The Use of Diuretics in Acute Kidney

1.Alere, Baxter, Gambro, Spectral Diagnostics, Otsuka 2.Speaking: 1.Alere, Gambro, Otsuka1.Alere, Baxter, Gambro, Spectral Diagnostics, Otsuka 2.Speaking: 1.Alere, Gambro, Otsuka1.Alere, Baxter, Gambro, Spectral Diagnostics, Otsuka 2.Speaking: 1.Alere, Gambro, Otsuka1.Alere, Baxter, Gambro, Spectral Diagnostics, Otsuka 2.Speaking: 1.Alere, Gambro, Otsuka

Sean M Bagshaw, MD, MSc

Division of Critical Care Medicine

University of Alberta

The Use of Diuretics in Acute Kidney

Disclosure

1.Consulting:

1.Alere, Baxter, Gambro,

Spectral Diagnostics, Otsuka

2.Speaking:

1.Alere, Gambro, Otsuka

Background ~ Loop Diuretics

1.“Established AKI” in critical illness

1.Few (if any) interventions

Background ~ Loop Diuretics

• Act in TAL LOH

• Inhibit Na-K-Cl

carrier

• Compete with Cl site

• Reduce net

Furosemide

Rationale for Loop Diuretics

1.Direct renal vasodilator

3.Attenuate medullary hypoxia by

inhibiting Na+/K+/2Cl- pump to

reduce tubular O2 demand

5.Attenuate

ischemic/reperfusion-induced apoptosis and associated

gene transcription

7.Mitigate fluid overload/accumulation

Kramer et al KI 1980; Aravindan et al Ren Fail 2007; Aravindan et al Ren Fail 2006; Grams et al CJASN 2011

“Unload” the Stressed Kidney?

1.Acute renal failure = “acute renal

3.If protective - why do we apply

strategies to ↑ GFR? Thurau et al Am J Med 1976

Variable Control Furosemide p-value

Cardiac output (L/min) 5.6 6.1 <0.001 Mean arterial pressure

Redfors et al CCM 2010

Per mmol Na reabsorbed: 1.9 mL O2 in AKI vs 0.82 mL O2 in Control

(2.4 x higher)

Redfors et al CCM 2010

Per mmol Na reabsorbed: 1.9 mL O2 in AKI vs 0.82 mL O2 in Control

(2.4 x higher)

Mehta et al JAMA 2002

• Secondary retrospective analysis from

the Project to Improve Care in Acute

Renal Disease (PICARD) database:

• Population: 552 (64%) critically ill patients

with AKI (defined as BUN>40 mg/dL,

sCr>2 mg/dL or sustained rise >1 mg/dL above baseline)

• Intervention/Exposure: Diuretic use at

any time in 7 days following nephrology

consultation

• Outcome: Death, non-recovery,

composite

Variable Crude OR (95% CI) Adjusted OR

(95% CI)

Propensity -Adjusted

OR (95% CI)

In-Hospital

Mortality

1.37 (0.97-1.92

)

3.15

Mehta et al JAMA 2002

“The risk was borne

largely by patients who

were relatively unresponsive to

and this

Mehta et al JAMA 2002

1. Secondary analysis of the Beginning

and Ending Support Therapy (BEST) for the Kidney database:

1. Population: 1,731 critically ill patients with

AKI (defined by: need for RRT; BUN>86 mg/

dL, K>6.5 mmol/L; oliguria <200mL/12hr; anuria)

2. Intervention/Exposure: Diuretic use after

study enrolment

3. Outcome: In-hospital death

Mehta et al JAMA 2002

Variable Diuretic

(n=1,117)

No Diuretic (n=626)

Length of ICU stay 11 (5-22) 9 (4-20)

Length of Hospital

stay

23 (12-45) 21 (9-44)ICU Mortality (%) 53.4 48.2

Hospital Mortality

Discharge Dialysis 32.7 38.2

Uchino et al CCM 2004

In-Hospital Mortality OR (95% CI)

Model 1 (Mehta et al) 1.21

Bagshaw et al Crit Care Resusc 2007

Mortality

Time to Normalize Creatinine/Urea

Time to Normalize SCr/Urea

Rate of Initiation of RRT

Rate of Initiation of RRT

Time to Achieve Diuresis >1500mL/day

Time to Achieve Diuresis >1500mL/day

Data generated from these trials:

1 Low quality/reporting

2 Single centre/small

3 Co-interventions (dopamine, mannitol)

4 Not all were critically ill

5 Prolonged periods of oligo-anuria

6 Already receiving RRT

7 High-dose bolus

8 No titration to physiologic end-points

1.Questionable internal validity

3.Limited applicability to modern ICU practice

5.Low generalizability

FACTT - Wiedemann et al NEJM 2006

Variable CON LIB p

3 6.0L vs 10.2L 6-day

cumulative, p<0.001

Grams et al CJASN 2011

Furosemide (per 100mg/d) on 60-d mortality OR 0.48 (95% CI, 0.28-0.81,

p=0.007)

CONSERVATIVE GROUP

1 More furosemide!

2 80 mg vs 23 mg per day, p<0.001

3 562 mg vs 159 mg

6-day cumulative,

Van der Voort et al CCM 2009

FUR (n=36)

PLAC (n=35 )

p

Urine Output (mL/

ClinicalTrials.gov Identifier:

NCT00978354

Principle Objectives:

1 Efficacy: in the primary outcome of

progression in severity of kidney injury,

defined as worsening RIFLE category AND/

OR initiation of RRT;

2 Safety: in terms of potential adverse events

associated with (attributed to) furosemide

or placebo;

3 Feasible: in recruitment of eligible patients,

Secondary Clinical Objectives:

1 Fluid balance, electrolyte and acid-base

homeostasis

2 Duration of AKI

3 Initiation of renal replacement therapy

4 Composite of major adverse kidney events

[MAKE] ~

1.Recovery of kidney function AND/OR

2.New or worse chronic kidney disease (CKD) AND/

1.Furosemide use is common in AKI

3.Data is conflicting on it efficacy

5.There is misalignment between

evidence and clinical practice

7.There is equipoise for a randomized trial

9.The SPARK Study proposes to

generate higher quality data to guide

on this issue

Thank You For Your

Attention!

Questions?

bagshaw@ualberta.ca