Sean M Bagshaw, MD, MScDivision 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 illness1.Few (if any) interventions2.Supportive

2.Many interventions require evidence:1.Better quality (i.e. randomized

trials)2.More applicable

Background ~ Loop Diuretics

• Act in TAL LOH• Inhibit Na-K-Cl

carrier• Compete with Cl site• Reduce net re-

absorption– Na, Cl, K, Mg, Ca– H20

• Action dependent on delivery to site of action:

Tubular Lumen

Peritubular Capillary

Furosemide

Rationale for Loop Diuretics

1.Direct renal vasodilator3.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/accumulationKramer 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 success”

2.↓ in GFR (mediated by TGF) = ↓ reabsorptive work1.Preserve renal O2 supply/demand +

medullary oxygenation2.Mitigate ischemic/hypoxic injury

3.If protective - why do we apply strategies to ↑ GFR? Thurau et al Am J Med 1976

Variable Control Furosemide p-valueCardiac output (L/min) 5.6 6.1 <0.001Mean arterial pressure (mmHg)

80.2 80.6 NSRenal plasma flow (mL/min)

802 779 NSGFR (mL/min) 89.1 78.5 <0.001

Na reabsorption (mmol/min)

12.0 7.7 <0.001FeNa (%) 1.8 29.4 <0.001Urine flow (mL/min) 2.4 23.3 <0.001RVO2 consumption (mL/min)

11.1 7.9 <0.001O2 extraction (renal) (%) 10.5 8.5 <0.05

Sward et al ICM 2005

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

Diuretic Given on Day 1

n (%) Dose (med

[10-90th])Furosemide 203 (62) 80 (20-320)Bumetanide 106 (58) 10 (2-29)Metolazone 106 (33) 10 (5-20)Hydrodiuril 13 (4) -Loop + Thiazide

105 (32) -

Diuretics were used in 59% (n=326)

Mehta et al JAMA 2002

Variable Diuretic(n=226)

No Diuretic(n=326)

p

Age (yr) 58.1 (17.1)

53.8 (18.0)

<0.01History of CHF (n, %) 87 (27) 30 (13) <0.01Nephrotoxic (n, %) 61 (19) 28 (12) 0.05Respiratory Failure (n, %) 241 (74) 143 (64) 0.01Cardiac Failure (n, %) 148 (45) 75 (33) <0.01BUN (mg/dL) 61.6

(34.6)72.3

(43.4)<0.01

sCr (mg/dl) 3.6 (1.9) 4.1 (3.3) <0.01

Variable Crude OR (95% CI)

Adjusted OR

(95% CI)

Propensity-Adjusted

OR (95% CI)In-Hospital

Mortality1.37

(0.97-1.92)

1.65 (1.05-2.58)

1.68 (1.06-2.64)

Non-Recovery 1.53 (1.08-2.15

)

1.70 (1.14-2.53)

1.79 (1.19-2.68)

Composite 1.48 (1.02-2.12

)

1.74(1.12-2.68)

1.77 (1.14-2.76)

Composite (Ever/Never, n=416)

2.01 (1.26-3.20

)

3.15 (1.74-5.62)

3.12 (1.73-5.62)

Mehta et al JAMA 2002

Furosemide dose-equivalent (mg/mL urine output/d) as surrogate for “diuretic responsiveness” – median 0.34 mg/mL

DE (dark circle) > 1.0 mg/mL – OR 2.94 (1.6-5.4) DE (triangle) < 1.0 mg/mL

– OR 1.15 (0.8-1.7)

Mehta et al JAMA 2002

“The risk was borne largely by patients who

were relatively unresponsive to

diuretics”…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

Diuretic Use n (%)

Any diuretic use 1,117 (60.8)Furosemide 1,098 (98.3)Other loop diuretic 29 (2.6)Mannitol 22 (2.0)Metolazone 19 (1.7)Spirolactone 18 (1.6)Thiazides 14 (1.3)Other 14 (1.3)

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 (%)*

62.4 57.1

Discharge Dialysis 32.7 38.2

Uchino et al CCM 2004

In-Hospital Mortality OR (95% CI)

Model 1 (Mehta et al) 1.21(0.96-1.50)

Model 2 (Propensity) 1.22 (0.91-1.60)

Model 3 (Multi-collinearity)

1.22 (0.92-1.60)

PICARD/BEST Studies

1.Caveats to consider to these studies:1. Observational → Confounding2. Selection/information bias3. Severe/advanced AKI at inclusion

(sCr>3.5)*4. No data on specifics of fluid

resuscitation5. No data on fluid overload/

accumulation6. No data on timing of diuretic use

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/reporting2. Single centre/small3. Co-interventions (dopamine, mannitol)4. Not all were critically ill5. Prolonged periods of oligo-anuria 6. Already receiving RRT7. High-dose bolus8. 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

Death (day 60) (%) 25.5 28.4 0.30

Ventilator-free days (d 1-28)

14.6 12.1 0.001

ICU-free days (d 1-28) 13.4 11.2 0.001

RRT (day 60) (%) 10 14 0.06

Grams et al CJASN 2011

Fluid balance (per L/day) on 60-day mortality

OR 1.61 (95% CI, 1.32-19.6, p<0.001)

CONSERVATIVE GROUP1. Less fluid!2. 0.9L vs. 2.2L per day,

p<0.0013. 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 GROUP1. More furosemide!2. 80 mg vs. 23 mg per

day, p<0.0013. 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/

hr)247 117 <0.0

1

Urine [Na](mmol/L) 73 37 <0.0

1

Recovery (%) 69.4 77.1 0.5

Iso-volemic furosemide infusion

(0.5 mg/kg/h)vs. placebo

Trial Design

The SPARK Study: A randomized controlled

trial of furoSemide in critically ill Patients with

eARly acute Kidney injuryClinicalTrials.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

homeostasis2. Duration of AKI3. Initiation of renal replacement therapy4. Composite of major adverse kidney events

[MAKE] ~ 1.Recovery of kidney function AND/OR2.New or worse chronic kidney disease (CKD) AND/

Summary

1.Furosemide use is common in AKI3.Data is conflicting on it efficacy5.There is misalignment between

evidence and clinical practice7.There is equipoise for a randomized

trial9.The SPARK Study proposes to

generate higher quality data to guide on this issue

Thank You For Your Attention!

Questions?bagshaw@ualberta.ca