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Acute kidney disease is common and associated with poor outcomes in patients with cirrhosis and acute kidney injury

Published:February 22, 2022DOI:https://doi.org/10.1016/j.jhep.2022.02.009

      Highlights

      • AKD develops in 1 in 3 patients with cirrhosis and AKI.
      • AKD is independently associated with worse 90- and 180-day survival.
      • AKD is independently associated with de novo chronic kidney disease.

      Background & Aims

      Acute kidney disease (AKD) is the persistence of acute kidney injury (AKI) for up to 3 months, which is proposed to be the time-window where critical interventions can be initiated to alter downstream outcomes of AKI. In cirrhosis, AKD and its impact on outcomes have been scantly investigated. We aimed to define the incidence and outcomes associated with AKD in a nationwide US cohort of hospitalized patients with cirrhosis and AKI.

      Methods

      Hospitalized patients with cirrhosis and AKI in the Cerner-Health-Facts database from 1/2009-09/2017 (n = 6,250) were assessed for AKD and were followed-up for 180 days. AKI and AKD were defined based on KDIGO and ADQI AKD and renal recovery consensus criteria, respectively. The primary outcome measure was mortality, and the secondary outcome measure was de novo chronic kidney disease (CKD). Competing-risk multivariable models were used to determine the independent association of AKD with primary and secondary outcomes.

      Results

      AKD developed in 32% of our cohort. On multivariable competing-risk analysis adjusting for significant confounders, patients with AKD had higher risk of mortality at 90 (subdistribution hazard ratio [sHR] 1.37; 95% CI 1.14-1.66; p = 0.001) and 180 (sHR 1.37; 95% CI 1.14-1.64; p = 0.001) days. The incidence of de novo CKD was 37.5%: patients with AKD had higher rates of de novo CKD (64.0%) compared to patients without AKD (30.7%; p <0.001). After adjusting for confounders, AKD was independently associated with de novo CKD (sHR 2.52; 95% CI 2.01-3.15; p <0.001) on multivariable competing-risk analysis.

      Conclusions

      AKD develops in 1 in 3 hospitalized patients with cirrhosis and AKI and it is associated with worse survival and de novo CKD. Interventions that target AKD may improve outcomes of patients with cirrhosis and AKI.

      Lay summary

      In a nationwide US cohort of hospitalized patients with cirrhosis and acute kidney injury, acute kidney disease developed in 1 in 3 patients and was associated with worse survival and chronic kidney disease. Interventions that target acute kidney disease may improve outcomes of patients with cirrhosis and acute kidney injury.

      Graphical abstract

      Keywords

      Introduction

      Acute kidney injury (AKI) is a frequent complication occurring in hospitalized patients with cirrhosis, where up to 53% have an AKI at the time of admission or develop it during hospitalization.
      • Huelin P.
      • Piano S.
      • Sola E.
      • Stanco M.
      • Sole C.
      • Moreira R.
      • et al.
      Validation of a staging system for acute kidney injury in patients with cirrhosis and association with acute-on-chronic liver failure.
      • Wong F.
      • O'Leary J.G.
      • Reddy K.R.
      • Garcia-Tsao G.
      • Fallon M.B.
      • Biggins S.W.
      • et al.
      Acute kidney injury in cirrhosis: baseline serum creatinine predicts patient outcomes.
      • Garcia-Tsao G.
      • Parikh C.R.
      • Viola A.
      Acute kidney injury in cirrhosis.
      • Patidar K.R.
      • Shamseddeen H.
      • Xu C.
      • Ghabril M.S.
      • Nephew L.D.
      • Desai A.P.
      • et al.
      Hospital-acquired versus community-acquired acute kidney injury in patients with cirrhosis: a prospective study.
      • Desai A.P.
      • Knapp S.M.
      • Orman E.S.
      • Ghabril M.S.
      • Nephew L.D.
      • Anderson M.
      • et al.
      Changing epidemiology and outcomes of acute kidney injury in hospitalized patients with cirrhosis - a US population-based study.
      In this setting, AKI is associated with high in-hospital mortality
      • Huelin P.
      • Piano S.
      • Sola E.
      • Stanco M.
      • Sole C.
      • Moreira R.
      • et al.
      Validation of a staging system for acute kidney injury in patients with cirrhosis and association with acute-on-chronic liver failure.
      • Wong F.
      • O'Leary J.G.
      • Reddy K.R.
      • Garcia-Tsao G.
      • Fallon M.B.
      • Biggins S.W.
      • et al.
      Acute kidney injury in cirrhosis: baseline serum creatinine predicts patient outcomes.
      • Garcia-Tsao G.
      • Parikh C.R.
      • Viola A.
      Acute kidney injury in cirrhosis.
      • Patidar K.R.
      • Shamseddeen H.
      • Xu C.
      • Ghabril M.S.
      • Nephew L.D.
      • Desai A.P.
      • et al.
      Hospital-acquired versus community-acquired acute kidney injury in patients with cirrhosis: a prospective study.
      • Desai A.P.
      • Knapp S.M.
      • Orman E.S.
      • Ghabril M.S.
      • Nephew L.D.
      • Anderson M.
      • et al.
      Changing epidemiology and outcomes of acute kidney injury in hospitalized patients with cirrhosis - a US population-based study.
      • Wong F.
      • Reddy K.R.
      • Tandon P.
      • O'Leary J.G.
      • Garcia-Tsao G.
      • Vargas H.E.
      • et al.
      Progression of stage 2 and 3 acute kidney injury in patients with decompensated cirrhosis and ascites.
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Bhogal H.
      • Lim J.K.
      • Ansari N.
      • et al.
      Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
      which is directly linked to the severity of injury.
      • Huelin P.
      • Piano S.
      • Sola E.
      • Stanco M.
      • Sole C.
      • Moreira R.
      • et al.
      Validation of a staging system for acute kidney injury in patients with cirrhosis and association with acute-on-chronic liver failure.
      ,
      • Wong F.
      • Reddy K.R.
      • Tandon P.
      • O'Leary J.G.
      • Garcia-Tsao G.
      • Vargas H.E.
      • et al.
      Progression of stage 2 and 3 acute kidney injury in patients with decompensated cirrhosis and ascites.
      • Belcher J.M.
      • Garcia-Tsao G.
      • Sanyal A.J.
      • Bhogal H.
      • Lim J.K.
      • Ansari N.
      • et al.
      Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
      • Piano S.
      • Rosi S.
      • Maresio G.
      • Fasolato S.
      • Cavallin M.
      • Romano A.
      • et al.
      Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.
      In patients without cirrhosis, AKI predisposes to the development of chronic kidney disease (CKD),
      • Inker L.A.
      • Astor B.C.
      • Fox C.H.
      • Isakova T.
      • Lash J.P.
      • Peralta C.A.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      • Chawla L.S.
      • Kimmel P.L.
      Acute kidney injury and chronic kidney disease: an integrated clinical syndrome.
      • Ponte B.
      • Felipe C.
      • Muriel A.
      • Tenorio M.T.
      • Liano F.
      Long-term functional evolution after an acute kidney injury: a 10-year study.
      • Chawla L.S.
      • Amdur R.L.
      • Amodeo S.
      • Kimmel P.L.
      • Palant C.E.
      The severity of acute kidney injury predicts progression to chronic kidney disease.
      supporting the concept that AKI and CKD may not always be mutually exclusive events and likely represent a continuum,
      • Chawla L.S.
      • Kimmel P.L.
      Acute kidney injury and chronic kidney disease: an integrated clinical syndrome.
      ,
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      where sustained AKI may develop into de novo CKD. Recently, this association has been described in patients with cirrhosis but limited to few single center studies.
      • Patidar K.R.
      • Shamseddeen H.
      • Xu C.
      • Ghabril M.S.
      • Nephew L.D.
      • Desai A.P.
      • et al.
      Hospital-acquired versus community-acquired acute kidney injury in patients with cirrhosis: a prospective study.
      ,
      • Bassegoda O.
      • Huelin P.
      • Ariza X.
      • Sole C.
      • Juanola A.
      • Gratacos-Gines J.
      • et al.
      Development of chronic kidney disease after acute kidney injury in patients with cirrhosis is common and impairs clinical outcomes.
      ,
      • Maiwall R.
      • Pasupuleti S.S.R.
      • Bihari C.
      • Rastogi A.
      • Singh P.K.
      • Naik V.
      • et al.
      Incidence, risk factors, and outcomes of transition of acute kidney injury to chronic kidney disease in cirrhosis: a prospective cohort study.
      Acute kidney disease (AKD) is the persistence of AKI for up to 3 months (at which point it is considered CKD) and has been proposed to be the window where interventions can be initiated to prevent poor downstream outcomes of AKI such as death and de novo CKD.
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      In patients with cirrhosis, AKD, its risk factors and impact on outcomes have been scantly investigated.
      • Tonon M.
      • Rosi S.
      • Gambino C.G.
      • Piano S.
      • Calvino V.
      • Romano A.
      • et al.
      Natural history of acute kidney disease in patients with cirrhosis.
      Furthermore, in this population, there is a paucity of studies examining the risk for de novo CKD in patients who develop AKD.
      • Tonon M.
      • Rosi S.
      • Gambino C.G.
      • Piano S.
      • Calvino V.
      • Romano A.
      • et al.
      Natural history of acute kidney disease in patients with cirrhosis.
      An improved understanding of incidence and risk factors associated with de novo CKD in cirrhosis is important given the known impact of CKD on patient outcomes.
      • Bassegoda O.
      • Huelin P.
      • Ariza X.
      • Sole C.
      • Juanola A.
      • Gratacos-Gines J.
      • et al.
      Development of chronic kidney disease after acute kidney injury in patients with cirrhosis is common and impairs clinical outcomes.
      ,
      • Wong F.
      • Reddy R.K.
      • O'Leary J.G.
      • Tandon P.
      • Biggins S.W.
      • Garcia-Tsao G.
      • et al.
      Impact of chronic kidney disease on outcomes in cirrhosis.
      ,
      • Cullaro G.
      • Verna E.C.
      • Lee B.P.
      • Lai J.C.
      Chronic kidney disease in liver transplant candidates: a rising burden impacting post-liver transplant outcomes.
      Hence, better characterization of AKD and its associated outcomes are critical to improving prognostication and to targeting personalized care during and after hospital discharge. Thus, the aim of this study is to define the incidence, risk factors and outcomes associated with AKD in a nationwide US cohort of hospitalized patients with cirrhosis and AKI.

      Patients and methods

      Data source

      Consecutive patients with cirrhosis who were hospitalized between January 1, 2009, and September 1, 2017, were identified in the Cerner Health Facts Database (Cerner Corporation, Kansas City, Missouri). Cerner Health Facts is a deidentified, Health Insurance Portability and Accountability Act compliant database that includes over 700 US hospitals and health care systems. Information contributed to the database includes hospital characteristics, vital sign data, laboratory data, pharmaceutical data, and procedural codes (through ICD 9th or 10th revision diagnosis codes and current procedural terminology codes) and the degree of data contributed varies by center/health system. Cirrhosis and its etiology, liver-related complications, comorbidities, infections, history of liver or kidney transplantation, and hemodialysis (HD) status were extracted through ICD-9 and 10 codes (primary or secondary diagnosis). We used previously validated ICD-9 and 10 codes where available,
      • Desai A.P.
      • Knapp S.M.
      • Orman E.S.
      • Ghabril M.S.
      • Nephew L.D.
      • Anderson M.
      • et al.
      Changing epidemiology and outcomes of acute kidney injury in hospitalized patients with cirrhosis - a US population-based study.
      ,
      • Schmidt M.L.
      • Barritt A.S.
      • Orman E.S.
      • Hayashi P.H.
      Decreasing mortality among patients hospitalized with cirrhosis in the United States from 2002 through 2010.
      ,
      • Mapakshi S.
      • Kramer J.R.
      • Richardson P.
      • El-Serag H.B.
      • Kanwal F.
      Positive predictive value of international classification of diseases, 10th revision, codes for cirrhosis and its related complications.
      summarized in Table S1. This study was approved by the Indiana University Institutional Review Board.

      Study population

      Patients with cirrhosis over the age of 18 with AKI (see Definitions: AKI, AKD, and CKD) were included. We excluded patients admitted for surgical reasons, those with inadequate data to discern AKD (see Definitions: AKI, AKD, and CKD), those who died or were discharged to a hospice prior to determining AKD, and those who had undergone a prior liver or kidney transplant. For patients with multiple qualifying AKI-related hospitalizations during the study period, we only considered the initial hospitalization.

      Outcomes

      Patients were followed-up from the time of AKI to assess outcomes. The primary outcome was mortality at 90 and 180 days from the time of AKD. The former time range was chosen to evaluate the impact of AKD on mortality within the AKD time-window (i.e., ≥7-90 days) and the latter was chosen to evaluate the longer term impact of AKD on mortality. The secondary outcome was the diagnosis of de novo CKD based on laboratory results showing diminished estimated glomerular filtration rate (eGFR) persisting for ≥3 months from the time of AKI.
      • Inker L.A.
      • Astor B.C.
      • Fox C.H.
      • Isakova T.
      • Lash J.P.
      • Peralta C.A.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      Because not all patients had laboratory data at 3 months, we considered the first available eGFR beyond 3 months and up to 6 months to determine the presence of CKD. The median time to this secondary outcome determination was 125 days.

      Definitions: AKI, AKD, AND CKD

      AKI

      AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO),
      • Palevsky P.M.
      • Liu K.D.
      • Brophy P.D.
      • Chawla L.S.
      • Parikh C.R.
      • Thakar C.V.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury.
      which have been endorsed by the International Club of Ascites (ICA)
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      as either: (1) a rise in serum creatinine (sCr) of ≥0.3 mg/dl from baseline within 48 hours or (2) increase in sCr to 1.5x baseline, which is known or presumed to have occurred within the prior 7 days. AKI stage was defined by the AKI-KDIGO staging system
      • Palevsky P.M.
      • Liu K.D.
      • Brophy P.D.
      • Chawla L.S.
      • Parikh C.R.
      • Thakar C.V.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury.
      which has also been endorsed by the ICA .
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Patients with AKI at the time of admission were considered to have community-acquired AKI .
      • Patidar K.R.
      • Shamseddeen H.
      • Xu C.
      • Ghabril M.S.
      • Nephew L.D.
      • Desai A.P.
      • et al.
      Hospital-acquired versus community-acquired acute kidney injury in patients with cirrhosis: a prospective study.
      Patients without AKI on admission who subsequently developed AKI during the hospitalization were considered to have hospital-acquired AKI .
      • Patidar K.R.
      • Shamseddeen H.
      • Xu C.
      • Ghabril M.S.
      • Nephew L.D.
      • Desai A.P.
      • et al.
      Hospital-acquired versus community-acquired acute kidney injury in patients with cirrhosis: a prospective study.
      ,
      • Broce J.C.
      • Price L.L.
      • Liangos O.
      • Uhlig K.
      • Jaber B.L.
      Hospital-acquired acute kidney injury: an analysis of nadir-to-peak serum creatinine increments stratified by baseline estimated GFR.
      AKI recovery was defined by the return of sCr to a value within 0.3 mg/dl of the baseline sCr value within 7 days of AKI onset.
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      Recurrent AKI was determined if a patient met KDIGO AKI criteria after 48 hours of AKI recovery .
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      Baseline sCr was also defined per the ICA,
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      which was based on the availability of sCr within the previous 3 months. If more than 1 sCr value was available, the closest to admission time was used. In patients who did not have a baseline sCr within the previous 3 months, the last sCr value between month 4 and 1 year before admission was used as the baseline. If a sCr was not available within 1 year of hospitalization, the first sCr value at hospitalization was considered as baseline as recommended by the ICA.
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      The median time between baseline sCr and admission sCr was 33 days.

      AKD

      AKD was defined by the Acute Disease Quality Initiative (ADQI) AKD and renal recovery consensus statement as AKI stage 1 or greater (as defined by KDIGO) that is present ≥7-90 days after an AKI episode.
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      AKD recovery was defined as return of sCr within 0.3 mg/dl of baseline sCr within 8-90 days of AKI onset.
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      Recurrent AKI was defined by the KDIGO AKI criteria utilizing the baseline sCr that was used for the index AKI hospitalization.

      CKD

      De novo CKD was defined per KDIGO guidelines, as the persistence of eGFR <60 ml/min per 1.73 m2 for ≥3 months from the time of the AKI event in patients who did not have baseline CKD.
      • Inker L.A.
      • Astor B.C.
      • Fox C.H.
      • Isakova T.
      • Lash J.P.
      • Peralta C.A.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      The Chronic Kidney Disease Epidemiology Collaboration equation was chosen to calculate eGFR.
      • Levey A.S.
      • Stevens L.A.
      • Schmid C.H.
      • Zhang Y.L.
      • Castro 3rd, A.F.
      • Feldman H.I.
      • et al.
      A new equation to estimate glomerular filtration rate.
      Since multiple eGFR values prior to hospitalization were not available for all patients, history of baseline CKD was determined by inpatient ICD-9/10 codes (Table S1). AKD that persisted beyond 90 days was also considered as de novo CKD as recommended by the ADQI AKD and renal recovery consensus statement.
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      De novo CKD was further classified as G3a (eGFR 45-59), G3b (eGFR 30-44), G4 (eGFR 15-29), and G5 (eGFR <15).
      • Inker L.A.
      • Astor B.C.
      • Fox C.H.
      • Isakova T.
      • Lash J.P.
      • Peralta C.A.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      Patients with AKD that persisted beyond 90 days but had an eGFR >60 ml/min per 1.73 m2 were classified as either stage 1 (eGFR >90) or stage 2 (eGFR 60-90).
      • Inker L.A.
      • Astor B.C.
      • Fox C.H.
      • Isakova T.
      • Lash J.P.
      • Peralta C.A.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.

      Hospitalization details

      Demographic details (age, sex, race, body mass index), co-morbid conditions (via Charlson comorbidity index
      • Charlson M.E.
      • Pompei P.
      • Ales K.L.
      • MacKenzie C.R.
      A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
      ,
      • Glasheen W.P.
      • Cordier T.
      • Gumpina R.
      • Haugh G.
      • Davis J.
      • Renda A.
      Charlson comorbidity index: ICD-9 update and ICD-10 translation.
      excluding liver disease component), hospital type (rural, urban teaching, urban non-teaching), mean arterial blood pressure (MAP) and laboratory data (white blood cell count, sodium, albumin, sCr, total bilirubin, international normalized ratio) at the time of AKI, as well as baseline sCr and sCr at time of AKD determination, were extracted. Pharmacological data on relevant cirrhosis-related medications (diuretics, non-selective beta blockers, and midodrine) that were administered after AKI were extracted. Cirrhosis etiology (alcohol, hepatitis C, non-alcoholic steatohepatitis [NASH], and other) and data on cirrhosis-related complications (esophageal variceal hemorrhage, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis [SBP]) and non-SBP infections were obtained via inpatient ICD-9 and 10 codes (see Table S1). In addition, intensive care unit (ICU) transfer, vasopressor and mechanical ventilation use, and the initiation of HD was extracted. We considered cirrhosis severity using the model for end-stage liver disease-sodium score (MELD-Na)
      • Kim W.R.
      • Biggins S.W.
      • Kremers W.K.
      • Wiesner R.H.
      • Kamath P.S.
      • Benson J.T.
      • et al.
      Hyponatremia and mortality among patients on the liver-transplant waiting list.
      at the time of AKI.

      Statistical analysis

      Patient clinical and laboratory characteristics were compared by AKD status (no-AKD and AKD). Continuous variables were presented as median IQR and categorical variables were presented as percentages. Differences across groups with respect to continuous variables were analyzed using the Wilcoxon rank sum tests and categorical variables were analyzed using chi-square tests.

      AKD risk factor analysis

      Univariate logistic regression analysis was performed to identify variables associated with AKD. Significant variables (p <0.1) were then entered into a multivariable model to determine the independent association of each risk factor with AKD development. The final list of covariates was also determined by removing variables that caused high collinearity, as accessed by variance inflation factors. Odd ratios (ORs) and their corresponding 95% CIs were reported.

      Primary outcome analysis

      Mortality with AKD and no-AKD was compared using Fine and Gray competing risks regression, with creation of a cumulative incidence function. Liver transplantation during the follow-up period was considered as a competing risk, and patients lost to follow-up were censored. Differences between cumulative incidence functions were determined using Gray's test. Univariate competing-risk regression analyses were performed to identify factors associated with the primary outcome. Variables that were significant on univariate analysis (p <0.1) for the primary outcome were then entered into a multivariable competing-risk analysis to determine the independent association between AKD and the primary outcome. Variance inflation factors were used to remove variables with high collinearity. Subdistribution hazard ratios (sHRs) and their corresponding 95% CIs were reported.

      Secondary outcome analysis

      The association between de novo CKD and AKD was assessed using Fine and Gray competing risks regression. Death or liver transplantation during the follow-up period were considered as competing risks. Patients who did not have a documented sCr within 90-180 days or had baseline CKD were excluded. Multivariable competing-risk analyses were performed to assess the association between AKD and de novo CKD. Final covariates chosen for multivariable modeling where those that were significant on univariate analysis (p <0.1). SHRs and their 95% CIs were reported.

      Sensitivity analysis

      A sensitivity analysis was performed for the primary outcome excluding patients with hepatorenal syndrome (HRS) and on HD. For the secondary outcome, a sensitivity analysis was performed excluding patients with persistent AKD beyond 90 days but with eGFR >60 ml/min per 1.73 m2.
      A 2-sided nominal p value <0.05 was considered statistically significant. All analytic assumptions were verified, and all analyses were performed using SAS v9.4 (SAS Institute, Cary, NC).

      Results

      Six thousand two-hundred and fifty patients met inclusion criteria and were analyzed. Characteristics between patients who were excluded and included were similar (Table S2). The median age (IQR) was 61 (53, 70) years and the majority were white (69.5%) and male (61.0%). The most common etiologies of cirrhosis were NASH (39.9%) followed by alcohol (25.2%) and hepatitis C (17.8%). The median baseline sCr was 1.0 (0.70, 1.63) mg/dl and 36.4% had CKD. The median MELD-Na score at the time of AKI was 23 (17, 28) and the incidence of AKD was 31.6% (n = 2,004). At the time of AKD determination, 313 patients were on hemodialysis.

      Comparisons of patient and clinical characteristics between AKD and no-AKD

      Demographic and clinical characteristics of patients with AKD and no-AKD are compared in Table 1. Patients with AKD were more likely to have CKD at baseline compared to patients without AKD, 55.8% vs. 27.2% (p <0.001) and had significantly higher median baseline sCr, 1.19 (0.79, 2.50) vs. 0.98 (0.70, 1.43) mg/dl (p <0.001), respectively. Patients with AKD were more likely to have a higher body mass index, NASH, hypertension, ascites, and community-acquired AKI (Table 1). In addition, patients with AKD had significantly higher median sCr at the time of AKI compared to patients without AKD, 2.51 (1.63, 4.50) vs. 1.51 (1.13, 2.13) mg/dl (p <0.001), respectively. Accordingly, MELD-Na scores were also significantly higher in patients with AKD (25
      • Palevsky P.M.
      • Liu K.D.
      • Brophy P.D.
      • Chawla L.S.
      • Parikh C.R.
      • Thakar C.V.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury.
      ,
      • Mindikoglu A.L.
      • Hernaez R.
      • Liu Y.
      • Kramer J.R.
      • Taylor T.
      • Rana A.
      • et al.
      Renal trajectory patterns are associated with postdischarge mortality in patients with cirrhosis and acute kidney injury.
      vs. 22
      • Tonon M.
      • Rosi S.
      • Gambino C.G.
      • Piano S.
      • Calvino V.
      • Romano A.
      • et al.
      Natural history of acute kidney disease in patients with cirrhosis.
      ,
      • Kim W.R.
      • Biggins S.W.
      • Kremers W.K.
      • Wiesner R.H.
      • Kamath P.S.
      • Benson J.T.
      • et al.
      Hyponatremia and mortality among patients on the liver-transplant waiting list.
      in no-AKD, p <0.001), a higher percentage of whom had stage 3 AKI at the time of diagnosis (22.3% vs. 13.2% in the no-AKD group). Patients with AKD also had higher rates of peak AKI stage 3 within 7 days of AKI onset, 60.8% vs. 16.5% in the no-AKD group, respectively. Correspondingly, patients with AKD had higher rates of albumin (p <0.001) and midodrine (p <0.001) use within 7 days of AKI onset (Table 1).
      Table 1Comparison of patient and clinical characteristics between patients with and without AKD.
      No-AKD

      n = 4,246
      AKD

      n = 2,004
      p value
      Age60 (52, 69)61 (53, 70)0.017
      Race, n (%)
       White3,033 (71.4)1,311 (65.4)<0.001
       Black557 (13.1)401 (20.0)
       Other656 (15.5)292 (14.6)
      Sex, n (%) male2,560 (60.3)1,254 (62.6)0.181
      Type of hospital, n (%)
       Rural863 (20.3)481 (24.0)
       Urban, non-teaching667 (15.7)328 (16.4)0.001
       Urban, teaching2,716 (64.0)1,195 (59.6)
      Etiology of cirrhosis, n (%)
       Hepatitis C731 (17.2)382 (16.6)0.081
       Alcohol1,164 (27.4)409 (20.4)<0.001
       Non-alcoholic steatohepatitis1,605 (37.8)888 (44.3)<0.001
       Other227 (17.6)108 (18.7)0.992
      Ascites, n (%)2,524 (59.4)1,411 (70.4)<0.001
      Hepatic encephalopathy, n (%)1,099 (25.9)544 (27.1)0.304
      Esophageal variceal hemorrhage, n (%)208 (4.9)52 (2.9)<0.001
      Charlson comorbidity index (excl. liver)
      Score is without liver disease component.
      2 (1, 4)3 (2, 6)<0.001
      BMI, kg/m227 (23, 33)28 (24, 34)<0.001
      Diabetes, n (%)2,197 (51.7)1,073 (53.5)0.192
      Hypertension, n (%)2,471 (58.2)1,340 (66.9)<0.001
      Chronic kidney disease, n (%)1,154 (27.2)1,118 (55.8)<0.001
      Baseline serum creatinine, mg/dl0.98 (0.70, 1.43)1.19 (0.79, 2.50)<0.001
      MAP at time of AKI, mmHg80 (71, 92)81 (72, 94)0.008
      Laboratory at time of AKI
       WBC, 1099.2 (6.1, 13.4)8.8 (6.1, 13.3)0.302
       Sodium, mmol/L134 (127, 139)134 (128, 138)0.489
       Creatinine, mg/dl1.51 (1.13, 2.13)2.51 (1.63, 4.50)<0.001
       Albumin, g/dl2.8 (2.3, 3.4)2.6 (2.1, 3.2)<0.001
       Total bilirubin, mg/dl1.7 (0.8, 4.0)1.5 (0.7, 3.7)0.008
       INR1.4 (1.2, 1.7)1.4 (1.2, 1.8)0.290
      MELD-Na score at time of AKI22 (16, 27)25 (21, 30)<0.001
      Stage of AKI at time of diagnosis, n (%)
       13,435 (80.9)1,219 (60.8)
       2564 (5.8)339 (16.9)<0.001
       3247 (13.3)446 (22.3)
      Community-acquired AKI, n (%)1,888 (44.5)1,042 (52.0)<0.001
      SBP, n (%)162 (3.8)83 (4.1)0.581
      Non-SBP infection, n (%)1,227 (28.9)672 (33.5)<0.001
      Peak AKI stage within 7 days post AKI, n (%)
       12,787 (65.6)373 (18.6)
       2759 (17.9)413 (20.6)<0.001
       3700 (16.5)1,218 (60.8)
      Midodrine use within 7 days post AKI263 (6.2)314 (15.7)<0.001
      NSBB use within 7 days post AKI628 (14.8)344 (17.2)0.017
      Diuretic use within 7 days post AKI1,076 (25.3)574 (28.6)0.006
      Albumin use within 7 days post AKI595 (14.0)488 (24.4)<0.001
      ICU admission within 7 days post AKI, n (%)915 (21.5)467 (23.3)0.127
      ICU interventions within 7 days post AKI, n (%)
       Mechanical ventilation417 (9.8)205 (10.2)0.647
       Vasopressor use226 (5.3)147 (7.3)0.002
      Serum creatinine at time of AKD determination, mg/dl1.05 (0.80, 1.46)2.56 (1.60, 4.29)<0.001
      Continuous variables presented as median (interquartile range) and categorical variables were presented as percentages. Differences across groups with respect to continuous variables were analyzed using the Wilcoxon rank sum tests and categorical variables were analyzed using chi-square tests.
      AKD, acute kidney disease; AKI, acute kidney injury; ICU, intensive care unit; INR, international normalized ratio; MAP, mean arterial pressure; MELD-Na, model for end-stage liver disease-sodium; NSBB, non-selective beta blocker; SBP, spontaneous bacterial peritonitis; WBC, white blood cell count.
      ∗∗ Score is without liver disease component.
      There were no significant differences between the 2 groups regarding ICU admission and mechanical ventilation use within 7 days of AKI onset or at any time during the hospitalization. However, patients with AKD had higher rates of vasopressor use within 7 days of AKI onset, 7.3% AKD vs. 5.3% no-AKD (p = 0.002) and for any use during the hospitalization, 20.0% AKD vs. 15.2% no-AKD (p <0.001). Patients with AKD had a significantly longer hospital length of stay compared to patients without AKD, 11 (6, 17) days vs. 9 (5, 14) days (p <0.001), and higher in-hospital mortality at 18.5% vs. 11.4% in patients without AKD (p <0.001).

      Factors associated with AKD

      Univariate analysis for factors associated with AKD are shown in Table S3. On multivariable analysis, independent risk factors for AKD were peak AKI stage 2/3 (OR 9.37; 95% CI 7.02, 12.50; p <0.001), CKD (OR 3.14; 95% CI 2.49, 3.96; p <0.001), ascites (OR 1.60; 95% CI 1.27, 2.00; p <0.001), obesity (OR 1.48; 95% CI 1.20, 1.86; p = 0.001), community-acquired AKI (OR 1.63; 95% CI 1.25, 2.14; p <0.001), serum albumin at time of AKI (OR 1.37; 95% CI 1.07, 1.75; p = 0.013), and MAP at time of AKI (per 1 mmHg decrease, OR 1.01; 95% CI 1.00, 1.03; p <0.001) (Table 2). Etiology of cirrhosis, presence of diabetes or hypertension, and requiring vasopressors within 7 days of AKI onset were not associated with AKD (Table 2).
      Table 2Multivariable analysis for acute kidney disease risk factors.
      Risk factorOR (95% CI)p value
      Age1.00 (0.99, 1.01)0.632
      Race (white vs. non-white)0.71 (0.56, 0.88)0.002
      Sex (male vs. female)1.03 (0.83, 1.27)0.820
      Obesity (BMI >30 kg/m2)1.48 (1.20, 1.86)0.001
      Type of hospital (urban vs. rural)1.02 (0.81, 1.29)0.977
      Ascites1.60 (1.27, 2.00)<0.001
      Variceal hemorrhage0.76 (0.46, 1.23)0.261
      Hepatitis C1.02 (0.73, 1.44)0.896
      Alcohol-associated liver disease0.87 (0.63, 1.20)0.405
      Non-alcoholic steatohepatitis1.33 (0.99, 1.80)0.062
      Hypertension1.01 (0.80, 1.28)0.923
      Chronic kidney disease3.14 (2.49, 3.96)<0.001
      MAP at time of AKI (per 1 mmHg decrease)
      no collinearity was found between the 2 variables.
      1.01 (1.01, 1.02)<0.001
      MELD-Na at time of AKI (per 1 unit increase)1.01 (1.00, 1.03)0.089
      Serum albumin at time of AKI (per 1 g/dl decrease)1.35 (1.18, 1.56)<0.001
      Vasopressor use within 7 days post AKI
      no collinearity was found between the 2 variables.
      0.91 (0.64, 1.30)0.602
      NSBB use within 7 days post AKI0.89 (0.68, 1.16)0.391
      Diuretic use within 7 days post AKI1.03 (0.82, 1.30)0.775
      Midodrine use within 7 days post AKI1.40 (1.03, 1.90)0.031
      Albumin use within 7 days post AKI1.37 (1.07, 1.75)0.013
      Any infection0.89 (0.71, 1.10)0.602
      Community-acquired vs. hospital-acquired AKI1.63 (1.25, 2.14)<0.001
      Stage of AKI at diagnosis (stage 2/3 vs. 1)
      no collinearity was found between the 2 variables.
      0.92 (0.68, 1.23)0.553
      Peak AKI stage within 7 days post AKI (stage 2/3 vs. 1)
      no collinearity was found between the 2 variables.
      9.37 (7.02, 12.50)<0.001
      Significant variables (p <0.1) found on univariate analysis (Table S3) were entered into a multivariable logistic regression model to determine the independent association of each risk factor for AKD development.
      AKI, acute kidney injury; MAP, mean arterial pressure; MELD-Na, model for end-stage liver disease-sodium; NSBB, non-selective beta blocker; OR, odds ratio.
      ^ no collinearity was found between the 2 variables.
      no collinearity was found between the 2 variables.

      Comparison of outcomes between AKD and no-AKD

      The distribution of patients analyzed for outcomes can be found in Fig. S1.

      Primary outcome

      Comparisons of the cumulative incidence of mortality between AKD and no-AKD groups can be found in Fig. 1. The cumulative incidence of mortality was significantly higher in patients with AKD compared to those without AKD: 90-day 31.7% (95% CI 0.30, 0.34) vs. 20.1% (95% CI 0.19, 0.21); 180-day 36.0% (95% CI 0.34, 0.38) vs. 24.0% (95% CI 0.23, 0.26) (p <0.001). On univariate competing-risk analysis, AKD was associated with an increased risk of death at 90 (sHR 1.66; 95% CI 1.49, 1.86; p <0.001) and 180 (sHR 1.61; 95% CI 1.45, 1.49; p <0.001) days. Additional factors associated with mortality are shown in Table S4. On multivariable competing-risk analysis (Table 3), AKD was independently associated with an increased risk of mortality at 90 (sHR 1.37; 95% CI 1.14, 1.65; p = 0.001) and 180 (sHR 1.37; 95% CI 1.14, 1.64; p = 0.001) days. Sensitivity analysis showed similar results when patients with HRS (n = 340) or on HD (n = 313) were removed from the analysis. Furthermore, to analyze if patients who did not recover from AKD had a worse prognosis than patients who recovered from AKD, a subgroup analysis was performed. After adjusting for significant factors associated with mortality (Table S5), patients with AKD non-recovery had a significantly higher risk of death at 90 (sHR 1.68; 95% CI 1.19, 2.39; p = 0.003) and 180 (sHR 1.64; 95% CI 1.18, 2.28; p = 0.004) days, compared to patients who recovered from AKD.
      Figure thumbnail gr1
      Fig. 1Comparisons of cumulative incidence of mortality between AKD and no-AKD.
      Differences between cumulative incidence functions were determined using Gray's test. AKD, acute kidney disease.
      Table 3Multivariable analysis for factors associated with 90- and 180-day mortality.
      90-day180-day
      sHR (95% CI)p valuesHR (95% CI)p value
      AKD
      no collinearity was found between the 2 variables.
      1.37 (1.14, 1.66)0.0011.37 (1.14, 1.64)0.001
      Age1.02 (1.02, 1.03)<0.0011.02 (1.02, 1.03)<0.001
      Sex (male vs. female)---
      not significant on univariate analysis.
      ---
      not significant on univariate analysis.
      1.08 (0.91, 1.26)0.382
      Ascites1.43 (1.19, 1.73)<0.0011.40 (1.17, 1.67)<0.001
      Variceal hemorrhage1.14 (0.82, 1.57)0.4151.18 (0.87, 1.60)0.292
      Hepatic encephalopathy1.83 (1.54, 2.17)<0.0011.75 (1.49, 2.05)<0.001
      Diabetes1.23 (1.03, 1.47)0.0201.25 (1.06, 1.48)0.009
      Hypertension0.80 (0.67, 0.96)0.0140.83 (0.70, 0.99)0.039
      Chronic kidney disease0.96 (0.79, 1.17)0.6810.94 (0.78, 1.13)0.497
      MAP at time of AKI (per 1 mmHg decrease)1.00 (0.99, 1.00)0.1220.99 (0.99, 1.00)0.040
      MELD-Na at time of AKI (per 1 unit increase)1.05 (1.04, 1.06)<0.0011.05 (1.02, 1.06)<0.001
      Any infection1.22 (1.03, 1.45)0.0241.19 (1.01, 1.41)0.034
      Peak AKI stage (stage 2/3 vs. 1)
      no collinearity was found between the 2 variables.
      1.17 (0.96, 1.43)0.1151.17 (0.93 - 1.34)0.240
      ICU transfer during hospitalization1.09 (0.91, 1.32)0.3501.09 (0.91, 1.30)0.340
      Mechanical ventilation during hospitalization2.07 (1.68, 2.54)<0.0011.94 (1.59, 2.35)<0.001
      Vasopressor use during hospitalization1.24 (1.03, 1.50)0.0241.33 (1.11, 1.56)0.002
      Any recurrent AKI during follow-up1.33 (1.13, 1.57)0.0011.43 (1.22, 1.67)<0.001
      Univariate competing-risk regression analyses were performed to identify factors associated with the primary outcome (Table S4). Variables that were significant on univariate analysis (p <0.1) for the primary outcome were then entered into a multivariable competing-risk analysis to determine the independent association between AKD and the primary outcome. Liver transplant was considered the competing risk and patients lost to follow-up were censored from the analysis.
      AKI, acute kidney injury; ICU, intensive care unit; MAP, mean arterial pressure; MELD-Na, model for end-stage liver disease-sodium; NSBB, non-selective beta blocker; OR, odds ratio; sHR, subdistribution hazard ratio.
      ^ no collinearity was found between the 2 variables.
      not significant on univariate analysis.

      Secondary outcome

      One thousand one hundred and forty-six patients were alive with available sCr within 90-180 days (n = 911 no-AKD and n = 235 AKD). The incidence of de novo CKD was 37.5% (n = 430), with the following distribution of CKD stages: G2 6.0% (n = 26), G3a 37.7% (n = 162), G3b 29.8% (n = 128), G4 18.1% (n = 78), and G5 8.4% (n = 36). Patients with AKD had significantly higher rates of de novo CKD at 64.0% (n = 150) compared to patients without AKD at 30.7% (n = 280) (p <0.001). Accordingly, patients with AKD had significantly higher sCr at the time of CKD determination compared to patients without AKD, 1.20 (0.84, 1.7) vs. 1.00 (0.74, 1.39) (p <0.001), respectively (Fig. 2). AKD, non-white race, female sex, peak AKI stage 2/3, ascites, and recurrent AKI were associated with de novo CKD on univariate competing-risk analysis (Table S6). On multivariable competing-risk analysis, AKD was found to be independently associated with de novo CKD (sHR 2.52; 95% CI 2.01, 3.15; p <0.001) (Table 4). A sensitivity analysis excluding patients with persistent AKD and eGFR >60 showed a continued independent association with de novo CKD, albeit the sHR was mildly reduced to 2.10 (95% CI 1.65, 2.68; p <0.001).
      Figure thumbnail gr2
      Fig. 2Time-course of serum creatinine from time of AKI (Day 0), AKD (Day 7), and CKD (Day 90+30) in 1,146 patients who survived at least 3 months with available serum creatinine data.
      Values are median and interquartile range. Comparisons at each time point were made by Wilcoxon rank sum test. ∗p <0.001. AKD, acute kidney disease; AKI, acute kidney injury; CKD, chronic kidney disease.
      Table 4Multivariable competing-risk analysis for factors associated with de novo chronic kidney disease.
      sHR (95% CI)p value
      AKD2.52 (2.01, 3.15)<0.001
      Sex (male vs. female)0.72 (0.59, 0.87)0.001
      Race (white vs. non-white)0.76 (0.62, 0.93)0.007
      Ascites1.17 (0.95, 1.45)0.147
      Hepatic encephalopathy0.62 (0.48, 0.81)<0.001
      Alcohol associated liver disease0.88 (0.71, 1.10)0.276
      Diabetes0.87 (0.72, 1.10)0.157
      Any infection0.78 (0.62, 0.98)0.031
      Peak AKI stage (stage 2/3 vs. 1)0.91 (0.73, 1.12)0.343
      Mechanical ventilation use during hospitalization0.52 (0.35, 0.77)0.001
      Any recurrent AKI during follow-up2.28 (1.86, 2.79)0.001
      Univariate competing-risk regression analyses were performed to identify factors associated with the primary outcome (Table S6). Variables that were significant on univariate analysis (p <0.1) for the secondary outcome were then entered into a multivariable competing-risk analysis to determine the independent association between AKD and secondary outcome. Liver transplant/death was considered the competing risk.
      AKD, acute kidney disease; AKI, acute kidney injury; sHR, subdistribution hazard ratio.

      Discussion

      In this large nationwide US cohort of hospitalized patients with cirrhosis and AKI we sought to define the incidence of AKD, its risk factors and impact on mortality and de novo CKD. We found AKD to be common, affecting 1 in 3 patients with AKI, and occurring more frequently in patients with CKD, obesity, ascites, higher stages of AKI, community-acquired AKI, and lower serum albumin. Interestingly, we did not find the etiology of cirrhosis (e.g. NASH), nor diabetes or hypertension to be independently associated with AKD; these factors were associated with AKD on univariate analysis but not on multivariable analysis. Possibly these results could have been confounded by obesity and CKD in the model. Importantly, patients with AKD (and AKD non-recovery) are at a significantly higher risk of short- and longer term mortality compared to patients without AKD. In addition, AKD remained significantly associated with mortality after adjusting for MELD-Na and AKI stage, suggesting that the effect is independent of underlying liver disease severity and AKI severity. Therefore, our findings suggest that prompt management of AKI, especially in those at risk of AKD, impacts outcomes and patients with AKD should be followed closely after discharge. Examples of the former and latter could be considering early nephrology consultation with follow-up
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      ,
      • Wavamunno M.D.
      • Harris D.C.
      The need for early nephrology referral.
      • Mehta R.L.
      • McDonald B.
      • Gabbai F.
      • Pahl M.
      • Farkas A.
      • Pascual M.T.
      • et al.
      Nephrology consultation in acute renal failure: does timing matter?.
      • Mindikoglu A.L.
      • Hernaez R.
      • Liu Y.
      • Kramer J.R.
      • Taylor T.
      • Rana A.
      • et al.
      Renal trajectory patterns are associated with postdischarge mortality in patients with cirrhosis and acute kidney injury.
      and frequent lab monitoring/medication adjustments based on kidney function during and after hospitalization,
      • Kane-Gill S.L.
      • Bauer S.R.
      AKD-the time between AKI and CKD: what is the role of the pharmacist?.
      ,
      • Barreto E.F.
      • Schreier D.J.
      • May H.P.
      • Mara K.C.
      • Chamberlain A.M.
      • Kashani K.B.
      • et al.
      Incidence of serum creatinine monitoring and outpatient visit follow-up among acute kidney injury survivors after discharge: a population-based cohort study.
      as well as evaluation for liver transplantation in eligible patients.
      In critically ill ICU patients with cirrhosis and AKI, maintaining higher MAP early after onset of injury has been found to be associated with AKI recovery.
      • Patidar K.R.
      • Peng J.L.
      • Pike F.
      • Orman E.S.
      • Glick M.
      • Kettler C.D.
      • et al.
      Associations between mean arterial pressure and poor ICU outcomes in critically ill patients with cirrhosis: is 65 the sweet spot?.
      Increasing MAP during vasoconstrictive therapy in patients with HRS has also been associated with improvement in kidney function.
      • Velez J.C.
      • Nietert P.J.
      Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a pooled analysis of clinical trials.
      In line with these studies, we found lower MAP to be significantly associated with AKD/AKI non-recovery. Hence, increasing MAP with sufficient volume replacement or aggressively treating hypotension via early use of vasoconstrictors could prevent AKD. Similarly, we found the rates of non-selective beta blocker and diuretic use within 7 days of AKI onset to be significantly higher in patients with AKD, both of which could reduce MAP. Thus, discontinuing hypotensive medications such as non-selective beta blockers and diuretics after the onset of injury could also reduce the occurrence of AKD. It is important to note, per current guidelines, the withdrawal of vasodilators (e.g., non-selective beta blockers) and diuretics are recommended once AKI is recognized.
      • Angeli P.
      • Gines P.
      • Wong F.
      • Bernardi M.
      • Boyer T.D.
      • Gerbes A.
      • et al.
      Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
      Hence, our results also provide insights into potential targets for focused quality improvement interventions for AKI management in cirrhosis. Further studies are needed to assess whether these strategies decrease AKD occurrence.
      De novo CKD after AKI and its risk factors have been well described in patients without cirrhosis.
      • Inker L.A.
      • Astor B.C.
      • Fox C.H.
      • Isakova T.
      • Lash J.P.
      • Peralta C.A.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      • Chawla L.S.
      • Kimmel P.L.
      Acute kidney injury and chronic kidney disease: an integrated clinical syndrome.
      • Ponte B.
      • Felipe C.
      • Muriel A.
      • Tenorio M.T.
      • Liano F.
      Long-term functional evolution after an acute kidney injury: a 10-year study.
      • Chawla L.S.
      • Amdur R.L.
      • Amodeo S.
      • Kimmel P.L.
      • Palant C.E.
      The severity of acute kidney injury predicts progression to chronic kidney disease.
      CKD is independently associated with poor outcomes in patients with cirrhosis
      • Bassegoda O.
      • Huelin P.
      • Ariza X.
      • Sole C.
      • Juanola A.
      • Gratacos-Gines J.
      • et al.
      Development of chronic kidney disease after acute kidney injury in patients with cirrhosis is common and impairs clinical outcomes.
      ,
      • Wong F.
      • Reddy R.K.
      • O'Leary J.G.
      • Tandon P.
      • Biggins S.W.
      • Garcia-Tsao G.
      • et al.
      Impact of chronic kidney disease on outcomes in cirrhosis.
      ,
      • Cullaro G.
      • Verna E.C.
      • Lee B.P.
      • Lai J.C.
      Chronic kidney disease in liver transplant candidates: a rising burden impacting post-liver transplant outcomes.
      and therefore identifying risk factors for de novo CKD, particularly after an AKI event, is crucial. AKD is the transitional disease state between AKI and CKD and could be an important modifiable risk factor for de novo CKD; it may help identify high-risk patients who require closer monitoring and potential therapeutic interventions.
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      In our study, we found an incidence of de novo CKD of 37.5% after AKI, while patients with AKD had significantly higher rates of de novo CKD (64%) compared to patients without AKD (30.7%). The former findings differ from prior single center studies where the incidence of de novo CKD ranged from 15%-26% after AKI.
      • Patidar K.R.
      • Shamseddeen H.
      • Xu C.
      • Ghabril M.S.
      • Nephew L.D.
      • Desai A.P.
      • et al.
      Hospital-acquired versus community-acquired acute kidney injury in patients with cirrhosis: a prospective study.
      ,
      • Bassegoda O.
      • Huelin P.
      • Ariza X.
      • Sole C.
      • Juanola A.
      • Gratacos-Gines J.
      • et al.
      Development of chronic kidney disease after acute kidney injury in patients with cirrhosis is common and impairs clinical outcomes.
      ,
      • Maiwall R.
      • Pasupuleti S.S.R.
      • Bihari C.
      • Rastogi A.
      • Singh P.K.
      • Naik V.
      • et al.
      Incidence, risk factors, and outcomes of transition of acute kidney injury to chronic kidney disease in cirrhosis: a prospective cohort study.
      The higher rates of de novo CKD in our study could be related to the lower observed rates of mortality compared to the aforementioned studies.
      Another relevant finding to our study was that AKD was independently associated with de novo CKD, where patients with AKD have a 2-fold increased risk. Females also had a higher risk of CKD. The underlying mechanisms for the latter are unknown but could be attributed to higher rates of mortality observed in men compared to women
      • Tapper E.B.
      • Parikh N.D.
      Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study.
      ,
      • Carrero J.J.
      • Hecking M.
      • Chesnaye N.C.
      • Jager K.J.
      Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.
      and potentially due to sex-based differences in eGFR calculation .
      • Carrero J.J.
      • Hecking M.
      • Chesnaye N.C.
      • Jager K.J.
      Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.
      ,
      • Mindikoglu A.L.
      • Regev A.
      • Seliger S.L.
      • Magder L.S.
      Gender disparity in liver transplant waiting-list mortality: the importance of kidney function.
      Interestingly, the severity of AKI was not associated with de novo CKD. Severity of AKI is a well-known factor associated with de novo CKD in the general population.
      • Chawla L.S.
      • Amdur R.L.
      • Amodeo S.
      • Kimmel P.L.
      • Palant C.E.
      The severity of acute kidney injury predicts progression to chronic kidney disease.
      ,
      • Amdur R.L.
      • Chawla L.S.
      • Amodeo S.
      • Kimmel P.L.
      • Palant C.E.
      Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.
      • Lo L.J.
      • Go A.S.
      • Chertow G.M.
      • McCulloch C.E.
      • Fan D.
      • Ordonez J.D.
      • et al.
      Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.
      • He L.
      • Wei Q.
      • Liu J.
      • Yi M.
      • Liu Y.
      • Liu H.
      • et al.
      AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms.
      The reasons for the lack of an association are unclear, though it could be related to our use of strict definitions of baseline sCr, exclusion of patients with CKD at baseline, younger patient population, and accounting death as a competing risk.
      • Hsu R.K.
      • Hsu C.Y.
      The role of acute kidney injury in chronic kidney disease.
      • Grams M.E.
      • Sang Y.
      • Ballew S.H.
      • Carrero J.J.
      • Djurdjev O.
      • Heerspink H.J.L.
      • et al.
      Predicting timing of clinical outcomes in patients with chronic kidney disease and severely decreased glomerular filtration rate.
      • Boucquemont J.
      • Heinze G.
      • Jager K.J.
      • Oberbauer R.
      • Leffondre K.
      Regression methods for investigating risk factors of chronic kidney disease outcomes: the state of the art.
      • Al-Wahsh H.
      • Tangri N.
      • Quinn R.
      • Liu P.
      • Ferguson Ms T.
      • Fiocco M.
      • et al.
      Accounting for the competing risk of death to predict kidney failure in adults with stage 4 chronic kidney disease.
      It is important to note that our findings are in line with a prior study in cirrhosis that also showed no independent association between severity of AKI and de novo CKD.
      • Maiwall R.
      • Pasupuleti S.S.R.
      • Bihari C.
      • Rastogi A.
      • Singh P.K.
      • Naik V.
      • et al.
      Incidence, risk factors, and outcomes of transition of acute kidney injury to chronic kidney disease in cirrhosis: a prospective cohort study.
      This study has several limitations. First, due to the nature of the dataset, we lacked additional granular details on several of the variables, such as details required to discern AKI and CKD phenotypes. Although it could be inferred that patients without AKD are likely to have hypovolemic or pre-renal AKI, a study that incorporated point of care echocardiography found 25% of patients with cirrhosis and AKI continued to be volume deplete after resuscitation.
      • Velez J.C.Q.
      • Petkovich B.
      • Karakala N.
      • Huggins J.T.
      Point-of-Care echocardiography unveils misclassification of acute kidney injury as hepatorenal syndrome.
      Nevertheless, accurate phenotyping of AKI and CKD, particularly HRS and HRS-CKD (formally known as type 2 HRS), would have both prognostic and therapeutic implications (e.g., HRS may not be regarded as AKD since therapy can last up to 14 days
      • Angeli P.
      • Garcia-Tsao G.
      • Nadim M.K.
      • Parikh C.R.
      News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond the International Club of Ascites (ICA) consensus document.
      ). Though, it is important to note that AKD continued to be independently associated with poor outcomes on sensitivity analysis when patients with HRS (via diagnosis code and those on treatment for HRS) were removed. This suggests that regardless of AKI phenotype, patients with cirrhosis and AKD have worse prognosis. Similarly, although we used validated ICD-9/10 codes to capture hospitalized patients with cirrhosis (positive predictive value >90%), the possibility of cirrhosis misclassification may exist. Moreover, since urine protein or urine micro-albumin and kidney imaging were not available, we were unable to classify stages of AKD
      • Chawla L.S.
      • Bellomo R.
      • Bihorac A.
      • Goldstein S.L.
      • Siew E.D.
      • Bagshaw S.M.
      • et al.
      Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
      or to further phenotype CKD.
      • Inker L.A.
      • Astor B.C.
      • Fox C.H.
      • Isakova T.
      • Lash J.P.
      • Peralta C.A.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      Further multicenter prospective studies with urine collection and incorporation of biomarkers would be needed to understand the transition from AKI to AKD and CKD and its phenotypes.
      Despite the limitations in our study, there were also several strengths. Our large sample size derived from a broad sample of urban and rural hospitals across the US provides a representative real-world estimate for AKD based on guideline-based definitions, which have not been described in detail in a US-based hospitalized cirrhotic population previously. Knowledge of these estimates can help guide the design of interventional studies focused on improving AKI/AKD recovery and survival in this population. Furthermore, knowledge of risk factors and disease course for AKD is important as it may help identify high-risk patients in whom strategies for post-discharge care (e.g., early nephrology consultation, medication management via pharmacist involvement, and liver transplantation referral in patients who qualify) can be appropriately implemented. In addition, with the long follow-up period after discharge, we were able to capture both de novo CKD as well as to evaluate risk factors associated with this outcome.
      In conclusion, pre-existing CKD, severe AKI, ascites, obesity, serum albumin at time of AKI, and MAP at time of AKI are independent risk factors for AKD. AKD and non-recovery from AKD are independently associated with worse short- and longer term mortality and patients with AKD are at a higher risk of de novo CKD. Therefore, patients with AKD should be monitored closely after discharge, and preventive/therapeutic strategies are urgently needed to improve outcomes. Ultimately, further prospective studies evaluating the natural history of AKI/AKD to CKD are needed to validate our findings and to determine the importance of AKD in this population.

      Abbreviations

      ADQI, Acute Disease Quality Initiative; AKI, acute kidney injury; AKD, acute kidney disease; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HD, hemodialysis; HR, hazard ratio; HRS, hepatorenal syndrome; ICA, International Club of Ascites; ICU, intensive care unit; KDIGO, Kidney Disease Improving Global Outcomes; MAP, mean arterial pressure; MELD-Na, model for end-stage liver disease-sodium; NASH, non-alcoholic steatohepatitis; OR, odds ratio; SBP, spontaneous bacterial peritonitis; sCr, serum creatinine; sHR, subdistribution hazard ratios.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Study Concept and Design: KRP and ESO. Data Analysis: KRP, MA, JES, and ESO. Manuscript Preparation: KRP and ESO. Critical Manuscript Review: All authors.

      Data availability statement

      The data that support the findings of this study are available from Cerner Health Facts. Restrictions apply to the availability of this data, which was used under license for this study. Data is available from Dr. Ananth Grama and Mr. Mobasshir Naved with the permission of Cerner Health Facts. Data in Health Facts is extracted directly from the electronic medical records from hospitals in which Cerner has a data use agreement. Encounters may include pharmacy, clinical and microbiology laboratory, admission, and billing information from affiliated patient care locations. All admissions, medication orders and dispensing, laboratory orders and specimens are date and time stamped, providing a temporal relationship between treatment patterns and clinical information. Cerner Corporation has established Health Insurance Portability and Accountability Act-compliant operating policies to establish de-identification for Health Facts. No data is reproduced from other sources.

      Conflicts of interest

      Dr. Naga Chalasani has ongoing paid consulting activities (or had in preceding 12 months) with Abbvie, Madrigal, Foresite, Galectin, Zydus, and Boehringer-Ingelheim, Altimmune. These consulting activities are generally in the areas of non-alcoholic fatty liver disease and drug hepatotoxicity. Dr. Chalasani receives research grant support from Exact Sciences, DSM, and Galectin Therapeutics where his institution receives the funding. He has equity interest in RestUp, a healthcare staffing start-up company Remaining authors have no disclosures to report. None of the aforementioned disclosures are related to the study.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Huelin P.
        • Piano S.
        • Sola E.
        • Stanco M.
        • Sole C.
        • Moreira R.
        • et al.
        Validation of a staging system for acute kidney injury in patients with cirrhosis and association with acute-on-chronic liver failure.
        Clin Gastroenterol Hepatol. 2017; 15: 438-445 e435
        • Wong F.
        • O'Leary J.G.
        • Reddy K.R.
        • Garcia-Tsao G.
        • Fallon M.B.
        • Biggins S.W.
        • et al.
        Acute kidney injury in cirrhosis: baseline serum creatinine predicts patient outcomes.
        Am J Gastroenterol. 2017; 112: 1103-1110
        • Garcia-Tsao G.
        • Parikh C.R.
        • Viola A.
        Acute kidney injury in cirrhosis.
        Hepatology. 2008; 48: 2064-2077
        • Patidar K.R.
        • Shamseddeen H.
        • Xu C.
        • Ghabril M.S.
        • Nephew L.D.
        • Desai A.P.
        • et al.
        Hospital-acquired versus community-acquired acute kidney injury in patients with cirrhosis: a prospective study.
        Am J Gastroenterol. 2020; 115: 1505-1512
        • Desai A.P.
        • Knapp S.M.
        • Orman E.S.
        • Ghabril M.S.
        • Nephew L.D.
        • Anderson M.
        • et al.
        Changing epidemiology and outcomes of acute kidney injury in hospitalized patients with cirrhosis - a US population-based study.
        J Hepatol. 2020; 73: 1092-1099
        • Wong F.
        • Reddy K.R.
        • Tandon P.
        • O'Leary J.G.
        • Garcia-Tsao G.
        • Vargas H.E.
        • et al.
        Progression of stage 2 and 3 acute kidney injury in patients with decompensated cirrhosis and ascites.
        Clin Gastroenterol Hepatol. 2021; 19: 1661-1669 e1662
        • Belcher J.M.
        • Garcia-Tsao G.
        • Sanyal A.J.
        • Bhogal H.
        • Lim J.K.
        • Ansari N.
        • et al.
        Association of AKI with mortality and complications in hospitalized patients with cirrhosis.
        Hepatology. 2013; 57: 753-762
        • Piano S.
        • Rosi S.
        • Maresio G.
        • Fasolato S.
        • Cavallin M.
        • Romano A.
        • et al.
        Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites.
        J Hepatol. 2013; 59: 482-489
        • Inker L.A.
        • Astor B.C.
        • Fox C.H.
        • Isakova T.
        • Lash J.P.
        • Peralta C.A.
        • et al.
        KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
        Am J Kidney Dis. 2014; 63: 713-735
        • Chawla L.S.
        • Kimmel P.L.
        Acute kidney injury and chronic kidney disease: an integrated clinical syndrome.
        Kidney Int. 2012; 82: 516-524
        • Ponte B.
        • Felipe C.
        • Muriel A.
        • Tenorio M.T.
        • Liano F.
        Long-term functional evolution after an acute kidney injury: a 10-year study.
        Nephrol Dial Transpl. 2008; 23: 3859-3866
        • Chawla L.S.
        • Amdur R.L.
        • Amodeo S.
        • Kimmel P.L.
        • Palant C.E.
        The severity of acute kidney injury predicts progression to chronic kidney disease.
        Kidney Int. 2011; 79: 1361-1369
        • Chawla L.S.
        • Bellomo R.
        • Bihorac A.
        • Goldstein S.L.
        • Siew E.D.
        • Bagshaw S.M.
        • et al.
        Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup.
        Nat Rev Nephrol. 2017; 13: 241-257
        • Bassegoda O.
        • Huelin P.
        • Ariza X.
        • Sole C.
        • Juanola A.
        • Gratacos-Gines J.
        • et al.
        Development of chronic kidney disease after acute kidney injury in patients with cirrhosis is common and impairs clinical outcomes.
        J Hepatol. 2020; 72: 1132-1139
        • Maiwall R.
        • Pasupuleti S.S.R.
        • Bihari C.
        • Rastogi A.
        • Singh P.K.
        • Naik V.
        • et al.
        Incidence, risk factors, and outcomes of transition of acute kidney injury to chronic kidney disease in cirrhosis: a prospective cohort study.
        Hepatology. 2020; 71: 1009-1022
        • Tonon M.
        • Rosi S.
        • Gambino C.G.
        • Piano S.
        • Calvino V.
        • Romano A.
        • et al.
        Natural history of acute kidney disease in patients with cirrhosis.
        J Hepatol. 2021; 74: 578-583
        • Wong F.
        • Reddy R.K.
        • O'Leary J.G.
        • Tandon P.
        • Biggins S.W.
        • Garcia-Tsao G.
        • et al.
        Impact of chronic kidney disease on outcomes in cirrhosis.
        Liver Transpl. 2019;
        • Cullaro G.
        • Verna E.C.
        • Lee B.P.
        • Lai J.C.
        Chronic kidney disease in liver transplant candidates: a rising burden impacting post-liver transplant outcomes.
        Liver Transpl. 2020; 26: 498-506
        • Schmidt M.L.
        • Barritt A.S.
        • Orman E.S.
        • Hayashi P.H.
        Decreasing mortality among patients hospitalized with cirrhosis in the United States from 2002 through 2010.
        Gastroenterology. 2015; 148: 967-977 e962
        • Mapakshi S.
        • Kramer J.R.
        • Richardson P.
        • El-Serag H.B.
        • Kanwal F.
        Positive predictive value of international classification of diseases, 10th revision, codes for cirrhosis and its related complications.
        Clin Gastroenterol Hepatol. 2018; 16: 1677-1678
        • Palevsky P.M.
        • Liu K.D.
        • Brophy P.D.
        • Chawla L.S.
        • Parikh C.R.
        • Thakar C.V.
        • et al.
        KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury.
        Am J Kidney Dis. 2013; 61: 649-672
        • Angeli P.
        • Gines P.
        • Wong F.
        • Bernardi M.
        • Boyer T.D.
        • Gerbes A.
        • et al.
        Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
        Gut. 2015; 64: 531-537
        • Broce J.C.
        • Price L.L.
        • Liangos O.
        • Uhlig K.
        • Jaber B.L.
        Hospital-acquired acute kidney injury: an analysis of nadir-to-peak serum creatinine increments stratified by baseline estimated GFR.
        Clin J Am Soc Nephrol. 2011; 6: 1556-1565
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • Zhang Y.L.
        • Castro 3rd, A.F.
        • Feldman H.I.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Charlson M.E.
        • Pompei P.
        • Ales K.L.
        • MacKenzie C.R.
        A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
        J Chronic Dis. 1987; 40: 373-383
        • Glasheen W.P.
        • Cordier T.
        • Gumpina R.
        • Haugh G.
        • Davis J.
        • Renda A.
        Charlson comorbidity index: ICD-9 update and ICD-10 translation.
        Am Health Drug Benefits. 2019; 12: 188-197
        • Kim W.R.
        • Biggins S.W.
        • Kremers W.K.
        • Wiesner R.H.
        • Kamath P.S.
        • Benson J.T.
        • et al.
        Hyponatremia and mortality among patients on the liver-transplant waiting list.
        N Engl J Med. 2008; 359: 1018-1026
        • Wavamunno M.D.
        • Harris D.C.
        The need for early nephrology referral.
        Kidney Int Suppl. 2005; : S128-S132
        • Mehta R.L.
        • McDonald B.
        • Gabbai F.
        • Pahl M.
        • Farkas A.
        • Pascual M.T.
        • et al.
        Nephrology consultation in acute renal failure: does timing matter?.
        Am J Med. 2002; 113: 456-461
        • Mindikoglu A.L.
        • Hernaez R.
        • Liu Y.
        • Kramer J.R.
        • Taylor T.
        • Rana A.
        • et al.
        Renal trajectory patterns are associated with postdischarge mortality in patients with cirrhosis and acute kidney injury.
        Clin Gastroenterol Hepatol. 2020; 18: 1858-1866 e1856
        • Kane-Gill S.L.
        • Bauer S.R.
        AKD-the time between AKI and CKD: what is the role of the pharmacist?.
        Hosp Pharm. 2017; 52: 663-665
        • Barreto E.F.
        • Schreier D.J.
        • May H.P.
        • Mara K.C.
        • Chamberlain A.M.
        • Kashani K.B.
        • et al.
        Incidence of serum creatinine monitoring and outpatient visit follow-up among acute kidney injury survivors after discharge: a population-based cohort study.
        Am J Nephrol. 2021; : 1-10
        • Patidar K.R.
        • Peng J.L.
        • Pike F.
        • Orman E.S.
        • Glick M.
        • Kettler C.D.
        • et al.
        Associations between mean arterial pressure and poor ICU outcomes in critically ill patients with cirrhosis: is 65 the sweet spot?.
        Crit Care Med. 2020; 48: e753-e760
        • Velez J.C.
        • Nietert P.J.
        Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a pooled analysis of clinical trials.
        Am J Kidney Dis. 2011; 58: 928-938
        • Tapper E.B.
        • Parikh N.D.
        Mortality due to cirrhosis and liver cancer in the United States, 1999-2016: observational study.
        BMJ. 2018; 362k2817
        • Carrero J.J.
        • Hecking M.
        • Chesnaye N.C.
        • Jager K.J.
        Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.
        Nat Rev Nephrol. 2018; 14: 151-164
        • Mindikoglu A.L.
        • Regev A.
        • Seliger S.L.
        • Magder L.S.
        Gender disparity in liver transplant waiting-list mortality: the importance of kidney function.
        Liver Transpl. 2010; 16: 1147-1157
        • Amdur R.L.
        • Chawla L.S.
        • Amodeo S.
        • Kimmel P.L.
        • Palant C.E.
        Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.
        Kidney Int. 2009; 76: 1089-1097
        • Lo L.J.
        • Go A.S.
        • Chertow G.M.
        • McCulloch C.E.
        • Fan D.
        • Ordonez J.D.
        • et al.
        Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.
        Kidney Int. 2009; 76: 893-899
        • He L.
        • Wei Q.
        • Liu J.
        • Yi M.
        • Liu Y.
        • Liu H.
        • et al.
        AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms.
        Kidney Int. 2017; 92: 1071-1083
        • Hsu R.K.
        • Hsu C.Y.
        The role of acute kidney injury in chronic kidney disease.
        Semin Nephrol. 2016; 36: 283-292
        • Grams M.E.
        • Sang Y.
        • Ballew S.H.
        • Carrero J.J.
        • Djurdjev O.
        • Heerspink H.J.L.
        • et al.
        Predicting timing of clinical outcomes in patients with chronic kidney disease and severely decreased glomerular filtration rate.
        Kidney Int. 2018; 93: 1442-1451
        • Boucquemont J.
        • Heinze G.
        • Jager K.J.
        • Oberbauer R.
        • Leffondre K.
        Regression methods for investigating risk factors of chronic kidney disease outcomes: the state of the art.
        BMC Nephrol. 2014; 15: 45
        • Al-Wahsh H.
        • Tangri N.
        • Quinn R.
        • Liu P.
        • Ferguson Ms T.
        • Fiocco M.
        • et al.
        Accounting for the competing risk of death to predict kidney failure in adults with stage 4 chronic kidney disease.
        JAMA Netw Open. 2021; 4e219225
        • Velez J.C.Q.
        • Petkovich B.
        • Karakala N.
        • Huggins J.T.
        Point-of-Care echocardiography unveils misclassification of acute kidney injury as hepatorenal syndrome.
        Am J Nephrol. 2019; 50: 204-211
        • Angeli P.
        • Garcia-Tsao G.
        • Nadim M.K.
        • Parikh C.R.
        News in pathophysiology, definition and classification of hepatorenal syndrome: a step beyond the International Club of Ascites (ICA) consensus document.
        J Hepatol. 2019; 71: 811-822