Clinical characteristics of enrolled patients with cirrhosis

Of 808 screened patients, 567 met the eligibility criteria and were included in the analysis (Supplementary Fig. 1). The baseline characteristics of the included patients are shown in Table 1. The median age of the 567 patients was 67 years, 50% were male, and the median BMI was 23.1 kg/m2. Ascites was present in 34% of the patients, with a median serum creatinine of 0.71 mg/dL. The predominant etiology of cirrhosis was viral hepatitis (40%), followed by alcohol-associated/related liver disease (ALD) (22%), metabolic dysfunction-associated steatohepatitis (MASH) (10%), and other causes (27%). The median Child–Pugh and MELD scores were 6 and 8, respectively. Assessment of amino acid concentrations showed a median BCAA level of 379 μmol/L, tyrosine level of 90 μmol/L, and BTR of 4.31. Regarding medications which can cause AKI, none of them took adefovir, 1% took tenofovir, and 3% received cisplatin due to HCC development.

Table 1 Baseline characteristics of patients with cirrhosis according to AKIComparison of patients with and without AKI development

As shown in Table 1, patients who developed AKI were more likely to be male, and the etiology of cirrhosis was significantly different from that of patients without AKI. In addition, patients who developed AKI had worse liver functional reserves in terms of ascites, Child–Pugh score, MELD score, international normalized ratio, platelet count, and albumin, bilirubin, sodium, ammonia, and zinc levels than those without AKI. Furthermore, patients who developed AKI had lower BMI and higher serum creatinine levels than those without AKI. Patients who developed AKI had a significantly lower BTR (3.14 vs. 4.70; p < 0.001), detailed by lower BCAA levels (322 vs. 393 μmol/L; p < 0.001) and higher tyrosine levels (100 vs. 88 μmol/L; p < 0.001) than those without AKI.

Incidence of AKI and other events in patients with cirrhosis

During a median follow-up period of 4.7 years (interquartile range, 1.1–5.5), 27% (n = 152) of patients with cirrhosis developed AKI. Of these, 66% (n = 101) were in stage 1, 19% (n = 29) were in stage 2, and 14% (n = 22) were in stage 3. The overall incidence rates of AKI at 1, 3, and 5 years were 14%, 23%, and 29%, respectively.

Regarding other events, OHE was developed in 16% (n = 91) and 73% (n = 66) were in grade 2, 20% (n = 18) were in stage 3, 4% (n = 4) were in grade 4, and 3% (n = 3) were in stage 5. The overall incidence rates of OHE at 1, 3, and 5 years were 7%, 12%, and 16%, respectively. HCC was detected in 13% (n = 73) and the overall incidence rates of at 1, 3, and 5 years were 3%, 10%, and 12%, respectively. Among the development of AKI, OHE, and HCC, 2% (n = 13) experienced all three events, 11% (n = 64) experienced two events, and 26% (n = 149) experienced one event.

Association between AKI development and mortality

During the follow-up period, 25% (n = 139) of the patients died of liver failure (n = 96; 69%), hepatocellular carcinoma (n = 17; 12%), and other causes (n = 26; 19%). The 1-, 3-, and 5-year overall survival rates were 90%, 80%, and 74%, respectively. The adjusted HRs for the factors associated with mortality, considering AKI and OHE as time-dependent covariates, are presented in Table 2. When analyzed using time-dependent covariates, AKI development (HR 6.25; 95% CI 3.98–9.80; p < 0.001) was significantly associated with mortality independent of the etiology of cirrhosis, Child–Pugh score, OHE development, and HCC development. Details of the multivariate analyses are shown in Supplementary Table 1.

Table 2 Adjusted HRs for factors related to mortality, including time-dependent covariates, in patients with cirrhosis

Cox proportional hazards regression also showed that patients who developed AKI stage 1 (HR 3.94; 95% CI 2.67–5.18; p < 0.001), stage 2 (HR 5.83; 95% CI 3.41–9.96; p < 0.001), and stage 3 (HR 9.39; 95% CI 5.55–15.90; p < 0.001) had significantly higher mortality than those without AKI development. The survival curve showed that patients who developed advanced AKI had significantly worse survival rates than those in earlier stages (Fig. 1, p < 0.001).

Fig. 1

Overall survival of patients with cirrhosis by stage of acute kidney injury

Factors associated with AKI development

Table 3 shows the adjusted SHRs for factors associated with AKI development. Multivariate Model 1 showed that ALD (SHR 2.12; 95% CI, 1.16–3.87; p = 0.014), MASH (SHR 2.72; 95% CI 1.22–6.06; p = 0.014), Child–Pugh score (SHR 1.24; 95% CI 1.03–1.49; p = 0.020), and BTR (SHR 0.78; 95% CI 0.63–0.96; p = 0.022) were independently associated with AKI development in patients with cirrhosis. In Model 2, BCAA (SHR 1.00; 95% CI 0.99–1.00; p = 0.031) and tyrosine (SHR 1.01; 95% CI 1.00–1.01; p = 0.045) were similarly associated with AKI development. Details of the multivariate analyses are shown in Supplementary Table 2. In addition, factors associated with amino acid imbalance (BTR ≤ 4.4) are shown in Supplementary Table 4.

Table 3 Adjusted SHRs for factors associated with AKI development in patients with cirrhosis

The cumulative incidences of AKI at 1, 3, and 5 years were 11%, 19%, and 23%, respectively, for viral hepatitis; 24%, 36%, and 43%, respectively, for ALD; 2%, 9%, and 27%, respectively, for MASH; and 15%, 23%, and 27%, respectively, for other causes (p < 0.001; Fig. 2a). Furthermore, the cumulative incidence of AKI at 1, 3, and 5 years was 5%, 9%, and 16% for Child–Pugh class A; 22%, 41%, and 45% for class B; and 40%, 52%, and 57% for class C, respectively (p < 0.001; Fig. 2b). Regarding amino acid imbalance, the cumulative incidence of AKI was significantly higher in patients with BTR ≤ 4.4 than in those with BTR > 4.4 (21%, 34%, and 42% vs. 7%, 10%, and 15% at 1, 3, and 5 years, respectively; p < 0.001; Fig. 3a), in patients with BCAA < 344 μmol/L than in those with BCAA ≥ 344 μmol/L (24%, 38%, and 47% vs. 9%, 15%, and 20% at 1, 3, and 5 years, respectively; p < 0.001; Fig. 3b), and in patients with tyrosine ≥ 98 μmol/L than in those with tyrosine < 98 μmol/L (18%, 30%, and 39% vs. 12%, 18%, and 23% at 1, 3, and 5 years, respectively; p < 0.001; Fig. 3c).

Fig. 2

Cumulative incidence of AKI in patients with cirrhosis according to a etiology of cirrhosis and b Child–Pugh class. AKI acute kidney injury, ALD alcohol-associated/related liver disease, MASH metabolic dysfunction-associated steatohepatitis

Fig. 3

Cumulative incidence of AKI in patients with cirrhosis according to a BTR ≤ 4.4 and > 4.4, b BCAA < 344 μmol/L and ≥ 344 μmol/L, and c tyrosine > 98 μmol/L and ≤ 98 μmol/L. AKI acute kidney injury, BCAA branched-chain amino acid, BTR branched-chain amino acid-to-tyrosine ratio

Association between of medications for cirrhosis and AKI development

Multivariate model to assess the relationship between medications for cirrhosis and AKI development is shown in Supplementary Table 3. The results revealed that diuretics (SHR 2.35; 95% CI 1.25–4.40; p = 0.008) and nonabsorbable disaccharides (SHR 0.41; 95% CI 0.17–0.97; p = 0.042) were associated with AKI development, while BCAA supplementation and rifaximin were not statistically significant.