ONLINE APPENDIX. mg/kg, and fentanyl, 1 µg/kg, as induction and were maintained with sufentanil boluses up to 4 to 5

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1 ONLINE APPENDIX Perioperative management of the patients. All patients continued their cardiac medications until surgery. Patients received thiopentone, 3 to 5 mg/kg, and fentanyl, 1 µg/kg, as induction and were maintained with sufentanil boluses up to 4 to 5 µg/kg associated with propofol continuous infusion at 3 mg/kg/hour. After orotracheal intubation, patients were ventilated with oxygen and air (fraction of inspired oxygen 50%), keeping partial pressure of carbon dioxide, arterial (Paco2) between 35 and 38 mm Hg. Rectal and cervical esophageal probes were employed for temperature monitoring, and acid-base equilibrium was maintained by the alpha-stat method. The extracorporeal circuit consisted of a roller or centrifugal pumps, hollow fiber oxygenator with integrated heat exchanger, arterial filter, cardiotomy reservoir and polyvinyl tubing system. In all cases, an `open' system was used for perfusion. The extracorporeal circuit was primed with 1000 ml electrolyte solution and 5000 IU bovine lung heparin (Liquemin; Roche, Italy). After systemic heparinization (300 U/kg), CPB was initiated and the activated clotting time was kept at >400 s with additional heparin. The pump flow was non-pulsatile in all operations. The flow rate was maintained at 2.4 l/min per m2 during cooling and rewarming phases, and at 2.0 l/min per m2 during stable hypothermia. The mean arterial pressure (MAP) during CPB was maintained between 60 and 90 mmhg, with CPB flows set as previously described, and vasoactive drugs were used to maintain the MAP in the desired range: if the MAP increased above the desired range, and was unresponsive to fentanyl or diazepam, sodium nitroporusside was started, but if the MAP fell below the desired range, norepinephrine, boluses or continuous infusion were added. Tepid hypothermia was used as standard, although higher degrees of hypothermia were allowed following clinical needs. CPB flows and pressures were downloaded from the monitor and recorded every 5 min during perfusion. Also any significant modification of the perfusion pattern during 5 min time intervals was recorded by the perfusionist.

2 Myocardial protection was achieved with blood or crystalloid cardioplegia, depending on surgeons preferences, administered antegradely and/or retrogradely just after aortic cross-clamping and every min of the aortic cross-clamp time. The hematocrit during CPB was maintained at 18-28%. After termination of CPB, heparin was antagonized with protamine sulfate at a 1:1 ratio (3 mg/kg). If necessary, inotropic and/or vasoconstrictor support was given when patients were weaned from CPB. Autologous blood and residual volume from the extracorporeal circuit were infused into the patient when volume supplementation was necessary. After surgery, patients were admitted to the intensive care unit (ICU) and treated according to a standardized protocol. The MAP was kept at mmhg, heart rate at beats/min, and the cardiac index was maintained at greater than 2.0 l/min per m2. Inotropic support was administered when necessary. Patients were ventilated to normocapnia, and an arterial oxygen tension of 80 mmhg with continuous positive-pressure ventilation until extubation was maintained according to the ICU regimen. Basic fluid administration consisted of 0.9% NaCl and polygelatine. Packed erythrocytes were infused when the hematocrit was <18% during CPB and <24% in the ICU. When their cardio-respiratory condition had stabilized, patients were transported to the ward for further recovery.

3 APPENDIX 2 (ONLINE ONLY) Patient variables considered in analyses Preoperative (n=33) 1. Age (years) 2. Gender (m/f) 3. Weight (Kg) 4. Body surface area (m2) 5. BMI 6. NYHA class (I-IV) 7. Additive EuroSCORE 8. Logistic EuroSCORE 9. Hypertension (y/n) 10. Never smoked (y/n) 11. Previous (discontinued > 6 months) smoker (y/n) 12. Current (> 10/day) smoker (y/n) 13. Diabetes (y/n) a. Diet-controlled diabetes (y/n) b. Oral drugs-controlled diabetes (y/n) c. Insulin-controlled diabetes (y/n) 14. Preoperative atrial fibrillation/flutter (y/n) 15. Preoperative ischemia at ECG (y/n) 16. Preoperative renal failure (y/n) 17. Preoperative IABP (y/n) 18. Preoperative inotropes 19. Preoperative vasoconstrictors 20. Preoperative adminitsration of anticoagulants (y/n) 21. Preoperative adminitsration of aspirin (y/n) 22. Preoperative adminitsration of diuretics (y/n) 23. Preoperative adminitsration of statins (y/n) 24. Preoperative adminitsration of heparin (i.v. or s.c.) Type of surgery (multiple selections can apply) 25. Coronary artery bypass (y/n) 26. Aortic valve replacement (y/n) 27. Mitral valve replacement (y/n) 28. Mitral valve repair (y/n) 29. Double or triple valve replacement/repair (y/n) 30. Ascending aorta replacement (y/n) 31. Arrhytmia (atrial or ventricular) surgery (y/n) 32. LV surgical remodelling (y/n) 33. Adult congenital (y/n) 34. Other (y/n) Intraoperative (n=12) 1. Intraoperative vasodilators administration (y/n) 2. Intraoperative inotropes administration (y/n) 3. Intraoperative vasoconstrictors administration (y/n) 4. Intraoperative diuretics administration (y/n) 5. Sinus rhythm after surgery (y/n) 6. Temporary pace-maker rhythm after surgery (y/n) 7. Intraoperative red blod cells transfusion (units) 8. Intraoperative plasma transfusion (units) 9. Intraoperative platelets transfusion (units) 10. CPB time (min) 11. Aortic crossclamp time (min) 12. Intraoperative new pump run (y/n) CPB management variables (n=37) Type of pump 1. Roller (y/n) 2. Centrifugal A (y/n)

4 3. Centrifugal B (y/n) 4. Other (y/n) Type of oxygenator 5. Oxygenator A (y/n) 6. Oxygenator B (y/n) 7. Oxygenator C (y/n) 8. Other (y/n) Arterial cannulation site 9. Ascending aorta (y/n) 10. Femoral aretry (y/n) Cardioplegia 11. Vehicle (crystalloid/blood) 12. Temperature (cold/warm) Route of cardioplegia delivery 13. Anterograde (y/n) 14. Retrograde (y/n) 15. Circulatory arrest (y/n) 16. Hypothermia < 27 C (y/n) 17. Theoretical CPB flow (ml/min) 18. Lowest flow during CPB (ml/min) 19. Oesophageal temperature when lowest flow during CPB occurred (*C) 20. Minutes with CPB flow was at least 10% lower than theoretical during CPB (min) 21. Highest arterial pressure during CPB (mmhg) 22. Oesophageal temperature at which highest arterial pressure during CPB occurred (*C) 23. Lowest arterial pressure during CPB (mmhg) 24. Oesophageal temperature at which lowest arterial pressure during CPB occurred (*C) 25. Lowest haemoglobin during CPB (mg/dl) 26. Lowest hematocrit during CPB (%) 27. Lowest rectal temperature during CPB ( C) 28. Lowest oesophageal temperature during CPB ( C) 29. Lowest activated clotting time during CPB (sec) 30. Theoretical heparin dose (ml) 31. Total heparin dose given during CPB (ml) 32. Cardioplegia administred during CPB (ml) 33. Mannitol administration during CPB (y/n) 34. Furosemide administration during CPB (y/n) 35. Fluid balance during CPB (ml) 36. Urine output during CPB (ml) 37. Positive fluid balance during CPB (y/n) Postoperative (n=9) 1. Postoperative vasodilators administration (y/n) 2. Postoperative vasoconstrictors administration (y/n) 3. Postoperative inotropes administration (y/n) 4. Postoperative diuretics administration (y/n) 5. Postoperative antiarrhytmic drugs administration (y/n) 6. Postoperative digitalis administration (y/n) 7. Postoperative red blod cells transfusion (units) 8. Postoperative plasma transfusion (units) 9. Postoperative platelets transfusion (units)

5 Synopsis of risk factors for AKI based based on the different groups of variables included in the model 4 categories 3 categories 2 categories 1 category Variable Effect Variable Effect Variable Effect Variable Effect Age (yrs) Age (yrs) Age (yrs) Age (yrs) Ins.dep. diabetes Add. EuroSCORE Add. EuroSCORE Add. EuroSCORE Previous smoker Ins.dep. diabetes Ins.dep. diabetes Ins.dep. diabetes Serum creatinine Serum creatinine Serum creatinine Serum creatinine Intra. inotropes Never smoked Intra. RBCs transf. Malignant ventric.. arrhythmias Hypertension Malignant ventric.. arrhythmias Crossclamp time DV replacement Arrhythmia surgery New pump run Intra. Inotropes Intra. inotropes CPB Furosemide Intra. RBCs transf. Intra. vasoconstr. CPB urine output CPB time Intra. diuretics Post. Vasoconstr. CPB theorical flow Intra. RBCs transf. Post. Inotropes Total heparin given Post. diuretics CPB urine output Post.antiarrhytmics Intra. diuretics Post. RBCs transf. DV replacement DV replacement Legend: 4 categories = preoperative, intraoperative, CPB-related, and postoperative variables included 3 categories = preoperative, intraoperative, and CPB-related variables included, postoperative variables excluded 2 categories = preoperative and intraoperative variables included, CPB-related and postoperative variables excluded 1 category = only preoperative variables included, intraoperative, CPB-related and postoperative variables excluded

6 Aknowledgements. The Authors gratefully aknowledge the contribution in data collection of the Monzino Research Group on Cardiac Surgery Outcomes: Veronica Myasoedova, Marcello Fonga, Davide Pedroletti, Rita Fabrizi, Gianluca Riva, Angelica Capozzoli, Daniela Manzone, Elisa Merati, Francesco Arlati, Giulio Tessitore, Laura Cavallotti, Sara Filippini, Andrea Daprati, Tommaso Generali, Gabriele Tamagnini, Moreno Naliato, Francesco Grillo, Samer Kassem, Maurizio Roberto, Giulio Pompilio, Marco Zanobini, Gianluca Polvani, Paola Moliterni, Nora Piazzoni, Sebastiana Gregu, Glauco Juliano, Guido Merli, Claudio Brambillasca, Luca Salvi, Erminio Sisillo.