUFAstoameliorate
dyslipidaemiainCKDpatients, withasix-monthstudyindialysispatientsreceiving960mg/day
EPAand600mg/dayDHAhavingnoeffectontriglyceridelevels, althoughthisstudydidseean
increaseinbothHDLandLDLlevels[151]. Severalotherinterventionstudieswith2–4g/dayfish
oilhavefailedtoseeanychangesinlipidlevelsaftertwomonths[152,153],sixmonths[154,155]or
12months[156]oftreatment. Thislackofaneffect,particularlyintrialsoflongerduration,hascast
somedoubtontheefficacyofn-3PUFAsinreducinghyperlipidaemia.
The variation in results observed in intervention studies may result from the small sample
sizes,shortdurationsanddifferencesinn-3PUFAdosingregimes[157]. Inarecentmeta-analysis,
subgroup analysis found that the TG lowering effect was greater in patients with higher baseline
TGlevels[158],whichmayaccountforthevariationseeninresultsfromthesesmallertrials. Inthe
trialbyTazikietal. thatfoundreductioninLDLcholesterolandincreaseinHDLcholesterolafter
a12-weekinterventionwith2g/dayn-3PUFAs,oneoftheinclusioncriteriawashyperlipidaemia
with no current lipid lowering medications [147]. Thus positive results are more likely to be seen
instudieswithpatientswhohadgreaterdegreesofhyperlipidaemiaatbaseline. Theabsorptionof
n-3PUFAsmaybeincreasedupto3-foldbetweenbeingtakenconcomitantlywithahighfatmeal
comparedwithalowfatmeal[159]andtimingofdosingandconcomitantfoodintakemayaffect
absorptionandsubsequenteffectoftheintervention. Themajorityofstudiesinstructedpatientsto
consumetheirregulardiet,andithasbeennotedthattheincreasingprevalenceoffunctionalfoods
fortifiedwithn-3PUFAsmaydilutetheeffectoftheseinterventiontrials[160]. Promisingly,arecent
meta-analysis that did subgroup analysis that looked at doses of less than 2 g per day found that
thismorephysiologicallyrelevantdosingwasabletosignificantlydecreaseTGandincreaseHDL
levels[161]. A2016meta-analysisconfirmedthatn-3PUFAsareabletolowerTGlevelsinHDpatients;
however,noeffectwasseenontotalcholesterolorLDLcholesterollevels[162]. Takentogether,the
evidencesuggeststhatdailyn-3PUFAsupplementationiseffectiveatreducingtriglyceridelevelsin
CKDpatientswithhyperlipidaemia.
8.2. n-3PUFAsandBloodPressure
CKDleadstothedevelopmentofhypertension,whichitselfcancontributetotheprogression
of CKD [163], and thus interventions that reduce blood pressure in CKD patients are required.
In the context of CKD, several studies have found that an eight-week intervention with 1840 mg
EPA and 1520 mg DHA per day resulted in decreases in blood pressure in patients with CKD
stages3–4[138]. IncontrasttothestudybyMorietal.[138],severalstudiesofsimilardurationand