Holistic Approach to Treatment Adequacy in AKI Claudio Ronco, MD Department of Nephrology, St. Bortolo Hospital, International Renal Research Institute Vicenza - Italy

AKI: historical notices During the bombing of London in world war II, Bywaters described cases of acute loss of kidney function in severely injured crush victims. Histological evidence for patchy necrosis of renal tubules at autopsy, suggested him to use the term Acute Tubular Necrosis (ATN) to describe this clinical entity.

AKI: historical notices ARF mortality approached 100% in World War II (no treatment available). Acute hemodialysis was first used clinically during the Korean War in 1950 to treat military casualties, decreasing ARF mortality to about 50%.

Courtesy of Coll. Dr: Paul Teschan

AKI: historical notices Fluid resuscitation on the battlefield with the rapid evacuation of the casualties to hospitals by helicopter was optimized further during the Vietnam War. For seriously injured casualties the incidence of ischemic ARF was one in 200 in the Korean War and one in 600 in the Vietnam War. This historical sequence of events suggested that early intervention could prevent the occurrence of ARF, at least in military casualties.

AKI: Changing Pattern Mortality 54 % Mortality 53 % In the last half century, much has been learned about the pathogenesis of ischemic and nephrotoxic ARF in experimental models, but there has been very little improvement in mortality. This may be explained by changing demographics: age and comorbidity of patients with ARF continue to rise, possibly obscuring any increased survival related to improved critical care. Vicenza Database 1974 – 1979 Total number of incident cases = 48 Vicenza Database 1995 – 2000 Total number of incident cases = 525 Mortality 54 % Mortality 53 %

Facts RRT is a cornerstone for the therapy of of AKI in the ICU Indications have changed over the years (replacement vs support) Mortality has changed over the years and so did the case mix We still have a number of unresolved issues or controversies Timing for therapy start and stop Correct prescription (Dose and Fluid balance) Modality and Schedule Monitoring and delivery Special treatments for special cases

We need additional clinical studies! About timing No consensus on “When” to initiate RRT Early initiation probably improves outcomes (but early means what? Admission? Creatinine? Other? RIFLE/AKIN Stage stratification may represent a surrogate of timing (severity) There is a rationale for early initiation There are draw backs for early initiation An objective algorithm has been proposed for RRT initiation We need additional clinical studies! 11

RCT: RR 0.64 (95% CI, 0.40-1.05) Cohort: RR 0.72 (95% CI, 0.64-0.82) Division of Nephrology, Hospital das Clinicas, University of São Paulo, São Paulo, Brazil. Mortality. Seabra et al AJKD 2008 12

Electronic Sniffers and RIFLE Alert Confirm You reached RIFLE class “RISK” Baseline Creatinine = 0.9 Actual creatinine = 1.55 x Baseline

IRRIV SCORE® IRRIV Score 0.61 1 0.57 2 0.60 0.73 0.52 1.5 0.63 0.47 Variable Thresholds Single AUCs Points added Mean arterial pressure Lowest on first day of ICU <= 65 mmHg 0.61 1 Temperature Highest on first day of ICU >= 38.2 °C 0.57 2 HCO3 Lowest on first day of ICU <= 23 mmol/L 0.60 Urinary output * Lowest on first day of ICU <= 40 ml/h SOFA Renal * On first day of ICU >= 2 0.73 Invasive Mechanical Ventilation On first day of ICU No MV 0.52 1.5 Change of SCr. during ICU stay (mg/dl) * (HS-Adm) >= 0.30 mg/dl 0.63 Fluid Accumulation *  >= 10 % 0.47 IRRIV Score To predict RRT and define late Initiation >= 3.5 pt. including one renal dysfunction markers (*) 0.81 Total: 0 - 11 Abbreviations HS: Hospital stay, Adm: admission, SOFA: Sequential organ failure assessment, SCr: serum creatinine

ROC curve for predicting RRT by IRRIV Score AUC of 0.81.

The red line marks 3.5 in score points. Calculated probability of staying free from RRT with increasing Score points IRRIV SCORE® The red line marks 3.5 in score points.

Intermittent HD in Critically Ill Patients Advantages Lower workload ? Patient free time from ET Limitations Severe clinical intolerance Fluid restriction required Limited efficiency (DPK) Dialysis nurse required

CRRT in Critically Ill Patients Advantages Excellent Clinical Tolerance Optimal Fluid Control Optimal uremic Control Excellent Homeostatic Control Continuous Clearance Limitations Long term exposure to EC Continuous anticoagulation Cost and work load

Modality Therapies are not one against the other Don’t use old studies to compare new treatment Whatever treatment is used, use it at its best performance Be flexible and try to prescribe the right therapy for the right patient Be ready to cross over from one treatment to another Make sure you are not underdialyzing the patient The ideal study will never be done

Facts RRT is a cornerstone for the therapy of of AKI in the ICU Indications have changed over the years (replacement vs support) Mortality has changed over the years and so did the case mix We still have a number of unresolved issues or controversies Timing for therapy start and stop Correct prescription (Dose and Fluid balance) Modality and Schedule Monitoring and delivery Special treatments for special cases ADEQUACY?

AD AEQUATUM = Equal to …….. ADEQUACY Let’s agree on the meaning of the term AD AEQUATUM = Equal to …….. Are we really able to obtain results similar to those achieved by the human kidney? Are we confusing the term “Adequate” with “minimal or sufficient” ? I personally would define adequate a treatment when further improvements will not result in further benefit. So far adequacy has been identified by the concept of dose (index, marker molecules).

Extracorporeal Hemodialysis S u r v i v a l Alwall – Kolff and Scribner et Al, 1966 Dose of Dialysis

Extracorporeal Hemodialysis THE MECHANISTIC ANALYSIS % Failure 70 60 50 40 30 20 10 .4 .5 .6 .7 .8 .9 1.0 1.1 1.2 1.3 1.4 1.5 Gotch & Sargent Av 0.57 Av 0.13 Kt/V Keshaviah NCDS: Gotch & Sargent 1985 S u r v i v a l Alwall – Kolff and Scribner et Al, 1966 Dose of Dialysis (Urea)

Extracorporeal Hemodialysis Dose vs Outcome Studies S u r v i v a l NCDS: Gotch & Sargent 1985 Alwall – Kolff and Scribner et Al, 1966 Dose of Dialysis (Urea)

Extracorporeal Hemodialysis Hemo Study S u r v i v a l Dose vs Outcome Studies NCDS: Gotch & Sargent 1985 Alwall Kolff and Scribner et Al, 1966 Dose of Dialysis (Urea)

Extracorporeal Hemodialysis Hemofiltration Trials 1982-1990 S u r v i v a l Dose vs Outcome Studies NCDS: Gotch & Sargent 1985 Alwall Kolff and Scribner et Al, 1966 Dose of Dialysis (Urea)

Extracorporeal Hemodialysis Variable HD online HDF p Time on RRT (years) 4.97 + 4.94 6.61 5.05 > 0.001 < 0.001 on - line HDF Treatment Time (min/s.) 241 20 246 Treatment Frequency > 3 s./wk (%) NS Mean Blood Flow ( mL /min) 325 47 331 50 Mean Dialysate Flow ( 506 45 543 99 Equil Kt/V 1.43 0.18 1.48 0.20 High Flux Polysulfone 97.9 100 online 4.7 4.8 Death Risk Reduction - 35 % MPO Study Treatment Flux ? Incident Patients? Membrane Flux Hemo Study S u r v i v a l Dose of Dialysis (urea and flux)

Extracorporeal Hemodialysis Membrane Flux Dialysis duration Treatment Flux Incident Patients Body Comp (V) Tx Time Race & Genetics Gender Diabetes & CVD Frequency of Tx S u r v i v a l Dose of Dialysis (Urea and beyond)

Extracorporeal Hemodialysis Correction of Anemia Survival + quality of Life Dose of Dialysis (Urea and Beyond)

Dose of Dialysis (urea and flux) PERITONEAL DIALYSIS Breaking Point 1.7 ? 2.0? 1994 ADEMEX Study S u r v i v a l CANUSA Study Dose of Dialysis (urea and flux)

AKI and CRRT Ronco et Al, The Lancet 356, 1, 26-30, 2000 Stork M, et Al. The Lancet 1991;337:452-455. 100 90 80 70 60 50 40 30 20 10 Uf = < 7 l/24h = 7.5 l/24h = 15 l/24h p < 0.05 Survival % 100 90 80 70 60 50 40 30 20 10 Group 1(n=146) ( Uf = 20 ml/h/Kg) Group 2 (n=139) = 35 ml/h/Kg) Group 3 (n=140) = 45 ml/h/Kg) p < 0.001 p n..s. Ronco et Al, The Lancet 356, 1, 26-30, 2000 S u r v i v a l Stork M, et Al. The Lancet 1991;337:452-455. 0.3 0.6 0.9 1.5 2.5 3.5 Dose of Dialysis (Urea + ?) L/h

AKI and CRRT S u r v i v a l Dose of Dialysis (ml/Kg/hr) Presence of Sepsis Early Intervention Honoré et Al. CCM, 2002 Saudan et Al, KI 2006 Ronco et Al, The Lancet 356, 1, 26-30, 2000 Bellomo et Al, NEJM 2009 S u r v i v a l Tolwani et Al, JASN 2008 Palewsky et Al, NEJM 2008 Stork M, et Al. The Lancet 1991;337:452-455. 10 20 30 40 50 60 70 80 Dose of Dialysis (ml/Kg/hr)

Dose-Dependent Region Renal Replacement Therapy in AKI Breaking Point? Practice-Dependent Region Dose-Dependent Region S u r v i v a l Dose of Dialysis (Urea and Beyond)

QUESTIONS Adequacy for what? What is the task and target of therapy?

Renal Replacement Therapy Indications Renal Replacement Therapy Renal Support Therapy “Absolute” Life Threatening conditions “Relative” Volume removal in FO patients Immuno-modulation in sepsis Nutrition support Cancer chemotherapy Attenuate ARDS-induced respiratory acidosis Volume homeostasis in multi-organ dysfunction/failure Solute control Homeostatic control Acid-base regulation

QUESTIONS Adequacy for what? What is the task and target of therapy? Is adequacy target the same for different patients?

RRT MORTALITY IN AKI % Mortality Number of failing organs A PROBLEM OF SEVERITY SCORE 100 80 60 40 20 % Mortality Kidney K + 1 K + 2 K + 3 Number of failing organs

Fluid Protocols & Balance Restrictive Fluid protocols Liberal Fluid protocols Diseased Heart Procedures Drugs R R T Normal Heart Risk of Complications Hypotension Tachycardia Shock Organ hypoperfusion Oliguria Renal Dysfunction Hypertension Peripheral Edema Impaired pulmonary exchanges Organ Congestion Renal Dysfunction Optimal Status Dehydration Fluid Balance Overhydration

CRRT: Impact on Outcomes The Cleveland Clinic Observation 100 90 80 High Dose (CRRT) 70 60 Survival % 50 Low Dose (IHD) 40 30 20 10 Severity of Disease

Does it make sense to treat them all with the same drug? Are patients all equal? Does it make sense to treat them all with the same drug? What about dialysis dose?

Patients with hypercatabolism Patients with hypercatabolism Urea Kinetics Dose A Dose B Dose C

QUESTIONS Adequacy for what? What is the task and target of therapy? Is adequacy target the same for different patients? Are adequacy targets constant over time?

Metabolism and Volume Azotemia F O % 120 100 80 60 40 20 60 50 40 30 60 50 40 30 20 10 Day 1 Day 3 Day 5 Day 7 Day 1 Day 3 Day 5 Day 7 Admission Admission

Bicarbonate levels in CVVH and Daily HD 32 30 D Short HD 28 D Ext.HD 26 HCO3 (mEq/l) 24 CVVH 22 20 18 16 14 6 12 18 24 30 36 42 48 Hours of observation

QUESTIONS Adequacy for what? What is the task and target of therapy? Is adequacy target the same for different patients? Are adequacy targets constant over time? Are prescription and delivery the same thing?

Vicenza Course International Surveys How do you prescribe therapy? 1998 2004 n. 345 n. 564

CRRT Prescription vs Delivery Venkataraman et al, J Crit Care, 2002 24.56.7 16.65.4 16.13.5 68% of prescribed dose 67% of total hours in day

DoReMi Database (N=865) Patients (%) Dose of CRRT (mL/kg/h) Ronco et al, 2009 Median delivered = 27 mL/kg/h Median prescribed = 34 mL/kg/h Patients (%) Dose of CRRT (mL/kg/h)

Delivered dose of CRRT ml/kg/h Adjusted for 24 hrs CVVHD CVVHDF CVVH 40 32 25 Adjusted for 24 hrs CVVHD CVVHDF CVVH 51

QUESTIONS Adequacy for what? What is the task and target of therapy? Is adequacy target the same for different patients? Are adequacy targets constant over time? Are prescription and delivery the same thing? Are adequacy targets similar for different modalities

Treatments for extracorporeal volume removal Technique Frequency Ultrafiltration Hemofiltration Hemodialiysis Hemodiafiltration Isolated Intermittent Daily Continuous

D short HD CVVH D Ext. HD BUN (mg/dl) Hours of treatment 120 100 80 60 40 D Ext. HD 20 6 12 18 24 30 36 42 48 54 Hours of treatment

Composition of fluid removed Continuous Hemofiltration allows for correction of sodium and water disorders by dissociating water and sodium removal Pl. Na+ 140 Uf 2 L 10 L Na+ Rem 280 1400 Repl. 8 L R Na+ - - - 130 Fluid Bal. - 2 Kg Na+ Bal. - 280 mmol - 360 mmol

Hemodynamic response Blood Volume Variation (%) Mean Art. Press. Hours of observation 6 12 18 24 30 36 42 48 +20 +10 -10 -20 -30 110 100 90 80 70 60 Mean 50 40 Art. Press. (mmHg) Blood Volume Variation (%) SCUF Uf = 3050 ml UF Uf = 3030 ml

Sequential BNP +BIVA measurements Uf / Refilling rate related hypotension Overall ECFV related hypotension Re l a t i ve Changes Blood Pressure Blood Volume a a1 Sequential BNP +BIVA measurements UF beginning UF end

CRRT-Associated Mortality in Major RCTs Clinical Trial Comparison APACHE II Endpoint Mortality Ronco et al (2000) CRRT Dose 22 15-day2 59%3 Mehta et al (2001) IHD vs CRRT 25.5 Hospital 66% Augustine et al (2004) IHD vs CRRT - Hospital 68% Saudan et al (2006) CRRT Dose 25 90-day 66%3 Vinsonneau et al (2006) IHD vs CRRT 25 60-day 68% Lins et al (2008) IHD vs CRRT 27 Hospital 58% Tolwani et al (2008) CRRT Dose 26 Hospital 60%3 ATN Trial (2008) Dialysis Dose 26.3 60-day 52.5%4 RENAL Trial (2009) CRRT Dose ~261 90-day 45% 1: APACHE III score 102-103 2: After CRRT cessation 3: Mortality in low-dose group 4: Overall (CRRT + IHD) mortality

Comparison of RENAL with ATN Variable RENAL VA/NIH Mortality day 90 44.7% Mortality day 60 52.5% RRT days (at 28 days) 7.4 13.1 Hospital LOS (days) 25.2 48 Dialysis dependence @day 28 13.3% 45.2% Dialysis dependence @day 60 24.6% Dialysis dependence @day 90 5.6% 59

Recovery from dialysis dependence 1 CRRT Recovery from dialysis dependence .8 .6 IRRT .4 Hypotension: IRRT: 24.0% CRRT: 11.1% .2 20 40 60 80 100 days Ucino et Al Int. J Artif Organs 2007

RRT dependent on day 90

QUESTIONS Adequacy for what? What is the task and target of therapy? Is adequacy target the same for different patients? Are adequacy targets constant over time? Are prescription and delivery the same thing? Are adequacy targets similar for different modalities Should I consider miltiple parameters to define adequacy?

Organ Substitution/Support Limitation of Oxidant stress Adequacy of Extracorporeal Support Urea-based Dosing Membrane Sieving Control of inflammation Timing and Schedule of Tx Organ Substitution/Support Spectrum of Solute MV Restoration of Homeostasis Volume Control Limitation of Oxidant stress Acid-Base Balance 63

Multidimensional View of Adequacy

Multidimensional View of Adequacy

Multidimensional View of Adequacy

Multidimensional View of Adequacy

Adequacy: Recipe not Index

SPECIAL FIBERS AND FILTERS HAVE BEEN DESIGNED FOR SPECIAL CONDITIONS AND PATIENTS Minifilters Ronco C, Brendolan A, Bragantini L, Chiaramonte S, Feriani M, Frigiola A, Menicanti L, La Greca G: Treatment of acute renal failure in newborns by Continuous Arterio-Venous Hemofiltration. Kidney International, 1984

Special treatments for special cases Apache SOFA 1 2 3 4 5 M O S T Score RRT RRT SCUF RRT SCUF ECLS RRT SCUF ECLS LiverS RRT SCUF ECLS LiverS HVHF-CPFA 100 80 60 40 20 $ % Mortality Kidney K + 1 K + 2 K + 3 K + 3 + Sepsis

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