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

IRA in ATI / reanimare

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 Knaus Ure > 36 mmol/L Cratinine > 310 mol/L Diurse < 156 ml/8 h < 479 ml/24 h Ncessit d EER, mais prdfinir les critres!

Criteriile RIFLE

Limitele criteriilor RIFLE

Aplicare neriguroasa a definitiei Excluderea 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).

Conceptual Model for AKI

Complications

AKI
Normal Increased risk Damage GFR Kidney failure Death

Antecedents Intermediate Stage AKI Outcomes

KDIGO & 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 <0.5 ml/kg/h for 6 hours.

Staging of AKI
Stage 1 SCr >1.5-1.9 times baseline OR 0.3 mg/dl increase >2.0-2.9 times baseline >3.0 times baseline OR increase in SCr to >4.0 mg/dl OR RRT Urine output <0.5 ml/kg/h for 612 hours <0.5 ml/kg/h for >12 hours <0.3 ml/kg/h for 24 hours OR Anuria for >12 hours

2 3

Insuficienta renala acuta

Incidenta 1982, clinici nefrologie in UK 1237 cazuri in 12 luni 22.2 / 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 acuta

Incidenta (cont.)
1990s, studiu prospectiv in comunitate (Feest) Durata de 2 ani, inclusi 440,000 pacienti creatinina > 500 umol/l 140 pmp / an
72% erau varstnici > 70 ani Incidenta de 17 / pmp daca pacientii erau < 50ani Incidenta de 949 pmp daca pacientii erau > 80 ani supravietuire 54% la 12 luni, 34% la 2 ani

Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney)
29 269 critically ill patients. 5.7% (5.5 - 6.0%) had ARF. 72% were treated with RRT.

Overall hospital mortality: 60.3% (58 - 63%).

Acute renal failure in the critically ill: a multinational study.
JAMA. 2005 294(7):813-8.

Insuficienta renala acuta

ETIOLOGIE
O larga varietate de patologii care pot aparea intr-o larga varietate de situatii clinice

ETIOLOGIE
pre-renala renala post-renala

Tipurile principale de IRA

Insuficienta Renala Acuta

Cauze pre-renale

Cauze renale

Cauze Post-renale

Necroza tubulara

Nefrita interstitiala (10% cazuri)

Glomerulonefrite acute (5% cazuri)

Ischemica (50% cazuri)

Toxica (35% cazuri)

Insuficienta renala acuta Prerenala 1. Reducerea volum circulant

hemoragii

Renala intrinseca Vasculare

Vasculite, HTA maligna, poliangeita microscopica

Postrenala Necroza tubulara acuta Obstructia sistemului colector sau a cailor urinare extrarenale
Strictura vezicala

GN

2. Reducere relativa a volumului circulant (volum arterial ineficient)

insuficienta cardiaca

acute
GN postinfectioase, Sdr Goodpasture

Nefrita interstitiala acuta

Nefrita interstitiala asociata cu medicamentele

Ischemica

Nefrotoxica

3. Stenoza / ocluzie de artera renala 4. Forme hemodinamice

- AINS - IECA sau sartani in stenoza unilaterala de artera renala sau insuficienta cardiaca

Exogena
Nefrotoxine : 1. Antibiotice (gentamicina) 2. substante de contrast iodate 3. Cisplatina

Endogena
1. Depunerea de pigmenti intratubular (hemoglobinuria, mioglobinuria) 2. depunere de proteine intratubular (mielom) 3. depunere de cristale intratubular (acid uric, oxalat)

Este IRA prerenala (functionala) o conditie frecventa?

Necroza tubulara acuta IRA functionala IRC acutizata IRA obstructiva, postrenala Glomerulonefrite, vasculite Nefrita interstitiala acuta Cauze vasculare 45% 21% 13% 10% 4% 2% 2%

Sdr de insuficienta renala acuta

Incidenta Cauza

Dobandite in comunitate Mica Unica pre>post>renal Buna 70-90%

Dobandita in spital Moderata (5%) Multipla pre>NTA>post Medie 30-50%

Dobandita in ATI Mare (10-20%) MSOF MSOF + NTA Redusa 10-30%

Supravietuire

Schrier & Gottschalk, Diseases of the Kidney, 1996

Causes of AKI: Exposures and susceptibilities

KDIGO & AKI Guideline 2010

Cauze de IRA in spital

Aetiological factors contributing to ARF SCOTIA TOATE CAZURILE

Factors Sepsis Hypotension Patients (%) 48.1 25.0 IRA (%) 52.5 27.2 IRC A (%) 35.4 18.7

Post-surgical
Hypovolaemia Nephrotoxins and drug induced Hepato-renal syndrome Myocardial infarction Rhabdomyolysis Urinary obstruction Glomerulonephritis

21.5
22.6 12.5 7.5 6.3 5.6 5.2 3.0

24.2
23.5 11.8 9.3 5.8 7.2 5.0 2.3

13.9
20.1 14.4 2.4 7.7 1.0 5.7 4.8

Pancreatitis
Myeloma

2.8
1.2

3.7
1.5

0.5
0.5

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 Kidney
Independent risk factors for mortality:
use of vasopressors (OR, 1.95; (1.50-2.55) P<0.001), mechanical ventilation (OR, 2.11; (1.58-2.82) P<0.001), septic shock (OR, 1.36; (1.03-1.79) P = .03),

cardiogenic shock (OR 1.41; (1.05-1.90) P = 0.02),

hepatorenal syndrome (OR 1.87; (1.07-3.28) P = 0.03).

Evolutia mortalitatii in IRA vs IRC in Europa

80

60
Mortalitate (%)
Mortalitatea la pacientii dializati pt IRA

40

20
Mortalitatea in primul an la pacientii cu BRC terminala raportata de ERA EDTA

0 1950 1960 1970

year

1980

1990

Proportia de varstnici (> 80 ani) cu IRA internati in ATI

50 50

Procent de varstnici din numarul total IRA

40 40

30 30

20 20

10 10

1978 1978 1980 1980 1982 1982 1984 19841986 19861988 19881990 19901992 19921994 1994 1996 1996

Ani

Akposso et al Intens Care Med 26:400-406,2000

Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients Metnitz 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 hemodinamica Teoria celulara Teoria interactiunilor celulare

Patofiziologia IRA

Teoria hemodinamica
Vascoconstrictia I/R Obstructie tubulara Retrodifuziune

IRA functionala
Deshidratare + Vasoconstrictie renala si scaderea coeficientului de ultrafiltrare Insuficienta cardiaca Sepsis

Angiotensina II

Oxid nitric Prostaglandine

+ Inervatie adrenergica + ADH

Feedback tubuloglomerular

Scaderea RFG

Blantz, KI, 53, 512-523, 1998.

Insuficienta renala acuta

Fiziologie renala NORMALA
Autoreglarea
Ca urmare a reducerii perfuziei renale scade tonusul arteriolei aferente I creste tonusul arteriolei eferente Procesul este ANGIOTENSIN II dependent Permite mentinerea presiunii capilare glomerulare si procesul de ultrafiltrare

Insuficienta renala acuta

Fiziologie renala
Feedback-ul tubuloglomerular
macula densa sesizeaza modificarile dependente de flux si ale conc de Cl- in fluidul tubular

Fluxul plasmatic la nivelul nefronului se ajusteaza prin alterarea rezistentei arteriolei aferente
Modificarile sunt dependente de SRAA, adenozina, prostaglandine

Autoreglarea fluxului plasmatic renal

150

Ischemia

Flux sangvin renal relativ (%)

100

Normal
50

0 0 50 100 150

Presiune de perfuzie renala (mm Hg)

Insuficienta renala acuta

Mecanisme Protectoare
Autoreglarea renala
Eicosanoizi vasodilatatori Angiotensina II NSAID ACE / AT1RA

Riscul de IRA la AINS asociata cu anumiti factori de risc

OR
No use of NSAID Current use of NSAID 15-64 yrs old > 65 yrs old Recent hospitalization Cardiovasular risk present Other nephrotoxic drugs

95% CI

1.0 4.1 1.0 3.5 6.9 2.7 4.0

1.5-10.8 1.3-9.8 2.9-16.2 1.0-7.3 1.4-11.4

Gutthann et al. Arch Int Med 156 2433-2439, 1996

Teoria hemodinamica (cont.)

Ischemia Nefrotoxine
Leziune tubulara (tub contort proximal si ram ascendent ansa Henle )

(1) Vasoconstrictie Sistem renina angiotensina Endotelina PGI2 NO

(2) Obstructie prin cilindri

(3) Retrodifuzie tublara

(4) Inflamatie interstitiala

Presiunea intratubulara

flux tubular

(5) ? Efect direct pe glomerul

GFR

Oligurie

Anatomical and physiologic features

of the renal cortex and medulla.
Blood flow 4.2 ml/min/g Cortical labyrinths Medullary rays PO2, ~ 10-20 mm Hg
Macula densa

PO2, ~ 50 mm Hg

Blood flow 1.9 ml/min/g

Outer medulla

Inner medulla

Cortex Renal vein Renal artery

Medullary tick ascending limbs

Brezis & Seymour, The New Engl. J. of Med., 332,647-655, 1995.

Heterogeneity of renal circulation

Countercurrent exchange of oxygen in the vasa recta

Brezis et al, The Kidney, 1991.

Cortical Medullary Junction:

ischemia/reperfusion

ISCHEMIE
Depletie ATP

REPERFUZIE
Acumulare de hipoxantine Xantine Generare de superoxid
SOD

Crestere Ca2+ citosolic Xantin oxidaza

Fe2+
Fenton reaction

Peroxid hidrogen

Fe3+

Activarea proteazei Ca calmodulin dependente Xantin dehidrogenaza

Radical hidroxyl

1) Stresul oxidativ

2) Inflammatory response

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

4) Role of NO
A
Pathways of oxygen-derived reactive species

Pathways of formation of reactive nitrogen species

disparitia posibiltatii de vasodilatatie

Induction of tubular epithelial cell injury

Microvillar Actin

NO NO
Integrins

Lumen

Cytoskeletal Targets of NO

Basolateral Membrane

Patofiziologia IRA

Teoria hemodinamica
Vascoconstrictia I/R Obstructie tubulara Retrodifuziune

Aspectul microscopic in NTA

Potential cytoskeletal targets for proteases during ischemia-reperfusion

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)
Normal renal epithelium

Sublethal injury

Presence of an excess of free RGD

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

Sediment urinar cu prezenta de cilindri epiteliali la un pacient cu NTA

Tamm Horsefall protein

Embolie de colesterol la PBR

Caracteristicile majore ale embolizarii acute cu emboli de colesterol

Exacerbarea brutala sau aparitia de novo a HTA IRA progresiva cu evolutie diferita de a NTA Afectare cutanata
Livedo reticularis Gangrene Cianoza/purpura

Febra Durere lombara, abdominala, membre inferioare

Patofiziologia NTA
Teoria celulara
Pierderea polaritatii celulare Necroza vs apoptoza Recuperare prin factori de crestere ca IGF-1, HGF, EGF

Anatomia patologica in NTA-faza de recuperare

Recovering ATN showing a tubular epithelial cell mitotic figure (arrow).

Fazele clinice si celulare in IRA ischemica

Pierdere BBM Exfoliere Obstructie tubulara

Leziune celulara

CMJ hipoxie
Leziune microvasculara Obstructie Inflamatie Coagulare

Intretinere
nediferentiere Migrare Proliferare

Rediferentiere Repolarizare

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

Insuficienta renala acuta

IRA CLINICA

Insuficienta renala acuta

IRA practica clinica corecta
Index inalt de suspiciune clinica Semnele si simptomele clinice initiale sunt nespecifice

Determinarea bazala a ureei si creatininei plasmatice pentru toate internarile in urgenta si TESTAREA REGULATA IN TIMPUL SPITALIZARII cuantificarea corecta intrari / iesiri, greutatea zilnica, TA in clino- si ortostatism Detectare/ recunoastere precoce si tratament prompt sau transfer cu toate documentele si investigatiile imagistice

Insuficienta renala acuta

IRA practica clinica incorecta
Preluarea cazului de mai multi medici, fara continuitate in urmarirea cazului Absenta foii de observatie no charts / records analize? Au fost cerute? Au fost vazute? S-a actionat in consecinta? Administrare de nefrotoxice; ignorarea determinarii nivelelor serice ale medicamentelor Fctie renala anormala ignorata pana vineri la ora 4.59pm Transferul pacientilor fara supraveghere, documentare corecta a cazului

2. afirmarea diagnosticului de insuficienta renala ACUTA

IRA Istoric Retentie azotata absenta IRC Dg anterior de nefropatie sau HTA / anemie / nocturie

Examen clinic
Anemia Modificari radiologice osoase Dimensiunile renale Consecintele prezentei HTA de lunga durata

Modificari cutanate absente

Absenta sau redusa in raport cu retentia azotata Absente Normale Absente

Modificari cutanate prezente. HTA

Prezenta Prezente, definitorii pentru boala osoasa renala Reduse, rinichi destructurat HTA prevalenta in 90% din cazurile cu IRC

Insuficienta renala acuta

IRA este posibila obstructia de tract urinar?
DA !!!!! La nivel prostata, uretra, vezica urinara, ureter, pelvis renal Cauze: litiaza, chirurgie, afectiuni ginecologice Obstructia completa este cauza de anurie totala, obstructia incompleta putand da alternanta oligurie/poliurie ATENTIE LA ASOCIEREA NTA + OBSTRUCTIE

Insuficienta renala acuta

IRA este posibila obstructia de tract urinar? ECOGRAFIE DE URGENTA RENALA SI VEZICALA
hidronefroza ureterohidronefroza Distensie vezicala Litiaza Neoplazii, inclusiv limfoame (adenopatii) Mase periaortice inflamatorii

Insuficienta renala acuta

IRA hidronefroza bilaterala
Nefrostomie bilaterala Sau, 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 acuta

IRA cauza posibila este GN?
GN acuta, LES, vasculitele sistemice Prognosticul este mai usor daca se cunoaste diagnosticul subiacent Istoric complet si examen fizic Microscopia urinii (din proba matinala, efectuata de medic)
Cilindri hematici

Determinarea de urgenta a ANCA, anti-GBM, ANA, VSH, CRP

Daca este suspiciune de LES, adaugate: Ac ds-DNA-binding, C3, C4

Acute renal failure

IRA este posibila o cauza vasculara?
Pacient varstnic, ateromatoza generalizata, fumator Dimensiuni si functie renala asimetrica Utilizarea 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 prerenala

1. Afirmarea diagnosticului de insuficienta renala 2. Afirmarea dg. de IRA 3. Afirmarea dg. de IRA prerenala
A/ Context etiologic sugestiv B/ Examen clinic sugestiv C/ Confirmare paraclinica
Indicii urinari Sedimentul urinar Altele

D/ Proba terapeutica

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALA

A/ CONTEXT ETIOLOGIC SUGESTIV A.1. Depletie reala a volumului extracelular
pierderi digestive: varsaturi, diaree, drenaj gastric sau intestinal; hemoragii exteriorizate pierderi renale: exces de diuretice pierderi respiratorii sau/si cutanate: transpiratii profuze, arsuri;

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALA

A/ CONTEXT ETIOLOGIC SUGESTIV A.2. Depletie relativa a volumului extracelular
sechestratie in al 3-lea sector: arsuri, zdrobiri tisulare, pancreatite, ascita, ocluzie intestinala; hemoragii ne-exteriorizate

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALA

A/ CONTEXT ETIOLOGIC SUGESTIV A.3. Hipotensiune arteriala
Colaps circulator de orice cauza Supradozaj de medicatie antihipertensiva Reducerea prea brusca a TA (la varstnici)

A.4. Hipoperfuzie renala selectiva

Exces de IECA la pacienti cu stenoza bilaterala de artera renala Exces de AINS pe fond de hipovolemie Droguri vasoconstrictoare artera renala - ciclosporina

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALA

A/ CONTEXT ETIOLOGIC SUGESTIV A.5. Stari edematoase (combina hTA si hipoperfuzia selectiva renala)
Insuficienta cardiaca congestiva severa Ciroza hepatica decompensata vascular Sindromul hepato-renal

3. afirmarea diagnosticului de insuficienta renala acuta PRERENALA

B/ EXAMEN CLINIC OBIECTIV CENTRAL = APRECIEREA STARII DE DESHIDRATARE Subiectiv: senzatie de sete, astenie Obiectiv:
recenta a greutatii corporeale, temperaturii cutanate turgorului cutanat cu pliu persistent pretoracic, mucoase uscate hTA, TA fata de antecedente, pseudo-normalizarea TA, modificari posturale patologice ale TA jugulare plate, colaps al venelor peroferice, presiunii intraoculare oligurie cu urini concentrate

Confirmarea paraclinica a diagnosticului de IRA prerenala:

C/ INDICI DIAGNOSTICI URINARI
Indicele urinar
Na urinar (mEq/L) Uree / Cr. Plasmatica (*)

IRA prerenala
< 20 40-60 (>20)

Densitatea urinara Osmolaritate urinara Osmolaritate u / p Uree u / p Creatinina u / p Fractia de excretie a Na

> 1016 > 500 > 1.5 >8 > 40 <1

IRA parenchimatoasa > 40 <20 Hipostenurie < 350 < 1.1 <3 < 20 >1

Fractia de excretie a Na urinar

Definitie: procentul din totalitatea Na filtrat prin glomerul care este excretat in urina Na excretat = Na urinar x volumul urinar Na filtrat = Na plasmatic x RFG
RFG = Cl. Creat = Cr.U x V / Cr.P

FE 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 > 0.30.5 mg/dL/zi (26-44umol/L/zi), tipica pentru NTA

Characteristics of an ideal biomarker for AKI

Prioritatile terapeutice in IRA (I)

Insuficienta renala acuta

IRA - prognostic
Scorul Apache II nu este un element prognostic Orice 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 acuta

IRA al cui teritoriu este ?
Nefrolog Generalist Intensivist Chirurg?

Acute renal failure

ARF - what does it all cost?
20-25,000 per ITU patient (~ 25 days)1 70,000 per ITU survivors leaving hospital (~ 90 days) if 1200 cases per year, and 200 saved ABOUT 35,000,000 / YEAR for ITU (E + W) or 0.1% of the total NHS budget
1{cf 20,000 per year per patient for maintenance dialysis}

Prioritatile terapeutice in IRA (I)

Identificarea si corectarea factorilor pre- si postrenali Revizuira medicatiei si stoparea nefrotoxicelor Optimizarea debitului cardiac si a fluxului plasmatic renal Refacerea / cresterea fluxului urinar Monitorizare 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 goal therapy (n = 130)

MODS* Baseline 6h 72 h Mortality 7.6 3.1 5.9 3.7 5.1 3.9 30.5 %

Standard therapy (n = 130)

7.3 3.1 6.3 3.7 6.4 4 46.5 %

p < 0.001 p < 0.001 p < 0.01

* Scale 0 - 24 (Marshall JC, Cook DJ. Crit. Care Med. 1995)

Mais, aucune valuation de la fonction rnale H72

IRA prerenala TRATAMENT

OBIECTIV CENTRAL Refacerea perfuziei renale prin:
Corectarea depletiei volemice absolute sau Corectarea 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
Lent, 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) diurezei
Limitata de functia renala si volumul urinar Impune un volum urinar de > 1000 mls / 24 h Excretia urunara de K+ redusa de medicamente (IECA, amiloride, spironolactona)

Insuficienta renala acuta

IRA de ce facem ceea ce facem ?
Corectie volemica Diuretice de ansa Mannitol Dopamina {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 SUCCESS

PA Catheter

Oesophageal doppler

Corectarea depletiei volemice

DEPLETIA VOLEMICA ABSOLUTA / REALA Transfuzii sanguine atunci cand etiologia este hemoragica sau oricand Hb < 10 g/L Etiologie non-hemoragica sau in absenta sangelui:
Abord vascular central permite monitorizarea PVC; +/flexula de calibru mare (14G) Determinarea PVC PVC < 2 cm H2O volemia insuficienta, necesitand refacere volemica Solutii cristaloide vs coloide?

Immediate response:- Fluid resuscitation!

Corectarea depletiei volemice

Daca 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

Na Secretie gastrica
Fistula pancreatica Diaree Transpiratii

K 10
5 30-60 5

H 90

HCO3

Cl 100-140

40-65
135-155 25-50 30-50

70-90 30-45

55-75 20-40 45-55

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 diminuate

I. Status 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 I
1. Restrictie sodata 2. Diuretic de ansa in doza conventionala (furosemid 40 mg iv, bumetanide 2 mg iv) 3. Diuretic de ansa in doze mari SI repetate (furosemid 200 mg la 6 ore) 4. Diuretic tiazidic urmat la 30 min de diuretic de ansa in doza mare 5. Diuretic de ansa in infuzie continua (furosemid 10-40 mg/hr) 6. Diuretic de ansa in doze mari diluat in albumina desodata perfuzat in 30 minute la fiecare 6 ore. 7. Ultrafiltrare

Corectarea perfuziei renale efective diminuate

II. Status edematos cu volum intravascular crescut + vasconstrictie pre-renala, secundara insuficientei cardiace Obiectiv: compensarea cardiaca si cresterea debitului cardiac Metode:
presarcinii prin nitrati sau utilizarea diureticelor (in cazurile refractare escaladarea masurilor de promovare a diurezei) postsarcinii prin vasodilatatoare, atentie la IECA Droguri inotrope pozitive

Corectarea perfuziei renale efective diminuate

III. Vasoconstrictie prerenala directa (hipercalcemia, radiocontrast, sdr. hepatorenal, ciclosporina) Dopamina in doze de stimulare a receptorilor dopaminergici 1-3 ug/min/kg Hidratare+diuretic de ansa Blocante ale canalelor de Ca Corticoizi, bifosfonati, calcitonina Monitorizarea nivelului terapeutic al ciclosporinei Antagonisti de endotelina

Diureticele de ansa
Ratiuni 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 pointuri: recuperarea functiei renale, dializa, decese

Diureticele de ansa in IRA: trial dublu-orb, randomizat

60 50 40 30 20 10 0 Urine flow Renal rec Dialysis Death d21
Shilliday et al. Nephrol Dial Transplant 11,1684,1996.

Percent

Tora Furo Placebo

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.
albumin

SAFE study N Engl J Med 2004;350:2247-2256.

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 potent Creste volumul de filtrat tubular, efect de spalare Reducerea edemului celulelor tubulare Creste volumul plasmatic si reduce Ht Actiune de scavanger al radicalilor liberi

Din nou, lipsa de date controlate

Vasopresoare

Supravietuirea pacientilor cu soc septic tratati cu vasopresoare

Norepinephrine

Other vasopressors

Martin et al Crit Care Med, 28: 2758-2765, 2000

Hospitalisation days

Efectul norepinefrinei asupra fluxului urinar in socul septic

180 160 140 120 100 80 60 40 20 0 3h before 1st 3 hour All patients NE alone NE+dob or dop

Norepinephrine dose and mortality

Norepinephrine dose (mg/kg/min) <0.1 0.1-0.3 >0.3 Mortality (%) 20 24 76

Insuficienta renala acuta

IRA de ce facem ceea ce facem ?

Piv dopamina
Sinteza in mod fiziologic I tubii contorti proximali din L-Dopa receptor DA-1 la nivel vase si tubi
Mai sensibili la dopamina Determina vasodilatatie si scade reabsorbtia tubulara de Na

receptor DA-2 localizat la nivel terminatii nervoase simpatice.

Efectul piv dopamina la subiectii normali

: DA1 receptor effect renal blood flow : receptor effect cardiac index and heart rate : receptor effect systemic vascular resistance index and arterial pressure

DOrio et al, Arch. Int. Physiol. Biochim., 92, S11-S20, 1985

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 failure
A Lauschke et al

CCM 2006;34:589-597

Algoritm de tratament in cazul absentei raspunsului la corectia volemiei

IRA oligurica < 30 ml/h
Pacient hipovolemic Da Corectie pana la PVC 10 cm H2O Nu Furosemid 80 mg iv bolus Raspuns

Absenta raspunsului Infuzie furosemid 2-4 mig/min dopamina 1-3 ug/kgc/min 4 ore

Raspuns
STOP furosemid Diureza se reduce Se reia furosemidul

Absenta raspunsului
Dializa

Diureza se mentine STOP dopamina Diureza se mentine

Diureza se reduce Se reia dopamina

Insuficienta renala acuta

Aminofilina
Actioneaza pe receptorii renali de adenozina si inhiba fosfodiesteraza Creste fluxul plasmatic renal, reduce reactivitatea vasculara

CCB
Limiteaza fluxul intracelular de Ca++ Multe date pe animale, efect maxim daca se administreaza anterior agresiunii

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

Trialuri clinice recente

Factori de crestere - IGF I Factor natriuretic atrial - ANF Antagonistii receptorilor endotelinei tiroxina PGE1

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 vasoconstriction Growth factors Stem cells

Fenoldopam and ARF in sepsis

Screa (mol/l)
106 104 102 100 98 96 94 92 90 88 86 84 1 3 5

Placebo Fenoldopam

days

Prevention of vasoconstriction
Fenoldopam dopamine A-1 receptor agonist
Systematic review of RCTs in ICU or major surgery 16 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/rezultate

Franklin 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 Kidney WT = wild type G2A = transfected with deficient eNOS eNOS = transfected with active eNOS

Insuficienta renala acuta

Factor natriuretc atrial
ANARITIDE study
Allgreen et al, NEJM, 1997, 336, 828-834 504 pacienti din ATI cu IRA, randomizati sa primeasca 24 h ANP sau placebo Util 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.

100 Placebo 80 Anaritide (atrial natriuretic peptide)

60

%
40

20

0 All subjects (n=504)

* p=0.005 A vs. P

Oliguric (n=121)

Non-oliguric (n=376)

Lewis et al, AJKD 2000

Coagulation
Anticoagulant
TM - thrombin
PC APC + PS
Degrades Va, VIIIa

Procoagulant

COAGULATION
Thrombin

(-) (-)

Xa X

VIIa

ATIII TFPI

T-ATIII complexes

TF
IXa IX

Prothrombin

24.7% 30.8%

19.4% relative redn

Treatment of hypotension in septic shock

Fluids Inotropes Others Definitely Definitely but.

Activated protein-c Yes (cost!!!)

Steroids and sepsis good news ?

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

European multi-centre PRCT underway

28-DAY SURVIVAL IN SEPTIC SHOCK (n=299)

1.0

ALL PATIENTS

Cumulative survival rate

0.8 0.6 0.4

TREATMENT 47% PLACEBO 39%

0.2
0.0

p=0.01
0 7 14 21 28

days

Treatment of hypotension in septic shock

Fluids Inotropes Others Definitely Definitely but.

Activated protein-c Yes (cost!!!) Steroids Probably

Methylene blue

* NO scavenger * NOS inhibitor * 2 mg/kg over 15

* 50% respond

Treatment of hypotension in septic shock

Fluids Inotropes Others Definitely Definitely but.

Activated protein-c Yes (cost!!!) Steroids Probably Methylene blue ? rescue

Vasopressin
Acts on V1 and V2 receptors
V2 receptors collecting tubules - water resorbtion V1 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

Vasopressin
VP 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 shock

Fluids Inotropes Others

Definitely Definitely but.

Activated Protein-c Yes (cost!!!) Steroids Probably Methylene blue ? rescue Vasopressin.maybe

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

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 yr Randomised 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<0.05) MOF with proven septic focus: 33 vs. 8 deaths MOF w/o detectable septic focus: 18 vs 14 deaths Dialysis/CVVHF: 64 (8.2) vs 37 (4.8)

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

Experimental Therapies in ARF

Haemodynamic Before Injury Diuretics Mannitol Dopamine Ca2+ antag. SOD anatag. anti-sense iNOS P-selectin antag. CTLA-4Ig RGD peptides After Injury ACEI PDE inhibitors ANP Endothelin antag. PAF antag. ICAM-1 antibody a-MSH

Cell Injury

Cell repair

IGF-1, EGF, HGF

IGF-1

Concluzii
Cercetarea 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 IRA

Marimea catabolismului
Mild Energy substrates AA/ protein (g/Kg/day) Nutrients used glucose 0.6 - 0.8 EAA (+NEAA) enteral formulae Moderate glucose + fat 0.8 - 1.2 EAA + NEAA glucose 50 - 70 % Severe glucose + fat 1.0 + 1.5 EAA + NEAA glucose 50 - 70%

Fat emulsion 10 or 20%

Insuficienta renala acuta

ARF Nutritie
CATABOLISMUL ESTE REGULA
Dat de rezistenta la insulina, efectul TSR, acidoza

Necesarul 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 Nutritie
Alti factori
Nr calorii / unitate volum Na, K, PO4 (reduce) Substante minerale (adaugate)

De preferat calea enterala daca intestinul este functional 35 Kcal, 1g proteine, 0.16g N / kg corp

Dialytic management of ARF

Johannes the baptist

Insuficienta renala acuta

IRA terapii de supleere renala
Indicatii de initiere
Oligurie (< 500 mls / d) urea > 30 mmol/l creatinina > 1000 umol/l potasiu > 6.5 mmol/l pH < 7.2 EPA refractar Pericardita uremica Encefalopatie uremica

Insuficienta renala acuta

IRA terapii de supleere renala - Conditii tehnice de realizare
Instituire rapida si usoara

Eficienta
Controlul volumului, fara limitarea alimentarii Corectia acidozei

Insuficienta renala acuta

IRA terapii de supleere renala

- Conditii tehnice de realizare
Biocompatibilate
Necesitati minime de anticoaglare sistemica sau regionala Efect minim/ absent asupra functiei renale, duratei IRA

Efect minim/absent asupra stabilitatii hemodinamice

Efecte farmacocinetice previzibile

Supravietuire: membrane bio-incompatibile vs bio-compatibile

RCTs only

Cellulose-acetate

Cuprophane

Odds ratio

0.5

1.5

2.0

2.5

Subramanian et al, KI, 62, 1819-1823, 2002

Insuficienta renala acuta

IRA terapii de supleere renala
Principii si optiuni
Convectie vs difuzie Continua sau intermitenta Membrane de celuloza sau sintetice Acces vascular (arterial, venos, pompa de sange) Utilizarea de fluid de inlocuire Necesitatea si durata anticoagularii {dializa peritoneala}

Insuficienta renala acuta

IRA terapii de supleere renala HD intermitenta
De trei x/sapt Zilnica high-flux

Hemofiltrare Hemodiafiltrare {Ultrafiltrare}

Insuficienta renala acuta

IRA terapii de supleere renala
difuzia
In hemodializa Foloseste membrane semipermeabile, pori de dimensiuni mici Gradient de presiune arterio-venos Deplasare transmembrnara bidirectionala intermitenta Frecvent efecte hemodinamice Clearance limitat (proportional cu durata)

Insuficienta renala acuta

IRA terapii de supleere renala convectia
Solvit deplasat prin membrana semipermeabila impreuna cu solventul prin filtrare determinata de gradient de presiune transmembranar Membrana cu porii foarte mari Este 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

Utilizarea IHD si a CRRT

80 70 60 50 40 30 20 10 0 Never <10 11-25 26-50 51-75 >75
% of ARF patients % of nephrologists

CRRT IHD PD

Terapia de supleere renala continua pt pacientii cu IRA

Avantaje
Ameliorarea stabilitatii hemodinamice Reducere aritmii cardiace Ameliorare nutritie Ameliorare schimburi gazoase pulmonare Ameliorare comtrol fluide Ameliorare parametrii biochimici Sedere mai scurta in ATI

Dezavantaje
Probleme abord vascular Risc crescut de sangerare Imobilizare prelungita Frecvent, ruperea capilarelor filtrului Cost ridicat Acidoza 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.
2000

Frecventa IHD necesara pt atingerea controlului corespunzator al azotemiei la pacientii cu IRA.

7

IHD Frequency (per week)

50 60 70 80 90 100

Urea clearance (ml/hr)

5
4

1000

3
2 50 60 70 80 90 100

Weight (Kg)
100 mg/dL 80 mg/dL 60 mg/dL

Weight (Kg)
60 mg/dL 80 mg/dL 100 mg/dL

Clark et al, JASN, 8, 804-812, 1997.

Efectul dozei de dializa asupra supravietuirii

100 % survival 75 50
high Kt/Vurea

25
CCF score outcome

0 0 2 4

low Kt/Vurea

6 8 10 12 14 CCF ICU ARF Score

16

18

20

Leblanc M, Paganini E Adv Ren Repl Ther 2: 255, 1995

Stabilitatea hemodinamica
110

p=NS
80 Mean Map Maxi fall Map 20

50

-10 CAVH IHD

Indepartarea citokinelor: studii clinice

plasma concentration, % of t=0
150

TNF IL-1b IL-6 *

100

50

* p<0.05
0 6 12 18 24

Time (hours)
De Vriese & Lameire, J Am Soc Nephrol 1999

HD zilnica si prognosticul pacientilor cu IRA

Schiffl et al NEJM 346: 305-310, 2002

HD zilnica si prognosticul pacientilor cu IRA

Schiffl et al NEJM 346: 305-310, 2002

Prognosticul imediat CRRT vs IHD

%
P= 0.02

P=0.02

70 60 50 40 30 20 10 0 ICU mortality Hospital mortality

N= 166

All CRRT IHD

Prognosticul pe termen lung al TSR la IRA in ATI

%
90 80 70 60 50 40 30 20 10 0 All patients Survived hospital at 6mnth Survived 6mnth at 12 mnth

N=979

Survived Died

CRRT: dezavantaje
sangerare Cost Inconvenienta Greseli in aprecierea balantei hidrice Tulburari electrolitice Hipotermia

IHD clasica 4 h, 3 ori/sapt

hemodiafiltrare lenta

(adaptabila si zilnica)

CRRT clasic

CVVHD cu volume mari CVVHD CVVH CAVHD CAVH

Slow Extended Daily Dialysis

Ofera 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 Dialysis

Impune evaluare zilnica in echipa nefrolog si intensivist Adaptatarea
Timp de dializa : de la HD continua la IHD Fluxului de sange si dializat pe aparat A ratei de hemofiltrare

Functie de necesitatile pacientului

Comparatia MAP in timpul EDD vs. CVVH.

100 90 80 70 60 50 40 30 20 10 0
CVVH EDD
P=NS P=NS P=NS

preMAP

midMAP

endMAP
Kumar et al, AJKD, 36, 294-300, 2000

SLEDD: anticoagulare
No heparin: 31.9% in SLEDD vs 2.7% in CCVH (p<0,05)
Heparin need in units/day
35000 30000 25000 20000 15000 10000 5000 0 Lowest dose Median dose Highest dose SLEDD CVVH

Kumar et al, AJKD, 36, 294-300, 2000

IHD vs CRRT in IRA: concluzii

Nu este demonstrata nici o superioritate a CRRT vs

IHD

Performanta IHD se poate ameliora prin: dializa

zilnica, HDF, tratament prelungit Evolutia catre terapii hiobrid este normala (SLEDD)

Recomandari actuale de tratament in IRA

HD intermitenta
Tratament de electie in IRA izolata , dar poate fi utilizata si in MSOF Asigurarea unei doze suficiente de dializa; este de preferat HD zilnica Se poate utiliza orice membrana (exceptie rabdomioliza sau substante contrast iodate High-Flux)

CRRT
Preferata in instabilitatea cardiocirculatorie, hiperhidratare, edem cerebral

Asigurarea unei doze suficiente de dializa (35 ml/kgh recomandata in CVVH )

Recomandari actuale de tratament in IRA

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

Determinanti majori ai terapiei:

Experienta personala

Disponibilitatile locale / circumstante locale

Concluzii
Pacientii cu IRA necomplicata au prognosy=tic bun cu HD conventionala Desi 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

A. Jrres 09-2005

A. Jrres 09-2005