Predictive Value Of Urinary Aquaporin 2 For Acute Kidney Injury in Patients With Acute Decompensated Heart Failure Ⅱ
May 08, 2024
3. Results
3.1. Patient Characteristics
Overall, 189 adult patients (129 male and 60 female) were investigated. AKI was diagnosed in 69 (36.5%) patients. Compared with patients in the non-AKI group, those in the AKI group had the following characteristics: they were older, were less likely to have LVEF and more likely to have chronic kidney disease (CKD) or hypertension, and had higher baseline serum creatinine, lower hemoglobin, and higher potassium levels (p < 0.05). Regarding the biomarkers of interest, the median serum BNP levels were 1210 pg/mL and 479 pg/mL, and the median UAQP2 levels were 61.5 ng/mL and 30.9 ng/mL, respectively, in the AKI and non-AKI groups (p < 0.001). To compensate for variation in urine dilution, urine UAQP2 values were adjusted according to UCr. The median UAQP2/Cr levels in the AKI and non-AKI groups were 1.09 fmol/mg and 0.35 fmol/mg, respectively (p < 0.001; Table 1). In addition, levels of both serum BNP and UAQP2 increased with AKI severity (Figure 1).
HOW LONG DOES IT TAKE FOR CISTANCHE TO WORK FOR KIDNEY DISEASE PATIENTS?
Table 1. Baseline characteristics of patients admitted due to heart failure with or without AKI.
AKI, acute kidney injury; BNP, brain natriuretic peptide; Hb, hemoglobin; LVEF, left ventricular ejection fraction; MAP, mean arterial pressure; UAQP2, urinary excretion of aquaporin 2; UCr, urine creatinine; WBC, white blood cell count. Continuous data are presented as mean ± standard deviation or median (25th, 75th percentile).
Figure 1. Levels of serum BNP (a) and urine AQP2 (b) across KDIGO stages. Abbreviations: AQP2, aquaporin 2; BNP, brain natriuretic peptide; KDIGO, Kidney Disease: Improving Global Outcomes. Abbreviations: BNP, brain natriuretic peptide; UAQP2, urinary excretion of aquaporin 2; UCr, urine creatinine. Figure 1. Levels of serum BNP (a) and urine AQP2 (b) across KDIGO stages. Abbreviations: AQP2, aquaporin 2; BNP, brain natriuretic peptide; KDIGO, Kidney Disease: Improving Global Outcomes. Abbreviations: BNP, brain natriuretic peptide; UAQP2, urinary excretion of aquaporin 2; UCr, urine creatinine.
Approximately half the AKI patients had stage 2 or 3 AKI (Table 2). Eventually, seven (11.1%) of the AKI patients underwent hemodialysis. A total of 24 patients had the composite outcome of AKI and in-hospital mortality. Patients in the AKI group had a significantly longer hospital stay. The patients also tended to have higher in-hospital mortality, higher readmission within 180 days, and higher readmission within 365 days than their non-AKI counterparts, although the difference was nonsignificant (Table 2).
Table 2. In-hospital outcome and readmission rate of patients admitted due to heart failure with or without AKI.
3.2. Association of Serum BNP, UAQP2, and the Risk of AKI
When known risks of AKI were not adjusted for, higher serum BNP, UAQP2, and normalized UAQP2 were significantly associated with an increased risk of AKI (Model 1 of Table 3). These biomarkers remained significantly associated with the risk of AKI despite further adjustments for all covariates (Model 5 of Table 3). By contrast, the association between these three biomarkers and the risk of the composite outcome (AKI stage 3 and in-hospital mortality) was not significant with adjustment for covariates.
Table 3. Association of BNP, UAQP2, and UAQP2/Cr with the risk of AKI and the composite of AKI stage 3 and in-hospital mortality
Table 4. Discriminating between AKI and the composite of AKI stage 3 and in-hospital mortality: receiver operating characteristic curve analysis of the biomarkers of heart failure and renal dysfunction.
3.4. 180-Day Survival Rates of High- and Low-Biomarker Subgroups
The optimal cutoffs of UAQP2 and normalized UAQP2 were >35.3 ng/mL and >0.83 fmol/mg, respectively (Table 4). However, whether UAQP2 was normalized or not, no significant difference in the 180-day survival rates of the high versus low subgroups was observed (Figure 3).
Figure 3. Cumulative mortality rates during 180-day follow-up of patients, with stratification of the optimal cutoff of UAQP2 (a) and UAQP2/UCr (b). Abbreviations: UAQP2, urinary excretion of aquaporin 2; UCr, urine creatinine.
4. Discussion
To our knowledge, this is the first study to evaluate UAQP2 levels in AKI among CCU patients with ADHF. Regardless of whether they were normalized by UCr, UAQP2 levels were significantly higher in those with AKI than in those without. In addition, UAQP2 levels increased with the AKI stage. Even after age, sex, diabetes mellitus, hypertension, mean arterial pressure, LVEF, and baseline creatinine were adjusted, the UAQP2 level was associated with the risk of AKI. UAQP2 also demonstrated fair discriminating AKI and the composite outcome of stage 3 AKI and in-hospital mortality. Our findings support the diagnostic potential of UAQP2 in AKI for individuals with ADHF.
Neurohormonal activation plays a key role in cardiorenal syndrome. As heart failure becomes more severe, blood pressure lowers and renal perfusion worsens, causing baroreceptor and renin-angiotensin-aldosterone system activation, respectively [34]. Neuhormonal activation further worsens already impaired cardiac function, which in turn leads to further deterioration of target organ function, forming a vicious cycle [35]. Among the complex neurohormonal activation pathways, AVP plays an important role in heart failure [36]. In patients with heart failure, decreases in effective circulatory blood volume paradoxically cause an increase [37,38]. In the kidney, AVP binds to the V2 receptor, leading to increased production of cyclic adenosine monophosphate, further causing AQP2 phosphorylation via protein kinase A and transporting AQP2 to the apical membrane of principal cells [39,40]. AVP-mediated water retention and dilutional hyponatremia are prevalent in patients with heart failure and after cardiac surgery [41,42]. Notably, the UAQP2 level is closely associated with the AQP2 in the kidney [23,24]. Our findings are consistent with current theories regarding the pathophysiological role of AVP in cardiorenal syndrome and support the diagnostic value of UAQP2 for detecting AKI in patients with ADHF.
AKI is common in individuals with ADHF, and a traditional diagnosis of AKI through the creatinine method is limited by its 24–72 h delay from onset to elevation [13]. Previous studies have also supported the use of biomarkers to improve the diagnosis and prognosis of AKI in the critically ill population [43,44]. Clinicians can deploy nephroprotective measures to improve patient outcomes if AKI is recognized early [6]. Although some experts have expressed doubt regarding the use of biomarkers for detecting AKI in ADHF patients due to their inconsistency, the current finding of UAQP2 elevation in AKI among patients with heart failure is promising because of its potential therapeutic role. Currently, V2 receptor antagonists such as tolvaptan are commercially available and are used for patients with conditions ranging from heart failure refractory to conventional diuretics [45]. A recent study by Imamura et al. proposed using UAQP2 for the prediction of the responsiveness to tolvaptan in patients with decompensated heart failure [46]. In a relatively preserved collecting duct, plasma AVP stimulates AQP2 phosphorylation and transport to the apical membrane of principal cells, and UAQP2 can be used as a functional biomarker for the collecting duct [46]. By contrast, UAQP2 is almost undetectable in patients unresponsive to tolvaptan therapy, such as patients with advanced CKD or diabetic nephropathy, possibly due to collecting duct function deterioration [46–49]. Moreover, a recent study also proposed changes in UAQP2 that could be used to predict the tolvaptan response in patients with autosomal dominant polycystic kidney disease [50]. Our finding of increased UAQP2 levels in AKI patients with ADHF may help with identifying a feasible candidate for patients responsive to tolvaptan therapy. In addition, the safety profile of tolvaptan was favorable, and patients experienced only minor side effects, such as thirst and a dry mouth [51]. Further investigation is required to assess the use of UAQP2-guided tolvaptan therapy in ADHF patients with AKI.
The UAQP2 elevation in ADHF-induced AKI may not be universal in all AKI scenarios. Decreases in exosomal UAQP2 levels have been measured in several animal models of AKI, including I/R, lipopolysaccharide (LPS)-induced, cisplatin-induced, and gentamicin-induced kidney injury [30–32,39,52]. Asvapromtada et al. reported significantly decreased levels of exosome UAQP2 during severe AKI induced by I/R. Apical trafficking of AQP2 in the principal cell also diminishes in I/R-induced kidney injury. In addition, in unilateral I/R AKI rats, decreased urine osmolality and increased urine volume were reported, suggesting a severe urinary concentration defect [30]. Additionally, in LPS-induced AKI, expression of AQP2 is also decreased despite a marked increase in serum AVP levels [53]. One explanation for such a difference in UAQP2 levels may be the varying pathophysiology of AKI; AKI is a syndrome with heterogeneous etiologies, and different AKI models have varying mechanisms of renal injury. For example, AVP plays an essential role in the pathophysiology of ADHF-related AKI but much less so in other types of AKI. In unilateral I/R AKI, an endothelin-1 increase may inhibit AVP-induced water permeability via endothelin type B receptors [30,54]. Accelerated degradation of AQP2 protein was proposed for LPS-induced AKI [53]. Another possible explanation may be the different timing of the measurement of UAQP2 relative to the onset event. We measured UAQP2 when patients were admitted to the CCU, whereas decreased UAQP2 levels may be observed on day 7 in a bilateral I/R rat model. Sequential measurement of UAQP2 in patients with ADHF may provide more insight. Unlike previous studies, which measured exosomal UAQP2, we analyzed the total UAQP2 in this study. AQP2 exists in both a soluble form and membrane-bound form in the urine, and UAQP2 is predominantly localized in the low-density exosome [55]. UAQP2 in the exosome is thus proportional to UAQP2 levels as a whole [20,55]. Similar to soluble UAQP2, the exosomal UAQP2 level is correlated with the renal AQP2 level [56]. ELISA was used in our study to quantify UAQP2, which measures both exosomal and soluble forms of UAQP2 with good performance [57]. Although exosomal UAQP2 measurement may be a good candidate, the optimal method for isolating exosomes is still debated [58]. Further study is required.
Our study has several limitations. First, we measured UAQP2 only once to predict AKI in ADHF patients. Sequential measurement of biomarkers may better reflect kidney injury and improve predictive power. In addition, plasma AVP levels were unavailable in our study. Second, both the roles and the expression of UAQP2 in AKI with ADHF require additional investigation. The mechanism of urinary secretion of AQP2 is still poorly understood. Further animal modeling may help to extrapolate the exact mechanism and applications of UAQP2 in ADHF with AKI. Third, urinary exosomes were not evaluated in our study due to technical limitations. Finally, additional prospective trials are warranted to explore the use of UAQP2 for AKI, given the small sample size and observational design of our study.
5. Conclusions
In summary, UAQP2 demonstrates acceptable discriminative power for early detection of AKI in patients with ADHF, as well as serum BNP. In addition, the combination of the two markers may serve as a novel, noninvasive biomarker to differentiate AKI. The combination had the highest AUROC; thus, it has the potential for early identification of AKI. Further study is required to evaluate the relation between UAQP2 levels and tolvaptan responsiveness in AKI for patients with ADHF.
Author Contributions: Conceptualization, C.-H.C. and Y.-C.C.; methodology, C.-H.C. and Y.-C.C.; software, M.-J.C.; validation, G.K. and C.-C.L.; formal analysis, M.-J.C., G.K. and C.-C.L.; investigation, P.-C.F. and C.-H.C.; resources, M.-J.C., C.-H.C. and Y.-C.C.; data curation, M.-J.C.; writing-original draft preparation, M.-J.C.; writing-review and editing, M.-J.C. and C.-H.C.; visualization, C.-H.C.; supervision, C.-H.C.; project administration, C.-H.C.; funding acquisition, C.-H.C. and M.-J.C. All authors have read and agreed to the published version of the manuscript.
Funding: This study was supported by grants from the Ministry of Science and Technology and the Chang Gung Memorial Hospital Research Program (NSC 103-2314-B-182A-040, 103-2314-B-182A-018- MY3, CORPG3J0591 and CORPG5H0081).
Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Chang Gung Memorial Hospital. (no. 201401993B0, approved on 6 February 2017).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy/ethical restrictions.
Acknowledgments: The authors thank Alfred Hsing-Fen Lin and Ben Yu-Lin Chou for their assistance in statistical analysis.
Conflicts of Interest: The authors declare no conflict of interest.
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