NEW METHODS IN DIAGNOSIS AND MANAGEMENT OF AKI

Stefano Picca, MD Department of Pediatrics, Dialysis Unit

“Bambino Gesù” Pediatric Research Hospital, IRCCS

ROMA, Italy

Third IPNA-ESPN Master for Junior Classes Leuven (Belgium), October 28-30th, 2016

1. Diagnosis: biomarkers and new AKI classifications

2. Treatment: methods and timing

OUTLINE

TIME WINDOWS FOR AKI MANAGEMENT

Modified from Sutton, 2002

-sCreatinine increase OR -Urine Output decrease

• AKI diagnosis traditionally dependent on changes in SCr • sCr as a marker of AKI: limitations of time, body habitus, sex, age, steady-state

measurement, patient condition • diagnosis of AKI is often delayed with barrier to effective early intervention

AKI in children: the diagnosis problem

research of novel AKI biomarkers research of new AKI classifications

Period Acute Myocardial Infarction

1960s LDH

1970s CPK, myoglobin

1980s CK-MB

1990s Troponin T

2000s Troponin I

Multiple Therapies 50% ↓ Mortality

Supportive Care High Mortality

Need early biomarkers of AKI for improved understanding, early treatment and better outcomes

Biomarkers: AMI versus AKI

Acute Kidney Injury

Serum creatinine

Serum creatinine

Serum creatinine

Serum creatinine

Serum creatinine

Courtesy of P. Devarajan

AKI biomarker = a sensitive and specific early marker of renal injury ( “kidney troponin”)

2 4 6 8 12 24 36 48 60 72 84 96 108 120

Post CPB Time (hours)

Urine N

GA

L (

ng

/ml)

No AKI

(n=51)

AKI

(n=20)

Serum Creatinine Rise

Detection of Urinary NGAL by ELISA

Urine NGAL is upregulated 15-fold within 2 hours after CPB in patients who later develop ARF

Mishra J et al: Lancet 2005

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

25

50

75

100

125

150

175

200

225

Zappitelli M et al. Critical Care, 2007; 11: R84

Urine NGAL is an early marker of acute kidney injury in critically ill

children

Mean uNGAL concentrations by pRIFLE

max strata

Mean concentrations of uNGAL

according to presence or absence of

sepsis

High

Specificity

High

Sensitivity sCreat ↑↑↑

sCreat ↑↑

sCreat ↑

UO ↓↓↓

UO ↓↓

UO ↓

pRIFLE AKIN KDIGO

Mortality increases with

RIFLE strata

in every study

Courtesy of SL Goldstein

Stuart L. Goldstein, MD

On Behalf of the AWARE Investigators

THE RENAL ANGINA APPROACH (1)

Basu, 2012; Goldstein, 2010

THE RENAL ANGINA APPROACH (2)

Basu, 2013

Sutherland SM, 2010

• n=297

•Data from ppCRRT

Registry

• ≤10% FO: 51.5%

• 10%-20% FO: 17.2%

• ≥20% FO: 31.3%

P= 0.07

P<.001 P<.001

ALL NEPHROLOGICAL NON NEPHROLOGICAL

DEAD

ALIVE

<5% <5% <5% 5-10% >10% >10% >10%

%FO %FO %FO

0%

20%

40%

60%

80%

100%

Surv

ival

0%

20%

40%

60%

80%

100%

0%

20%

40%

60%

80%

100%

5-10% 5-10%

n= 131

Overall survival: 45,8%

I want my p< 0,05 !!!!!

Hey, Dr. Dialysis what the hell do you want???

The ped-AKI Arena: Dr. Dialysis and Mr. Underlying Disease

Akcan-Arikan (2007), n=123: • 71% of patients who attained pRIFLE F AKI did not receive RRT.

• “pRIFLE criteria is overly sensitive for identifying severe AKI…” Mehta A (2010), n= 80: All pts needing RRT belonged to F group

• “pRIFLE important in determining RRT” Almaslamani T (2010), n= 95:

• “AKI acc. to RIFLE: only 37% of RRT… not a good predictor” Plotz FB (2008), n= 103:

• 6/103 required RRT: only 1 was pRIFLE F

TRANSLATING CLASSIFICATION INTO MANAGEMENT. IS IT POSSIBLE?

Duzova A, 2010

Let’s classify….. Hurry, he’s about to die….

AKI DEFINITION: FACING THE EXTREMES…

TIME WINDOWS FOR AKI MANAGEMENT

Nephroprotection?

Modified from Sutton, 2002

Fluids

Drugs

RRT

?

FENOLDOPAM AND NEPHROPROTECTION: MECHANISM

FENOLDOPAM MESYLATE

Short-acting selective DA-1 dopaminergic receptor agonist

INDUCES:

• Increased cAMP-PKA production in renal arteries smooth muscle:

arterial relaxation and

increased renal blood flow

• Increased cAMP concentration in tubular cells and inhibition of Na-H and Na-K ATPase: increased natriuresis

• Decreased aldosterone production:

increased natriuresis

M Ranucci Minerva Anestesiol 2010 Z Ricci Interact CardioVasc Thorac Surg 2008

n= 80 AKI (pRIFLE>0): 50% in group F 72% in group C (P = 0.08)

Factors involved in the decision for dialysis in AKI

“MODERN” • Fluid overload control • Inflammatory mediators removal with

CRRT • “Anticipation” (based on AKI staging,

clinical conditions, etc)

“TRADITIONAL” • Reliance on criteria for maintenance dialysis initiation (medically

refractory acidosis, hyperkalemia, threshold creatinine) simply wrong • Fluid restriction failure restriction hard to establish, often induces late indication to

dialysis • “Waiting” for renal function reprise undefined duration in often undefined AKI diagnosis

2 M. 5 yrs • BMT • Sepsis, SIRS, hypotension • 2 pressors • Fluid overload +10%. •UO 3.1 ml/kg/h with Lasix • sCreat 0.5 mg/dl

2 CLINICAL CASES

1 F. 14 mos • HUS • Diarrhea, dehydration • Anuria • rehydration • Fluid overload 15% • sCreat 1.3 mg/dl.

TREATMENT ?

PD Peritoneal Dialysis •Continuous • Low cost, easy application •Good CV tolerance •No extracorporeal circuit •No anticoagulation •Low ultrafiltration

PD DEFINITION

Dialysate +

Filtrate

Diaysate

HD HemoDialysis •Intemittent •Poor CV tolerance •Anticoagulation •Quick depuration of small molecules and water •Highly specialized equipment and expertise

HD DEFINITION

Filtrate- Diaysate

Dialysate

CVVH (postdilution) Continuous VenoVenous Hemofiltration •Continuous •Good CV tolerance •Slow depuration of small molecules and water •Anticoagulation •Highly specialized equipment and expertise

CRRT DEFINITION

Filtrate

collecting

device

Replace-ment

fluid

Courtesy of Z. Ricci

Pediatric patients in the range of 2-10 kgs

(approximate BSA of 0.15–0.5 m2)

DESIGNED BY THE INTERNATIONAL RENAL RESEARCH INSTITUTE OF

VICENZA (2011)

OPBG EXPERIENCE

- 12 neonates

- About 32 sessions

- 50% times 0.075 m2

- Weight range 2.1-3.5 kg

- CVVH 100% pre

- Qb 5-14 ml/min

- Q rep 20-30 ml/kg/h

- NETQuf 10-20 ml/h

- Vasc access 6.5F, 4F

or two 20-24G cannulas

Courtesy of Z. Ricci

time

Solutes/

fluid

PD

HD

CRRT

1. Adana (Dr. Aysun Karabay BAYAZIT)

2. Ankara (Dr. Ali DUZOVA)

3. Berlin (Dr. Uwe QUERFELD)

4. Bern (Dr. Giacomo SIMONETTI)

5. Bologna (Dr. Francesca Mencarelli)

6. Budapest (Dr. Peter SALLAY)

7. Bordeaux (Dr. Jerome HARAMBAT)

8. Firenze (Dr. Marco MATERASSI)

9. Hamburg (Dr. Jun OH)

10. Heidelberg ( Dr. Claus SCHMITT)

11. Innsbruck (Dr. Gerard CORTINA)

12. Istanbul (Dr. Salim CALISKAN)

13. Istambul (Dr. Sevinc EMRE)

14. Izmir (Dr. Pelin ERTAN)

15. Izmir (Dr. Pelin MIR)

16. Izmir (Dr. Ebru YILMAZ)

17. London (Dr. Rukshana SHROFF)

Lyon (Dr. Bruno RANCHIN)

Dialysis Treatment of AKI in Europe:

The 4C Study Group Survey

19. Lodz (Dr. Marcin TKACZY)

20. Katowice (Dr. Maria SZCZEPANSKA)

21. Kaunas (Dr. Sarunas RUDAITIS)

22. Kocaeli (Dr. Zelal Ekinci)

23. Koln (Dr. Lutz WEBER)

24. Malatya (Dr. Yilmaz TABEL)

25. Marburg (Dr. Guenter KLAUS)

26. Milano (Dr. Gianluigi ARDISSINO)

27. Padova (Dr. Enrico VIDAL)

28. Porto (Dr. Helena PINTO)

29. Rome (Dr. Isabella GUZZO, Dr. Stefano PICCA)

30. Rostock (Dr. Hagen STAUDE)

31.Strasbourg (Dr. Michel FISCHBACH)

32. Vilnius (Dr. Augustina JANKAUSKIENE)

33. Warsaw (Dr. Ryszard GRENDA)

34. Wien (Dr. Klaus ARBEITER)

• 34 participating centers

CRRT

PD

HD

0%

10%

20%

30%

40%

50%

60%

1995 1999 2003 Warady et al, Pediatr Neph 2003, 15:11-3

0

10

20

30

40

50

60

70

% o

f tr

eate

d p

atients

Picca, European Survey 2013,

unpublished

European Survey of AKI

treatment with dialysis

in children

n= 903

author n Time to PD start Pts with negative fluid

balance

Survivors

Lowrie (2000) 17 NA 35% 24%

Fleming (1995) 21 2.5 days (1-6) after surgery 36% 38%

Golej (2002) 116 NA, but 43% of pts started on PD

when CVP>10 mmHg

53% 47%

Werner (1996) 23 2.6±0.6 days 100% 53%

Santos (2012) 23 4.8±16.8 hrs 100% 56.6%

Chien (2009) 7 1.2±0.4 days after AKI onset NA 57%

Dittrich (1999) 27 In the OR or first hrs in ICU 100% 73%

Sorof (1999) 20 22 hrs 100% 80%

PD AFTER HEART SURGERY IN CHILDREN:

FLUID BALANCE AND SURVIVAL THROUGH THE YEARS

Survival > 50% occurs only when all patients reach a negative fluid

balance with PD

AKI RISK IDENTIFICATION AND MANAGEMENT

EASILY PREDICTABLE/ PREDICTABLE: Heart surgery,

initial sepsis, BMT, LT, nephrotoxicity, etc

HARDLY PREDICTABLE/ UNPREDICTABLE:

Late referral, ATN, metabolic diseases , etc

Classification/biomarkers most useful

pRIFLE-AKIN-KDIGO

Classification/biomarkers less useful

RRT

Most of the times =

Fluid overload

Preventive interventions possible

volume

diuretics

fenoldopam

RRT ?

“Is he so sick because he has a horrible disease or because someone (may be me…) waited too long?”

ACKNOWLEDGEMENTS

• Nephrology Unit: Isabella Guzzo, MD and Lara De Galasso, MD for OPBG CRRT database and EurAKId website

• CICU: Zaccaria Ricci, MD

• PICU: Matteo Di Nardo,MD; Emanuele Rossetti, MD

• NICU: Andrea Dotta, MD

• All ICUs nurses

• All Dialysis Unit nurses

• Tim Bunchman, Stu Goldstein, Claudio Ronco for precious advices and friendship through the years . Thanks!

Dialysis Unit, “Bambino Gesù” Pediatric Hospital

Roma, Italy.

Doctor:

S. Picca

Headnurse:

V. Bandinu

Nurses:

N. Avari

D. Ciullo

E. Iacoella

P. Iovine

P. Lozzi

L. Stefani

Nurse Coordinator:

M. D’Agostino

stefano.picca@opbg.net

Available information mainly coming from one multicenter study (ppCRRT) utilizing

only one modality (CRRT) in one patient population (critical)

DIALYSIS in PEDIATRIC AKI:

ARE OUTCOME AND DIALYSIS MODE RELATED?

PROBLEMS AFFECTING STUDIES

Retrospectively:

•No standardized AKI definition

•Indication to the modality depending on local facilities/expertise

•Changing modalities in the same patient Prospectively:

•Paucity of patients

•Ethical issues for randomized studies

•Organization issues with ICUs

LACK of RANDOMIZED

STUDIES

Peritoneal vs Extracorporeal Dialysis in AKI: Pediatric Studies

AA (yr) n PD n CRRT n IHD Type

of study

Mortality P

Fleming (1995) 17 17 - retrospective 38% vs 37% NS

Bunchman

(2001)

59 61 106 retrospective 51% vs 60% vs 19% <0.01

Bandeira

(2005)

82 36 - retrospective - NS

Krause

(2011)

81 31 18 retrospective 52% vs 83% vs 8% <0.01

Retrospective Studies comparing different Dialysis Modalities are affected by

the attitude of addressing the patient to a specific modality according to the

severity of illness

AKI Definitions to 2002

• Over 30 definitions in published literature – Nearly all based on absolute or change in serum

creatinine concentration

• Few prospective pediatric studies – Retrospective studies assess AKI causes

– Control group without AKI not assessed to determine risk factors for AKI

Courtesy of SL Goldstein

?

PCCM 2006

LIMITATIONS: •RANDOMIZATION •FENOLDOPAM 0,1 mcg/Kg/min •LATE AKI MARKERS WITH LOW SENSIBILITY AND SPECIFICITY

Fenoldopam in newborn patients undergoing cardiopulmonary bypass: controlled clinical trial

Ricci Z et al. Interactive CardioVascular and Thoracic Surgery 7 (2008) 1049–1053

Goldstein, 2010

KDIGO 2012

CHANGE IN THE EPIDEMIOLOGY OF AKI

Primary renal disease AKI as complication of

systemic diseases

Single organ failure

Renal ward/ Dialysis Unit

MODS

ICU

+

Courtesy of E. Vidal, modified

Day N

(% total) Nephrotoxins Diuretics

Cumulative

Fluid

Balance

% FO KDIGO 2-3

by Cr

KDIGO 2-3 by

UOP

1 4730

(90.4) 37.1% 14.7% 604

(200-1266)

3.6

(1.1-6.8) 7.8% 2.4%

2 2937

(56.1) 42.0% 23.9% 870

(289-1685)

5.4

(1.6-10) 10.1% 1.9%

3 2085

(39.9) 42.3% 30.9% 1050

(339-2042)

6.3

(1.9-8.4) 11.3% 2.3%

4 1563

(29.9) 39.4% 35.6% 1145

(353-2518)

7.5

(2.1-14.6) 14.0% 2.8%

5 1225

(23.4) 40.7% 38.8% 1299

(391-2502)

8.7

(2.7-16.5) 11.6% 3.2%

6 985

(18.8) 41.5% 40.4% 1454

(469-2794)

10

(3.1-18.9) 12.9% 2.4%

7 837

IN NEONATES

“Immature” newborn kidney

Torres de Melo Bezerra, NDT 2013

Low GFR

High Urine Output

To accomplish the physiologic extracellular post-natal fluid reduction (10% weight loss)

To manage the large water load coming from breast feeding

nRIFLE

Ricci, Ronco, adapted from Torres de Melo Bezerra, NDT 2013

Jetton, Askenazi, adapted from Koralkar R, 2011

“MAXIMAL”(?) EFFICIENCY IN CVVH ADULT-CHILD-NEONATE

BW

(kg)

TBW

(l)

Qb

(ml/min)

UF/h

(=K urea)

(l/h)

K urea per

liter of TBW

(l/h)

NEONATE 3 2.4 30 0.25 0.10

CHILD 25 15 80 1.2 0.08

ADULT 70 42 150 2.5 0.05

DISEASE AND SURVIVAL

Diagnosis N Survival Diagnosis N %Survival

BMT 26 42% HUS 16 94%

TLS/Malig 17 58% ATN 46 67%

CHD 47 39% Liver Tx 22 17%

Heart Tx 13 67% Sepsis 39 33%

Bunchman TE et al: Ped Neph 16:1067-1071, 2001

Slide courtesy of T.E.B.

Pts on Vasopressors survival = 35%

Pts not on Vasopressors survival = 89%

(p < 0.01)

• Fluid overload independently associated with mortality

• OR 8.5 for mortality (95% CI 2.8-25.7)

Courtesy of SL Goldstein

CRRT O.R. 95% CI p

Days in PICU before CRRT 1,069 1,002 1,141 0,043

Fluid Overload 1,039 1,010 1,069 0,009

Fluid Overload>10% 2,993 1,431 6,258 0,004

N° pressors 1,878 1,332 2,648 0,000

Vasoactive score 1,082 1,034 1,132 0,001

Dopamine 1,278 0,982 1,663 0,068

AKI 2,974 1,346 6,572 0,007

MODS 9,644 4,051 22,958 0,000

Hypotension 4,488 1,858 10,842 0,001

Diuretics 2,623 1,271 5,412 0,009

CRRT

Qr 0,998 0,993 1,003 0,482

Qd 0,999 0,996 1,003 0,648

Qb 0,980 0,860 1,118 0,767

THE OPBG CRRT REGISTRY: RETROSPECTIVE DATA. UNIVARIATE ANALYSIS

Guzzo, 2013, unpublished

Need for dialysis

AKI definition pRIFLE

AKIN

KDIGO

sCreat or UO changes

OVER THE YEARS…