Aktuelle klinische Studien zum ANV

• Epidemiologie

• Prävention

• Konservatives Management

• Nierenersatztherapie

Agenda 10:20

• Epidemiologie

• Prävention

• Konservatives Management

• Nierenersatztherapie

Agenda 10:20

Natürlicher Verlauf des ANV

Cerda et al. Clin J Am Soc Nephrol 2008

16,968 critically ill patients with KDIGO

stage 2-3 AKI

Reversal of AKI was defined as alive and no longer meeting criteria

for even stage 1

Recovery was defined as reversal at hospital

discharge

Natürlicher Verlauf des ANV

Kellum et al. Am J Respir Crit Care Med 2016

Natürlicher Verlauf des ANV

Kellum et al. Am J Respir Crit Care Med 2016

Das AKD-CKD Kontinuum

Ferenbach & Bonventre. Nat Rev Nephrol 2015

Mortalität und CKD nach ANV

Sawhney et al. Br Med J Open 2015

Mortalität CKD

Parr & Siew. Adv Chron Kidney Dis 2016

Morbidität und CKD nach ANV

cohort study using data from Kaiser Permanente Northern California population: 43,611 adult patients hospitalized between 2008 and 2011 key exclusions:

– no documented blood pressure within 1 year prior to hospitalization – SBP >140 or DBP >90 within 1 year prior to hospitalization – prior diagnostic code for hypertension (x 2 or more) – no serum creatinine within 1 year prior to hospitalization – dialysis or transplant patients – no documented BP in 2 years after hospitalization

primary predictor: AKI (defined using KDIGO creatinine criteria) outcome: SBP >140 or DBP >90 during any ambulatory visit within 2

years after discharge

Bluthochdruck nach ANV

Hsu et al. J Am Soc Nephrol 2016

graded association between AKI severity and risk of elevated BP

Hsu et al. J Am Soc Nephrol 2016

Bluthochdruck nach ANV

cohort study using Department of Defense databases population: 3,846 critically injured US military personnel wounded in Iraq

or Afghanistan from 2002-2011, followed until 2013 key exclusions:

prior diagnosis of hypertension (only 84 out of 6000+) primary predictor: AKI defined using KDIGO creatinie criteria outcome: hypertension defined using ICD9 codes (401.x, 402.x)

if diagnosis assigned within first 90 days of injury, then a second diagnosis required after 90 days to confirm

results: adjusted HR 1.66 (1.28-2.14, P<0.001) for hypertension adjusted for demographics, Injury Severity Score (ISS), burn injury,

HR & MAP at time of injury HR for CKD 4.79 (2.53-9.08, P<0.001)

Stewart et al. Circulation 2015

Bluthochdruck nach ANV

• 10 studies with 90,251 patients • graded association between AKI severity and CHF risk (p=0.01

for interaction); limiting to studies that adjusted for baseline EF, association still holds

Odutayo et al. J Am Soc Nephrol 2017

Herzinsuffizienz nach ANV

HR 1.53 [95% CI: 1.50-1.57]

Re-Hospitalisierung nach ANV

• 111,778 matched pairs

• 18% re-hospitalized

• heart failure (13%)

• AKI (6%)

Silver et al. Am J Med 2016

Siew et al. J Am Soc Nephrol 2016

Risikofaktoren für rekurrentes ANV

1.3.1: Assess patients 3 months after AKI to evaluate the completeness of resolution, the detection of new-onset CKD or worsening of pre-existing CKD (1C)

Das AKD-CKD Kontinuum

• Epidemiologie

• Prävention

• Konservatives Management

• Nierenersatztherapie

Agenda 10:20

Statine und KM-induziertes ANV

Lee et al. PloS One 2014

Statine und OP-induziertes ANV

Lewicki et al. Cochrane Rev 2015

• 199 Patienten ohne Statin randomisiert zu: • 80 mg Atorvastatin 1 Tag vor dem Eingriff, 40 mg am

Morgen vor OP und danach 40 mg täglich (n=102),

oder

• Placebo (n = 97)

• 416 Patienten mit Statin randomisiert zu: • 80 mg Atorvastatin am Morgen der OP und danach

40 mg (n = 206), oder

• Placebo an beiden Tagen (n = 210)

Statine und OP-induziertes ANV

Billings et al. JAMA 2016

Statine und OP-induziertes ANV

Billings et al. JAMA 2016

200 Patienten ohne Statin randomisiert zu 80 mg Atorvastatin vor dem Eingriff, 40 mg am Morgen vor OP und danach 40 mg

Atorvastatin täglich, oder Placebo

Statine und OP-induziertes ANV

Park et al. Intensiv Care Med 2016

Remote Ischemic PreConditioning

• 240 Patienten mit hohem Risiko für ANV vor

herzchirurgischem Eingriff

• Aufpumpen einer Manschette am Oberarm auf

50 mmHg über individuellen systolischen Blutdruck

• 3 Zyklen über 10 Minuten direkt vor dem Eingriff: • 5 Minuten aufpumpen (Ischämie)

• 5 Minuten ablasen (Reperfusion)

Präkonditionierung und ANV

Zarbock et al. JAMA 2015

Präkonditionierung und ANV

Zarbock et al. JAMA 2015

Präkonditionierung und ANV

Meybohm et al. N Engl J Med 2015

Präkonditionierung und ANV

Meybohm et al. N Engl J Med 2015

Präkonditionierung und ANV

Gallagher et al. Kidney Int 2015

86 Patienten mit eGFR <60 ml/min/1,73m² vor Bypass-OP

Präkonditionierung und ANV

Gallagher et al. Kidney Int 2015

86 Patienten mit eGFR <60 ml/min/1,73m² vor Bypass-OP

Samstag 19.11.2016

High Impact Clinical Trials

Veighey K – Portsmouth (UK) Remote ischaemic preconditioning leads to sustained improvement in allograft function following live donor kidney transplantation

Veighey et al. ASN 2016

multi-centre multinational randomized controlled double blind clinical trial to determine if remote ischaemic preconditioning (RIPC) improves renal function after adult live donor kidney transplantation

2 x 2 factorial design – control

– early RIPC

– late RIPC

– dual RIPC

primary endpoint: iohexol GFR at 12 months

early RIPC placebo

late RIPC

dual 102

late alone 103

placebo early alone 102

placebo 99

Veighey et al. ASN 2016

High Impact Clinical Trials

3.08 (-0.89 to 7.04) Adjusted mean difference 1.19 (-2.77 to 5.15)

p value 0.128 0.555

n 159 172 166 165

55,9

58,3

56,8 57,6

50

51

52

53

54

55

56

57

58

59

60

Control Early Control Late

RIPC und eGFR nach 12 Monaten

Veighey et al. ASN 2016

eGFR

(ml/m

in/1

,73m

²)

• overall, eGFR difference between early RIPC and control:

4.82; 95% CI 1.60 to 8.03; p=0.003

• adjusted mean differences in

eGFR (ml/min/1.73m2) between

control & early RIPC groups:

1 year 3.77 (p=0.049)

2 years 3.94 (p=0.052)

3 years 5.16 (p=0.015)

4 years 5.55 (p=0.039)

5 years 5.05 (p=0.104) 30

40

50

60

eGFR

(ml/m

in/1

.73m

²)

3 12 24 36 48 60Time (months)

Mean +/- Standard Error:Control Late RIPCEarly RIPC

Veighey et al. ASN 2016

Early RIPC und eGFR nach 5 Jahren

30

40

50

60

eGFR

(ml/m

in/1

.73m

²)

3 12 24 36 48 60Time (months)

Mean +/- Standard Error:Control Late RIPC

• adjusted mean differences in

eGFR (ml/min/1.73m2) between

control & late RIPC groups:

1 year 1.03 (p=0.591)

2 years 1.42 (p=0.483)

3 years 1.86 (p=0.382)

4 years 5.89 (p=0.029)

5 years 2.00 (p=0.519)

• overall, eGFR difference between late RIPC and control:

1.62; 95% CI: -1.59 to 4.83; p=0.323

Veighey et al. ASN 2016

Late RIPC und eGFR nach 5 Jahren

30

40

50

60

eGFR

(ml/m

in/1

.73m

²)

3 12 24 36 48 60Time (months)

Mean +/- Standard Error:Control RIPC

• adjusted mean differences in eGFR

(ml/min/1.73m2) between control &

dual RIPC groups:

1 year 4.22 (p=0.058)

2 years 3.94 (p=0.096)

3 years 6.22 (p=0.012)

4 years 10.67 (p=0.001)

5 years 8.02 (p=0.027)

• overall, eGFR difference between RIPC and control:

4.21; 95% CI: 0.45 to 7.98; p=0.028

Veighey et al. ASN 2016

Dual RIPC und eGFR nach 5 Jahren

A

0%

2%

4%

6%

8%

Per

cent

with

gra

ft lo

ss

204 194 193 189 136 84Early RIPC 202 188 185 181 128 72Control

Number at risk

0 12 24 36 48 60Time (months)

Control Early RIPC

C

0%

2%

4%

6%

8%

Per

cent

with

gra

ft lo

ss

205 195 193 189 136 83Late RIPC 201 187 185 181 128 73Control

Number at risk

0 12 24 36 48 60Time (months)

Control Late RIPC

E

0%

2%

4%

6%

8%

Per

cent

with

gra

ft lo

ss

307 290 288 281 204 123Any RIPC 99 92 90 89 60 33Control

Number at risk

0 12 24 36 48 60Time (months)

Control Any RIPC

Veighey et al. ASN 2016

RIPC und Transplantatverlust

• 208 CKD Patienten (Serum-Kreatinin ≥1,7 mg/dl) • ACE-Hemmer bzw. AT1-Rezeptorblocker wurden mindestens 24 Stunden vor dem Herzkatheter in randomisierter Reihenfolge abgesetzt oder belassen

RAS-Hemmer und ANV

Bainey et al. Am Heart J 2015

RAS-Hemmer und ANV

Bainey et al. Am Heart J 2015

• Epidemiologie

• Prävention

• Konservatives Management

• Nierenersatztherapie

Agenda 10:20

Zielorientierte Therapie und ANV

Kellum et al. Am J Respir Crit Care Med 2016

Zielorientierte Therapie und ANV

Kellum et al. Am J Respir Crit Care Med 2016

EGDT – early goal-directed therapy (targeted fluids, vasoactive medication, and blood transfusions to central venous oxygen saturation (as a measure of oxygen delivery to the tissues) PSC – protocol-based standard care (simpler structured approach based on blood pressure and heart rate, and the clinical assessment by the study team)

Zielorientierte Therapie und ANV

Kellum et al. Am J Respir Crit Care Med 2016

early goal-directed therapy

protocol-based standard care

standard care

Kellum et al. Am J Respir Crit Care Med 2016

Zielorientierte Therapie und ANV

Kristalloide und ANV

Kristalloide und ANV

• double-blind, cluster-randomized, crossover design

• randomization occurred at the ICU level (n=2,278)

• frequency, dose, and rate of fluid prescription were at the

discretion of the treating clinician

• the primary end point was incidence of AKI

Young et al. JAMA 2015

Serum-Kreatinin Nierenersatztherapie

Young et al. JAMA 2015

Kristalloide und ANV

Kristalloide und ANV

Young et al. JAMA 2015

0.9% normal saline as the solution of choice

patients with alkalosis and hypochoremia (e.g. profound vomiting) patients with head injuries and brain edema

Buffered crystalloids as the solution of choice patients with evidence of sepsis patients with CKD patients requiring large amounts of fluid replacement

Kristalloide und ANV

Yunos. ASN 2016

Kristalloide und ANV

Plasma-Lyte 148® vs. Saline Study (PLUS) • ClinicalTrials.gov NCT02721654

• multi-centre, blinded, RCT

• estimated enrolment: 8,800 patients

• inclusion criteria includes fluid resuscitation of at least 500 ml or at least 5ml/kg

• patients who have previously received fluid resuscitation excluded

Balanced Solution vs. Saline in Intensive Care Study (BaSICS) • ClinicalTrials.gov NCT02721654

• multi-centre, blinded, RCT (2x2 factorial design)

• estimated enrolment: 11,000 patients

• Plasma-Lyte vs. saline; fast Infusion (999 mL/h) vs. slow Infusion (333 mL/h)

Agenda 10:20

• Epidemiologie

• Prävention

• Konservatives Management

• Nierenersatztherapie

Dialysebeginn bei ANV

Zarbock et al. JAMA 2015

231 kritisch kranke Patienten mit ANV und Plasma-NGAL

>150 ng/ml wurden randomisiert zu: • frühen Nierenersatztherapie

Beginn innerhalb 8 Stunden nach der Diagnose des ANV

ab KDIGO Stadium 2 (n = 112), oder

• späten/keiner Nierenersatztherapie

Beginn innerhalb 12 Stunden nach der Diagnose eines ANV im

KDIGO Stadium 3 (n = 119)

Dialysebeginn bei ANV

Zarbock et al. JAMA 2015

Dialysebeginn bei ANV

Zarbock et al. JAMA 2015

Dialysebeginn bei ANV

Gaudry et al. N Engl J Med 2016

Dialysebeginn bei ANV

Gaudry et al. N Engl J Med 2016

620 schwerstkranke beatmete Patienten mit ANV ab KDIGO Stadium 3 wurden randomisiert zu: • frühen Nierenersatztherapie Beginn sofort nach Randomisierung, oder • späten/keiner Nierenersatztherapie Beginn nur bei:

• schwerer Hyperkaliämie • schwerer metabolischer Azidose • Lungenödem • Serum-Harnstoff >112 mg/dl, oder • Oligurie länger als 72 Stunden nach Randomisierung

Dialysebeginn bei ANV

Gaudry et al. N Engl J Med 2016

Dialysebeginn bei ANV

Gaudry et al. N Engl J Med 2016

Donnerstag 17.11.2016

CKD and AKI Clinical Trials

Bridoux F – Paris (France) Treatment of myeloma cast nephropathy: a randomized study comparing high cut-off hemodialysis with standard hemodialysis Hutchison CA – Birmingham (UK) European trial of free light chain removal by extended haemodialysis in cast nephropathy: a randomised controlled trial

ASN 2016

MYRE study • 98 patients • bortezomib based

chemotherapy • intensive dialysis:

• 8 sessions (5 hrs.) over 10 days then thrice weekly

• HCO-HD vs. HF-HD • similar FLC levels at 3 months • dialysis independence:

• 43% vs. 33% (NS) at 3 months • 60% vs. 38% (p< 0.03) at 6

months

EuLITE trial • 90 patients • bortezomib based

chemotherapy • alternate day HCO-HD

• 2 filters in series • HF-HD at discretion of

nephrology • FLC levels similar at 3 weeks • dialysis independence:

• 52% vs. 56% (NS) at 3 months • 58% vs. 66% (NS) overall • no difference of eGFR at 2

years

HCO HD bei Myelom-Leichtketten

ASN 2016

0 2 4 6 8 10 12

0.0

0.2

0.4

0.6

0.8

1.0

Months

Cum

ulat

ive

inci

denc

e of

HD

inde

pend

ence

ControlHCO

Months

Sur

viva

l Pro

babi

lity

0 7 14 21 28 35 42 49 56 63 70

0.0

0.2

0.4

0.6

0.8

1.0

47 39 30 16 11 6 6 2 1 Arm=Control

46 42 31 22 15 10 7 5 2 Arm=HCO

Arm=Control Arm=HCO

MYRE study

Myeloma + proven MCN + hemodialysis requirement conventional high-flux dialyser vs. HCO Theralite

renal survival

p = 0.047

ASN 2016

Months

Survi

val P

roba

bility

0 6 12 18 24 30 36 42 48 54 60 66

0.00.2

0.40.6

0.81.0

48 41 35 22 15 11 7 6 4 1 1 Arm=Control

46 42 38 25 18 14 9 7 5 4 2 Arm=HCO

Arm=ControlArm=HCO

overall survival

p = 0.46

HCO – 56% HF – 52% p = NS

EuLITE trial

Renal function by 3 and 12 months

ASN 2016

HF – 66% HCO – 58% p = NS

3 months 12 months

total HCO-HD (43)

HF-HD (47)

0-3 months 68 40 28 infections 34 22 12* catheter related 9 5 4 lung 15 12 3 sepsis 4 2 2 others 6 3 3 non-infections 34 18 16

*p = 0.022

Serious adverse events

ASN 2016

EuLITE trial

Vielen Dank!

Agenda 10:20