Las dos caras de la cretinina sérica The two sides of serum creatinine ASOCIACION COSTARRICENSE DE MEDICINA INTERNA San José, Costa Rica June 2017 Kianoush B. Kashani, MD, MSc, FASN, FCCP 2013 MFMER 3322132-1
Disclosure I have no COI regarding this activity 2013 MFMER 3322132-2
Outlines AKI definitions Bad side Limitations Clinical impact Good side Sarcopenia index Outcome prediction 2013 MFMER 3322132-3
RIFLE Criteria GFR criteria Urine output criteria Risk Increased creatinine x1.5 or GFR decrease >25% UO <0.5 ml kg -1 h -1 x6 hr High sensitivity Injury Increased creatinine x2 or GFR decrease >50% UO <0.5 ml kg -1 h -1 x12 hr Failure Increased creatinine x3 or GFR decrease >75% or creatinine 4 mg/ 100 ml (acute rise of 0.5 mg/100 ml dl) UO <0.3 ml kg -1 h -1 x24 hr or anuria x12 hr High specificity Loss Persistent ARF = complete loss of renal function >4 weeks ESRD End-stage renal disease Bellomo et al; Critical Care 2004, 8:R204-R212 2013 MFMER 3322132-4
AKIN Definition for AKI Stage I Inc Scr 0.3 mg/dl or >150-200% from baseline <0.5 ml/kg/hr for >6 hr Stage II Inc Scr >200-300% from baseline <0.5 ml/kg/hr for >12 hr Stage III Inc Scr >300% Scr >4 with acute min rise of 0.5 mg/dl Need for RRT <0.3 ml/kg/hr for 24 hr Anuria for 12 hr Mehta et al; Critical Care 2007, 11:R31 2013 MFMER 3322132-5
KDIGO Definition for AKI Stage I Scr 0.3 mg/dl OR 1.5 1.9 times baseline <0.5 ml/kg/hr for >6 hr Stage II 2.0 2.9 times baseline <0.5 ml/kg/hr for >12 hr Stage III 3.0 times baseline OR Scr > 4 mg/dl OR Initiation of RRT OR <18 yrs in egfr to <35 ml/min per 1.73 m 2 <0.3 ml/kg/hr for 24 hr Anuria for 12 hr Kidney International Supplements (2012) 2, 19 36 2013 MFMER 3322132-6
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ICC (95% CI) per Days Before Admission Estimated Method 7-365 days 7-730 days 1-730 days Most recent outpatient Mean outpatient Nadir outpatient Most recent inpatient or outpatient 0.84 0.83 0.74 (0.80-0.88) a (0.78-0.86) b (0.68-0.79) c 0.91 0.81 0.71 (0.88-0.92) a (0.77-0.84) b (0.65-0.76) c 0.83 0.64 0.68 (0.76-0.87) a (0.46-0.75) b (0.31-0.83) c 0.88 0.88 0.80 (0.85-0.91) d (0.85-0.91) d (0.76-0.84) e Siew at al: Clin J Am Soc Nephrol 7:712 719, 2012 2013 MFMER 3322132-10
Intraclass correlations based on CKD Status Estimation Method Most recent outpatient Mean outpatient Nadir outpatient egfr <60 ml/min per 1.73 m 2 (n=259) 0.80 (0.74-0.85) 0.87 (0.83-0.90) 0.76 (0.66-0.83) ICC (95% CI) egfr 60 ml/min per 1.73 m 2 (n=120) 0.58 (0.42-0.70) 0.75 (0.65-0.83) 0.65 (0.48-0.76) Most recent inpatient or outpatient 0.85 (0.81-0.88) 0.65 (0.53-0.75) Siew at al: Clin J Am Soc Nephrol 7: 712 719, 2012 2013 MFMER 3322132-11
60-day mortality (%) Fluid Balance Impact on SCr (n=7696) 100 No fluid correction Fluid correction No AKI before and after adjustment 80 60 AKI before but No AKI after adjustment 1.19 40 20 0 37,6 40,1 30,3 28,3 16,4 15,9 5,7 5,4 0 Stage 1 Stage 2 Stage 3 No AKI before but AKI after adjustment AKI before and after adjustment 2.00 3.38 0 1 2 3 4 5 Odds ratio for 60-day mortality Thongprayoon et al: J Nephrol 29(2): 221-227 2013 MFMER 3322132-12
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Difference Observed vs. estimated (MDRD GFR=75)Scr 67% had pre-admission creatinine; (n=1314; 46% CKD) 25 25 10 r = 0.49 10 r = 0.39 0 0-10 -10-25 -25.1 5 10 15 20.1 5 10 15 20 Average Average ICU admission At study enrollment Bagshaw et al: Nephrol Dial Transplant 24: 2739-2744, 2009 2013 MFMER 3322132-14
Difference Observed vs. estimated (MDRD GFR=75)Scr CKD excluded 25 r = 0.9 25 r = 0.84 10 0-10 10 0-10 -25-25.1 5 10 15 20.1 5 10 15 20 Average Average ICU admission At study enrollment Bagshaw et al: Nephrol Dial Transplant 24: 2739-2744, 2009 2013 MFMER 3322132-15
60-Day mortality (%) Scr at Admission vs. MDRD 75 When Baseline SCr unavailable (n=3504; 45% of whole cohort) 50 40 MDRD 75 Admission SCr 30 22,7 32,1 25,1 29,9 20 18,0 10 5,1 6,0 11,7 0 0 Stage 1 Stage 2 Stage 3 Thongprayoon et al: BMC Nephrology 17:6, 2016 2013 MFMER 3322132-16
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AKI risk Discrimination vs. Calibration Pre-disease state No AKI Early AKI (Stage 1, risk) Pre-disease AKI signal AKI Time ADQI XV 2013 MFMER 3322132-18
Therapeutic Window High Risk Volume Responsive AKI Hypovolemia Euvolemia Volume Unresponsive AKI Hypervolemia Therapeutic Window Sensitive Biomarkers Traditional Kidney Function Mortality Himmelfarb et al: Clin J Am Soc Nephrol 3:962, 2008 2013 MFMER 3322132-19
Time Course of Development of Increasing Serum Creatinine in Hospitalized HF Patients 100 % 80 60 40 20 0.1 0.2 0.3 0.4 0.5 0 0 3 6 9 12 15 Days Gottlieb et al: J Card Fail 8:136, 2002 2013 MFMER 3322132-20
MELD Equation MELD =(0.957 log(creatinine) + 0.378 x log(bilirubin) +1.12 log(inr) +0.643) x 10 http://www.mayoclinic.org/gi-rst/mayomodel6.html 2016 MFMER 3572290-21
MELD Equation MELD =(0.957 log(creatinine) + 0.378 x log(bilirubin) +1.12 log(inr) +0.643) x 10 http://www.mayoclinic.org/gi-rst/mayomodel6.html 2016 MFMER 3572290-22
Sample MELD Scores INR Bilirubin Creatinine MELD 1 1 1 6 2 1 1 19 1 3 1 11 1 1 3 17 3 3 3 33 2016 MFMER 3572290-23
Mortality rate per 1000 patients Transplant Benefit by MELD Score 10000 1000 Waitlist Transplant 100 10 1 HR=3.64 P<0.001 HR=2.35 P<0.001 HR=1.21 P=0.41 HR=0.62 P<0.01 HR=0.38 P<0.001 6-11 12-14 15-17 17-20 21-23 24-26 27-29 30-39 40+ MELD HR=0.22 P<0.001 HR=0.18 P<0.001 HR=0.07 P<0.001 HR=0.04 P<0.001 2016 MFMER 3572290-24
Survival GFR and Waitlist Survival 660 LTx candidates at Mayo (90-99) 1.0 0.8 0.6 0.4 60 (n=482) 30-59 (n=134) <30 (n=44) 0.2 P<0.001 0.0 0.0 0.5 1.0 1.5 2.0 Years Lim: J Hep 52:523, 2010 2016 MFMER 3572290-25
Probability (%) Waitlisted 20% Less Likely Than to Undergo Liver Transplantation 100 80 60 UNOS 2002-2011 Transplant Male Female 40 20 Death 0 0 2 4 6 8 10 Years since activation Allen AM. Tall, Male, and What Else? Disparities in Liver Transplantation Based On Gender and Height Transplantation 2014 (98) S-725 2016 MFMER 3572290-26
Factors That Disadvantage Women Women Men Shorter Small body Height MELD exceptions More hepatocellular carcinoma = MELD exception points Less muscle mass Lower creatinine = lower MELD? 2016 MFMER 3572290-27
Creatinine MELD points Women Receive Fewer Creatinine-Meld Points Than Men With Similar Renal Function 8 6 Male Female 1.34 1.54 4 2.37 1.15 2 1.74 0 80 70 60 50 40 30 20 Measured GFR (ml/min/bsa) 2016 MFMER 3572290-28
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Availability Serum creatinine Urine output BL serum creatinine Contextual data, comorbidities, medications, organ failure, biomarkers Sensitivity Specificity ADQI 15th 2016 MFMER 3572290-31
Creatinine HR BUN/Cr Glucose Potassium Age Sodium Prior ICU Bilirubin Platelets SVP AVPU Hb DBP AST 26 24 23 18 16 14 14 11 10 9 9 8 7 6 5 5 4 4 2 2 2 1 1 1 1 52 49 0 20 40 60 80 100 66 Variable importance 100 Koyner et al: Clin J Am Soc Nephrol 11, 2016 2016 MFMER 3572290-32
Complementary to injury biomarkers Biomarker Negative Biomarker Positive Creatinine Negative No functional changes or damage Damage without loss of function Subclinical AKI Prerenal AKI Creatinine Positive Loss of function without damage Damage with loss of function True AKI 10 th ADQI Consensus Conference. Adapted from Murray PT et al. Kidney International 2013 2013 MFMER 3322132-33
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20 10 5 2.5 1.0 Absolute mortality rate (%) Relative risk 30 25 20 Observational cohort study in Dutch 154,308 ICU patients Hospital mortality, increasing for BMI <18.5 kg/m 2 0.5 0.25 10 20 30 40 Body-mass index (kg/m 2 ) 50 15 BMI 30-39.9 kg/m 2 had the lowest risk of death with an adjusted OR of 0.86 (0.83-0.90) 2013 MFMER 3322132-36
Mortality (%) LOS in ICU (Days) 50 40 30 ICU LOS Mortality 2 3 A retrospective cohort study of 11,291 adult patients Mayo Clinic Hospital Rochester ICUs 20 1 Between 2003 and 2006 10 n= 0 0.4 0.4-0.6 0.6-0.8 0.8-1.0 1.0-1.4 1.4-1.6 1.6-1.9 1.9 25 350 665 2558 4545 941 764 1443 0 Creatinine concentration in mg/dl 2013 MFMER 3322132-37
Multicenter, binational, retrospective cohort study ANZICS 1.5 million admission 175 ICUs 2000 2013 2013 MFMER 3322132-38
Patients Flow Chart All records for the period 2000-2013 in ANZICS =1,250,449 Admissions Exclusions 62585 Readmissions (during the same hospital stay) 5904 Missing vital status at hospital discharge 361 Post kidney transplant 34902 Receiving chronic renal replacement therapy 54979 Missing peak plasma CR concentration in first 24 hrs 1,045,718 Admissions 2013 MFMER 3322132-39
Results N =1,047,518 N =96,630; Ht & Wt available 2013 MFMER 3322132-40
In-hospital mortality (%) Low Admission Scr 4 3,6 3 2 2,8 2,4 Observational cohort study in 73,994 patients Mayo Clinic Hospital Rochester ICUs 1 1,0 0,8 1,0 1,3 Between 2011 and 2013 0 0.4 0.5-0.6 0.7-0.8 0.9-1.0 1.1-1.2 1.3-1.4 1.5 Serum creatinine at hospital admission (mg/dl) Cheungpasitporn W, Thongprayoon C, Kashani K. The American Journal of Medicine (2016) 2013 MFMER 3322132-41
OR of in-hospital mortality Low Admission Scr Hospital Mortality (Independent of BMI) 4 3 2 Adjustments: Age, sex, race, BMI, principal diagnosis, CCI, CAD, CHF, PVD, CVA, DM, COPD, cirrhosis, hemi/paraplegia 1 0 0.4 0.5-0.6 0.7-0.8 0.9-1.0 1.1-1.2 1.3-1.4 1.5 Serum Creatinine at Hospital Admission (mg/dl) Cheungpasitporn W, Thongprayoon C, Kashani K. The American Journal of Medicine (2016) 2013 MFMER 3322132-42
All-cause mortality hazard ratio Mild Moderate Severe Very severe 2.0 1.8 1.6 1.4 1.2 Recommended range Overweight Obesity 121,762 patients receiving HD 3 times/wk 1.0 0.9 0.8 0.7 0.6 Reference Unadjusted Case-mix Case-mix & MICS Years 2001-2006 Outpatient dialysis facilities (DaVita) Body-mass index (kg/m 2 ) Kalantar-Zadeh, K., et al. (2010). Mayo Clinic Proceedings 85(11): 991-1001 2013 MFMER 3322132-43
All-cause mortality hazard ratio 2.4 2.0 1.6 Unadjusted Case-mix Case-mix & MICS 1.2 1.0 0.8 Small muscle mass Reference Large muscle mass 0.6 Moderate muscle mass 0.4 <4 4 to <6 6 to <8 8 to <10 10 to <12 12 to <14 14 Serum creatinine (mg/dl) Kalantar-Zadeh, K., et al. (2010). Mayo Clinic Proceedings 85(11): 991-1001 2013 MFMER 3322132-44
All-cause mortality hazard ratio 1.6 1.4 Unadjusted Case-mix Case-mix & MICS 1.2 Reference Gained muscle mass 1.0 0.9 0.8 Lost muscle mass No change in muscle mass <-2-2 to -1-1 to +1 +1 to +2 >+2 Serum creatinine (mg/dl) Kalantar-Zadeh, K., et al. (2010). Mayo Clinic Proceedings 85(11): 991-1001 2013 MFMER 3322132-45
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ICU cohort N=226 high risk ICU patients with no AKI 105 had an abdominal CT scan within 4 weeks from ICU admission Median (IQR) 0.5 (0.1 to 2.4) days 2013 MFMER 3322132-49
Sarcopenia index SI correlation with CT Muscle mass measurement SI = (serum creatinine/serum cystatin C) x 100 Muscle surface area (MSA; n=105) and SI 1,4 1,2 r = 0.62 P<0.0001 1,0 0,8 0,6 0,4 0,2 Sarcopenia index = 65 Sarcopenia index = 44 0,0 50 100 150 200 250 Muscle surface area (cm 2 ) Kashani et al: Crit Care Med, 2016 2013 MFMER 3322132-50
ICU mortality Hospital mortality 90-d mortality Nutritional indicator AUC (p) AUC (p) AUC (p) Sarcopenia index 0.63 (0.1) 0.67 (0.0007) 0.7 (<0.0001) Body mass index 0.63 (0.2) 0.56 (0.3) 0.58 (0.1) Para-spinal muscle surface area (cm 2 ) 0.72 (0.2) 0.79 (0.01) 0.79 (0.002) Admission serum creatinine 0.5 (0.9) 0.59 (0.09) 0.53 (0.5) NUTrition Risk In the Critically ill score (NUTRIC) 0.67 (0.06) 0.67 (0.006) 0.72 (<0.001) Kashani et al: Crit Care Med, 2016 2013 MFMER 3322132-51
Clinical model without SI Clinical models with SI ICU mortality Variable OR 95% CI P OR 95% CI P APACHE III 0.96 0.94-0.98 0.0008 0.96 0.947-0.98 0.0009 SI 1.02 0.99-1.06 NS C-stat (95% CI 0.72 (0.65-0.77) 0.74 (0.68-0.8) Hospital mortality Variable OR 95% CI P OR 95% CI P APACHE III 0.97 0.95-0.99 0.0003 0.97 0.95-0.99 0.0003 SI 1.04 1.02-1.07 0.001 C-stat (95% CI 0.70 (0.63-0.76) 0.75 (0.69-0.81) 90-d mortality OR 95% CI P OR 95% CI P Age 0.97 0.94-0.99 0.01 0.97 0.94-0.99 0.046 APACHE III 0.97 0.95-0.99 0.0002 0.97 0.95-0.98 0.0001 SI 1.05 1.03-1.08 <0.0001 C-stat (95% CI 0.77 (0.7-0.82) 0.8 (0.74-0.85) Kashani et al: Crit Care Med, 2016 2013 MFMER 3322132-52
Ture positive sensitivity Sarcopenia Index 1,0 Prediction of 90 day mortality 0,8 0,6 0,4 Critically ill patients Mayo Clinic Hospital, Rochester ICU October 2008- December 2010 0,2 ROC-AUC = 0.81 0,0 0,0 0,2 0,4 0,6 0,8 1,0 1-specificity false positive Odds ratio Lower 95% Upper 95% P Age 0.97 0.94 0.99 0.05 Body mass index 1.02 0.99 1.1 0.2 Sarcopenia index 1.05 1.03 1.1 0.001 APACHE III 0.97 0.95 0.98 0.0004 Kashani et al: Crit Care Med, 2016 2013 MFMER 3322132-53
SI correlation with length of Mechanical ventilation Patients on mechanical ventilator N= 131 Duration of mechanical ventilation predicted by sarcopenia index 1 d for each 10 unit of sarcopenia index 95% CI 1.4 to 0.2; p = 0.006 Sarcopenia index = 65 Sarcopenia index = 44 MV length 2 days shorter Kashani et al: Crit Care Med, 2016 2013 MFMER 3322132-54
L2L3 area Pre-Lung Transplant Cohort (n=40) 300 250 r 2 = 0.2 p =.03 200 150 100 50 60 70 80 90 100 110 120 130 140 Sarcopenia index 2013 MFMER 3322132-55
Summary Creatinine as a marker of kidney function has several limitations Knowing these limitations allows its appropriate use Heart failure Liver disease Low admission serum creatinine is as impactful in clinical outcomes as high admission Scr Sarcopenia Index could be utilized at bedside to estimate muscle mass/nutritional status 2013 MFMER 3322132-56
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