Ira Varianta 2010 2011

Acute Renal Failure

IRA si studentul la medicina

Stabilirea unei definitii medicale

Definitia insuficientei renale acute (IRA)IRA este un sindrom definit printr-un declin rapid al ratei de filtrare glomerulara, caracterizat clinic de o crestere impotanta a ureei si creatininei serice.

Oligoanuria este prezenta in 30-40% din cazuri. Unele cazuri se pot prezenta cu poliurie.

IMPORTANTA IRA (AKI)AKI is common.AKI imposes a heavy burden of illness (morbidity and mortality).The cost per person of managing AKI is high.AKI is amenable to early detection and potential prevention. There is considerable variability in practice

Dfinitii ?

Cratinine srique> 2 mg/dl> 3 mg/dl + 44.2umol/L, Cr. de base < 221umol/l + 20% si Cr. de base > 221 umol/l (Singri,JAMA2003) Doublement de la cratinine / dosage antrieur / admission Dfaillance rnale de KnausUre > 36 mmol/LCratinine > 310 mol/LDiurse< 156 ml/8 h< 479 ml/24 h Ncessit dEER, mais prdfinir les critres!IRA in ATI / reanimare

Criteriile RIFLE

Limitele criteriilor RIFLEAplicare neriguroasa a definitieiExcluderea pac cu afectare renala preexistenta

Neincluderea IRA- community acquired

Debitul urinar- f frecvent necuantificat

Acute and Chronic Kidney Disease Conceptual model for integration of AKI, CKD, and AKD. Overlapping ovals show the relationships among AKI, AKD, and CKD. AKI is a subset of AKD. Both AKI and AKD without AKI can be superimposed upon CKD. Individuals without AKI, AKD, or CKD have no known kidney disease (NKD).

DeathConceptual Model for AKIComplicationsNormalIncreased riskKidney failureDamage GFRAKIKDIGO & AKI Guideline 2010

Definition and Staging of AKI Increase in SCr by >0.3 mg/dl within 48 hours; or Increase in SCr by >1.5-fold above baseline, which is known or presumed to have occurred within 7 days; or Urine volume

Staging of AKI

StageSCrUrine output1>1.5-1.9 times baselineOR0.3 mg/dl increase2.0-2.9 times baseline12 hours3>3.0 times baselineORincrease in SCr to >4.0 mg/dlORRRT12 hours

Insuficienta renala acuta Incidenta -1982, clinici nefrologie in UK1237 cazuri in 12 luni22.2 / 1,000,000 populatie

- Sfarsitul anilor 1980 in Scotia 71 / 1,000,000 populatie

1990s, Irlanda de Nord 127 / 1,000,000 populatie (40% au necesitat dializa)

Insuficienta renala acutaIncidenta (cont.)1990s, studiu prospectiv in comunitate (Feest)Durata de 2 ani, inclusi 440,000 pacienticreatinina > 500 umol/l140 pmp / an72% erau varstnici > 70 ani Incidenta de 17 / pmp daca pacientii erau < 50aniIncidenta de 949 pmp daca pacientii erau > 80 anisupravietuire 54% la 12 luni, 34% la 2 ani

Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) 29 269 critically ill patients.Acute renal failure in the critically ill: a multinational study.JAMA. 2005 294(7):813-8. 5.7% (5.5 - 6.0%) had ARF. 72% were treated with RRT. Overall hospital mortality: 60.3% (58 - 63%).

Number and incidence of patients with ARF receiving RRT by age and sexFemale Male Total

Age group (years)pmpGroup A154469 > 75469Total212Group B154412 >75288Total74All15448145642966574844 75757Total286

Insuficienta renala acuta ETIOLOGIEO larga varietate de patologii care pot aparea intr-o larga varietate de situatii clinice

ETIOLOGIEpre-renalarenalapost-renala

Tipurile principale de IRAInsuficienta Renala AcutaCauze pre-renaleCauze renaleCauze Post-renaleNecroza tubularaNefrita interstitiala(10% cazuri)Glomerulonefrite acute(5% cazuri)Ischemica(50% cazuri)Toxica(35% cazuri)

Este IRA prerenala (functionala)o conditie frecventa?Necroza tubulara acuta45%IRA functionala21%IRC acutizata 13%IRA obstructiva, postrenala 10%Glomerulonefrite, vasculite4%Nefrita interstitiala acuta2%Cauze vasculare2%

Sdr de insuficienta renala acuta Dobandite in comunitate Dobandita in spital Dobandita in ATIIncidenta Mica Moderata (5%) Mare (10-20%)

Cauza Unica Multipla MSOF pre>post>renal pre>NTA>post MSOF + NTA

Supravietuire Buna Medie Redusa 70-90% 30-50% 10-30%Schrier & Gottschalk, Diseases of the Kidney, 1996

Causes of AKI: Exposures and susceptibilitiesKDIGO & AKI Guideline 2010

Cauze de IRA in spital Sepsis

Aetiological factors contributing to ARF SCOTIA TOATE CAZURILE

FactorsPatients(%)IRA (%)IRC A (%)Sepsis48.152.535.4Hypotension25.027.218.7Post-surgical21.524.213.9Hypovolaemia22.623.520.1Nephrotoxins and drug induced12.511.814.4Hepato-renal syndrome7.59.32.4Myocardial infarction6.35.87.7Rhabdomyolysis5.67.21.0Urinary obstruction5.25.05.7Glomerulonephritis3.02.34.8Pancreatitis2.83.70.5Myeloma1.21.50.5

Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Most common factor - septic shock 47.5% (45 - 49%).

30% of patients had pre-admission renal dysfunction. Dialysis dependent survivors: 14% (11- 16%).JAMA. 2005 294(7):813-8.

BEST KidneyIndependent risk factors for mortality: use of vasopressors (OR, 1.95; (1.50-2.55) P

806040200Mortalitatea in primul an la pacientii cu BRC terminala raportata de ERA EDTA Mortalitatea la pacientii dializati pt IRA1950 1960 1970 1980 1990yearMortalitate (%)Evolutia mortalitatii in IRA vs IRC in Europa

Proportia de varstnici (> 80 ani) cu IRA internati in ATI197819801982198419861988199019921994199601020304050Ani Procent de varstnici din numarul total IRA19781980198219841986198819901992199419961020304050Akposso et al Intens Care Med 26:400-406,2000

Copyright restrictions may apply.Prescott, G. J. et al. Nephrol. Dial. Transplant. 2007 22:2513-2519; doi:10.1093/ndt/gfm264Survival of patients in group A by comorbidity risk group

Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patientsMetnitz PG et al.Crit Care Med. 2002 Sep;30(9):2051-8. ARF associated with four-fold increased mortality Controlled for underlying disease severity using case controls Mortality significantly higher in ARF patients (62.8 vs. 38.5%)

Patofiziologia IRA

Teoria hemodinamicaTeoria celularaTeoria interactiunilor celulare

Patofiziologia IRA

Teoria hemodinamicaVascoconstrictia I/RObstructie tubulara Retrodifuziune

IRA functionalaBlantz, KI, 53, 512-523, 1998.Vasoconstrictie renala si scadereacoeficientului de ultrafiltrare Deshidratare Angiotensina IIInervatie adrenergicaADH Insuficienta cardiaca SepsisOxid nitricProstaglandineScaderea RFGFeedback tubuloglomerular

Insuficienta renala acuta Fiziologie renala NORMALAAutoreglarea Ca urmare a reducerii perfuziei renale scade tonusul arteriolei aferente I creste tonusul arteriolei eferente Procesul este ANGIOTENSIN II dependentPermite mentinerea presiunii capilare glomerulare si procesul de ultrafiltrare

Insuficienta renala acutaFiziologie renalaFeedback-ul tubuloglomerularmacula densa sesizeaza modificarile dependente de flux si ale conc de Cl- in fluidul tubularFluxul plasmatic la nivelul nefronului se ajusteaza prin alterarea rezistentei arteriolei aferenteModificarile sunt dependente de SRAA, adenozina, prostaglandine

Presiune de perfuzie renala (mm Hg)Flux sangvin renal relativ (%)150100500050100150Autoreglarea fluxului plasmatic renalNormalIschemia

Insuficienta renala acutaMecanisme Protectoare Autoreglarea renala Eicosanoizi vasodilatatoriNSAIDAngiotensina IIACE / AT1RA

Riscul de IRA la AINS asociata cu anumiti factori de riscGutthann et al. Arch Int Med 156 2433-2439, 1996

OR

95% CI

No use of NSAID

1.0

Current use of NSAID

4.1

1.5-10.8

15-64 yrs old

1.0

> 65 yrs old

3.5

1.3-9.8

Recent hospitalization

6.9

2.9-16.2

Cardiovasular risk present

2.7

1.0-7.3

Other nephrotoxic drugs

4.0

1.4-11.4

(1)VasoconstrictieSistem renina angiotensinaEndotelina PGI2 NO(2)Obstructieprin cilindri(3)Retrodifuzie tublaraIschemiaNefrotoxineLeziune tubulara(tub contort proximal si ram ascendent ansa Henle )(5)? Efect direct pe glomerul GFR

Oligurie flux tubularPresiunea intratubularaTeoria hemodinamica (cont.)(4)Inflamatie interstitiala

Anatomical and physiologic features of the renal cortex and medulla.Brezis & Seymour, The New Engl. J. of Med., 332,647-655, 1995. Medullary raysCortical labyrinthsBlood flow4.2 ml/min/gMacula densaCortexRenal veinRenal arteryMedullary tickascending limbsBlood flow1.9 ml/min/gOuter medullaInnermedullaPO2,~ 50mm HgPO2,~ 10-20 mm Hg

Brezis et al, The Kidney, 1991.Countercurrent exchange of oxygen in the vasa rectaHeterogeneity of renal circulation

Cortical Medullary Junction: ischemia/reperfusion

ISCHEMIEDepletie ATPREPERFUZIEAcumulare de hipoxantine Xantine Generare de superoxidPeroxid hidrogenRadical hidroxyl1) Stresul oxidativ SODCrestere Ca2+ citosolicActivarea proteazei Ca calmodulin dependenteXantin oxidazaXantin dehidrogenazaFe2+Fe3+Fenton reaction

2) Inflammatory response

PMNInflamatia microvasculara si tubulointerstitiala in IRA

Modified from Rabb and StarARF (chapter 6):p 89,2001 and Burne-Taney and RabbCurr Opin Nephrol Hypert 12: 85-90,2003

3) Rolul calciului in leziunile de ischemie-reperfuzie renale.Paller & Greene, Ann; Acad. Science, 723, 1994

Cell injury to hypoxic rat proximal is reduced by chelation of extracellular Ca2+.Wetzels et al, J. Pharmacol. Exp. Ther., 267, 176, 1993

AB Pathways of oxygen-derived reactive speciesPathways of formation of reactive nitrogen species4) Role of NO disparitia posibiltatii de vasodilatatie

Pathophysiologic consequences of:reduced NO production through eNOS and increased NO generation through iNOS.Goligorsky and Noiri, Sem. in Nephrol., 3, 263-271, 1999.NORMAL NO FUNCTIONS Antithrombogenic properties of endothelium Decrease PMN adhesion Vasodilatation Enhanced PMN motility Induction of tubular epithelial cell injury Loss of vasomotioneNOSiNOS

Cytoskeletal Targets of NOMicrovillar ActinIntegrinsBasolateral MembraneNOLumenNOInduction of tubular epithelial cell injury

Patogeneza IRA ischemica: Ca NO - inflamatiaSchrier et al, J Clin Invest 2004, 114:5-14

I/R:Other relevant issues

Expression of HIF2 in different kidney zones in experimental ARFRosenberger et al Kidney Int 2005, 67: 531-542.

Influence of furosemide on inner stripe HIF-1 expressionRosenberger et al Kidney Int 2005, 67: 531-542.

Role of EPOProtection of kidney I/R damage by EPOSharples et al JASN 2004, 15:2115-2124.

Patofiziologia IRA

Teoria hemodinamicaVascoconstrictia I/RObstructie tubulara Retrodifuziune

Aspectul microscopic in NTA

Potential cytoskeletal targets for proteases during ischemia-reperfusion

Semiquantitative scoring of thedistribution of proximal tubularcells in post-ischemic kidneysScoring of thedistribution0.00.51.01.5Group IGroup IINa/KATPaseFodrinAnkyrinAlejandro et al. Kidney Int 48:1308,1995.

Afectarea subletala a cel. tubulare renale determina exfolierea cel. epiteliale viabile si adeziune intercelulara aberanta mediata de 1-integrina ( Noiri et al. Kidney Int 46:1050, 1994)

Niori et al, KI, 48, 1375-1385, 1995.

Normal renal epithelium

Sublethal injury

Presence of an excess of free RGD

Effects of ischemia on renal tubules in the pathogenesis of ischemic ARF Schrier et al, J Clin Invest 2004, 114:5-14

Sediment urinar cu prezenta de cilindri epiteliali la un pacient cu NTATamm Horsefall protein

Embolie de colesterol la PBR

Caracteristicile majore ale embolizarii acute cu emboli de colesterolExacerbarea brutala sau aparitia de novo a HTAIRA progresiva cu evolutie diferita de a NTAAfectare cutanata Livedo reticularis Gangrene Cianoza/purpuraFebra Durere lombara, abdominala, membre inferioare

Patofiziologia NTATeoria celularaPierderea polaritatii celulareNecroza vs apoptozaRecuperare prin factori de crestere ca IGF-1, HGF, EGF

Ischemiareperfusion results in reversible or irreversible injury to the proximal tubular cell(J Bonventre)

Anatomia patologica in NTA-faza de recuperareRecovering ATN showing a tubular epithelial cell mitotic figure (arrow).

Different characteristics between apoptosis and necrosisAPOPTOSISCell breaks into small fragmentsCell fragments are phagocytizedNo inflammationNECROSISCell rupturesCell contents are releasedExtensive inflammation

Gupta S, Verfaille C et al, Kidney Int 62(4),1285-1290, 2002. Extrarenal cells participate in the regenerationof renal injury in human ARF- intrarenal presence of Y chromosome in male recipient of female donorMale recipient male donor+ controlFemale patient with minimal change- controlMale recipient Female kidney with ATNMale recipient female kidneyResolving ATN

Sutton et al Kidney Int 62:1539-1549,2002

CMJ hipoxie Leziune microvascularaObstructieInflamatieCoagularenediferentiereMigrareProliferare RediferentiereRepolarizarePierdere BBMExfoliereObstructie tubulara

Leziune celularaFazele clinice si celulare in IRA ischemicaExtensiePrerenalaIntretinere ReparatieInitiere

Relatia intre fazele clinice si celulare ale IRA ischemice si impactul asupra functiei renale reprezentat de RFGThimothy & Bruce, Sem in Nephrol., 18, 5, 490-497, 1998.Faze clinice Faze celulareAzotemie prerenala

Initiere

Stare

RecuperareAdaptare vasculara si celulara

Depletie ATP leziune celulara

Reprare, migrare, apoptoza, proliferare

Diferentiere celulara

GFRGFRGFR

Insuficienta renala acutaIRA CLINICA

Insuficienta renala acutaIRA practica clinica corecta Index inalt de suspiciune clinicaSemnele si simptomele clinice initiale sunt nespecifice Determinarea bazala a ureei si creatininei plasmatice pentru toate internarile in urgenta si TESTAREA REGULATA IN TIMPUL SPITALIZARIIcuantificarea corecta intrari / iesiri, greutatea zilnica, TA in clino- si ortostatismDetectare/ recunoastere precoce si tratament prompt sau transfer cu toate documentele si investigatiile imagistice

Insuficienta renala acutaIRA practica clinica incorectaPreluarea cazului de mai multi medici, fara continuitate in urmarirea cazuluiAbsenta foii de observatie no charts / recordsanalize? Au fost cerute? Au fost vazute? S-a actionat in consecinta?Administrare de nefrotoxice; ignorarea determinarii nivelelor serice ale medicamentelorFctie renala anormala ignorata pana vineri la ora 4.59pm Transferul pacientilor fara supraveghere, documentare corecta a cazului

2. afirmarea diagnosticului de insuficienta renala ACUTA

IRAIRCIstoricRetentie azotata absentaDg anterior de nefropatie sau HTA / anemie / nocturie Examen clinicModificari cutanate absenteModificari cutanate prezente. HTAAnemiaAbsenta sau redusa in raport cu retentia azotataPrezentaModificari radiologice osoaseAbsentePrezente, definitorii pentru boala osoasa renalaDimensiunile renaleNormaleReduse, rinichi destructuratConsecintele prezentei HTA de lunga durataAbsenteHTA prevalenta in 90% din cazurile cu IRC

Insuficienta renala acutaIRA este posibila obstructia de tract urinar?DA !!!!!La nivel prostata, uretra, vezica urinara, ureter, pelvis renalCauze: litiaza, chirurgie, afectiuni ginecologiceObstructia completa este cauza de anurie totala, obstructia incompleta putand da alternanta oligurie/poliurieATENTIE LA ASOCIEREA NTA + OBSTRUCTIE

Insuficienta renala acutaIRA este posibila obstructia de tract urinar?

ECOGRAFIE DE URGENTA RENALA SI VEZICALAhidronefrozaureterohidronefrozaDistensie vezicalaLitiaza Neoplazii, inclusiv limfoame (adenopatii)Mase periaortice inflamatorii

Acute renal failureARF - is urinary obstruction a possibility?If pelvicalyceal dilatation (hydronephrosis) confirmed,percutaneous nephrostomyrarely, retrograde ureterography / stentrepeat U/S after relief of obstructionif U/S doubtful, consider CT of kidneys, retroperitoneum and pelvis

Insuficienta renala acutaIRA hidronefroza bilateralaNefrostomie bilateralaSau, din start, de ales rinichiul mai accesibil sau cu dilatatie mai importanta, cu conditia sa existe cortex renal pe acea parte (obstructia indelungata duce la atrofie corticala severa cu pierderea functiei renale)De retinut rolul diagnostic si prognostic al nefrostomiei (exp. pionefroza)

Insuficienta renala acutaIRA cauza posibila este GN?GN acuta, LES, vasculitele sistemicePrognosticul este mai usor daca se cunoaste diagnosticul subiacent Istoric complet si examen fizicMicroscopia urinii (din proba matinala, efectuata de medic)Cilindri hematiciDeterminarea de urgenta a ANCA, anti-GBM, ANA, VSH, CRPDaca este suspiciune de LES, adaugate: Ac ds-DNA-binding, C3, C4

Acute renal failureIRA este posibila o cauza vasculara?Pacient varstnic, ateromatoza generalizata, fumatorDimensiuni si functie renala asimetricaUtilizarea IECA, deshidratare, prabusirea TA Embolii cardiace (FA, boli valvulare), de la nivel arc aortic (spontan; dupa cateterizare), al aortei abdominale (similar anterior)

Diagnosticul pozitiv de IRA prerenala1. Afirmarea diagnosticului de insuficienta renala2. Afirmarea dg. de IRA3. Afirmarea dg. de IRA prerenalaA/ Context etiologic sugestivB/ Examen clinic sugestivC/ Confirmare paraclinicaIndicii urinariSedimentul urinarAlteleD/ Proba terapeutica

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALAA/ CONTEXT ETIOLOGIC SUGESTIVA.1. Depletie reala a volumului extracelularpierderi digestive: varsaturi, diaree, drenaj gastric sau intestinal;hemoragii exteriorizatepierderi renale: exces de diuretice pierderi respiratorii sau/si cutanate: transpiratii profuze, arsuri;

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALAA/ CONTEXT ETIOLOGIC SUGESTIVA.2. Depletie relativa a volumului extracelularsechestratie in al 3-lea sector: arsuri, zdrobiri tisulare, pancreatite, ascita, ocluzie intestinala; hemoragii ne-exteriorizate

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALAA/ CONTEXT ETIOLOGIC SUGESTIVA.3. Hipotensiune arterialaColaps circulator de orice cauzaSupradozaj de medicatie antihipertensivaReducerea prea brusca a TA (la varstnici)

A.4. Hipoperfuzie renala selectivaExces de IECA la pacienti cu stenoza bilaterala de artera renalaExces de AINS pe fond de hipovolemieDroguri vasoconstrictoare artera renala - ciclosporina

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALAA/ CONTEXT ETIOLOGIC SUGESTIVA.5. Stari edematoase (combina hTA si hipoperfuzia selectiva renala)Insuficienta cardiaca congestiva severaCiroza hepatica decompensata vascularSindromul hepato-renal

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALAB/ EXAMEN CLINIC OBIECTIV CENTRAL = APRECIEREA STARII DE DESHIDRATARESubiectiv: senzatie de sete, astenieObiectiv: recenta a greutatii corporeale, temperaturii cutanate turgorului cutanat cu pliu persistent pretoracic,mucoase uscatehTA, TA fata de antecedente, pseudo-normalizarea TA,modificari posturale patologice ale TA jugulare plate, colaps al venelor peroferice, presiunii intraoculareoligurie cu urini concentrate

Confirmarea paraclinica a diagnosticului de IRA prerenala: C/ INDICI DIAGNOSTICI URINARI

Indicele urinarIRA prerenalaIRA parenchimatoasaNa urinar (mEq/L)< 20> 40Uree / Cr. Plasmatica (*)40-60 (>20) 1016HipostenurieOsmolaritate urinara> 500< 350Osmolaritate u / p> 1.5< 1.1Uree u / p> 8< 3Creatinina u / p> 40< 20Fractia de excretie a Na< 1> 1

Fractia de excretie a Na urinarDefinitie: procentul din totalitatea Na filtrat prin glomerul care este excretat in urinaNa excretat = Na urinar x volumul urinarNa filtrat = Na plasmatic x RFGRFG = Cl. Creat = Cr.U x V / Cr.PFE Na = NaU x V / NaP x [(Cr.U x V):Cr.P] = NaU x Cr.P / NaP x Cr.U

Confirmarea paraclinica a diagnosticului de IRA prerenala: Sedimentul urinar SARAC = fara celule, cilindri, detritusuri celulare, proteinurie absenta

Dinamica creatininei zilnice cu fluctuatii dependente de perfuzia renala vs crestere > 0.3-0.5 mg/dL/zi (26-44umol/L/zi), tipica pentru NTA

Characteristics of an ideal biomarker for AKI

Prioritatile terapeutice in IRA (I)

Insuficienta renala acutaIRA - prognosticScorul Apache II nu este un element prognosticOrice sistem local computerizat care poate da un prognostic, poate fi validat daca este testat prospectiv si independent in IRA de diverse etiologii, pe pacienti cu varste variate, in alte unitati si spitale

Insuficienta renala acutaIRA al cui teritoriu este ?NefrologGeneralist Intensivist Chirurg?

Acute renal failureARF - what does it all cost?20-25,000 per ITU patient (~ 25 days)170,000 per ITU survivors leaving hospital (~ 90 days)if 1200 cases per year, and 200 savedABOUT 35,000,000 / YEAR for ITU (E + W)or 0.1% of the total NHS budget1{cf 20,000 per year per patient for maintenance dialysis}

Prioritatile terapeutice in IRA (I)Identificarea si corectarea factorilor pre- si postrenaliRevizuira medicatiei si stoparea nefrotoxicelorOptimizarea debitului cardiac si a fluxului plasmatic renalRefacerea / cresterea fluxului urinarMonitorizare zilnica ingesta/excreta, greutate zilnica

GENERAL MANAGEMENT

IRA - PEUT-ON LA PREVENIR ?

IRA - PEUT-ON LA PREVENIR ?Early goal-directed therapy in the treatment of severe sepsis and septic shock(Rivers et al. N. Eng. J. Med. 2001; 345 : 1368-1377)

Early goalStandard therapy therapy (n = 130) (n = 130)

MODS*Baseline7.6 3.17.3 3.16 h5.9 3.76.3 3.7p < 0.00172 h5.1 3.96.4 4p < 0.001Mortality 30.5 % 46.5 %p < 0.01

* Scale0 - 24 (Marshall JC, Cook DJ. Crit. Care Med. 1995)

Mais, aucune valuation de la fonction rnale H72

IRA prerenalaTRATAMENTOBIECTIV CENTRALRefacerea perfuziei renale prin:

Corectarea depletiei volemice absolutesauCorectarea perfuziei renale efective diminuate

REPREZINTA O URGENTA !

Prioritati terapeutice in IRA (II)Identificarea si tratarea complicatiilor acute (hiperkalemia, hiponatremia, acidoza, EPA)

Asigurarea suportului nutritional

Identificarea si tratarea agresiva a infectiilor

Initierea dializei inainte de aparitia complicatiilor uremice

Adaptarea dozelor de medicamente la Cl. Crr.

Oprirea si repararea leziunilor celulare active

Insuficienta renala acuta IRA tratamentul in urgenta al hiperkaliemiei

monitorizarea K+ plasmatic si ECG

Ultrarapid, beneficiu dispare rapid :Gluconat calciu 10 ml 10% x 1- 4

Rapid, beneficiu de scurta durata (ore) 50 ml dextroza 50% , 10 U actrapidMonitorizarea BM stix orar timp de 6 h dupa administrare

Insuficienta renala acutaIRA tratamentul in urgenta al hiperkaliemieiRapid dar problematicSolutie 1.26%, 4.2% sau 8.4% NaHCO3Volum, osmolaritateIritant venosScadere rapida a 2,3 DPG; scadere rapida a Ca ionicSer fiziologic hipertonVolum, osmolaritateRapid, util daca se monitorizeaza atent:PIV salbutamol (0.5 mg over 15 mins) Salbutamol inhalator (10 mg)

Insuficienta renala acutaIRA tratamentul in urgenta al hiperkaliemieiLent, dar eliminare reala a K Rasini schimbatoare ioni - calcium resonium (15 g po, 30 g clisma)Se poate continua un timp dar determina constipatie(fortarea) diurezeiLimitata de functia renala si volumul urinarImpune un volum urinar de > 1000 mls / 24 hExcretia urunara de K+ redusa de medicamente (IECA, amiloride, spironolactona)

Insuficienta renala acutaIRA de ce facem ceea ce facem ?Corectie volemicaDiuretice de ansaMannitolDopamina{aminofilina}{CCB}{factor natriuretic atrial}

Clase de dezechilibre hidrice in ATI

DRY-DRY

deshidratare

WET-DRY

-IC cu deshirdratare prin tratatament diuretic si hipoperfuzie renala

-IC cu hipoperfuzie renala in ciuda hiperhidratarii generale

DRY-WET

Spatiul trei: hiperhidratare, darlichidul nu e in circulatie

WET-WET

Hiperhidratare evidenta

MONITORING - KEY TO SUCCESSPA CatheterOesophageal doppler

Corectarea depletiei volemiceDEPLETIA VOLEMICA ABSOLUTA / REALATransfuzii sanguine atunci cand etiologia este hemoragica sau oricand Hb < 10 g/LEtiologie non-hemoragica sau in absenta sangelui:Abord vascular central permite monitorizarea PVC; +/- flexula de calibru mare (14G)Determinarea PVCPVC < 2 cm H2O volemia insuficienta, necesitand refacere volemicaSolutii cristaloide vs coloide?

Corectarea depletiei volemice Solutii cristaloide vs coloide?Review al trialurilor randomizate publicate - solutiile coloidale:Se asociaza cu un risc de deces crescutEficacitate similara cu NaCl izotonaSunt mai scumpe

CONCLUZIE: NaCl izotona va fi preferata pana in momentul stabilizarii hemodinamice. Exceptie posibila colapsul circulator deoarece solutiile coloidale, macromoleculare sau saline hipertone corecteaza TA si volumul circulator mai rapid.

Immediate response:- Fluid resuscitation!

Corectarea depletiei volemiceDaca PVC > 8 cm H2O, se opreste aportul sodat si se reconsidera situatia tonicitatea si continutul electrolitic al lichidelor de substitutie se modifica in functie de tipul pierderilor si de dinamica constantele plasmatice

In formele cu hTA si PVC > 10 cm H2O se presupune existenta unui soc cu rasunet cardiac si se recurge la droguri cardiotonice sau/si vasoactive.

Corectia volemica ulterioara functie de tipul pierderilor

NaKHHCO3ClSecretie gastrica40-651090100-140Fistula pancreatica135-155570-9055-75Diaree25-5030-6030-4520-40Transpiratii30-50545-55

Corectarea depletiei volemice

La pacientii la care IRA este prerenala, diureza si functia renala excretorie se vor ameliora semnificativ dupa corectarea volumului intravascular si a TA.

Daca debitul urinar orar ramine scazut (< 30 ml/hr.), vor fi utilizate si alte masuri pentru ameliorarea functiei renale.

Corectarea perfuziei renale efective diminuateStatus edematos cu volum intravascular redus si redistribuirea fluidului spre compartimentul extravascular (SN, ciroza, sepsis)

Obiectiv: rata diurezei = rata de reumplere vasculara

Metode: in cazurile refractare escaladarea masurilor de promovare a diurezei

Solutii terapeutice pt IRestrictie sodataDiuretic de ansa in doza conventionala (furosemid 40 mg iv, bumetanide 2 mg iv)Diuretic de ansa in doze mari SI repetate (furosemid 200 mg la 6 ore)Diuretic tiazidic urmat la 30 min de diuretic de ansa in doza mareDiuretic de ansa in infuzie continua (furosemid 10-40 mg/hr)Diuretic de ansa in doze mari diluat in albumina desodata perfuzat in 30 minute la fiecare 6 ore. Ultrafiltrare

Corectarea perfuziei renale efective diminuateII. Status edematos cu volum intravascular crescut + vasconstrictie pre-renala, secundara insuficientei cardiaceObiectiv: compensarea cardiaca si cresterea debitului cardiacMetode: presarcinii prin nitrati sau utilizarea diureticelor (in cazurile refractare escaladarea masurilor de promovare a diurezei) postsarcinii prin vasodilatatoare, atentie la IECADroguri inotrope pozitive

Corectarea perfuziei renale efective diminuateIII. Vasoconstrictie prerenala directa (hipercalcemia, radiocontrast, sdr. hepatorenal, ciclosporina)Dopamina in doze de stimulare a receptorilor dopaminergici 1-3 ug/min/kgHidratare+diuretic de ansaBlocante ale canalelor de CaCorticoizi, bifosfonati, calcitoninaMonitorizarea nivelului terapeutic al ciclosporineiAntagonisti de endotelina

Diureticele de ansaRatiuni teoretice pentru utilizarea diureticelor de ansa:inhiba pompa Na/K/Cl din lumenul ramurii groase ascendente a ansei Henle, diminind astfel semnificativ activitatea metabolica la acest nivel si deci necesarul de oxigen;cresc fluxul de urina intratubular, prevenind / reducind obstructia tubulara;inhiba procesul de feedback tubuloglomerular;reduc rezistenta la nivelul vasculaturii renale si cresc astfel, fluxul sanguin renal (mecanism mediat prin prostaglandine).

Insuficienta renala acuta IRA de ce facem ceea ce facem ?Diuretice de ansa (furosemid, bumetanid)Shilliday et al (NDT, 1997, 12)Trial prospectiv, dublu-orb, placebo controlat care a folosit diureticele de ansa la 278 pacienti cu cr > 180. End point-uri: recuperarea functiei renale, dializa, decese

Acute renal failureARF - why do we do what we do ?Loop-diuretics (frusemide, bumetamide)Shilliday et al (NDT, 1997, 12)excluded 25% who recovered after hydration, 40% already given loop or osmotic diuretic or refusedall given dopamine 2ug/kg/min and mannitol 100 mls 20% solution 6 hrly for max 72 hrsrandomised to torasemide iv, or placeboTHOSE ON DIURETIC HAD A DIURESIS !No effect on dialysis, or survival

Diureticele de ansa in IRA: trial dublu-orb, randomizatShilliday et al. Nephrol Dial Transplant 11,1684,1996.Percent

Sheet:

Urine flow

Renal rec

Dialysis

Death d21

Tora

Furo

Placebo

Efectul diureticelor asupra mortalitatii si lipsei de recuperare a functiei renaleMehta et al JAMA 288: 2547-2553, 2002

OR (95% CI)

Variable

Unadjusted

Covariate adjusted

Covariate and propensity score adjusted

In-hospital mortality

1.37 (0.97-1.92)

1.65 (1.05- 2.58)

1.68 (1.06-2.64)

Nonrecovery of renal function

1.53 (1.08-2.15)

1.70 (1.14-2.53)

1.79 (1.19-2.68)

Death or nonrecovery

1.48 (1.02-2.12)

1.74 (1.12-2.68)

1.77 (1.14-2.76)

Diureticele, mortalitatea si lipsa de recuperare a functiei renale in IRA MEHTA et al. JAMA 288: 2547-2553, 2002

Curba de supravietuire Kaplan-Meier la pacientii critici tratati fie cu albumina sau ser fiziologic.SAFE study N Engl J Med 2004;350:2247-2256.

albumin

Mortalitatea globala in studiul SAFE la pacienti critici (albumina vs ser fiziologic)SAFE study N Engl J Med 2004;350:2247-2256.

Insuficienta renala acuta IRA de ce facem ceea ce facem ??Piv manitol Diuretic osmotic potentCreste volumul de filtrat tubular, efect de spalareReducerea edemului celulelor tubulareCreste volumul plasmatic si reduce HtActiune de scavanger al radicalilor liberiDin nou, lipsa de date controlate

Vasopresoare

Supravietuirea pacientilor cu soc septic tratati cu vasopresoareMartin et al Crit Care Med,28: 2758-2765, 2000NorepinephrineOther vasopressorsHospitalisation days Patient survival

Efectul norepinefrinei asupra fluxului urinar in socul septicml.h

Sheet:

3h before

1st 3 hour

All patients

NE alone

NE+dob or dop

Norepinephrine dose and mortality

Insuficienta renala acuta IRA de ce facem ceea ce facem ?Piv dopaminaSinteza in mod fiziologic I tubii contorti proximali din L-Dopareceptor DA-1 la nivel vase si tubiMai sensibili la dopaminaDetermina vasodilatatie si scade reabsorbtia tubulara de Nareceptor DA-2 localizat la nivel terminatii nervoase simpatice.

Efectul piv dopamina la subiectii normaliDOrio et al, Arch. Int. Physiol. Biochim., 92, S11-S20, 1985 : DA1 receptor effectrenal blood flow : receptor effectcardiac index and heart rate : receptor effectsystemic vascular resistanceindex and arterial pressure

Plot showing relative risks(diamonds) and 95% confidence intervals (lines) for all studies and for subgroups A,B, and C.Use of dopamine in ARF: a meta-analysisA:excluding studies using contrastB: Studies limited to heart diseaseC: excluded statistical outliers Kellum and Decker Crit Care Med 29:1526-1531,2001

Meta-analiza: dopamina in doze mici creste fluxul urinar dar nu previne disfunctia renala sau decesul FRIEDRICH et al. Ann Intern Med 142:510-24, 2005

Kidney International (2006) 69, 16691674'Low-dose' dopamine worsens renal perfusion in patients with acute renal failureALauschke et alCCM 2006;34:589-597

Insuficienta renala acuta Aminofilina Actioneaza pe receptorii renali de adenozina si inhiba fosfodiesterazaCreste fluxul plasmatic renal, reduce reactivitatea vasculara CCBLimiteaza fluxul intracelular de Ca++Multe date pe animale, efect maxim daca se administreaza anterior agresiunii

Meta-analysis of effects of Ca-entry blockers in RTx DELAYED GRAFT FUNCTIONLadefoged, Andersen, Clin. Transplantation, 8, 128, 1994.

Influenta ACC asupra functiei renale dupa expunere la substante de contrast iodateTepel et al. NEJM 343,2000

Contrast nephropathy and N-ACP=NSP= 0.09Durham et al, Kidney Int, 2202-2207, 2002

Sheet:

All subjects

Diabetes

Placebo

N-AC

Trialuri clinice recenteFactori de crestere - IGF IFactor natriuretic atrial - ANFAntagonistii receptorilor endotelineitiroxinaPGE1

What therapies MIGHT alter the outcome in acute renal failure?

There will not be a single answer but given what we know of pathophysiology, what might help in some cases (if we knew which to go for)?

Prevention of renal vasoconstrictionGrowth factorsStem cells

Fenoldopam and ARF in sepsisMorelli et al, Crit Care Med, 2005daysScrea (mol/l)

Sheet:

Placebo

Fenoldopam

Fenoldopam and ARF in sepsisMorelli et al, Crit Care Med, 2005daysScrea (mol/l)P=0.006P=NSP=NS

Sheet:

ARF>150mol/l

ARF>300mol/l

ICU mortality

Placebo

Fenoldopam

Prevention of vasoconstrictionFenoldopam dopamine A-1 receptor agonist

Systematic review of RCTs in ICU or major surgery16 studies, 1290 patients

Reduced risk of acute kidney injury OR 0.43 (0.32-0.59)Reduced need for RRT OR 0.54 (0.34-0.84)Reduced in hospital death OR 0.64 (0.45-0.91)

Stimulation of regeneration rhIGF-1, man

IGF-1 studii clinice/rezultateFranklin et al.(AJP 272:F257, 1997) a administrat IGF-1 (100g/kg s.c. la 12 hr x 6 doze) sau placebo imediat dupa chirurgia aortei suprarenal sau a arterei renale la to 54 pacienti. Nici unul nu a dezvoltat IRA. Reducerea postoperatorie a RFG a aparut mai rar la pacientii care au primit IGF-1 (22 vs 33%).Hirschberg et al. (Kidney Int 55: 2423,1999) a administrat IGF-1 sau placebo (100g/kg s.c. la 12 hr x 14 zile) la 72 pacienti cu IRA constituita de etiologie mixta. Nu au fost diferente intre RFG, Cr serica, flux urinar sau mortalitate intre cele 2 grupuri.

Stimulation of regeneration epo: how might it work in ATN?

Stimulation of regeneration epo at time of ischaemic renal injury (animal)

Stimulation of regeneration epo 6 hours after ischaemic renal injury (animal)

Stimulation of regeneration epo in patients with ATN receiving renal replacement therapy

Retrospective cohort study (not RCT) on ICUs of Washington University hospital

Epo (71 patients); no epo (116 patients)

No effect on requirement for blood transfusion when adjusted for baseline haemoglobin

No effect on renal recovery OR 0.63 (0.30-1.3)

Stimulation of regeneration HUVEC infusion immediately after ischaemic renal injury (animal)

Stimulation of regeneration infusion of cells that do and do not express eNOS immediately after ischaemic renal injury (animal)

HEK = Human Embryonic KidneyWT = wild typeG2A = transfected with deficient eNOSeNOS = transfected with active eNOS

Insuficienta renala acuta Factor natriuretc atrial ANARITIDE studyAllgreen et al, NEJM, 1997, 336, 828-834504 pacienti din ATI cu IRA, randomizati sa primeasca 24 h ANP sau placeboUtil in grupul oliguric (55/60 necesita dializa vs. 44/60 dupa ANP, p = 0.008)? Daunator in alte cazuri (79/195 necesita dializa vs. 95/183 after ANP, p = 0.03)

21-Day Dialysis-Free Survivorship.%* p=0.005 A vs. PLewis et al, AJKD 2000

Sheet:

All subjects (n=504)

Oliguric (n=121)

Non-oliguric (n=376)

Placebo

Anaritide (atrial natriuretic peptide)

CoagulationAnticoagulantProcoagulantCOAGULATION

Treatment of hypotension in septic shockFluidsDefinitelyInotropesDefinitely but.OthersActivated protein-cYes (cost!!!)

French multi-centre PRCT (n=299) - just completedLow dose hydrocortisone (50 qds) + fludrocortisonein early septic shock (within 6 hours) significant reduction in relative mortality!! European multi-centre PRCT underway

28-DAY SURVIVAL IN SEPTIC SHOCK (n=299)p=0.01TREATMENT 47%07142128daysPLACEBO 39%ALL PATIENTSCumulative survival rate

Treatment of hypotension in septic shockFluidsDefinitelyInotropesDefinitely but.OthersActivated protein-cYes (cost!!!)SteroidsProbably

Methylene blueNO scavengerNOS inhibitor2 mg/kg over 1550% respond

Treatment of hypotension in septic shockFluidsDefinitelyInotropesDefinitely but.OthersActivated protein-cYes (cost!!!)SteroidsProbably Methylene blue? rescue

VasopressinActs on V1 and V2 receptorsV2 receptors collecting tubules - water resorbtionV1 receptors vascular smooth muscle - vasoconstriction Anti-diuretic action/regulation of plasma osmolarity (5-10 pg/ml)Levels are dramatically increased (often >100 pg/ml) early in stress

VasopressinVP levels very low later in septic shock 3 vs. 22 pg/ml in cardiogenic shock (Landry et al, Circulation 1997)BP restored by small bolus doses of VP or low dose infusion (0.01-0.04 U/min)infusions up to 0.26 U/min had no pressor effect in normal humans

Treatment of hypotension in septic shockFluidsDefinitelyInotropesDefinitely but.OthersActivated Protein-c Yes (cost!!!)SteroidsProbably Methylene blue? rescueVasopressin.maybe

Rivers et al, NEJM 2001; 345: 1368-77

Van Den Berghe et al, NEJM 2001; 345: 1359-67

1548 admissions to 1 surgical ICU (Belgium) in 1 yrRandomised to receive insulin to keep blood sugar at: 80-110 mg/dl [4-6 mmol/l] or standard Rx of 180-200 mg/dl [9-11 mmol/l])Mortality reduced from 8 to 4.6% (p

Experimental Therapies in ARFBefore InjuryAfter InjuryHaemodynamicDiureticsACEIMannitolPDE inhibitorsDopamineANPCa2+ antag.Endothelin antag.

Cell InjurySOD anatag.PAF antag.anti-sense iNOSICAM-1 antibodyP-selectin antag.a-MSHCTLA-4IgRGD peptides

Cell repairIGF-1, EGF, HGFIGF-1

ConcluziiCercetarea elaborata si intensiva in NTA a dus la o intelegere mai buna a proceselor implicate In ciuda noilor cunostinte, nici un nou agent terapeutic nu si-a dovedit eficienta in conditii clinice. prevenirea si tratamentul precoce ale IRA/NTA sunt inca cele mai eficiente masutri terapeutice.

Suportul nutritional in IRAMarimea catabolismuluiFat emulsion 10 or 20%

Mild

Moderate

Severe

Energy substrates

glucose

glucose + fat

glucose + fat

AA/ protein (g/Kg/day)

0.6 - 0.8

EAA (+NEAA)

0.8 - 1.2

EAA + NEAA

1.0 + 1.5

EAA + NEAA

Nutrients

used

enteral formulae

glucose

50 - 70 %

glucose

50 - 70%

Insuficienta renala acuta ARF Nutritie

CATABOLISMUL ESTE REGULADat de rezistenta la insulina, efectul TSR, acidozaNecesarul de calorii creste si mai mult daca pacientul este septic Mortalitatea este direct proportionala cu balanta azotului Nu sunt date controlate care sa sustina efectul benefic al suportului nutritional asupra supravietuirii.

Insuficienta renala acuta ARF NutritieAlti factoriNr calorii / unitate volumNa, K, PO4 (reduce)Substante minerale (adaugate)De preferat calea enterala daca intestinul este functional35 Kcal, 1g proteine, 0.16g N / kg corp

Dialytic management of ARF

Johannes the baptist

Insuficienta renala acutaIRA terapii de supleere renalaIndicatii de initiere

Oligurie (< 500 mls / d)urea > 30 mmol/lcreatinina > 1000 umol/lpotasiu > 6.5 mmol/lpH < 7.2EPA refractarPericardita uremicaEncefalopatie uremica

Indications for dialysis in ARF in the ICUallowing often repetitive fluid challenges in a patient with apparent hypovolemia allowing the administration of high volume and/or sufficient protein nutrition

Insuficienta renala acutaIRA terapii de supleere renala

- Conditii tehnice de realizare Instituire rapida si usoaraEficienta Controlul volumului, fara limitarea alimentariiCorectia acidozei

Insuficienta renala acutaIRA terapii de supleere renala

- Conditii tehnice de realizare BiocompatibilateNecesitati minime de anticoaglare sistemica sau regionalaEfect minim/ absent asupra functiei renale, duratei IRAEfect minim/absent asupra stabilitatii hemodinamice Efecte farmacocinetice previzibile

Supravietuire bio-incompatibile vs bio-compatibileSchiffl* Kurtal Assouad* Neveu Albright *HimmelfarbJorres* Gastaldello*

TotalSubramanian et al, KI, 62, 1819-1823, 2002Relative risk 0.2 0.5 1 2 1.37*= randomized controlled trial

Odds ratio 0.5 1 1.5 2.0 2.5 3RCTs onlyCellulose-acetateCuprophaneSubramanian et al, KI, 62, 1819-1823, 2002Supravietuire: membrane bio-incompatibile vs bio-compatibile

Insuficienta renala acutaIRA terapii de supleere renalaPrincipii si optiuniConvectie vs difuzieContinua sau intermitentaMembrane de celuloza sau sintetice Acces vascular (arterial, venos, pompa de sange)Utilizarea de fluid de inlocuireNecesitatea si durata anticoagularii{dializa peritoneala}

Insuficienta renala acutaIRA terapii de supleere renala HD intermitenta De trei x/saptZilnica high-fluxHemofiltrareHemodiafiltrare{Ultrafiltrare}

Insuficienta renala acutaIRA terapii de supleere renaladifuziaIn hemodializaFoloseste membrane semipermeabile, pori de dimensiuni miciGradient de presiune arterio-venos Deplasare transmembrnara bidirectionalaintermitentaFrecvent efecte hemodinamice Clearance limitat (proportional cu durata)

Insuficienta renala acutaIRA terapii de supleere renalaconvectiaSolvit deplasat prin membrana semipermeabila impreuna cu solventul prin filtrare determinata de gradient de presiune transmembranarMembrana cu porii foarte mariEste de obicei o terapie continua Impune utilizarea de lichid de inlocuire Permite o epurare eficienta Poate fi combinata cu dializa in contra-curent in hemodiafiltrare

dialysate at high flow (up to 500ml/min)need for online water treatment

no dialysate; ultra-pure substitution fluidprecise ultrafiltration control DiffusionConvectionIHD vs CRRT: Definitii

Utilizarea IHD si a CRRT% of ARF patients% of nephrologistsMehta et al, Am J Nephrol, 1999

Sheet:

Never

75

CRRT

IHD

PD

Decision on treatment parameters Canada%patientsHyman et al, Am J Nephrol, 2002, 29-34

Sheet:

Nephrologist

Intensivist

Shared

PD

IHD

CRRT

Terapia de supleere renala continua pt pacientii cu IRA AvantajeAmeliorarea stabilitatii hemodinamiceReducere aritmii cardiaceAmeliorare nutritieAmeliorare schimburi gazoase pulmonareAmeliorare comtrol fluideAmeliorare parametrii biochimiciSedere mai scurta in ATI DezavantajeProbleme abord vascularRisc crescut de sangerareImobilizare prelungita Frecvent, ruperea capilarelor filtruluiCost ridicatAcidoza lactica la utilizarea de solutii lactat

Pe primul plan ,Eficienta

Clearanceul de uree necesar in CCRT pt atingerea controlului corespunzator al azotemiei la pacientii cu IRA.Frecventa IHD necesara pt atingerea controlului corespunzator al azotemiei la pacientii cu IRA.200010000Urea clearance (ml/hr)50 60 70 80 90 10050 60 70 80 90 100Weight (Kg)Weight (Kg)765432IHD Frequency (per week)100 mg/dL80 mg/dL60 mg/dLClark et al, JASN, 8, 804-812, 1997.60 mg/dL80 mg/dL100 mg/dL

Efectul dozei de dializa asupra supravietuirii1007550250% survival0 2 4 6 8 10 12 14 16 18 20 CCF ICU ARF Scorelow Kt/Vureahigh Kt/VureaCCF score outcomeLeblanc M, Paganini E Adv Ren Repl Ther 2: 255, 1995

Calculation of dose of dialysis in ARF- Urea clearance is dependent on the urea generation rate (UGR)Non-catabolic patientUGR=Protein (g/kg/day)/3,13-NUNExample: Body weight 70 kgProtein intake 1.3 g/kg= 91 g/day

Urea clearance required: l/day= UGR (g/day)/ s-urea (g/dl)Target urea = 112 mg/dl

26.7 g/day/ 1,12 g/l = 25 L/day

NUN = non-urea nitrogen appearance rate31 mg/kg body weight/dayCatabolic patientUGR=[(U24h - U0h)] x TBW + UUN(UUN= urea in urine, dialysate, UF)

Example:70 kg (TBW=42 l), anuricU0h= 112 mg/dl, U24h= 168 mg/dlUUN= CVVH UF = 24 x 1.4 g/l = 33.6 g/ dayUGR = 0.56 g/l x 42 l + 33.6 g/day = 57.1 g/ day

Urea clearance required:57.1 g / day / 1.12 g/ l = 50 L /day

How much ultrafiltration needed in acute renal failure?Dialysis mode

Continuous( CVVH, CVVHD)

Intermittent 3 x 4 h per week

5 x 4 h per weekUF-rate needed in case of anuria

2400 ml/day = 100 ml/h

5600 ml / HD = 1400 ml /h

3360 ml / HD = 840 ml / h

2400 ml/HD = 600 ml/h

Nutrition30 kcal/kg/day(75 kg = 2250 kcal

1000 ml AA 10 %750 ml Glucose 40 %350 ml Lipids 20 % +i. v. medication

about 3000 ml / day7 x 4 h per week

Kaplan-Meier curve of patient survival with different doses of veno-venous hemofiltration45 ml/kg.hr35 ml/kg.hr20 ml/kg.hrC Ronco et al The Lancet 356:26-30, 2000

Comparison of hemodynamic tolerance between CAVH and HDCAVHIHDmean MAPmaxi fall MAP%MAP drops>10mmHgmmHgmmHgMisset et al Int Care Med 22:742, 1996742,1996.mm Hg or percent0255075100125150

Hemodynamic stabilityMisset et al, Int Care Med, 22, 742, 1996p=NS

Sheet:

CAVH

IHD

Dobu g/kg/min

Dopa g/kg/min

Epinephrine mg/h

Stabilitatea hemodinamica Misset et al, Int Care Med, 22, 742, 1996p=NS

Sheet:

CAVH

IHD

Mean Map

Maxi fall Map

IHD: Hemodynamic stability and technical adaptationsTonelli et al, Kidney Int, 62, 1075-1080, 2002Use of Blood volume monitoring in IHD for ARF in the ICU

Concordance between BVM and hypotension = chance Rate and/or slope of BVM not predictive for hypotension

Conclusion: online BVM monitoring is unlikely to be of help in prevention of hypotension in ICU-related ARF

t=1t=6t=12t=13t=18t=240102030Time (hours) removal rate, % of inlet rateCytokine removal: clinical studiesDe Vriese & Lameire, J Am Soc Nephrol 1999

0612182450100150TNFIL-1bIL-6*** p

0612182420060010001400Time (hours)Ratio anti/proinflammatory cytokinesCytokine removal: pro/anti-inflammatory balanceDe Vriese & Lameire, J Am Soc Nephrol 1999

HD zilnica si prognosticul pacientilor cu IRA Schiffl et al NEJM 346: 305-310, 2002

Outcome CRRT vs IHDOdds ratioN= 349N= 268N= 227P= 0.01P= 0.37P= 0.72Swartz et al, AJKD,34, 424-432 , 1999

Sheet:

All patients

Subgroup1

Subgroup 2

Odds ratio

ICU daysRen recovery %Mortality %0255075Comparison of CVVHD and intermittent HD-Cleveland ClinicCVVHDIHD

Prognosticul imediat CRRT vs IHDN= 166P= 0.02P=0.02Mehta et al, Kidney Int, 2001, 1154-1163%

Sheet:

ICU mortality

Hospital mortality

All

CRRT

IHD

Prognosticul pe termen lung al TSR la IRA in ATIN=979Morgera et al, AJKD 40, 275-279, 2002%

Sheet:

All patients

Survived hospital at 6mnth

Survived 6mnth at 12 mnth

Survived

Died

Overview of comparative studies CRRT&IHDVanholder & Lameire Nephrology 6:57-61,2001# Odds of death 1.09 after correction (NS)

Survival CRRT IHDStudyYearA journalProspectiveSimpson&Allison1993NoYes6917Van Bommel1995YesNo4359Kresse et al1999NoNo2040Swartz et al1999YesNo##Mehta et al2001YesYes4058

Survival IHD vs CRRTA meta analysis based on literature search:2028 studies on outcome CRRT vs IHDonly 116 acceptable qualityonly 6 randomized controlled trialsonly 2 reported as full paper 4,5, 3 as abstract1)Simpson et al, 19932)Kierdorf et al, 19943)Sandy et al, 19984)John et al, 20015)Mehta et al, 20016)Uehlinger et al, 2001Tonelli et al, AJKD, 40, 875-885, 2002

Survival IHD vs CRRTSimpson

Kierdorf

Sandy Johns

Mehta Uehlinger

TotalTonelli et al, AJKD, 40, 875-885, 2002Relative risk (IHD) 0.2 0.5 1 2 10

CRRT: DisadvantagesBleeding:3.5 to 10% of deaths attributable to use of anticoagulation (Martin, AJKD, 24, 806-82, 1994)

25% of new episodes of bleeding attributable to anticoagulation (Ward, Kidney Int, 43, S237-S244, 1993)

CRRT: DisadvantagesCost:Higher cost of CRRT mainly due to:Expensive filter setsExpensive replacement fluid(monitoring) anticoagulation

CRRT: DisadvantagesManns et al, Crit Care Med, 31, 449-455, 2003

Cost (US$)/day

CVVH

CVVHD

CVVHDF

IHD

Total

(not including nursing costs)

(includuding nursingcosts)

No antico

564

601

592

344

Heparin

498

526

527

Citrate

NA

NA

731

CRRT: dezavantajesangerare CostInconvenienta Greseli in aprecierea balantei hidriceTulburari electrolitice Hipotermia

IHD clasica 4 h, 3 ori/sapt

hemodiafiltrare lenta (adaptabila si zilnica)

CVVHD cu volume mariCVVHDCVVHCAVHDCAVH

CRRT clasic

Slow Extended Daily DialysisOfera alegerea intre avantajele unui monitor IHDF (eficienta mare, cost mic, control precis al ultrafltrarii) combinate cu aavantajele CRRT (durata mare de tratament, control metabolic) intr-o maniera modulara, utilizand un singur tip de aparat

Slow Extended Daily DialysisImpune evaluare zilnica in echipa nefrolog si intensivistAdaptatarea Timp de dializa : de la HD continua la IHDFluxului de sange si dializat pe aparatA ratei de hemofiltrareFunctie de necesitatile pacientului

Slow Extended Daily DialysisTypical: start as an intermittent CRRT, and gradual increase in efficiency and decrease in duration of treatmentIf needed or wantedpotential to perform on-line hemodiafiltration!!!!!!!TAKE CARE OF WATER QUALITY!!!!!!!!Potentially more safe to use high-flux dialyzers without HDF, speculating on backfiltration

Slow Extended Daily DialysisCost containment:No need for expensive all -in setsUse of conventional artificial kidneys and tubings (better price-setting negotiation, no stock problems)No need for expensive substitution fluid bagsHigher precision of ultrafiltration controlMore possibilities for interventions (CT-scan, isotopes, surgery, mobilization) Reduced need for anticoagulationreduced time;possibility of no-heparin dialysis in view of low cost

Total number, duration, and median number of treatments performedKumar et al. Am J Kidney Dis 36:294-300,2000

EDD

CVVH

Total no of treatment days

367

113

Median duration daily treatment(h)

7.5 (6-8)

19.5 (13.4-24)

Median no of treatments/patient

9 (3-39)

6 (3-15)

Comparatia MAP in timpul EDD vs. CVVH.Kumar et al, AJKD, 36, 294-300, 2000P=NSP=NSP=NS

Sheet:

preMAP

midMAP

endMAP

CVVH

EDD

Percentage of treatment days requiring inotropic support.% of treatment daysKumar et al, AJKD, 36, 294-300, 2000

Sheet:

1 Inotrope

2 Inotropes

3+ Inotropes

CVVH

EDD

SLEDD: anticoagulareHeparin need in units/dayKumar et al, AJKD, 36, 294-300, 2000 No heparin: 31.9% in SLEDD vs 2.7% in CCVH (p

SLEDD: AdequacySchlaefer et al, KI, 56, suppl 7, S20-S23

SLEDD

CRRT

Blood flow (ml/min)

100-300

100-200

Dialysate flow (ml/min)

100

15-35

Daily urea clearance (l)

80-90

20-40

Daily Kt/V

2,4

0,9-1,4

Daily dialysate cost (US$)

10

50-100

Single Pass Batch Hemodialysis System (GENIUS): preparation of dialysis water and dialysate RO UnitAquatorPreparatorDialysismachineDry saltconcentratesUV radiatorwaterUV radiatorRecirculation andUV irradiation of RO water tosuppress bacterialgrowth Mixing of dry salt concentrates withRO water toproduce dialysateHeating and UV irradiationof dialysateduring fillingof the tankthermalinsulation

The Genius dialysis System.Fassbinder, NDT, 13, 3010-3012, 1998.

Bacteriology of GENIUS DialysateTechnique: At the end of a 5 hour hemodialysis session mixing of the dialysate in the tank, filtration of 4.0 liters through a Swinnex-filter (0,22 m), incubation of the filter membrane on TGE Agar for 7 days at 23C. Counting of colonies.

Results: No colony forming units (CFU) in the 4-liter-samples (n = 15).

Bacterial growth < 0.00025 CFU/mlLonnemann et al, Nephrol Dial Transplant 15:1189; 2000

IHD vs CRRT in IRA: concluziiNu este demonstrata nici o superioritate a CRRT vs IHDPerformanta IHD se poate ameliora prin: dializa zilnica, HDF, tratament prelungit Evolutia catre terapii hiobrid este normala (SLEDD)

Recomandari actuale de tratament in IRAHD intermitenta Tratament de electie in IRA izolata , dar poate fi utilizata si in MSOFAsigurarea unei doze suficiente de dializa; este de preferat HD zilnica Se poate utiliza orice membrana (exceptie rabdomioliza sau substante contrast iodate High-Flux)CRRTPreferata in instabilitatea cardiocirculatorie, hiperhidratare, edem cerebral Asigurarea unei doze suficiente de dializa (35 ml/kgh recomandata in CVVH )

Slow extended daily dialysis (SLEDD)Combina unele din avantajele CRRT si IHDConsiderabil mai ieftina decat CRRT

Determinanti majori ai terapiei:Experienta personalaDisponibilitatile locale / circumstante localeRecomandari actuale de tratament in IRA

ConcluziiPacientii cu IRA necomplicata au prognosy=tic bun cu HD conventionalaDesi initiatorii CRRT raporteaza avantajeale tratamentului, nu a putut fi demonstrat un beneficiu major asupra supravietuirii la acesti pacienti Individualizarea prescriptiei de dializa alaturi de experienta fiecarui centru in parte determina cele mai bune solutii pt fiecare centru de dializa in parte

Incidence of acute radiocontrast-induced renal dysfunction in patients with chronic renal failure according to the presence or absence of DM, therapy with a calcium channel blocker, and attempted prevention with half-isotonic saline alone or in combination with mannitol or furosemide.Solomon et al, NEJM, 331, 1416, 1994.

Prof. Dr. Achim Jrres Dept. of Nephrology and Medical Intensive CareCharit University Hospital Campus Virchow Klinikum Berlin, Germany

Extracorporeal Management of Patients With Acute Renal Failure

Scope of PresentationWhen to initiate acute dialysis ?Treatment optionsIntermittent hemodialysis vs. CRRTHybrid approaches (SLEDD)Dialysis membranesBuffersAnticoagulationDialysis dose

When to initiate acute dialysis ?Generally accepted indicationsAcute (life-threatening) hyperkalemiaSevere volume overload (pulmonary edema)Severe metabolic acidosisUremic organ complications (e.g. pericarditis)

Prophylactic dialysis:Creatinine clearance, e.g. 0.1-0.15 ml/kg/min ?Serum urea concentrations, e.g. 150, 200, ... mg/dl ?

Retrospective analysis (100 trauma patients, 1989-97)Early: BUN 60 mg/dlEarly starters had significantly better survival compared to late starters: 39% vs. 20.3% (p=0.041)A. Jrres 09-2005

106 ventilated, oliguric Pat.Prospective, randomised: Early High-Vol.: 72-96 L/24h Early Low-Vol: 24-36 L/24h Late Low-Vol: 24-36 L/24h (i.e. usual criteria) Result: No difference regarding 28-day survivalCrit. Care Med. 2002;30: 2205-11A. Jrres 09-2005

CRRT or IHD ?Acute Renal Failure in the ICU

Continuous versus intermittent RRT for acute renal failure in the ICU: Randomized multicenter trial

% ICU % Hosp. ICU Hosp. % complete N mortality length of stay renal recoveryAll pts.16650.656.616.520.934.9CRRT 8459.565.515.118.633.3IHD 8241.547.617.923.236.6P -0.020.02NSNSNS

Mehta et al, 29th ASN Annual Meeting; JASN 1996; 7: 1457

Continuous versus intermittent RRT for acute renal failure in the ICU: Randomized multicenter trial

CRRTIHD PAPACHE II 25.320.6

A randomized, stratified, dose equivalent comparison of CVVHD vs IHD support in ICU acute renal failure patientsDesign:Prospective, randomised, stratified (Cleveland Clinic ARF Score)Equivalent groups; CVVHD n=39, IHD n=40Results: No significant differences regardingMortalityRenal recoveryICU treatment daysAcute haemodynamics (CO, MAP, SVR, inotropic support)

Sandy et al, 31st ASN Annual Meeting, 1998; Poster S253

Mortality n ORCVVHDF 47.1% 70 -IHD 50.9% 55 0.36 p=0.36 Uehlinger et al, NDT 2005; 20: 1630-37NO difference regarding:

Hospital / ICU length of stay Duration of RRT

A. Jrres 09-2005

Marshall et al, NDT 2004; 19: 877-84Treatment: 8 hrs / day with Fresenius 4008S (dialysate flow 200 ml/min + on-line HDF 100 ml/min)24 critically ill ARF patients, 56 treatmentsObserved mortality (46%) = expected mortality (APACHE II)No complications, no intra-dialytic hypotension

A. Jrres 09-2005

Extended daily high-flux HD20 patients with ARF / MODSGenius; F60; QB and QD 70 ml/min 18 h treatmentcheap; excellent cardiovascular stabilityLonnemann, Nephrol. Dial. Transplant. 2000; 15: 1189-93

Genius-SLEDD in ARF Prospective RCT in 39 ventilated critically ill patients with oliguric ARF (85% had sepsis)CVVH 30 mL/kg/h for 24 hours vs. Genius-SLEDD, 12 hoursSimilar URR (53% +/- 2% vs. 52% +/- 3%; P =n.s.)Correction of acidosis was accomplished faster with extended dialysis than CVVH (P

Which membrane ?

Transport characteristics:Hydraulic permeability and selectivityHydraulic permeability: Water permeability at a given trans-membrane pressure (TMP). Primarily related to membrane thickness. KUF [ml / h / mmHg TMP]

Selectivity:Permeability for specific molecules. Primarily related to pore size, but also to membrane charge / hydrophilicity."cut-off" [Dalton]

Hydraulic permeability / membrane fluxU.S. FDA classification (based on water permeability):Low-Flux:KUF < 8 ml / h / mmHgHigh-flux:KUF 8 ml / h / mmHgNIH Hemo study* (based on solute permeability)Low-Flux:2M clearance < 10 ml/minHigh-flux:2M clearance > 20 ml/minKUF 14 ml / h / mmHg*Cheung et al., JASN 1999 ; 10: 117-127

Clearance of molecules according to sizeMolecular weight (Dalton)Clearance (% of blood flow)UreaCreatinineInulin2-MGAlbuminDiffusionConvection

BiocompatibilityA. Jrres 09-2005

Membranes in ARF: Clinical Studies Hakim RM, Wingard RL, Parker RAEffect of the dialysis membrane in the treatment of patients withacute renal failure.N Engl J Med 1994 Nov 17;331(20):1338-42

Schiffl H, Lang SM, Knig A, Strasser T, Haider MC, Held EBiocompatible membranes in acute renal failure: prospective case-controlled study.Lancet 1994 Aug 27;344(8922):570-2

European multicenter study of the effect of dialysis membranes on the mortality of patients with ARF*0.30.40.50.60.70.8CuprophanN=76PMMAN=84TotalN=160Probability of SuccessOdds ratio for failure with Cuprophan: 1.07 (0.54 - 2.11) *Jrres et al., Lancet 1999 (Oct 16); 354: 1337-41

Effect of Biocompatibility of Hemodialysis Membranes on Mortality in Acute Renal Failure: A Meta-Analysis of Controlled Trials. StudyCountryYearPts.Risk Ratio 95% CISchifflGermany1994 52 1.780.97-3.27KurtalGermany1995 57 0.890.62-1.28GastaldelloBelgium 1996 134 0.77 0.52-1.13Assouad USA1996 51 0.90 0.58-1.40Himmelfarb USA 1998 153 1.25 0.91-1.70Jrres Germany 1998 160 1.03 0.79-1.33Albright USA 1998 66 0.96 0.72-1.28OVERALL 673 1.01 0.87-1.18

Karsou SA et al., J. Am. Soc. Nephrol. 1999;10:286A

No survival difference between high- and low-flux polysulfone in ARFGastaldello et al, NDT 2000; 15: 224-30 Prospective RCT, 159 patients

Cellulose diacetate vs. high- and low-flux polysulfone in IHD

No significant differences in survival

Which Buffer ?

Not randomised, cross-over, 54 MOF patientsAt least 24h CVVH with both buffers Faster and better control of acidosis, higher MAP less inotropes with lactate-fres dialysateKidney Int. 2000; 58: 1765-72A. Jrres 09-2005

Randomised, multicentric 117 patients with CVVH Better control of acidosis with bicarbonate less cardiovascular complicationsKidney Int. 2000; 58: 1751-57A. Jrres 09-2005

Optionen fr die Antikoagulation No anticoagulationunfractionated heparinLow-molecular heparinRegional anticoagulationheparin / protamincitrateProstacyclinDirect thrombin inhibitorsHirudinArgatroban (Murray PT, Kidney Int. 2004; 60: 2246-53)

Extracorporeal therapy without anticoagulationHigh blod flow (200-300 ml/min)(Pump-driven) filtrate rate ~2000 ml/hPre-dilutionNaCl flush every 30 mins

Mean filter times ~ 32 h (40 circuits / 12 pat. with ARF)(Tan, Intensive Care Med 2000;26:1652)

Unfractionated HeparinProcedure for IHD/CVVH: Rinsing with (5,000-20,000 U); Systemic bolus (2,000 5,000 U); continuous infusion (400-1,000 U/h)Monitoring:pre-filter aPTT (target 35-45 s)Pre-filter ACT (target 180-210 s)Complications:10 50 % bleeding episodes 1 3% thrombocytopenia / HIT-2

Regional AnticoagulationCitrateCitrate chelates divalent cations (Ca++, Mg++)One Mol citrate converted to 3 Moles BicarbonatOne Mol Trinatriumcitrat converted to 3 Moles Sodium

Potential complications:Hypocalcaemia, hypomagnesiaemiaMetabolic alkalosisHypernatraemia

Regionale AntikoagulationCitrateTolwani, Kidney Int 2001; 60: 370

Which Dialysis Dose ?

Mortality in CVVH patients is related to the volume of replacement fluidRonco et al, Lancet 2000; 356: 26-30 Prospective RCT of different doses in CVVH treatment of ARF

425 patients

Primary endpoint: survival @15 days after stopping CVVH

Significantly better survivalwith 35 or 45 ml/kg/min vs. 20 ml/kg/min

Reduced mortality in ARF patients receiving daily intermittent hemodialysisSchiffl et al, NEJM 2002; 346: 305-310

Current recommendations for extracorporeal treatment of ARF (1)Intermittent HD Treatment of choice in isolated ARF, but also viable option in MOFDeliver sufficient dialysis dose; daily HD treatment recommendedMay use any membrane (potential exceptions: rhabdomyolysis or elimination of radio contrast media High-Flux)CRRTProbably preferable in cardiocirculatory instability, volume overload or cerebral edemaDeliver sufficent treatment dose (35 ml/kgh recommended in CVVH )

Current recommendations for extracorporeal treatment of ARF (2)Slow extended daily dialysis (SLEDD)Combines some advantages of CRRT and IHDConsiderably cheaper than CRRT

Major determinants for choice between therapies:Personal experienceLocal availability / circumstances

Nephrology Consultation in ARF: Does Timing Matter ?215 pat. with ARF in 4 U.S. academic centersIn 67 pat. consultation of nephrologist only after > 48 h (median 4 days)In this group, mortality was significantly higher: 74% vs. 49% (p=0.006) in pat. with RRT 53% vs. 22% (p=0.01) in pat. without RRT Likewise, ICU and hospital length of stay significantly longerMehta R et al. Am. J. Med. 2002; 113: 456-461

... What else is important:

A. Jrres 09-2005

**********Fig 7. Pathways of oxygen-derived reactive species (A); pathways of formation of reactive nitrogen species (B).For explanation see text).*29*6.Influence of furosemide on inner stripe morphology and hypoxia-inducible transcription factor (HIF)-1 expression 2 hours after complete acute renal failure (ARF) protocol [combined delivery of indomethacin, iothalamate, and NG-nitro-l-arginine methyl ester (L-NAME). Hematoxylin and eosin staining. (A and C). (A and B) and (C and D) are pairs of parallel sections. 2 is thin limbs, 3 is thick ascending limb of the loop of Henle (mTAL), 4 is collecting duct, and VB is vascular bundle. Complete ARF protocol induces cellular damage consisting of cytoplasmic fragmentation, nuclear pyknosis, and tubular collapse [area outlined in (A)]. HIF-1 appeares mainly in collecting ducts, but damaged areas are almost void of signals [area outlined in (B)]. Furosemide leads to tubular preservation (C), and to an increased HIF-1 staining, especially in mTAL (magnification 400 ). **Fig.1. Immunofluorescent photomicrographs of kidney biopsies. (A) Male recipient and male donor (positive control) with moderate tubulointerstitial rejection. Both tubular cells (green) and interstitial cells (unstained) contain the Y chromosome signal (red dot; arrows) in nuclei. Magnification 200. (B) Female patient with minimal change disease (negative control). No Y chromosomes are seen. Some CD45 positive cells are seen in the interstitium (arrowheads). Magnification 100. (C) Male recipient of female kidney with resolving acute tubular necrosis (ATN). Multiple cells in this tubule contain Y chromosomes (arrows). Some interstitial cells also contain Y chromosomes and stain positive for CD45 (red staining; arrowhead). Magnification 200. (D) Male recipient of female kidney with resolving ATN and superimposed mild acute tubulointerstitial rejection. Multiple cells in this tubule contain Y chromosomes (arrows). Some interstitial cells also contain Y chromosomes. Magnification 400.

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