SUPPLEMENTARY INFORMATION

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1 Supplementary information S1 Studies of the effect of AKI duration on outcomes Study Study group (n) Criteria for AKI Definition of RR Outcomes Uchino et al. All patients admitted to (2010) 1 a university-affiliated hospital (20,126) Coca et al. Diabetic patients (2010) 2 from 123 Veterans Affairs medical centres undergoing their first non-cardiac surgery. (35,302) Kellum et al. Academic medical centre (2015) 3 database of critically ill patients who were classified according to the maximum KDIGO criteria met during hospitalization (32,045) Sood et al. AKI of any RIFLE severity (2014) 4 prevalent at shock (5,443) Brown et al. Patients undergoing (2010) 5 cardiac surgery (4,987) Perinel et al. Critically ill patients with (2015) 6 ICU stay >3 days (447) and UO and UO Reversal to no AKI RIFLE class within 72 h of AKI onset Reversal of to <17.7 μmol/l (<0.2 mg/dl) above the preoperative value within 48 h Reversal to no AKI KDIGO class within 3 days Reversal of to baseline value within 24 h Reversal to no AKI RIFLE class within 72 h of AKI onset Reversal of oliguria (in the absence of diuretic treatment) and/or 50% decrease in and/or return to the baseline value RR in 14.8% of patients; persistent AKI in 29.1% Patients with TA had a significantly higher odds ratio for hospital mortality (2.26; 95% CI ) than patients without AKI Mortality was lowest in those with AKI duration 2 days, regardless of stage Median survival was 3.5 years for patients with short duration AKI (<2 days), 2.9 years for those with medium-duration AKI (3 6 days), and 2.1 years for patients with long-duration AKI ( Likelihood of death or dialysis at 1 year was higher in patients with persistent AKI than in those with transient AKI (excluding death or RRT during the index hospitalization) RR in 21.2% of patients; persistent AKI in 53.0% RR within 1 2 days in 18% of patients; persistent AKI (for 3 6 days) in 11%; >7 days in 9% RR in 29.6% of patients; persistent AKI in 38.9% AKI, acute kidney injury; ICU, intensive care unit; RR, rapid reversal of AKI; RRT, renal replacement therapy;, serum creatinine; TA, transient azotaemia, UO, urine output. Supplementary information S2 Tests to differentiate rapid reversal of AKI from persistent AKI Study Test Summary Brown et al. Risk score Perioperative predictors of AKI duration following cardiac surgery (2012) 7 Schnell et al. Resistive (2012) 8 index Dewitte et al. Resistive (2012) 9 index Platt et al. Resistive (1991) 10 index Darmon et al. Resistive (2011) 11 index Ninet et al. Resistive (2015) 12 index de Geus et al. Cystatin C (2011) 13 and NGAL Basu et al. Cystatin C (2014) 14 and NGAL Basu et al. Biomarkers (2014) 14 and renal angina index In patients with AKI, resistive index predicted persistent AKI Resistive index was similar in transient and persistent AKI Resistive index performed well for diagnosing persistent AKI Intermediate level of resistive index 0.71 ( ) in the transient AKI group Meta-analysis of resistive index studies AKI, acute kidney injury; NGAL, neutrophil gelatinase-associated lipocalin. Urinary NGAL differentiated rapid reversal from persistent AKI on admission Cystatin C and NGAL demonstrated greater likelihood ratios than changes in serum creatinine for persistent AKI Plasma NGAL, matrix metalloproteinase 8 and neutrophil elastase improve the net reclassification index for the renal angina index

2 Supplementary information S3 Studies of recovery including nondialysis-requiring AKI using serum creatinine Study Population (n) AKI definition Recovery definition (outcome) Lins et al. Prospective, (2006) 15 Belgium (145) Ali et al. Retrospective, UK (2007) 16 (474) Liano et al. Retrospective, (2007) 17 Spain (187) Jones et al. Retrospective, (2012) 18 propensity score-matched, hospitalized with normal baseline kidney function, USA (3,809) Bucaloiu et al. Retrospective, (2012) 19 propensity score-matched, USA (5,262) Pannu et al. Retrospective, (2013) 20 Canada (3,239) Korenkevych et al. (2015) 21 Retrospective, hospitalized surgical patients, USA (46,299) >2 mg/dl* and survived hospitalization RIFLE + peak >1.7 mg/dl (males) or 1.5 mg/dl (females) ATN, >2 mg/dl with baseline <1.4 mg/dl ICD % increase in and recovery 50% increase in and recovery KDIGO CrCl >60 (32%) CrCl (58%) CrCl <15 (10%) Full: below threshold or baseline (68%) Partial: above threshold (5%) None: RRT at 90 days (n = 2) Unknown (27%) Complete: 1.4 mg/ dl (42%) Partial: > mg/ dl (57%) None: near peak or still on RRT at discharge (1%) Within 10% of baseline (19%) Timing of recovery assessment At discharge Future mortality recovery status 90 days recovery status At discharge (mean stay 54 days) Within 7 days of discharge Patients with complete recovery had better survival than those with nonrecovery All-cause mortality: RR 1.08 ( ) among those who did not recover <90% baseline egfr 90 days Recovered AKI versus no AKI: ahr 1.50 (95% CI ) Within 25% of baseline (70% achieved overall) KDIGO 1 3 Complete: within 50% of baseline (74%) Partial: >50% but not on RRT (22%) None: RRT (4%) With incident CKD added: ahr 1.18 (95% CI ) 90 days Recovered versus non-recovered: ahr 1.26 (95% CI ) Discharge Mortality at 90 days versus no AKI ahr Full recovery: Stage 1: 1.48 ( ) Stage 2: 2.16 ( ) Stage 3: 5.73 ( ) Partial recovery: Stage 1: 2.73 ( ) Stage 2: 8.81 ( ) Stage 3: ( ) None: ( ) Future renal outcome Incident CKD: AKI versus no AKI HR 3.82 ( ) among those who did not recover Recovered AKI versus no AKI: ahr 1.95 (95% CI ) Recovered versus non-recovered for doubling of or ESRD: ahr 4.13 (95% CI )

3 Supplementary information S3 (cont.) Studies of recovery including nondialysis-requiring AKI using serum creatinine Heung et al. Retrospective, US (2015) 22 veterans (104,764) Kellum et al. Prospective, septic (2016) 23 shock (1,243) KDIGO 1 3 KDIGO stage 2 3 To within 0.3 mg/dl of baseline : 67% within 2 days 13% between 3 10 days 12% still elevated after 10 days 8% unknown Complete recovery: return to within 1.5 x baseline Partial: improvement of one KDIGO stage but not complete 2 days, 3 10 days, >10 days Discharge Not evaluated 1 year survival Complete: 64% Partial: 64% No recovery: 13% No AKI: 61% RR of incident CKD at 1 year, recovered versus no AKI: 2 days: Stage 1: 1.43 ( ) Stage 2: 1.80 ( ) Stage 3: 1.96( ) 3 10 days: Stage 1: 2.00( ) Stage 2: 1.91( ) Stage 3: 2.20( ) Still elevated >10 days: Stage 1: 2.65 ( ) Stage 2: 3.31 ( ) Stage 3: 3.59 ( ) Unknown: Stage 1: 1.48 ( ) Stage 2: 2.08 ( Stage 3: 2.21 ( ) *Multiply by 88.4 to obtain value in μmol/l. ahr, adjusted hazard ratio; AKI, acute kidney injury; ATN, acute tubular necrosis; CCl, creatinine clearance (units ml/ min/1.73 m 2 ); CKD, chronic kidney disease; egfr, estimated glomerular filtration rate; ESRD, end-stage renal disease; RR, relative risk; RRT, renal replacement therapy;, serum creatinine.

4 Supplementary information S4 Studies of non-creatinine-based biomarkers to predict or assess renal recovery after AKI Study Setting Biomarkers Recovery outcomes Performance Hall et al. 91 adult kidney (2009) 24 transplant recipients Srisawat et al. 189 adults with (2011) 25 community-acquired pneumonia (post hoc analysis of GenIMS) Srisawat et al. 76 adults with (2011) 26 dialysis-requiring AKI from the ATN Study (BioMaRK) Hall et al. 78 adult kidney (2011) 27 transplant recipients Zhang et al. 232 adults AKI on (2012) 28 CRRT Murugan et al. 817 critically Ill adults (2014) 29 (BioMaRK) Meersch et al. 50 adult cardiac (2014) 30 surgery patients Pianta et al. 56 transplant (2015) 31 recipients Koyner et al. 692 critically Ill adults (2015) 32 with Stage 1 AKI (Sapphire study) Wang et al. 114 hospitalized (2015) 33 adults with AKIN stage 3 and nephrology consultation Urine NGAL, IL 18, KIM1 at 0, 6, 12, and 18 h after transplantation Plasma NGAL ungal, HGF, Ucyst, uil 18, NGAL/ MMP 9, urinary creatinine Plasma NGAL, IL 18, serum cystatin C discharge Dialysis-free survival for 60 days AUCs: NGAL IL KIM AUC 0.74 (95% CI ) AUCs for renal recovery: ungal, 0.70; Ucyst, 0.61; uil 18, 0.42; HGF, 0.74; ungal/mmp 9, 0.53; urinary creatinine, 0.66 Combining biomarkers with clinical variables improved the AUC (0.94) and NRI (63.3%). No difference in NGAL or IL 18 between patients with and without DGF Day 1 cystatin C AUC 0.83 (95% CI ) Serum cystatin C Dialysis independence AUC for nonrecovery 0.91(95% CI ) Plasma IL 1β, IL 6, IL 8, IL 10, IL 18, MIF, TNF, TNFR1, TNFR2, DR 5, GM CSF TIMP 2*IGFBP7, NGAL Urine TIMP2*IGFB7, VEGF A, MCP 1, TFF3, CXCL16 TIMP 2*IGFBP7 Urine L FABP Dewitte et al. (2015) critically Ill adults Urine TIMP 2*IGFBP7, pngal at inclusion and 24 h later Pike et al. 817 critically (2015) 35 ill adults with dialysis-requiring AKI (BioMaRK) Reese et al. 1,304 deceased (2015) 36 donor urine samples Plasma IL 6, IL 8, IL 10, IL 19, MIF, TNFR1, TNFR2, DR 5 Donor urine NGAL, KIM 1, IL 18, L FABP, microalbuminuria 60 days Renal recovery at discharge (return to baseline ) All-cause mortality or RRT at 9 months Alive without need for RRT, AKIN 3, and minimum CrCl of 20 ml/min at discharge 1.5 times baseline or 0.35 mg/dl* with reversal of oliguria within 48 h 60 days DGF (RRT within Increased concentrations of plasma IL 8, IL 18, MIF and TNFR1 were associated with slower renal recovery and increased mortality TIMP 2*IGFBP7 AUC 0.79 (95% CI ) NGAL AUC 0.48 (95% CI ) AUCs for predicting DGF (utimp 2*IGFBP7 0.76; VEGF A 0.81; utimp ; uigfbp7 0.71) Adjusted HRs: 1.44 (95% CI ) for levels > (95% CI ) for levels >2.0 AUC for nonrecovery 0.91 (95%CI ) AUCs: TIMP 2*IGFBP pngal AUC ranges High donor ungal levels were significantly associated with recipient DGF with RR 1.21 (highest versus lowest tertiles) Addition of urinary biomarkers did not improve AUC, IDI, and NRI At 6 months, donor urinary biomarkers added minimal value in predicting allograft function. *Multiply by 88.4 to obtain value in μmol/l. AKI, acute kidney injury; AUC, area under the curve; CrCl, creatinine clearance; CRRT, continuous renal replacement therapy; CXCL16, C X C motif chemokine 16; DGF, delayed graft function; DR 5, death receptor; GenMS, genetic and inflammatory markers of sepsis study; HGF, hepatocyte growth factor; GM CSF, granulocyte macrophage colony-stimulating factor; IDI, integrated discrimination index; IGFBP, insulin-like growth factor-binding protein; KIM 1; kidney injury molecule 1 (also known as hepatitis A virus cellular receptor 1); L FABP, liver-type fatty acid binding protein; MCP 1, monocyte chemotactic protein 1; MIF, macrophage migration inhibitory factor; MMP 9, matrix metalloproteinase 9; NGAL, neutrophil gelatinase-associated lipocalin; pngal, plasma NGAL;, serum creatinine; NRI, net reclassification index; RRT, renal replacement therapy; TIMP, metalloproteinase inhibitor; TFF3, trefoil factor 3; TNF, tumour necrosis factor; TNFR, TNF receptor; Ucyst, urine cystatin C; uil 18, urinary IL 18; VEGF A, vascular endothelial growth factor A.

5 Supplementary information S5 The relationship between patient characteristics before RRT and kidney recovery Patient characteristics/factors Effect on renal recovery Effect on patient recovery Age Inverse association Inverse association Lower baseline kidney function Inverse association Inverse association AKI aetiology Uncertain effect Uncertain effect Comorbidities Inverse association Inverse association Non-renal organ dysfunction Inverse association Inverse association Fluid overload Inverse association Inverse association Recurrent AKI episode Inverse association Unknown effect Congestive heart failure Inverse association Unknown effect AKI, acute kidney injury. Supplementary information S6 Other factors involved in the care of patients with RRT-dependent AKI that might affect recovery Factors Effect on renal recovery Effect on patient recovery Logistics (for example, training, resource availability) No studies Unknown Transition from one RRT modality to another No studies Unknown Concurrent care (for example, antibiotic dosing, other medications, diuretics, transfusion, erythropoiesis stimulating agents) AKI, acute kidney injury; RRT, renal replacement therapy. No studies Anaemia is not associated with delayed recovery Unknown 1. Uchino, S., Bellomo, R., Bagshaw, S. M. & Goldsmith, D. Transient azotaemia is associated with a high risk of death in hospitalized patients. Nephrol. Dial. Transplant. 25, (2010). 2. Coca, S. G. et al. The duration of postoperative acute kidney injury is an additional parameter predicting long-term survival in diabetic veterans. Kidney Int. 78, (2010). 3. Kellum, J. A. et al. Classifying AKI by urine output versus serum creatinine level. J. Am. Soc. Nephrol. 26, (2015). 4. Sood, M. M. et al. Early reversible acute kidney injury is associated with improved survival in septic shock. J. Crit. Care 29, (2014). 5. Brown, J. R., Kramer, R. S., Coca, S. G. & Parikh, C. R. Duration of acute kidney injury impacts long-term survival after cardiac surgery. Ann. Thorac. Surg. 90, (2010). 6. Perinel, S. et al. Transient and persistent acute kidney injury and the risk of hospital mortality in critically ill patients: results of a multicenter cohort study. Crit. Care Med. 43, e269 e275 (2015). 7. Brown, J. R. et al. Determinants of acute kidney injury duration after cardiac surgery: an externally validated tool. Ann. Thorac. Surg. 93, (2012). 8. Schnell, D. et al. Renal resistive index better predicts the occurrence of acute kidney injury than cystatin C. Shock 38, (2012). 9. Dewitte, A. et al. Doppler resistive index to reflect regulation of renal vascular tone during sepsis and acute kidney injury. Crit. Care 16, R165 (2012). 10. Platt, J. F., Rubin, J. M. & Ellis, J. H. Acute renal failure: possible role of duplex Doppler US in distinction between acute prerenal failure and acute tubular necrosis. Radiology 179, (1991). 11. Darmon, M. et al. Diagnostic accuracy of Doppler renal resistive index for reversibility of acute kidney injury in critically ill patients. Intensive Care Med. 37, (2011). 12. Ninet, S. et al. Doppler-based renal resistive index for prediction of renal dysfunction reversibility: a systematic review and meta-analysis. J. Crit. Care 30, (2015). 13. de Geus, H., Bakker, J., Lesaffre, E. & lenoble, J. Neutrophil gelatinase-associated lipocalin at ICU admission predict for acute kidney injury in adult patients. Am. J. Respir. Crit. Care Med. 183, (2011). 14. Basu, R. K. et al. Incorporation of biomarkers with the renal angina index for prediction of severe AKI in critically ill children. Clin. J. Am. Soc. Nephrol. 9, (2014). 15. Lins, R. L., Elseviers, M. M. & Daelemans, R. Severity scoring and mortality 1 year after acute renal failure. Nephrol. Dial. Transplant. 21, (2006). 16. Ali, T. et al. Incidence and outcomes in acute kidney injury: a comprehensive population-based study. J. Am. Soc. Nephrol. 18, (2007). 17. Liano, F. et al. Long-term outcome of acute tubular necrosis: a contribution to its natural history. Kidney Int. 71, (2007). 18. Jones, J. et al. Association of complete recovery from acute kidney injury with incident CKD stage 3 and allcause mortality. Am. J. Kidney Dis. 60, (2012). 19. Bucaloiu, I. D. et al. Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury. Kidney Int. 81, (2012). 20. Pannu, N., James, M., Hemmelgarn, B., Klarenbach, S. & Alberta Kidney Disease Network. Association between AKI, recovery of renal function, and long-term outcomes after hospital discharge. Clin. J. Am. Soc. Nephrol. 8, (2013). 21. Korenkevych, D. et al. The pattern of longitudinal change in serum creatinine and 90 day mortality after major surgery. Ann. Surg. 263, (2016). 22. Heung, M. et al. Acute kidney injury recovery pattern and subsequent risk of CKD: an analysis of Veterans Health Administration Data. Am. J. Kidney Dis. 67, (2016). 23. Kellum, J. A. et al. The effects of alternative resuscitation strategies on acute kidney injury in patients with septic shock. Am. J. Respir. Crit. Care Med. 193, (2016). 24. Hall, I. E. et al. IL 18 and urinary NGAL predict dialysis and graft recovery after kidney transplantation. J. Am. Soc. Nephrol. 21, (2009). 25. Srisawat, N. et al. Plasma neutrophil gelatinaseassociated lipocalin predicts recovery from acute kidney injury following community-acquired pneumonia. Kidney Int. 80, (2011). 26. Srisawat, N. et al. Urinary biomarkers and renal recovery in critically ill patients with renal support. Clin. J. Am. Soc. Nephrol. 6, (2011). 27. Hall, I. E., Doshi, M. D., Poggio, E. D. & Parikh, C. R. A comparison of alternative serum biomarkers with creatinine for predicting allograft function after kidney transplantation. Transplantation 91, (2011). 28. Zhang, Z., Xu, X., Ni, H. & Jin, N. Serum cystatin C is associated with renal function recovery in critically ill patients undergoing continuous renal replacement therapy. Nephron Clin. Pract. 122, (2012). 29. Murugan, R. et al. Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy. Nephrol. Dial. Transplant. 29, (2014). 30. Meersch, M. et al. Urinary TIMP 2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery. PLoS ONE 9, e93460 (2014). 31. Pianta, T. J. et al. Evaluation of biomarkers of cell cycle arrest and inflammation in prediction of dialysis or recovery after kidney transplantation. Transpl. Int. 28, (2015). 32. Koyner, J. L. et al. Tissue inhibitor metalloproteinase 2 (TIMP 2)IGF-binding protein 7 (IGFBP7) levels are associated with adverse long-term outcomes in patients with AKI. J. Am. Soc. Nephrol. 26, (2015). 33. Wang, L. et al. Urinary liver-type fatty acid-binding protein predicts recovery from acute kidney injury. Clin. Nephrol. 84, (2015). 34. Dewitte, A. et al. Kinetic egfr and novel AKI biomarkers to predict renal recovery. Clin. J. Am. Soc. Nephrol. 10, (2015). 35. Pike, F. et al. Biomarker enhanced risk prediction for adverse outcomes in critically ill patients receiving RRT. Clin. J. Am. Soc. Nephrol. 10, (2015). 36. Reese, P. P. et al. Associations between deceased-donor urine injury biomarkers and kidney transplant outcomes. J. Am. Soc. Nephrol. 27, (2016).