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? Early vs Late RRT in AKI BUN pre-rrt (mg/dl) Survival (%) No Consensus Indications for initiation of RRT Appropriate timing of initiation of RRT Conventional Indications Refractory fluid overload Metabolic acidosis Hyperkalemia Uremia Drug overdose 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 1972 Retro 500 <93 >163 71 58 al 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 Early vs Late Initiation of CVVH RCT Earlier-Start vs Usual-Start Dialysis in Patients with Community-Acquired AKI: A RCT Time between inclusion and RRT (hrs) Predialysis BUN (mg/dl) Survival (%) (p = 0.8) Early High Volume Group (n = 35) Early Low Volume Group (n = 35) Late Low Volume Group (n = 36) 6.0 (3.0 9.7) 7.0 (5.0 10.0) 41.8 (21.4 72.0) 45.7 (38.4 57.7) 47.9 (40.3 65.8) 104.8 (61.6-116.0) 74.3 68.8 75 208 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) Bouman CS, et al. Critical Care Med 2002; 30:2205-2211 Jamale TE et al. Am J Kidney Dis. 2013

Earlier-Start Dialysis Dialysis Parameters Usual-Start Dialysis Difference (95% CI) P RCT: RR 0.64 (95% CI, 0.40-1.05) 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) Duration of dialysis support Recovered without dialysis 7.4 ± 5.3 10.4 ± 3.3 +3.0 (1.8 to 4.2) <0.001 7.13 ± 8.58 5.30 ± 4.58 1.8 ( 3.71 to 0.05) 0.06 9 (8.4) 18 (16.9) +0.08 ( 0.008 to 0.17) Cohort: RR 0.72 (95% CI, 0.64-0.82) Jamale TE et al. Am J Kid Dis. 2013 Seabra et al AJKD 2008 Early vs Late RRT in AKI Meta Analysis: All 15 studies Karvellas C et al. Crit Care 2011 Karvellas C et al. Crit Care 2011 Timing of Intervention: Determinants Indication and Timing of Dialysis for AKI Renal Replacement vs Renal Support Level of renal function Demand on renal capacity Goals for clinical management Prevention of organ dysfunction Renal toxicity Other organ toxicity Mehta: Blood Purification 2000 Mehta. Blood Purif. 2001

AKI in ICU Potential Indications for Dialysis in ICU Patients Surgeon/Intensivist Maintain tissue O2 delivery Increased cardiac output Enhance ventilation Maintain blood pressure Prevent hypermetabolism Provide adequate nutrition Treat primary process Goals for treatment Nephrologist Fluid management Solute control Electrolyte balance Acid -Base balance 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 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 Survival (fraction) % Fluid Overload > 10% %Fluid Overload 10% 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) Mean % FO at dialysis cessation Nonsurvivors P Survivors 13.0% 22.1% 0.004 Bouchard J et al. KI 2009 Effect of Fluid Balance on Mortality Effect of Dialysis Modality on Fluid Balance Bouchard J et al. KI 2009 Bouchard J et al. KI 2009

Fluid Balance and Patient Outcomes in the RENAL Trial KEY POINTS-Updates Volume 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 The RENAL Replacement Therapy Study Investigators. Crit Care Med.2012 Jun; 40(6):1753-60 KEY POINTS-Board Review Key issues for boards: RRT for AKI 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 When should therapy be initiated? What are the critical elements of the RRT prescription? Type of technique Dose of RRT Anticoagulation RRT MODALITIES CRRT Intermittent Continuous Potential Advantages Potential Disadvantages IHD PIRRT CRRT PD Hemodynamic stability Labor intensive SCUF Increased clearance Increased fluid removal Requires ICU level care Patient Immobility CVVH Fewer fluctuations in Requires continuous CVVHD intracranial pressure anticoagulation CVVHDF

Access I CRRT Modalities CRRT in Management of ICP Effluent SCUF No solute clearance; Used for fluid removal Return Effluent CVVH Access Return Replacement (pre or post dilution) Solute clearance: convection; Operative fluid: RF Dialysate Effluent CVVHD Access Return Solute clearance: diffusion; Operative fluid: dialysate Dialysate CVVHDF Effluent Access Return Replacement (pre or post dilution) Solute clearance: diffusion & convection; Operative fluids: RF & dialysate Fall in serum osmolality Intracranial pressure mmhg Davenport, A. Sem Dialysis, 2009 Fluid Balance: CRRT vs IHD Augustine et al, AJKD 2004 Hemodynamic Stability: CRRT vs IHD Augustine et al, AJKD 2004 IHD CVVHD 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. Mortality, renal recovery CAV/VVHDF 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 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 Rabindranath 2007 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 Vinsonneau 2006 France Multicentre (21) IHD vs. CVVHDF Mortality, renal recovery Lins 2008 Belgium Multicentre (9) IHD vs. CVVH Mortality *ICU mortality ** Hospital mortality

Choice of RRT Modality and Dialysis Dependence after AKI: A Systematic Review and Meta-analysis SLED Using a Single Pass Batch System in AKI RCT Schneider AG et al. 2013 Schwenger et al. Critical Care 2012, 16:R140 SLED Using a Single Pass Batch System in AKI RCT SLED Using a Single Pass Batch System in AKI RCT Schwenger et al. Critical Care 2012, 16:R140 Schwenger et al. Critical Care 2012, 16:R140 SLED Using a Single Pass Batch System in AKI RCT 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 Conclusion: SLED associated with reduced nursing time and costs compared to CRRT Therapy of choice for AKI patients with acute brain injury or other causes of increased intracranial pressure or generalized brain edema Schwenger et al. Critical Care 2012, 16:R140

Use of Peritoneal Dialysis in AKI: A Systematic Review Key issues for boards: RRT for AKI 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 When should therapy be initiated? What are the critical elements of the RRT prescription? Type of technique Dose of RRT Anticoagulation Chionh CY, et al. Clin J Am Soc Nephrol 8: 1649 1660, 2013 Dose of Acute RRT Clinical Trials Evaluating Dialysis Dose in AKI 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 Bouchard et al. AJKD 2009 Calculating Solute Clearance Filtration Fraction Generic Clearance = Mass removal rate / Blood concentration Effluent flow rate x Effluent concentration/blood concentration K = Q E x C E /C B Using urea as solute Q E << Q B ( 17-50 ml/min vs. 150-200 ml/min) Equilibrium achieved (C E = C B ) C E /C B = = Sieving Coefficient Sieving coefficients for small MW molecules such as urea = 1 Filtration Fraction (FF) = Q UF / Q P Q UF = Ultrafiltration Rate Q P = 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 Convection vs. Diffusion Decreases filtration fraction Diminishes solute clearance by diluting blood reaching dialyzer Dilution Factor: Q ------------------------------------ B Blood flow 150 ml/min Blood flow 150 ml/min Q B + Q R Pre-dilutional CVVH clearance K = Q E x [Q B / (Q B + Q R )] Convective Clearance Diffusive Clearance 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 Brunet et al. AJKD 1999; 34: 486-492 HF Compared to HD for AKI: Systematic Review and Meta-analysis HF Compared to HD for AKI: Systematic Review and Meta-analysis Few RCTs comparing HF vs. HD for AKI 19 RCTs 16 used CRRT 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 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 HVHF for Septic AKI: A Systematic Review and Meta-analysis 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 HVHF group: Higher incidence of hypophosphatemia Higher incidence of hypokalemia Underdosing of antibiotics Joannes-Boyau et al. Int Care Med. 2013 Primary outcome: 28-day mortality Secondary outcomes: Recovery of kidney function Lengths of ICU and hospital stay Vasopressor dose reduction Clark E, et al. Crit Care 2014

HVHF for Septic AKI HVHF for Septic AKI Clark E, et al. Crit Care 2014 Clark E, et al. Crit Care 2014 Results Overview of Study Design No mortality reduction with HVHF No reduction in vasopressor requirements No difference in renal recovery Management Strategy Intensive 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 Clark E, et al. Crit Care 2014 *target Kt/V: 1.2-1.4 per treatment VA/NIH ATN study, Palevsky et al. Management of IHD Management of CVVHDF Intensive Management Strategy (N=563) Less-Intensive Management 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 BUN pre-dialysis post-dialysis Kt/V urea First treatment Subsequent treatments 45±25 16±12 1.13±0.31 1.32±0.37 70±33 25±15 1.13±0.32 1.31±0.33 Intensive Management Strategy (N=563) Less-Intensive Management 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) Prescribed Delivered 36.2±3.8 35.8±6.4 21.5±4.3 22.0±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 RENAL Trial Odds Ratio: 1.09 95% CI: 0.86-1.40 P=0.47 Intensive 53.6% 1508 patients 35 sites 3 years Randomization Less-Intensive 51.5% Intensive CRRT (post-dilution CVVHDF at 40 ml/kg/hr of effluent) (750 patients) Conventional CRRT (post-dilution CVVHDF at 25 ml/kg/hr of effluent) (750 patients) Process of Care in RENAL Mortality Outcomes in RENAL 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 Renal vs ATN Renal vs ATN

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 (K P) 17.62 ± 0.96 28.10 ± 1.44 <0.0001 Estimated clearance (K E) 15.79 ± 2.47 25.10 ± 3.16 <0.0001 Urea clearance (K U) 15.55 ± 3.07 23.31 ± 5.30 <0.0001 Creatinine clearance (K C) 15.67 ± 3.88 21.62 ± 5.5 <0.0001 CVVHDF Clearance Comparisons * * * * Group 20 ml/kg/hr * p < 0.001 Group 35 ml/kg/hr Lyndon W. et al. 2011 Delivered RRT Dose and Survival Key Points: Board Review Dosing of RRT in AKI Intermittent hemodialysis No need to provide treatments more than 3x/week so long as a target Kt/V urea 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 Kellum JA and Ronco C Nature Reviews Nephrology; 2010 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. 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

Prescribed vs Delivered Dose Filtration Fraction (Q UF /Q P ) 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 (Q UF /Q P ) 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 - PGI 2, PGE 1 Why Citrate? Citrate and Bleeding Why Citrate? Citrate and Circuit Patency Zhang et al. Int Care Med. 2012 Zhang et al. Int Care Med. 2012

Citrate Anticoagulation Citrate Anticoagulation Intrinsic pathway XII XIIa XI XIa IX IXa X VIII Extrinsic pathway VIIa Ca++ Tissue factor Ca++ V Prothrombin Fibrin XIIIa Cross linked fibrin Xa VII Coagulant active phospholipid (e.g. platelet membrane) Thrombin Fibrinogen 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 citrate Biologically inactive measurable as total Ca Citrate Metabolism Citric acid has plasma half life of 5 mins Rapidly metabolized by liver, kidney and muscle cells Na 3 Citrate + 3H 2 CO 3 Citric Acid + 3NaHCO 3 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 3H 2 CO 3 + H 2 O + 3NaHCO 3 4H 2 O + 6CO 2 Flanagan MJ et al. AJKD 27: 519-24, 1996 Citrate Citrate Anticoagulation in CRRT: Regional Effect in the Circuit Normal blood levels of citrate: 0.05 mmol/l Bleeding time at citrate levels of 4 to 6 mmol/l (ica 2+ < 0.25 mmol/l) Levels of 12 to 15 mmol/l required for stored blood products for transfusion therapy Calcium is infused through a separate central line to replace Ca 2+ lost in ultrafiltrate Returning blood combines with venous blood in body, normalizing ica 2+ and preventing systemic anticoagulation Post filter ica 2+ is monitored and used to titrate citrate rate to assure anticoagulation Calcium-free dialysate Citrate chelates free ionized Ca 2+ Citrate is metabolized primarily in liver to HCO - 3 Bound Ca 2+ is released Effluent Citrate

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 ica 2+ Escalating Ca 2+ infusion requirements Total Ca 2+ :Systemic ica 2+ Ratio> 2.5:1 (increas. Ca 2+ gap) Meier-Kriesche HU et al. Crit Care Med. 2001, 29:748-752 Calcium Gap KEY POINTS-Board Review Summary mmol/l 3 2 1 Total calcium Complexed calcium Protein bound calcium Ionized calcium Calcium citrate 12 8 4 mg/dl 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