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NEPHROLOGY Renal failure and its Learning objectives treatment Afterreadingthisarticle,youshouldbeableto: C classifyrenalfailure MonalisaMishra C understandthecausesofrenalfailure SarahNg C understanditsprevalenceandoutcome JamesHanison C classifythetreatment of renal failureincludingthedifferent modalitiesofrenalreplacementtherapy C understand the methods of anticoagulation used in renal replacementtherapy Abstract Acutekidneyinjury(AKI)isacommoncomplicationofacuteillness.It isassociatedwithsignicantmorbidityandmortalityaswellasahigh cost to healthcare systems. There are a broad range of causes of Aetiology AKI which should be considered in a systematic fashion to avoid ThereareabroadrangeofcausesofdevelopingAKI.Differential missingmultiplepotentialcausativefactors.Theseincludepre-renal diagnosismustbeconsidered in asystematicfashion to avoid causesfromhypovolaemia,intrinsicrenalcausessuchasglomerular missingmultiplefactorsthatmaybecontributingtothecondi- diseases and post-renal obstructive causes. In the intensive care tion.Traditionally,AKIisdividedintopre-renal,renalandpost- unit,two-thirdsofAKIcasesresultfromrenalhypoperfusion,sepsis, renal causes. Pre-renal causes include hypovolaemia or a contrastandnephrotoxicagents;upto5%willrequirerenalreplace- decreasedeffectivearterialvolume.Intrinsicrenalcausescanbe menttherapy.Modalitiesofrenalreplacementtherapyincludeinter- consideredunder differentanatomiccomponentsof thekidney mittent haemodialysis, peritoneal dialysis and continuous (vascular supply; glomerular, tubular and interstitial disease). haemoltration. Continuous haemoltration is usually favoured in the Post-renal obstructiverenal failureisusuallydiagnosedbyuri- intensivecaresettingas ithas greaterhaemodynamic stabilityand nary tractdilation on renal ultrasound. In thehospital setting, greatercapacitytoextractuidfrompatientswithfluidoverload.Anti- pre-renal andacutetubularnecrosis(ATN) accountforthema- coagulationoptions canbeachieved withsystemic anticoagulation jorityof AKI cases. Thesearealsooftensuperimposedonpre- suchasheparinorregionalanticoagulationwithcitrate. existing chronic kidney disease (CKD). In the intensive care unit,two-thirdsofcasesofAKIarearesultofthecombinationof Keywords Acuterenalfailure;haemoltration;haemodialysis;renal impairedrenalperfusion,sepsisandnephrotoxicagents. RoyalCollegeofAnaesthetistsCPDMatrix:1A01,2C04 Prevalenceandoutcome UncomplicatedATNtypicallyrecoversin2e3weeks.Thiscould, however, be complicated by superimposed renal insults. Epi- Acutekidneyinjury sodes of hypotension induced by haemodialysis may lead to Currentdefinitionandclassification additionalischaemiclesionsanddelayrenalfunctionalrecovery, Acutekidneyinjury(AKI)isaclinicalsyndromecharacterizedby especially in patients who have multiple comorbidities. It is a sudden decline in glomerular fltration rate (GFR) causing becoming increasingly recognized that even lesser degrees of decreasedeliminationof nitrogenouswasteproductsandurae- kidney injury have important implications for health as AKI mic toxins. Kidney Disease: Improving Global Outcomes represents a heterogeneous clinical syndrome with multiple (KDIGO)defnesAKI asanyofthefollowing:increaseinserum causesratherthanonedisease. creatinineby(226.5mmol/lwithin48hours;increaseinserum TheincidenceofAKI inunselectedhospitalizedpatientshas creatinineto1.5timesbaseline,whichisknownorpresumedto been estimated to be18%, and AKI accountsfor 1e4% of all haveoccurredwithintheprior7days,orurinevolume<0.5ml/ hospitaladmissions.AKIhasthehighestincidenceamongthose kg/h for 6 hours. AKI is staged for severity according to the aged65andolder.PatientswitheGFR<30ml/min/1.73m2have criterialistedinTable1. a30-to40-foldhigherriskofdevelopingAKI.AKI isassociated with high costs and adverse clinical outcomes, including increasedmortality,lengthofstayanddevelopmentorprogres- sionof CKD. Thecostof AKI totheNHSinEnglandwasesti- MonalisaMishraMBBSMDFNBisaSeniorClinicalFellowinIntensive matedtobe£1.4billioneachyear.ThenumberofcasesofAKI CareMedicineatManchesterUniversityNHSFoundationTrust, increasedfromover600,000in2001toover3millionin2011, Manchester,UK.Conflictsofinterest:nonedeclared. although mortality has signifcantly decreased from 21.9% to 9.1%in2001.ThemortalityofAKIrangesfrom8.1%inpatients SarahNgMBChBMRCP isaSpecialtyRegistrarinNephrologyand IntensiveCareMedicineinHealthEducationNorthWest,UK. withAKI stage1e33% inpatientswithAKI stage3. Conflictsofinterest:nonedeclared. Theincidences of CKD and end-stagerenal disease(ESRD) afterAKI were25.6and8.6per100person-years, respectively. JamesHanisonBScMBChBFRCAFFICMPGCertisaConsultantin TheannualabsoluteriskfordevelopingESRDafteranepisodeof AnaestheticsandIntensiveCareMedicineatManchesterUniversity NHSFoundationTrust,Manchester,UK.Conflictsofinterest:none AKIrangesfrom0.6%to1.2%inthosewithmildAKIcompared declared. to 9% in those with pre-existing CKD. Patients should be ANAESTHESIAANDINTENSIVECAREMEDICINE22:7 398 Ó2021PublishedbyElsevierLtd. NEPHROLOGY StagingofAKI (KDIGOcompositestaging) AcuteKidneyInjuryNetwork(AKIN)andRIFLEclassifcationsofAcuteKidneyInjury AKINStaging Urineoutput RIFLE SerumCreatinine Class SerumcreatinineorGFR Stage1:Increaseofx1.5frombaseline <0.5ml/kg/hfor>6hr Risk Increaseinserumcreatininex1.5or or 26.5mmol/l GFRdecrease>25% Stage2:Increaseofx2frombaseline <0.5ml/kg/hfor>12hr Injury Serumcreatininex2orGFR decreased>50% Stage3:Increaseofx3frombaseline, <0.3ml/kg/hfor24hor Failure Serumcreatininex3,orserumcreatinine or 354mmol/lwithanacuteincrease anuriafor12hr 354mmol/lwithanacuterise>44 ofatleast44mmol/loronRRT mmol/lorGFRdecreased>75% Loss Persistentacuterenalfailure¼complete lossofkidneyfunctionforlongerthan 4weeks End-stagekidney ESRD>3months disease Table1 followedupat3monthsafterAKI forresolution, new-onsetor resuscitation in critically ill patients havebeen associated with worseningofpre-existingCKD. worse renal outcomes and increased mortality. The Fluid and Catheter Treatment Trial (FACTT) indicates that after initial AKIintheintensivecareunit resuscitation, aconservativeapproach tofuidadministration is AKIisanindependentriskfactorfordeathandupto40%ofICU associatedwithfaster weaningfrommechanical ventilationand patients develop AKI. Up to 5% of ICU patients require renal decreasedICUlengthofstaywithoutanydeteriorationofkidney replacementtherapy.Factorsthatexacerbateacutekidneyinjury functionorworseoutcomesinpatientswithacutelunginjury.The includehypovolaemiaintheperioperativeperiod,repeatedexpo- VasopressinandSepticShockTrial(VASST)showedthatthebest suretocontrastandnephrotoxicagentsandinfammatorystates. survival outcomesarewith apositivefuid balanceof approxi- Mortality is attributed to infection, haemorrhage or persistent mately3litreswithin12hours.Therefore,aliberalfuidapproach shockdespiteoptimalcare. appearstobebenefcial inthefrsthoursofshock,whileacon- servativeapproachfollowingresolutionofshockispreferred. AcutemanagementofAKI KDIGO AKI guidelines recommend isotonic crystalloids Primaryprevention andearlydiagnosisof AKI areessential in insteadofcolloidsforintravascularexpansioninpatientsatrisk improvingoutcomes and preventingresidual effects of kidney ofAKI.Incriticallyillpatientsreceivingmechanicalventilation, damage. All patientsshouldhavearisk assessmenttoidentify respiratorychangesinleftventricularstrokevolumecanpredict andreverseriskfactors.MajorriskfactorsforAKIincludethose fuidresponsiveness.Inhypovolaemicpatients,positive-pressure witholderage(>75years), diabetes, hypertension, sepsis, ma- ventilation may induce a fall in venous return and lead to a lignancy,surgicalpatientsandpre-existingcardiacdisease. decreaseincardiacoutput. AkeyfactorinpreventingAKIishaemodynamicstabilization withoptimizationofcardiacoutputandbloodpressuretoensure Preventionofdrugandnephrotoxin-inducedacute adequaterenal perfusion.Adequatevolumeexpansionisessen- kidneyinjury tial indecreasingrisk of AKI intheperioperativeperiodinthe Riskfactorsfordevelopingnephrotoxicityincludeageolderthan60 initial phase,butthisneedstobebalancedwithpreventingthe years,pre-existingCKD,volumedepletion,diabetes,heartfailure, undesirablesideeffects of fuid accumulation and overload. It andsepsis. Drugmonitoringof nephrotoxinsiscrucial in at-risk canbeparticularlychallengingtomanagepatientswithsevere patients. Preventative measures include correctly estimating the congestivecardiacfailureor diastolicdysfunction, whererenal GFRbeforeinitiationoftherapy,adjustingthedosageofpotential perfusionisinadequatedespitenormalvolumestatus.Excessive nephrotoxins,andmonitoringrenalfunctionduringtherapy. fuid replacement istolerated poorly in thispatient group and mayprecipitatepulmonaryoedema. Contrast-inducednephropathy(CIN) The International Guidelines for Sepsis Management by the AKI secondarytocontrastnephropathy(defnedasanincrease SurvivingSepsiscampaignrecommendsinitialfuidresuscitation in creatinineof >44mmol/l) typically occursin patientswith withcrystalloidsforaminimumof30ml/kgandaddingalbumin underlyingrenalimpairmentandisrarelyseeninpatientswith in patients who continueto requiresubstantial amounts of cr- normalrenalfunction.Itmayoccurwithintravenousandintra- ystalloid to maintain adequate mean arterial pressure (MAP). arterial contrast, but not with oral contrast. Theincidenceof Fluidchallengeshouldbecontinuedfor aslongashaemodyna- CIN is 20% in patients with creatinine levels of more than mic parameters continueto improve. Lateand aggressivefuid 176mmol/l and50% whenlevelsaremorethan440mmol/l. ANAESTHESIAANDINTENSIVECAREMEDICINE22:7 399 Ó2021PublishedbyElsevierLtd. NEPHROLOGY Other risk factorsincludediabeticnephropathy, advancedage obstruction. Physical examination, especially assessment of (older than 75years), congestiveheart failure, volumedeple- volumestatusisparticularlyhelpful.Trendsindailyintakeand tion, andhighor repetitivedosesof radiocontrastagents. The outputvolumesassistindeterminingtheextracellularfuidvol- KDIGOAKI guidelinesrecommend volumeexpansion with ei- ume of the critically ill patient. Abdominal examination can therisotonicsodiumchlorideorsodiumbicarbonatesolutionsin reveal importantinformation, suchasadistendedbladder sug- patientsatriskofCIN unlesstherearecontraindications.Mea- gesting lower urinary tract obstruction, or a tense distended surestoreduceAKI risk shouldbeimplementedinthosewith abdomen which may point towards abdominal compartment eGFR<45ml/min/1.73m2. syndrome.Intra-abdominalpressurecanbemeasuredintheICU and a diagnosis of abdominal compartment syndrome made TreatmentofAKI whenpressuresexceed20mmHg. Inrecentyears,therehasbeenalotoffocusonimprovingtimely Fever,skinrashandarthralgiasmaypointtowardssingsofa diagnosis and earlier recognition of AKI as it is becoming systemicdiseasesuchassystemiclupuserythematous,vasculitis, increasinglyrecognizedthatserumcreatinineisarelativelylate endocarditis,oradrugallergywithacuteinterstitialnephritis.A indicator of renal injury. Initial management of AKI includes leukocytoclasticrashonthelowerextremitiescouldbeHenoch- thoroughassessmentof thecauseof renal dysfunctionandthe Schonleinpurpuraorcryoglobulinaemiainapatientwithhepa- volaemic status. Nephrotoxic agents should be avoided and titisC.Inpatientswithrecentaorticcatheterization,itisimpor- exposuretointravascularradiocontrastdyeneedstobecarefully tanttolookforlivedoreticularisoradiscolouredtoeastheycould rationalized. Gadolinium-basedcontrastagentsshouldbeavoi- helpwithdiagnosingcholesteroloratheromatousemboli. dedduetotheriskofdevelopingnephrogenicsystemicfbrosis. Antimicrobialagentssuchasaminoglycosides,amphotericinand Diagnostic work-up acyclovir should beavoided when possible, with doses calcu- Evaluation of urinevolume, urinary sediment and serum and latedaccordingtorenalfunction. urinebasicmetabolicpanelisimportantforthediagnosisofAKI. Careneedstobetakentorecognizeandmanagetreatmentof Urinalysisisoneof thekeyteststoevaluatekidneydisease AKI complications.Whenfuidoverloadoccursinpatientswith although this is less helpful in the ICU setting as most urine AKI, fuid intake should be restricted with a trial of diuretics specimensarecollectedfromaurinary catheter. Ultrasound is beforedialysisinitiation.Inexperimentalstudiesontheisolated commonly used to ruleout obstructiverenal disease. Contrast perfused kidney, furosemide has been shown to reduce renal CTs areoften needed to identify retroperitoneal fbrosis, renal medullary injury during hypoxic conditions. Furosemide may veinthrombosis,renalinfarctionornephrocalcinosisascauseof improvetheoxygensupplyanddemandbalancebyinhibitingNa- acute kidney injury. It is important to remember the risks of K-Cl2 co-transporter activity and increasing prostaglandin pro- contrast-inducednephropathyinpatientswithrenalimpairment duction andbloodfow. Morphineandnitratescan beusedto aswell astherisk of nephrogenicsystemicfbrosisin patients alleviaterespiratorysymptoms. When fuidoverloadcannotbe exposedtogadolinium. correctedinatimelymannerwithmedicalmanagement,positive- Arenalbiopsyshouldbeconsideredforpatientsinwhompre- pressure ventilation may need to be initiated with or without renal andpost-renal AKI havebeenexcludedandif acauseof endotrachealintubationanddialysis. intrinsicrenal diseaseissuspectedyetremainsunclear. Exam- HyperkalaemiaisafrequentcomplicationofAKI andcanbe ples where it would be useful include rapidly proliferative managed by administering parenteral glucose and insulin in- glomerulonephritis (RPGN), vasculitis, systemic lupus erythe- fusionsandsodiumbicarbonateto promoteshift of potassium matosus,andacuteinterstitialnephritis.Askidneybiopsiespose intotheintracellular space. Dialysisinterventionsfor thetreat- a signifcant risk it is crucial to consider if the pathological mentofAKIshouldbeconsideredinthebroaderclinicalcontext, diagnosiswouldultimatelychangemanagement. withtrendsoflaboratorytestsratherthanonesinglereadingand withdueconsiderationofwhethertheconditioncanbemanaged AKIbiomarkersandearlydetectionofAKI byinitiationofrenalreplacementtherapy(RRT). Increasingly, research efforts havebeen focussed on theearly Nutritional supportisanimportantbutfrequentlyneglected detection of AKI as it has been known to improveoutcomes. aspect in themanagement of AKI. Patients with AKI havean Novel serum and urine biomarkers, such as kidney injury increased risk of protein-energy malnutrition because of poor molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin nutritional intake and high catabolic rate. Patients with AKI (NGAL), cystatin C, interleukin (IL-18), urinary cystatin C and shouldreceiveabasicintakeof0.8e1.0gofprotein/kg/dayand otherssuggestpotential atprognostication andidentifyingspe- atotalenergyintakeof20e30kcal/kg/day.InpatientsonRRT, cifccausesofAKI. 1.0e1.5 g of protein per kg/day should be given up to a maximumof1.7g/kg/dayinhypercatabolicpatients. Chronic kidneydisease Diagnostic approachtoAKI Chronickidneydisease(CKD)isdefnedasabnormalitiesofkidney Priorcreatinineconcentrationandevidenceofunderlyingkidney structureorfunction,presentfor>3months,withimplicationsfor should beevaluated fromthemedical history and hospital re- health.ThecriteriafordiagnosisofCKDincludealbuminuria,urine cords. Particular attention should be given to the medication sedimentabnormalities,electrolyteandotherabnormalitiesdueto history especially any over-the-counter medications. Painless tubulardisorders,abnormalitiesdetectedbyhistology,structural haematuriamay suggest glomerulonephritis or agenitourinary abnormalities detected by imaging, history of kidney trans- malignancy, whilepainful haematuria is moreconsistent with plantation, or an estimated eGFR below 60 ml/min/1.73m2 ANAESTHESIAANDINTENSIVECAREMEDICINE22:7 400 Ó2021PublishedbyElsevierLtd. NEPHROLOGY persistingfor 3monthsor moreirrespectiveof thecause. CKD adequaterenal replacement for 48hoursor more. Thisensur- shouldbeclassifedbasedonGFRcategory(G1toG5,withG3split es that the treatment is intermittent and the patient can be into3aand3b)andalbuminuriacategory(A1,A2andA3basedon disconnectedformthecircuitforprolongedperiodsoftime.Itis urinaryalbumin/creatinineratioinanearlymorningspoturine possible to run slower fows of dialysate through the device sample).ClarifcationsshouldbemadetoincludethesuffxTfor (100ml/minfow),butthisreducestheeffciencyofthesolute patientswithrenalallograftsandDtoidentifyCKDstage5patients clearance and necessitates more prolonged sessions; this low ondialysis. effciencysetupiscalledSLED(sustainedloweffciencydialysis). SLEDisahybridformof renal replacementtherapythatcom- Renalreplacementtherapy binesthedesirablepropertiesofbothintermittenthaemodialysis and continuous renal replacement therapy (CRRT). Haemody- Inthefaceof untreatedacuterenal failure, thepatientwill die namically, itisbetter toleratedthanintermittenthaemodialysis from accumulation of unexcreted solutes (urea, potassium, as the rate of solute and fuid removal is slower and the hydrogenions)orfuidoverload.Itisonlyinthelastcenturythat metabolic control is equivalent to CRRT. It provides renal wehavebeenabletofullyunderstandandtreatthis. The20th replacementtherapyforextendedperiodsoftime(6e12hours) century has seen therapid riseand subsequent refnement of butisintermittent(threetimesaweek).Thisallowsforgreater severalmodalitiesofrenalreplacementtherapy.Inthe1940s,Dr mobilization and rehabilitation of the patients because of Willem Kolff developed the frst drum dialysis machines for scheduledtimeoffdialysis. haemodialysis.Inthesamedecade,DrJacobFinedevelopedthe Figure 1 gives a schematic of the process of dialysis. The processofperitoneal dialysis.Inthe1960s,DrBerlandScribner fgure is simplifed, instead of a single tube constructed of a developedcontinuousarteriovenoushaemofltrationandDrBe- semipermeablemembrane,moderndialysersconsistofhundreds rnardCanauddevelopedcontinuousvenovenoushaemofltration ofsmallhollowfbresencasedinalargercylinder.Thishasthe in the1980s. Sincethesediscoveries, theprocesseshavebeen beneftofvastlyincreasingthesurfaceareaofmembrane(usu- furtherrefnedtoimprovesafety,effciencyandreliability.Asa ally0.8e2.5m2)thatbloodisincontactwith,therebyincreasing resultoftheseadvances,wenowhavearangeofoptionsforthe therateofdiffusionandthereforesoluteclearance.Historically, provisionofrenalreplacementinacuterenalfailure. the membrane was composed of cellulose, although this has largely been replaced with synthetic materials such as poly- Intermittenthaemodialysis sulfoneandpolyacrylonitrile. Oncetheprimemodalityofrenal replacementintheacuteand chronicsetting,thishasbecomefarlesspopularincriticalcarein Peritonealdialysis favourofcontinuousmodesofrenalreplacement.Itremainsfar Theperitoneumisavascularstructurecoveredwiththinmeso- morepopularoutsideofcriticalillnessduetothecapacitytobe thelium.Thestructurecoversthegutandotherintra-abdominal runintermittentlyratherthancontinuouslytherebyliberatingthe organsandthesurfaceoftheabdominalcavity.Ithasasurface patientfromthemachineforlongperiodsoftime. area of 1e2 m2 which is enhanced by themicrovillaeon the Theprincipleofhaemodialysisisthepassingofbloodovera surfaceofthemesothelium.Duetotheseproperties,itisanideal semipermeable membrane. A dialysate is then passed on the membranefor thetransfer of water andlow molecular weight other side of the semipermeable membrane. The dialysate is molecules. passedintheoppositedirectiontothebloodfow (countercur- DrHenryTenchkoffdevelopedtheso-calledTenchkoffcath- rent fow) to maximize the concentration gradient across the eterinthe1960s.Itremainslargelyunchangedtoday;asynthetic membraneandenhancetheeffciencyofthesystem.Adialysate tubewitheitherafangeorDacroncuff(usually2Dacroncuffs) is a solution of specially treated mains-supply water with an to ensure fxed placement is inserted through the anterior addedconcentrateof sodium, calcium, potassium, magnesium, abdominal wall intotheperitoneal cavity. Thiscanbeinserted chloride,acetate,citrate,bicarbonateandglucose.Mainssupply withaSeldinger(blind)technique,laparoscopicallyorviaopen waterisrequiredduetohighvolumesofliquidinvolvedinthe surgicalapproach. process (500e800 ml/min of dialysate fow countercurrent Adialysateisinstilledintotheperitoneal cavity.Itisusually againstabloodfow of 250e400ml/min). Water andlow mo- comprised of sodium, calcium, magnesium, chloride, lactate, lecularweightsubstances(roughly10kDaorlessbutdependent bicarbonateandglucose. Usual volumeis1.5e3L.Thefuidis on thedevice) diffuseacross themembrane. This process re- usually instilled, permitted to dwell in the peritoneum while quiresthepresenceofanosmoticgradientbetweenthetwosides soluteexchangeoccursandthenitisexpelled.Thisusuallyoc- of the membrane (blood and dialysate). Brownian (random) cursviaautomateddevicewhilethepatientisasleepovernight. particlemovementwillfavourabulkmovementofsolute(small Adoseofdialysatecanbelefttodwellinthepatientduringthe particlessuchasurea) tothesideofhighconcentrationtolow day for ongoingcontinuous ambulatory dialysisor thepatient concentrationandwateralongsideit.Therefore,waterwillpass canbeleft’dry’duringthedaywithnoindwellingfuid. acrossthemembraneonlyifthedialysateissuitablyhypertonic Theperitoneumis asemipermeablemembrane; as such, it compared to blood, and electrolytes (such as sodiumand po- actsakintothemembraneinadialysismachineandallowssmall tassium) will only beremoved fromtheblood if thedialysate molecules such as urea to diffusefromtheblood to thefuid containslowerconcentrationsoftheelectrolytesthantheblood. acrossalongtheconcentration gradient. Theosmolality of the Thisprocessofsoluteremovalifreferredtoasdiffusion. dialysate(largely dueto high glucosecontent) also createsan Soluteclearanceisgreater than normal renal clearanceand osmoticpressurethatdragswaterandsolutesintothefuidvia itispossibleforasessionofdialysislasting2e4hourstoprovide ultrafltration. ANAESTHESIAANDINTENSIVECAREMEDICINE22:7 401 Ó2021PublishedbyElsevierLtd. NEPHROLOGY Haemodialysis Bubble detector + clamp Fresh dialysate in Pump Used dialysate out Anticoagulant infusion Figure1 Severalfactorsmakethismethodofdialysislessfavourablein larger cylinder. Thedifferenceliesinthemechanismbywhich criticallyill patients, includingthereducedcontrol offuidbal- thesolutesandwaterpassacrossthemembrane.Unlikedialysis, ance,variablesoluteclearance,peritonealinfectionrisk,protein ahydrostaticpressureismaintainedwithinthefbresoftheflter. lossandincreaseinabdominalpressures.Peritonealdialysishas This pressureacross themembrane(so called transmembrane beendemonstratedtoconferahighermortalityriskascompared pressuree TMP)drivessolutesandwateracrossthemembrane tocontinuoushaemofltrationincriticalcare. without therequirement of an osmoticgradient to promoteit. The mechanism of driving the solutes across the membrane Continuous haemofiltration usingpressureisreferredtoasconvection. Thismethodofrenal replacementtherapyisthemostrecentto The rate of ultrafltrate production (Qf) depends upon the bedevelopedascomparedtoother modalities, butithasrisen membranepermeabilitycoeffcient(Km)andtheTMP: intopositionasthemostpreferredmethodofrenalreplacement therapy in critical care, especially in high resource countries. Qf ¼Km TMP Thereareseveralreasonsforthisincluding: improvedhaemodynamicstability Figure2givesaschematicoftheequipmentarrangementfor greatercontrolofpHandelectrolyteimbalances CVVHF.Bloodfowisusuallystaticatapproximately200ml/min. greater capacity to extract fuid from the vascular ApumpcontrollingtheultrafltrateremovalmanipulatestheTMP compartmentinfuidoverloadedpatients bycontrollingthepressureonthatsideofthecircuit.Thisensures less rise in intracranial pressure as compared to other that theultrafltratefow can bemaintained at aconstant rate methods evenasthemembranepermeabilityalters(ittendstoreduceover lowinfectionrisk time). Another key differencebetween haemodialysis and hae- norequirementforspecifctreatedwatersupply mofltration is theremoval of water and electrolytes from the simpletouseandtrainstafftooperate patient. Thisistargetedby thecomposition of thedialysatein Originally,thecontinuoushaemofltrationwasdesignedtobe dialysis;inhaemofltration,waterandallsubstancessmallerthan connected to thepatient viaadesignated arterial cannulaand theporesizeofthesemipermeablemembranearefltered.This venous cannula. Blood fowed through the circuit from the resultsinlargevolumesoffuidandelectrolytelosswhichmuch arterial access to venous return under mean arterial pressure. bereplacedinthecircuit.Replacementfuidcanbeaddedbefore This has subsequently been replaced by dual lumen venous the flter (predilution), after (postdilution), or a mix of both. cathetersthatprovideaccessandreturnportsinthesamecan- Replacementfuidcontainswaterandmostelectrolytespresentin nulaandtheadditionofpumpswithinthecircuittoensurethat plasma. It is usually buffered with lactate and bicarbonate. thefowisindependentofpatientbloodpressureandavoidsthe Phosphateisoften absent fromreplacement fuid and it isnot requirement for arterial vascular access. This is referred to as uncommonforpatientstorequirephosphatereplacementwhen continuousvenovenoushaemofltration(CVVHF). receivinghaemofltration.Predilutionreducesthehaematocritof Theprocess has similarities to dialysis, insofar as blood is theblood and potentially increases theuseablelifetimeof the pumped out of the patient and passed over a semipermeable flterbeforeitclotsbutreducestheeffciencyoftheflter.Ultra- membranewheresolutesandwater passthrough poresin the fltratedoseisprescribedaccordingtoweight(ml/kg/h). There membrane. Theflter (likeadialyser) isalsoarrangedashun- has been virtually no demonstrated beneft from high volume dredsof hollow fbresof themembranematerial encased in a haemofltration (35e40 ml/kg/h) as compared to low volume ANAESTHESIAANDINTENSIVECAREMEDICINE22:7 402 Ó2021PublishedbyElsevierLtd. NEPHROLOGY Continuous venovenous haemofltration Anticoagulant reversal (if used) Bubble detector + clamp Replacement fuid Effuent out Pump Anticoagulant infusion Figure2 haemofltration(20e25ml/kg/h)inacutekidneyinjuryandlow pathways. This results in formation of blood clots within the volumeprescriptionsareusuallyfavoured. circuit,specifcallyclottingandfailureofthedialyser/flter.Im- ItispossibletomodifyaCVVHFcircuittopassadialysateover provementsinmaterialshavereducedthiseffectovertimeandit thesemipermeablemembraneinacountercurrentfow(Figure3). is possible to run both dialysis and haemofltration circuits Thisisreferredtoascontinuousvenovenoushaemodiafltration withoutanticoagulation,butitremainsrecommendedthatanti- (CVVHDF) and it enhances soluteclearanceby permittingcon- coagulationisusedtoreducetheriskofcircuitfailure. vectionanddiffusiontooccur. Forcontinuousrenal replacementtherapiesthereareseveral options Anticoagulation systemicanticoagulationwithunfractionatedheparin Whenbloodispassedinanextracorporealcircuitandexposedto regionalanticoagulationwithunfractionatedheparin synthetic materials it triggers activation of the coagulation regionalanticoagulationwithcitrate. Continuous venovenous haemodiafiltration Anticoagulant reversal (if used) Replacement Bubble detector fuid + clamp Fresh dialysate in Pump Used dialysate out Anticoagulant infusion Figure3 ANAESTHESIAANDINTENSIVECAREMEDICINE22:7 403 Ó2021PublishedbyElsevierLtd. NEPHROLOGY Chelation of calcium by sodium citrate O O– O– O Ca2+ Na+O– O– Na+ O O OH O O– +3[Ca2+] OH +6[Na+] Na+ O– O + Na+O– O Ca2+ O– O OH O O OH O– O– Na+ Na+ Ca2+ O O– O– O Figure4 Systemicanticoagulationinvolvesanticoagulatingthepatient normalizedpriortore-enteringthepatient.Thisisnowuncom- andtheextracorporealcircuitbyaddingheparinviaabolusand monly used as patients with a bleeding risk are now usually continuousinfusion. Theactivatedpartial thromboplastin time fltered without anticoagulation or with regional citrate anti- (APTT)ischeckedandatargetAPTTratioof1.5e2.5isusual.In coagulationifavailable. patientswithahighbleedingrisk,itispossibletoaddthehep- Regional citrateanticoagulation involvesaddingsodiumcit- arin in theafferent limb of thecircuit, theeffect can then be ratetotheafferentlimbofthecircuit. Thischelatescalciumin reversedintheefferentlimbofthecircuitwithacalculateddose thebloodandinhibitscoagulationinthecircuit(Figure4). An ofprotamine.Thisisreferredtoasregionalanticoagulation,with infusion of calciumchlorideor gluconateisthen addedto the anticoagulanteffectonlypresentinthebloodbetweenthehep- efferentlimbofthecircuittoovercometheeffectofthecitrate arin and protamine infusions, the blood coagulation status is andnormalizecoagulationbeforeitre-entersthepatient.Serum Citrate cycle Glycolysis Exogenous Citrate Acetyl CoA Coenzyme A from anticoagulation H O 2 Citrate Oxaloacetate H O NADH 2 NAD+ cis-Aconitate Malate H O H O 2 2 Fumarate Isocitrate FADH NAD+ FAD NADH CO Succinate 2 α–Ketoglutarate GTP NAD+ GDP+Pi Succinyl CoA NADH CO 2 Figure5 ANAESTHESIAANDINTENSIVECAREMEDICINE22:7 404 Ó2021PublishedbyElsevierLtd. NEPHROLOGY ionized calciumlevels aremeasured fromthepatient and the Serumlactateismeasuredtohelpidentifythosewhoareatrisk calciumreplacementistitratedaccordingly.Thecitrateismostly ofdevelopingcitratetoxicity. removedviatheflter,anyremainingcalcium/citratecomplexes Prostacyclin can also be used to anticoagulated for renal arethenmetabolizedintheliverwhereitentersthecitratecycle replacementtherapy.Itishaspotentvasodilator,anti-thrombotic asanenergysubstrate(Figure5).Theexcesscitrateamountstoa andanti-plateletproperties.Theagenthasbeenusedasheparin signifcant alkali load and specialized replacement fuids with sparingmoleculeduringrenalreplacementtherapy. A reducedbicarbonateareneeded. Regional citrateanticoagulationhasbeenshowntoincrease the circuit life and decrease the rate of complications as Keylearningpoints compared to systemic heparin anticoagulation. However, implementation of regional citrate anticoagulation requires C Acutekidneyinjuryhassignifcantmorbidityandmortality established protocols and extensive staff training in order to C Itcanbecausebepre-renal,renalorpost-renalcauses.IntheICU avoidpotentialcomplications. settingitisoftenmulti-factorial Citrateaccumulation/toxicity: oneof thepotentiallyse- C Optimizingfuidmanagementandpreventingnephrotoxinsiskey verecomplications of regional citrateanticoagulation. It inpreventionandmanagementofAKI occurswhenbodyisunabletometabolizeallthecalcium C Dialysisworksviadiffusion citratecomplexes.Patientsathighriskarethosewithliver C Filtrationworksviaconvection failure, cardiogenic shock and elevated serum lactate. C Peritoneal dialysisisinferiortohaemodialysisandhaemofltra- Citrate accumulation is suggested by high anion gap tioninacuterenalfailurebutmaybeappropriateinalow metabolicacidosis, escalatingcalciumsubstitution needs resourcesetting andanelevatedtotaltoionizedcalciumratio(>2.5). C Anticoagulationisrecommendedandsystemicheparin,regional Citrate overload: morecommon and easily manageable citrateorzeroanticoagulationaretheusualoptions complications of regional citrate anticoagulation. Meta- bolicconversionfromaccumulatedcitratecanresultinan excessivealkaliloadandmetabolicalkalosis. Systemicionizedcalciumrequiresmonitoring. Normal (1.15 e1.3 mmol/l) ionized calcium levels should be maintained FURTHERREADING throughout therapy. Baseline measurement should be taken DaugirdasJT,BlakePG,IngTS.Handbookofdialysis.5thEdn.Phil- beforestartingthetherapywhich isusedto setinitial calcium adelphia:WoltersKluwerHealth,2015. infusionrate.Total/ionizedcalciumratioiscalculated;incaseof JohnsonRJ,FeehallyJ,FloegeJ.Comprehensiveclinicalnephrology. citrateaccumulation,non-metabolizedcalciumcitratecomplexes 5thEdn.Philadelphia:ElsevierSaunders,2015. continuetocirculateinthebloodeffectivelyincreasingthenon- Kidneydisease:improvingglobaloutcomes(KDIGO)acutekidney ionized fraction of total calcium. A total/ionized calciumratio injuryworkgroupKDIGOclinicalpracticeguidelineforacutekidney over 2.5ishighlysuggestiveof calciumaccumulation/toxicity. injury.KidneyIntSuppl2012;2:1e138. ANAESTHESIAANDINTENSIVECAREMEDICINE22:7 405 Ó2021PublishedbyElsevierLtd.