ASN Board Review: Acute Renal Replacement Therapies

ASN Board Review:Acute Renal Replacement

Therapies

Ashita Tolwani, M.D., M.Sc.

University of Alabama at Birmingham

2014

Key issues for boards: RRT for AKI

•When should therapy be initiated?

•What are the critical elements of the RRT prescription?

•Type of technique

•Dose of RRT

•Anticoagulation

When to initiate RRT?

No Consensus Indications for initiation of RRT Appropriate timing of initiation of RRT

Conventional Indications Refractory fluid overload Metabolic acidosis Hyperkalemia Uremia Drug overdose

Early vs Late RRT in AKI

Study Year Design N Early Late Early Late

Parsons et al 1961 Retro 33 120-150 >200 75 12

Fischer et al 1966 Retro 162 150 >200 43 26

Kleinknecht et al

1972 Retro 500 <93 >163 71 58

Conger 1975 Prosp 18 50 120 64 20

Gillum et al 1986 Prosp 34 60 100 41 53

Gettings et al 1999 Retro 100 <60 >60 39 20

Bouman et al 2002 Prosp 106 47 105 71 75

BUN pre-RRT (mg/dL) Survival (%)

Early vs Late Initiation of CVVH RCT

Bouman CS, et al. Critical Care Med 2002; 30:2205-2211

Early High Volume Group

(n = 35)

Early Low Volume Group

(n = 35)

Late Low Volume Group

(n = 36)

Time between inclusion and RRT (hrs)

6.0 (3.0 – 9.7) 7.0 (5.0 – 10.0) 41.8 (21.4 – 72.0)

PredialysisBUN (mg/dl)

45.7 (38.4 – 57.7) 47.9 (40.3 – 65.8) 104.8 (61.6 -116.0)

Survival (%)(p = 0.8)

74.3 68.8 75

Earlier-Start vs Usual-Start Dialysis in Patients with Community-Acquired AKI: A RCT

208 patients with community-acquired AKI randomized to early- vs. usual-start RRT IHD

Early-start RRT: BUN >70 mg/dL and/or serum creatinine >7.0 mg/dL

Usual-start RRT: refractory hyperkalemia, volume overload, acidosis, nausea, anorexia, etc.

Mortality: 20.5% for early-start; 12.2% for usual-start (RR, 1.67; 95% CI, 0.88-3.17; P = 0.2)

Jamale TE et al. Am J Kidney Dis. 2013

Dialysis Parameters

Earlier-Start Dialysis

Usual-Start Dialysis

Difference (95% CI) P

BUN at dialysis initiation (mg/dL)

71.7 ± 21.7 100.9 ± 32.6 +29.2 (21.8 to 36.8) 0.01

Creatinine at dialysis initiation (mg/dL)

7.4 ± 5.3 10.4 ± 3.3 +3.0 (1.8 to 4.2) <0.001

Duration of dialysis support

7.13 ± 8.58 5.30 ± 4.58 −1.8 (−3.71 to 0.05) 0.06

Recovered without dialysis

9 (8.4) 18 (16.9) +0.08 (−0.008 to 0.17)

Jamale TE et al. Am J Kid Dis. 2013 Seabra et al AJKD 2008

RCT: RR 0.64 (95% CI, 0.40-1.05)

Cohort: RR 0.72 (95% CI, 0.64-0.82)

Early vs Late RRT in AKI

Karvellas C et al. Crit Care 2011

Meta Analysis: All 15 studies

Karvellas C et al. Crit Care 2011

Timing of Intervention: Determinants

Level of renal function

Demand on renal capacity

Goals for clinical management

Prevention of organ dysfunction

Renal toxicity

Other organ toxicity

Indication and Timing of Dialysis for AKI Renal Replacement vs Renal Support

Mehta: Blood Purification 2000Mehta. Blood Purif. 2001

AKI in ICU

Surgeon/Intensivist Nephrologist

Maintain tissue O2 delivery Fluid management

Increased cardiac output

Enhance ventilation

Maintain blood pressure Solute control

Prevent hypermetabolism

Provide adequate nutrition

Treat primary process Electrolyte balance

Acid -Base balance

Goals for treatment

Potential Indications for Dialysis in ICU Patients

Renal Replacement

Life threatening indications Hyperkalemia

Acidemia

Pulmonary edema

Uremic complications

Solute control

Fluid removal

Regulation of acid-base and electrolyte status

Renal Support Nutrition

Fluid removal in congestive heart failure

Cytokine manipulation in sepsis

Tumor lysis

Respiratory acidosis in ARDS

Fluid management in multi-organ failure

Fluid Accumulation in Critically Ill Children with AKI

Fluid Overload is Associated with Poorer Outcomes in AKI

Bouchard J et al. KI 2009

• 396 patients with AKI requiring dialysis

• PICARD study

– Prospective cohort

– 5 teaching U.S. hospitals

– Between 1999 and 2001

RESULTS

• %FO >10% at dialysis initiation: 2 fold increase in mortality

• Duration and correction of fluid overload influences mortality rates-%FO >10% at dialysis cessation: 2.5 fold increase in mortality

%Fluid Overload ≤ 10%

% Fluid Overload > 10%

Sur

viva

l (fr

actio

n)

p = 0.007

After adjusting for APACHE III and dialysis modality, fluid overload at dialysis initiation remained associated with a 2.07 fold increase in the odds of death (95% CI 1.27-3.37)

SurvivorsNon‐

survivorsP

Mean % FO at dialysis cessation

13.0% 22.1% 0.004

Effect of Fluid Balance on Mortality


Effect of Dialysis Modality on Fluid Balance


Fluid Balance and Patient Outcomes in the RENAL Trial

The RENAL Replacement Therapy Study Investigators. Crit Care Med.2012 Jun; 40(6):1753-60

KEY POINTS-UpdatesVolume status and AKI

Fluid therapy is integral to the acute resuscitation of critically ill patients

A threshold may exist beyond which the perceived benefit of additional fluid therapy after resuscitation may contribute to harm

Volume overload may delay recognition of AKI and is associated with poorer outcomes in AKI

Prevention of fluid overload may be an important and under-appreciated determinant of survival and is evolving as a primary trigger for initiation of RRT

KEY POINTS-Board Review

RCT’s have not demonstrated any mortality benefit in starting RRT early vs late, but there is emerging evidence that starting therapy early may improve outcomes.

RRT should be initiated prior to the development of overt symptoms and signs of renal failure





•Dose of RRT

•Anticoagulation

RRT MODALITIES

Intermittent

IHD PIRRT

Continuous

CRRT

SCUFSCUF

CVVHCVVH

CVVHDCVVHD

CVVHDFCVVHDF

PD

CRRT

Potential Advantages

Hemodynamic stability

Increased clearance

Increased fluid removal

Fewer fluctuations in

intracranial pressure

Potential Disadvantages

Labor intensive

Requires ICU level care

Patient Immobility

Requires continuous

anticoagulation

Access

Return

Effluent

SCUFNo solute clearance;

Used for fluid removal

CVVHSolute clearance: convection;

Operative fluid: RF

CVVHDSolute clearance: diffusion;

Operative fluid: dialysate

CVVHDFSolute clearance: diffusion & convection;

Operative fluids: RF & dialysate

CRRT Modalities

Replacement(pre or post dilution)

Access

Return

Effluent

Access

Return

Effluent

Dialysate

Replacement(pre orpost dilution)I

Access

Return

Effluent

Dialysate

CRRT in Management of ICP

Davenport, A. Sem Dialysis, 2009

Fa

ll in

ser

um o

smo

lalit

yIn

trac

rani

al p

ress

ure

mm

Hg

Fluid Balance: CRRT vs IHDAugustine et al, AJKD 2004

IHD CVVHD

Hemodynamic Stability: CRRT vs IHDAugustine et al, AJKD 2004

RRT Modality in AKI: Evidence

Author Year Country Sites (No.) Design Primary Outcome

Simpson 1993 UK Single IHD vs. CVVHD Mortality

Kierdorf 1994 Germany Single IHD vs. CVVH Mortality

John 2001 Germany Single IHD vs. CVVH Hemodynamics, acid-base status

Mehta 2001 USA Multicentre (4) IHD vs.

CAV/VVHDF

Mortality, renal recovery

Gasparovic 2003 Croatia Single IHD vs. CVVH Mortality

Augustine 2004 USA Single IHD vs. CVVHD Mortality, renal recovery

Uehlinger 2005 Switzerland Single IHD vs. CVVHDF Mortality

Vinsonneau 2006 France Multicentre (21) IHD vs. CVVHDF Mortality, renal recovery

Lins 2008 Belgium Multicentre (9) IHD vs. CVVH Mortality

Summary of Meta-analyses on Mortality (CRRT vs IHD)

Study N RR Mortality CI

Tonelli 2002 >600 0.96 0.88-1.08

Kellum 2002 1400 0.93 0.79-1.09

Rabindranath2007

1550 1.06*

1.01**

0.90-1.26*

0.92-1.12**

Bagshaw 2008 1403 0.99 0.78-1.72

Pannu 2008 918 1.1 0.99-1.23

*ICU mortality

** Hospital mortality

Choice of RRT Modality and Dialysis Dependence after AKI: A Systematic Review and Meta-analysis

Schneider AG et al. 2013

SLED Using a Single Pass Batch System in AKI RCT

Schwenger et al. Critical Care 2012, 16:R140







Conclusion: SLED associated with reduced nursing time and costs compared to CRRT

KEY POINTS-Board Review CRRT vs IHD

Despite the theoretical benefits apparent from the more physiologic nature of CRRT, no study has conclusively demonstrated a survival benefit of CRRT over IHD in AKI

Advantages

Hemodynamic stability, correction of volume overload, better solute removal

Therapy of choice for AKI patients with acute brain injury or other causes of increased intracranial pressure or generalized brain edema

Use of Peritoneal Dialysis in AKI: A Systematic Review

24 studies identified

19/24 from Asia, Africa, and South America

13 studies with PD only

11 studies with PD and EBP

7 observational

4 randomized

Chionh CY, et al. Clin J Am Soc Nephrol 8: 1649–1660, 2013



•What are the critical elements of the RRT prescription?•Type of technique

•Dose of RRT

•Anticoagulation

Dose of Acute RRT

There are no well-established standard methods for assessing efficacy of RRT in AKI

Assessment of Dose in AKI limited to:

Urea kinetics in for IHD

BUN levels

Effluent volume in CRRT

Clinical Trials Evaluating Dialysis Dose in AKI

Bouchard et al. AJKD 2009

Calculating Solute Clearance

Generic Clearance = Mass removal rate / Blood concentration Effluent flow rate x Effluent concentration/Blood

concentration

K = QE x CE/CB

Using urea as solute QE << QB ( 17-50 ml/min vs. 150-200 ml/min) Equilibrium achieved (CE = CB)

CE/CB = = Sieving Coefficient

Sieving coefficients for small MW molecules such as urea = 1

Filtration Fraction

Filtration Fraction (FF) = QUF / QP

QUF = Ultrafiltration Rate

QP = Plasma Flow Rate

Filter clotting with FF > 30%

FF = 1500 / [6000 x (1-0.30)] = 0.36

Post-dilutional CVVH Parameters:Blood Flow Rate = 100 mL/min HCT 30%Ultrafiltration Rate = 1500 mL/hr

Pre-Dilution Replacement Fluid

Decreases filtration fraction

Diminishes solute clearance by diluting blood reaching dialyzer

Dilution Factor: QB------------------------------------

QB + QR

Pre-dilutional CVVH clearance

K = QE x [QB / (QB + QR)]

Diffusive ClearanceConvective Clearance

Convection vs. Diffusion

Brunet et al. AJKD 1999; 34: 486-492

Key points

•Clearance Effluent Rate for small molecular weight particles

•Increasing effluent rate increases solute clearance

•CVVH clearance = CVVHD clearance for same effluent rates for small molecular weight particles

Blood flow 150 mL/min Blood flow 150 mL/min

HF Compared to HD for AKI: Systematic Review and Meta-analysis

Friedrich JO, Wald R, Bagshaw SM, Burns KE, Adhikari NK. Crit Care.2012 Aug 6; 16(4):R146

• 19 RCTs• 16 used CRRT

HF Compared to HD for AKI: Systematic Review and Meta-analysis

Few RCTs comparing HF vs. HD for AKI

No benefit of outcomes of HF vs. HD, but confidence intervals wide

HF may increase clearance of medium to larger molecules, but may also shorten filter life

Additional pilot trials are needed to evaluate the impact of HF vs. HD on outcomes

Friedrich JO, Wald R, Bagshaw SM, Burns KE, Adhikari NK. Crit Care.2012 Aug 6; 16(4):R146

HVHF vs SVHF for Septic Shock Patients with AKI (IVOIRE study): A Multicentre RCT

• 140 Patients with septic shock and AKI randomized to CVVH: 70 mL/kg/hr vs. 35 mL/kg/hr

• RF pre- and post- 1/3-2/3• BF 200 – 320 mL/min• Anticoagulation: UFH• Trial stopped early and underpowered

Joannes-Boyau et al. Int Care Med. 2013

HVHF group:• Higher incidence of

hypophosphatemia• Higher incidence of hypokalemia • Underdosing of antibiotics

Objective: To evaluate the effects of HVHF compared with SVHF for

septic AKI

Methods: Publications between1966 and 2013

RCTs that compared HVHF (effluent rate >50 ml/kg/hr) vs. SVHF in the treatment of sepsis and septic shock

Primary outcome: 28-day mortality

Secondary outcomes: Recovery of kidney function

Lengths of ICU and hospital stay

Vasopressor dose reduction

HVHF for Septic AKI: A Systematic Review and Meta-analysis

Clark E, et al. Crit Care 2014

HVHF for Septic AKI


HVHF for Septic AKI


Results

No mortality reduction with HVHF

No reduction in vasopressor requirements

No difference in renal recovery


Overview of Study Design

Management StrategyIntensive Less-Intensive

Hemodynamically Stable Patients

IHD* 6x/week 3x/week

Hemodynamically Unstable Patients

CVVHDF 35 mL/kg/hr 20 mL/kg/hr

SLED* 6x/week 3x/week

*target Kt/V: 1.2-1.4 per treatmentVA/NIH ATN study, Palevsky et al.

Management of IHD

Intensive Management

Strategy(N=563)

Less-IntensiveManagement

Strategy(N=561)

Treatments per week (95% CI) 5.4 (5.2-5.6) 3.0 (2.8-3.1)

Interval between treatments (days, 95% CI) 1.1 (1.1-1.2) 2.1 (2.0-2.2)

Median treatment length (hours, IQR) 4.0 (3.3-4.5) 4.0 (3.5-4.5)

Blood flow rate (mL/min) 360±59 360±62

Dialysate flow rate (mL/min) 730±123 710±135

Net ultrafiltration (L) 1.7±1.2 2.1±1.4

BUNpre-dialysispost-dialysis

45±2516±12

70±3325±15

Kt/VureaFirst treatmentSubsequent treatments

1.13±0.311.32±0.37

1.13±0.321.31±0.33

Management of CVVHDF

Intensive Management

Strategy(N=563)

Less-IntensiveManagement

Strategy(N=561)

Median daily treatment duration (hours, IQR) 20.9 (13.0-23.7) 21.0 (13.0-24.0)

Blood flow rate (mL/min) 150±33 140±40

Dialysate flow rate (mL/hr) 1410±346 820±250

Replacement fluid flow rate (mL/hr) 1390±316 830±249

Net ultrafiltration (mL/hr) 130±135 130±189

24-hour effluent volume (L) 49.6±22.4 30.5±14.3

Effluent flow rate (mL/kg/hr)PrescribedDelivered

36.2±3.835.8±6.4

21.5±4.322.0±6.1

Mean daily BUN (mg/dL) 33±18 47±23

Percent of prescribed dose of therapy delivered 89±39 95±35

Results from the VA/NIH ATN study, Palevsky et al.

60-Day All Cause Mortality

Intensive – 53.6%

Less-Intensive – 51.5%

Odds Ratio: 1.0995% CI: 0.86-1.40P=0.47

RENAL Trial

1508 patients35 sites3 years

IntensiveCRRT

(post-dilution CVVHDF at 40 ml/kg/hr

of effluent)(750 patients)

Randomization

ConventionalCRRT

(post-dilution CVVHDF at 25 ml/kg/hr

of effluent)(750 patients)

Low dose High dose p

Number of patients 743 722

Total number of study days 4190 4179

Mean Days of Study treatment/patient

5.9 (7.7) 6.3 ( 8.7) 0.35

Daily effluent (mls/hr)/patient 1772 (1257) 2698 (1154) <0.001

Dose delivered mls/kg/hr 22.0 (17.8) 33.4 (12.8) <0.001

% of prescribed 88 84 <0.001

Filters/day/patient 0.84 (0.81) 0.93 (0.86) <0.001

Patients treated with IHD in ICU 52 (7.0%) 55 (7.6%) 0.64

Process of Care in RENAL Mortality Outcomes in RENAL

Renal vs ATN Renal vs ATN

JKim

Sticky Note

can't see text in black box

Effluent Volume in CRRT Overestimates the Delivered Dose of Dialysis

Solute Clearance in CRRT: Prescribed vs Actual Delivered Dose

Standard dose(20 mg/kg/h)

High dose(35 mg/kg/h)

P

Prescribed clearance (KP) 17.62 ± 0.96 28.10 ± 1.44 <0.0001

Estimated clearance (KE) 15.79 ± 2.47 25.10 ± 3.16 <0.0001

Urea clearance (KU) 15.55 ± 3.07 23.31 ± 5.30 <0.0001

Creatinine clearance (KC) 15.67 ± 3.88 21.62 ± 5.5 <0.0001

CVVHDF Clearance Comparisons

*

Group 20 ml/kg/hr Group 35 ml/kg/hr

*

*

*

* p < 0.001 Lyndon W. et al. 2011

Kellum JA and Ronco C Nature Reviews Nephrology; 2010

Delivered RRT Dose and Survival Key Points: Board ReviewDosing of RRT in AKI

Intermittent hemodialysis

No need to provide treatments more than 3x/week so long as a target Kt/Vurea of 1.2-1.4 per treatment is achieved

Continuous renal replacement therapy

An effluent flow of at least 20 mL/kg/hr is sufficient, so long as there is careful attention to ensuring that the target dose of therapy is actually delivered

Delivered dose is less than prescribed dose

Clearances should be measured in routine care and used to optimize dose

Please indicate which ONE of these statements is true:

A. Recent randomized controlled trials demonstrate that early initiation of renal replacement therapy is associated with improved patient outcomes.

B. The ATN trial (VA/NIH Acute Renal Failure Trial Network, Palevsky et al.) was a “modality” study, which demonstrated that there is no difference in survival between CRRT and IHD

C. Recent studies (the ATN and the RENAL trials) have shown that “high” or “low”, the dose of dialysis is unimportant and is not a determinant of patient survival.

D. Studies have shown that intermittent Hemodialysis is associated with fluid gains and increased hemodynamic instability, when compared with CRRT

E. Recent randomized controlled trials have conclusively demonstrated that renal functional recovery is superior among patients treated with CRRT, as compared with IHD.


•When should therapy be initiated



•Dose of RRT

•Anticoagulation

Prescribed vs Delivered Dose Filtration Fraction (QUF/QP)

High UF Rate & low Blood Flow = CLOTTING

Case Example:

100 kg M placed on post-dilution CVVH, BFR 150 mL/min, desired CVVH dose 25 mL/kg/hr; hct 30% (desired UF Rate = 2500 mL/hr)

FF = 2500/(0.7 X 150 X 60) = 40% !!!

Filtration Fraction (QUF/QP)

Which of the following options will decrease the effect of the filtration fraction in the previous case ?

A. Add Anticoagulation

B. Change to a diffusive therapy (CVVHD)

C. Increase Blood Flow Rate

D. Change to Pre-dilution Replacement Fluid

E. All of the above

Anticoagulation

• No anticoagulation

• Unfractionated heparin

• LMW Heparins

• Thrombin antagonists

• Citrate

• Prostaglandins - PGI2, PGE1

Why Citrate? Citrate and Bleeding

Zhang et al. Int Care Med. 2012

Why Citrate? Citrate and Circuit Patency

Zhang et al. Int Care Med. 2012

Citrate Anticoagulation

Intrinsic pathway

Extrinsic pathway

XIIXIIa

XIXIa

IXIXa

VIIVIIa

VIII Ca++ Tissue factor

X XaCa++

V

Prothrombin Thrombin

FibrinogenFibrin

Cross linked fibrinXIIIa

Coagulant active phospholipid(e.g. platelet membrane)

Citrate Anticoagulation

Chelates free Ca+2 in extracorporeal circuit

Prevents activation of Ca+2-dependent procoagulants

Anticoagulant effect measured by iCa+2

Anticoagulation reversed by Ca+2 infusion

Citrate + iCa Calcium citrateBiologically inactivemeasurable as total Ca

Citrate Metabolism

Citric acid has plasma half life of 5 mins

Rapidly metabolized by liver, kidney and muscle cells

Na3Citrate + 3H2CO3

Citric Acid + 3NaHCO3

3H2CO3 + H2O + 3NaHCO3

4H2O + 6CO2

Flanagan MJ et al. AJKD 27: 519-24, 1996

Which of the following is indicative of adequate anticoagulation of citrate for CRRT?

A. CRRT circuit ionized calcium level of 0.3 mmol/L

B. CRRT circuit ionized calcium of 0.7 mmol/L

C. Systemic ionized calcium level of 0.7 mmol/L

D. Serum citrate level of 1 mmol/L

E. Total calcium level of 2.2 mmol/L

Citrate

Normal blood levels of citrate: 0.05 mmol/L

Bleeding time at citrate levels of 4 to 6 mmol/L (iCa2+ < 0.25 mmol/L)

Levels of 12 to 15 mmol/L required for stored blood products for transfusion therapy

Calcium-freedialysate

Citrate chelatesfree ionized Ca2+

Citrate

Effluent

Post filter iCa2+ is monitoredand used to titrate citrate rateto assure anticoagulation

Citrate is metabolizedprimarily in liver to HCO3

-

Bound Ca2+ is released

Calcium is infusedthrough a separatecentral line to replaceCa2+ lost in ultrafiltrate

Returning blood combineswith venous blood in body,normalizing iCa2+ and preventingsystemic anticoagulation

Citrate Anticoagulation in CRRT: Regional Effect in the Circuit

Metabolic Consequences

Metabolic alkalosis Citrate overdose/toxicity

Metabolic acidosis Citrate toxicity in setting of severe liver disease or

hypoperfusion

Hypernatremia Hyperosmolar citrate solutions

Hypocalcemia and hypercalcemia Inappropriate calcium supplementation

Citrate Toxicity

Risk Factors

Liver Disease

Nursing or pharmacy errors: overdose

Shock liver; severe hypoperfusion states

Detection

Rising anion gap, worsening metabolic acidosis

Falling systemic iCa2+

Escalating Ca2+ infusion requirements

Total Ca2+:Systemic iCa2+ Ratio> 2.5:1 (increas. Ca2+ gap)

Meier-Kriesche HU et al. Crit Care Med. 2001, 29:748-752

Calcium Gap

Ionizedcalcium

Totalcalcium1

2

3

mm

ol/L

Complexedcalcium

4

8

12

mg/dL

Calciumcitrate

Proteinbound

calcium

KEY POINTS-Board ReviewSummary

Modality: No overall benefit to CRRT compared to IHD, though CRRT may be better for patients at risk of increased ICP and for volume control.

Dose: No benefit to “intensive” therapy, but delivered dose of both CRRT and IHD must be monitored to ensure minimum adequate dose

Anticoagulation: Citrate is gaining wider acceptance as the preferred anticoagulation for CRRT

Documents

ASN Board Review: Acute Renal Replacement Therapies