Las dos caras de la cretinina sérica The two sides of serum creatinine

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1 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

2 Disclosure I have no COI regarding this activity 2013 MFMER

3 Outlines AKI definitions Bad side Limitations Clinical impact Good side Sarcopenia index Outcome prediction 2013 MFMER

4 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-R MFMER

5 AKIN Definition for AKI Stage I Inc Scr 0.3 mg/dl or > % from baseline <0.5 ml/kg/hr for >6 hr Stage II Inc Scr > % 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:R MFMER

6 KDIGO Definition for AKI Stage I Scr 0.3 mg/dl OR times baseline <0.5 ml/kg/hr for >6 hr Stage II 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, MFMER

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10 ICC (95% CI) per Days Before Admission Estimated Method days days days Most recent outpatient Mean outpatient Nadir outpatient Most recent inpatient or outpatient ( ) a ( ) b ( ) c ( ) a ( ) b ( ) c ( ) a ( ) b ( ) c ( ) d ( ) d ( ) e Siew at al: Clin J Am Soc Nephrol 7: , MFMER

11 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 ( ) 0.87 ( ) 0.76 ( ) ICC (95% CI) egfr 60 ml/min per 1.73 m 2 (n=120) 0.58 ( ) 0.75 ( ) 0.65 ( ) Most recent inpatient or outpatient 0.85 ( ) 0.65 ( ) Siew at al: Clin J Am Soc Nephrol 7: , MFMER

12 60-day mortality (%) Fluid Balance Impact on SCr (n=7696) 100 No fluid correction Fluid correction No AKI before and after adjustment AKI before but No AKI after adjustment ,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 Odds ratio for 60-day mortality Thongprayoon et al: J Nephrol 29(2): MFMER

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14 Difference Observed vs. estimated (MDRD GFR=75)Scr 67% had pre-admission creatinine; (n=1314; 46% CKD) r = r = Average Average ICU admission At study enrollment Bagshaw et al: Nephrol Dial Transplant 24: , MFMER

15 Difference Observed vs. estimated (MDRD GFR=75)Scr CKD excluded 25 r = r = Average Average ICU admission At study enrollment Bagshaw et al: Nephrol Dial Transplant 24: , MFMER

16 60-Day mortality (%) Scr at Admission vs. MDRD 75 When Baseline SCr unavailable (n=3504; 45% of whole cohort) MDRD 75 Admission SCr 30 22,7 32,1 25,1 29, ,0 10 5,1 6,0 11,7 0 0 Stage 1 Stage 2 Stage 3 Thongprayoon et al: BMC Nephrology 17:6, MFMER

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18 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

19 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, MFMER

20 Time Course of Development of Increasing Serum Creatinine in Hospitalized HF Patients 100 % Days Gottlieb et al: J Card Fail 8:136, MFMER

21 MELD Equation MELD =(0.957 log(creatinine) x log(bilirubin) log(inr) ) x MFMER

22 MELD Equation MELD =(0.957 log(creatinine) x log(bilirubin) log(inr) ) x MFMER

23 Sample MELD Scores INR Bilirubin Creatinine MELD MFMER

24 Mortality rate per 1000 patients Transplant Benefit by MELD Score Waitlist Transplant 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< MELD HR=0.22 P<0.001 HR=0.18 P<0.001 HR=0.07 P<0.001 HR=0.04 P< MFMER

25 Survival GFR and Waitlist Survival 660 LTx candidates at Mayo (90-99) (n=482) (n=134) <30 (n=44) 0.2 P< Years Lim: J Hep 52:523, MFMER

26 Probability (%) Waitlisted 20% Less Likely Than to Undergo Liver Transplantation UNOS Transplant Male Female Death Years since activation Allen AM. Tall, Male, and What Else? Disparities in Liver Transplantation Based On Gender and Height Transplantation 2014 (98) S MFMER

27 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

28 Creatinine MELD points Women Receive Fewer Creatinine-Meld Points Than Men With Similar Renal Function 8 6 Male Female Measured GFR (ml/min/bsa) 2016 MFMER

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31 Availability Serum creatinine Urine output BL serum creatinine Contextual data, comorbidities, medications, organ failure, biomarkers Sensitivity Specificity ADQI 15th 2016 MFMER

32 Creatinine HR BUN/Cr Glucose Potassium Age Sodium Prior ICU Bilirubin Platelets SVP AVPU Hb DBP AST Variable importance 100 Koyner et al: Clin J Am Soc Nephrol 11, MFMER

33 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 MFMER

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36 Absolute mortality rate (%) Relative risk Observational cohort study in Dutch 154,308 ICU patients Hospital mortality, increasing for BMI <18.5 kg/m Body-mass index (kg/m 2 ) BMI kg/m 2 had the lowest risk of death with an adjusted OR of 0.86 ( ) 2013 MFMER

37 Mortality (%) LOS in ICU (Days) ICU LOS Mortality 2 3 A retrospective cohort study of 11,291 adult patients Mayo Clinic Hospital Rochester ICUs 20 1 Between 2003 and n= Creatinine concentration in mg/dl 2013 MFMER

38 Multicenter, binational, retrospective cohort study ANZICS 1.5 million admission 175 ICUs MFMER

39 Patients Flow Chart All records for the period in ANZICS =1,250,449 Admissions Exclusions Readmissions (during the same hospital stay) 5904 Missing vital status at hospital discharge 361 Post kidney transplant Receiving chronic renal replacement therapy Missing peak plasma CR concentration in first 24 hrs 1,045,718 Admissions 2013 MFMER

40 Results N =1,047,518 N =96,630; Ht & Wt available 2013 MFMER

41 In-hospital mortality (%) Low Admission Scr 4 3, ,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 Serum creatinine at hospital admission (mg/dl) Cheungpasitporn W, Thongprayoon C, Kashani K. The American Journal of Medicine (2016) 2013 MFMER

42 OR of in-hospital mortality Low Admission Scr Hospital Mortality (Independent of BMI) Adjustments: Age, sex, race, BMI, principal diagnosis, CCI, CAD, CHF, PVD, CVA, DM, COPD, cirrhosis, hemi/paraplegia Serum Creatinine at Hospital Admission (mg/dl) Cheungpasitporn W, Thongprayoon C, Kashani K. The American Journal of Medicine (2016) 2013 MFMER

43 All-cause mortality hazard ratio Mild Moderate Severe Very severe Recommended range Overweight Obesity 121,762 patients receiving HD 3 times/wk Reference Unadjusted Case-mix Case-mix & MICS Years Outpatient dialysis facilities (DaVita) Body-mass index (kg/m 2 ) Kalantar-Zadeh, K., et al. (2010). Mayo Clinic Proceedings 85(11): MFMER

44 All-cause mortality hazard ratio Unadjusted Case-mix Case-mix & MICS 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): MFMER

45 All-cause mortality hazard ratio Unadjusted Case-mix Case-mix & MICS 1.2 Reference Gained muscle mass Lost muscle mass No change in muscle mass <-2-2 to -1-1 to to +2 >+2 Serum creatinine (mg/dl) Kalantar-Zadeh, K., et al. (2010). Mayo Clinic Proceedings 85(11): MFMER

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49 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

50 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 0,8 0,6 0,4 0,2 Sarcopenia index = 65 Sarcopenia index = 44 0, Muscle surface area (cm 2 ) Kashani et al: Crit Care Med, MFMER

51 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, MFMER

52 Clinical model without SI Clinical models with SI ICU mortality Variable OR 95% CI P OR 95% CI P APACHE III SI NS C-stat (95% CI 0.72 ( ) 0.74 ( ) Hospital mortality Variable OR 95% CI P OR 95% CI P APACHE III SI C-stat (95% CI 0.70 ( ) 0.75 ( ) 90-d mortality OR 95% CI P OR 95% CI P Age APACHE III SI < C-stat (95% CI 0.77 ( ) 0.8 ( ) Kashani et al: Crit Care Med, MFMER

53 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 December ,2 ROC-AUC = ,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 Body mass index Sarcopenia index APACHE III Kashani et al: Crit Care Med, MFMER

54 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 = Sarcopenia index = 65 Sarcopenia index = 44 MV length 2 days shorter Kashani et al: Crit Care Med, MFMER

55 L2L3 area Pre-Lung Transplant Cohort (n=40) r 2 = 0.2 p = Sarcopenia index 2013 MFMER

56 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

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