Development of a Physiologically Based Pharmacokinetic Population Model for Diabetic Patients and its Application to Understand Disease-drug-drug Interactions.

INTRODUCTION: The activity changes of cytochrome P450 (CYP450) enzymes, along with the complicated medication scenarios in diabetes mellitus (DM) patients, result in the unanticipated pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interactions (DDIs). Physiologically based pharmacokinetic (PBPK) modeling has been a useful tool for assessing the influence of disease status on CYP enzymes and the resulting DDIs. This work aims to develop a novel diabetic PBPK population model to facilitate the prediction of PK and DDI in DM patients. METHODS: First, mathematical functions were constructed to describe the demographic and non-CYP physiological characteristics specific to DM, which were then incorporated into the PBPK model to quantify the net changes in CYP enzyme activities by comparing the PK of CYP probe drugs in DM versus non-DM subjects. RESULTS: The results show that the enzyme activity is reduced by 32.3% for CYP3A4/5, 39.1% for CYP2C19, and 27% for CYP2B6, while CYP2C9 activity is enhanced by 38% under DM condition. Finally, the diabetic PBPK model was developed through integrating the DM-specific CYP activities and other parameters and was further used to perform PK simulations under 12 drug combination scenarios, among which 3 combinations were predicted to result in significant PK changes in DM, which may cause DDI risks in DM patients. CONCLUSIONS: The PBPK modeling applied herein provides a quantitative tool to assess the impact of disease factors on relevant enzyme pathways and potential disease-drug-drug-interactions (DDDIs), which may be useful for dosing regimen optimization and minimizing the DDI risks associated with the treatment of DM.

Model informed drug development: HSK21542 PBPK model supporting dose decisions in specific populations.

HKS21542, a highly selective activator of peripheral kappa opioid receptor agonists, plays a critical role in antinociception and itch inhibition during clinical development. Due to its indication population and elimination characteristics, it is imperative to evaluate the potential HSK21542 systemic exposure in individuals with renal impairment, hepatic impairment, the elderly, and the geriatric population. Here, a physiologically-based pharmacokinetic (PBPK) model for HSK21542 was developed based on in vitro metabolism and transport characteristics and in vivo elimination mechanism. Meanwhile, the potential systemic exposure of HSK21542 in specific populations was evaluated. The predicted results indicated increased systemic exposure in patients with renal impairment, hepatic impairment and in the elderly. Compared to the healthy volunteers aged 20-60 years, the AUC0-24h increased by 52 %-71 % in population with moderate to severe renal impairment, by 46 %-77 % in those with mild to severe hepatic impairment, and by 45 %-85 % in the elderly population aged 65-95-years. Conversely, the pediatric population demonstrated a potential decrease in systemic exposure, ranging from 20 % to 37 % in patients aged 0-17 years due to the physiological characteristics. Combined with the predicted results and the exposure-response relationship observed for HSK21542 and its analog (CR845), dosage regimens were designed for the target population with renal and hepatic impairment, supporting the successfully conducted trials (CTR20201702 and CTR20211940). Moreover, the observed exposure of HSK21542 in the elderly closely matched the predicted results within the same age group. Additionally, based on the predicted results, potential reductions in systemic exposure in pediatric patients should be carefully considered to avoid potential treatment failure in future clinical trials.

Dose decision of HSK7653 oral immediate release tablets in specific populations clinical trials based on mechanistic physiologically-based pharmacokinetic model.

HSK7653, an oral dipeptidyl peptidase-4 inhibitor administered every 2 weeks, is a candidate for the treatment of type 2 diabetes mellitus. The major elimination pathway of HSK7653 in vivo is renal excretion, and hepatic metabolism and fecal excretion of unchanged compound contribute less to the systemic clearance of HSK7653. Considering the disposition characteristics and the potential indication population of HSK7653, evaluating the HSK7653 exposure in patients with renal impairment and geriatric populations is a prerequisite for bringing more benefits to the patients. Here, a PBPK model was developed based on in vitro experimental results, such as dissolution, permeability, and metabolism, and the in vivo renal clearance, to evaluate the effects of physiological factors and food on HSK7653 exposure in specific populations, including adult and elder individuals with renal impairment and geriatric populations. Simulation results showed that the AUC of HSK7653 increased by 46%, 82%, and 129% in adult patients with mild, moderate, and severe renal impairment, and by 56%, 78%, and 101% in patients aged 65-75, 75-85 and 85-95 years, respectively. The AUC increased in the range of 62%-83%, 98%-133%, and 153%-195% in elderly patients (65-95 years) with mild, moderate, and severe renal impairment, respectively. Moreover, two different absorption model development methods (dissolution profile method and the diffusion layer model method) predicted that food had no effect on the exposure of the same simulated population. Since the predicted AUC of HSK7653 at the 10 mg dose in various specific populations was still within the relatively flat results of the exposure-response analysis, the 10 mg dose of HSK7653 was first used to explore the exposure in the renal impairment population (CTR20221952).

Development of a PBPK model to quantitatively understand absorption and disposition mechanism and support future clinical trials for PB-201.

PB-201 is the second glucokinase activator in the world to enter the phase III clinical trials for the treatment of type 2 diabetes mellitus (T2DM). Combined with the efficacy advantages and the friendly absorption, distribution, metabolism, and excretion characteristics, the indication population of PB-201 will be broad. Because the liver is the primary organ for PB-201 elimination, and the elderly account for 20% of patients with T2DM, it is essential to estimate PB-201 exposure in specific populations to understand the pharmacokinetic characteristics and avoid hypoglycemia. Despite the limited contribution of CYP3A4 to PB-201 metabolism in vivo, the dual effects of nonspecific inhibitors/inducers on PB-201 (substrate for CYP3A4 and CYP2C9 isoenzymes) exposure under fasted and fed states also need to be evaluated to understand potential risks of combination therapy. To grasp the unknown information, the physiologically-based pharmacokinetic (PBPK) model was first developed and the influence of internal and external factors on PB-201 exposure was evaluated. Results are shown that the predictive performance of the mechanistic PBPK model meets the predefined criteria, and can accurately capture the absorption and disposition characteristics. Impaired liver function and age-induced changes in physiological factors may significantly increase the exposure under fasted state by 36%-158% and 48%-82%, respectively. The nonspecific inhibitor (fluconazole) and inducer (rifampicin) may separately increase/decrease PB-201 systemic exposure by 44% and 58% under fasted state, and by 78% and 47% under fed state. Therefore, the influence of internal and external factors on PB-201 exposure deserves attention, and the precision dose can be informed in future clinical studies based on the predicted results.

Low BMI and high waist-to-hip ratio are associated with mortality risk among hemodialysis patients: a multicenter prospective cohort study.

Background: Data are limited on the relationship between waist-to-hip ratio (WHR) and mortality risk among maintenance hemodialysis (MHD) patients. Moreover, the combined association of body mass index (BMI) and WHR with mortality remains uncertain. Therefore, we aimed to explore the individual and combined association of BMI and WHR with the all-cause and cardiovascular disease (CVD) mortality. Methods: In this multicenter prospective cohort study, we enrolled 1034 MHD patients. The primary outcome was all-cause mortality and secondary outcome was CVD mortality. Multivariable Cox proportional hazards models were used to evaluate the individual and combined association of BMI and WHR with the risk of mortality. Results: A nonlinear inverse relationship was found between BMI and risk of all-cause mortality (P for nonlinearity <.05). Being underweight (<18.5 kg/m2) was associated with higher all-cause mortality risk (HR 1.45; 95% CI 1.08-1.94) compared with normal weight (18.5-23.9 kg/m2), while being overweight (24-27.9 kg/m2; HR 0.96; 95% CI 0.70-1.31) and obese (≥28 kg/m2; HR 1.19; 95% CI 0.62-2.26) showed no significant differences. Of note, WHR was independently and positively associated with all-cause mortality (per standard deviation increase, HR 1.13; 95% CI 1.00-1.27). When analyzed jointly, patients with low BMI (<18.5 kg/m2) and high WHR (≥0.95) had the highest risk of all-cause mortality. Similar results were obtained for CVD mortality. Conclusions: In patients undergoing hemodialysis from China, low BMI and high WHR were individually and jointly associated with higher risk of mortality. Our results emphasize that BMI and WHR may jointly affect the prognosis of MHD patients.

A simple LC-MS/MS method for the simultaneous quantification of drug metabolic enzymes.

OBJECTIVE: The aim of this study is to develop a LC-MS/MS method for the quantitation of seven cytochrome P450 (CYP450) enzymes. METHODS: A high-performance liquid chromatography-tandem mass spectrometry method was developed using multiple reaction monitoring mode with positive electrospray ionization. The method was validated with selectivity, linearity, stability, accuracy and precious. In addition, the abundance of seven CYP450 enzymes in human liver microsomes and CYP3A4 in placenta were determined using the current method. RESULTS: The linear range for CYP1A2, CYP2B6 and CYP2C8 was 0.036-3.6 nM and for CYP2C9, CYP2C19, CYP2D6 and CYP3A4 was 0.090-9.0 nM. No interference was found between the blank matrix and each specific peptides. The accuracy and precious results were in accord with the requirement of analytical methods for biological samples in Chinese Pharmacopoeia. In addition, the peptides were stable under current stability conditions. The content of CYP3A4 in placenta and the seven CYP450 enzymes in human liver microsomes were accurately quantified. CONCLUSION: The developed method is sensitive and specific and can be applied to the quantification of enzymes abundance in different human derived samples like placenta and liver microsomes.

Potential drug-drug interaction of olverembatinib (HQP1351) using physiologically based pharmacokinetic models.

Olverembatinib (HQP1351) is a third-generation BCR-ABL tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) (including T315I-mutant disease), exhibits drug-drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4, CYP2C9, CYP2C19, CYP1A2, and CYP2B6. A physiologically-based pharmacokinetic (PBPK) model was constructed based on physicochemical and in vitro parameters, as well as clinical data to predict 1) potential DDIs between olverembatinib and CYP3A4 and CYP2C9 inhibitors or inducers 2), effects of olverembatinib on the exposure of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 substrates, and 3) pharmacokinetics in patients with liver function injury. The PBPK model successfully described observed plasma concentrations of olverembatinib from healthy subjects and patients with CML after a single administration, and predicted olverembatinib exposure increases when co-administered with itraconazole (strong CYP3A4 inhibitor) and decreases with rifampicin (strong CYP3A4 inducer), which were validated by observed data. The predicted results suggest that 1) strong, moderate, and mild CYP3A4 inhibitors (which have some overlap with CYP2C9 inhibitors) may increase olverembatinib exposure by approximately 2.39-, 1.80- to 2.39-, and 1.08-fold, respectively; strong, and moderate CYP3A4 inducers may decrease olverembatinib exposure by approximately 0.29-, and 0.35- to 0.56-fold, respectively 2); olverembatinib, as a "perpetrator," would have no or limited impact on CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activity 3); systemic exposure of olverembatinib in liver function injury with Child-Pugh A, B, C may increase by 1.22-, 1.79-, and 2.13-fold, respectively. These simulations inform DDI risk for olverembatinib as either a "victim" or "perpetrator".

Prediction of pyrotinib exposure based on physiologically-based pharmacokinetic model and endogenous biomarker.

Pyrotinib, a novel irreversible epidermal growth factor receptor dual tyrosine kinase inhibitor, is mainly (about 90%) eliminated through cytochrome P450 (CYP) 3A mediated metabolism in vivo. Meanwhile, genotype is a key factor affecting pyrotinib clearance and 4ß-hydroxycholesterol is an endogenous biomarker of CYP3A activity that can indirectly reflect the possible pyrotinib exposure. Thus, it is necessary to evaluate the clinical drug-drug interactions (DDI) between CYP3A perpetrators and pyrotinib, understand potential exposure in specific populations including liver impairment and geriatric populations, and explore the possible relationships among pyrotinib exposure, genotypes and endogenous biomarker. Physiologically-based pharmacokinetic (PBPK) model can be used to replace prospective DDI studies and evaluate external and internal factors that may influence system exposure. Herein, a basic PBPK model was firstly developed to evaluate the potential risk of pyrotinib coadministration with strong inhibitor and guide the clinical trial design. Subsequently, the mechanistic PBPK model was established and used to quantitatively estimate the potential DDI risk for other CYP3A modulators, understand the potential exposure of specific populations, including liver impairment and geriatric populations. Meanwhile, the possible relationships among pyrotinib exposure, genotypes and endogenous biomarker were explored. With the help of PBPK model, the DDI clinical trial of pyrotinib coadministration with strong inhibitor has been successfully completed, some DDI clinical trials may be waived based on the predicted results and clinical trials in specific populations can be reasonably designed. Moreover, the mutant genotypes of CYP3A4*18A and CYP3A5*3 were likely to have a limited influence on pyrotinib clearance, and the genotype-independent linear correlation coefficient between endogenous biomarker and system exposure was larger than 0.6. Therefore, based on the reliable predicted results and the linear correlations between pyrotinib exposure and endogenous biomarker, dosage adjustment of pyrotinib can be designed for clinical practice.

Astragaloside IV protects against ischemia/reperfusion (I/R)-induced kidney injury based on the Keap1-Nrf2/ARE signaling pathway.

Background: This study sought to investigate the protective effects of Astragaloside IV (AS-IV) on ischemia-reperfusion (I/R) renal injury based on the keap1-Nrf2/ARE signaling pathway. Methods: A total of 36 male Sprague-Dawley rats (aged: 8 weeks; weighing: 200-220 g) were randomly divided into the following 6 groups (n=6 per group): (I) the control group; (II) the sham operation group; (III) the kidney I/R injury group (the I/R group); (IV) the kidney I/R injury group treated with 2 mg/kg of AS-IV (the low-dose group); (V) the kidney I/R injury group treated with 5 mg/kg of AS-IV (the mid-dose group); and (VI) the kidney I/R injury group treated with 10 mg/kg of AS-IV (the high-dose group). Serum creatinine (CRE), serum urea, malondialdehyde (MDA), and superoxide dismutase (SOD) were examined using enzyme-linked immunoassay kits. Cell apoptosis and the pathological damage to the renal tissue were determined by terminal deoxynucleotidyl transferase dUTP nick end labeling, hematoxylin and eosin, and periodic acid-Schiff (PAS) staining. The immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), and western blot methods were used to determine the expression of Nrf2, HO-1, Bcl-2 and Bax in the kidney tissue. Results: In the I/R rat model, the serum CRE level was increased. In the acute kidney injury (AKI) and chronic kidney disease (CKD) models, AS-IV treatment significantly decreased serum CRE levels in a dose-dependent manner. AS-IV treatment also reduced the injury of renal tubular epithelial cells, increased the expression levels of Nrf2 and HO-1, decreased the rate of apoptosis, downregulated the level of MDA, and elevated the activity of SOD. In the CKD rat model, the AS-IV treatment groups had reduced renal tubular epithelial cell injury, increased expression levels of Nrf2 and HO-1, decreased MDA levels, and increased SOD activity compared to the I/R group. Conclusions: AS-IV induced the expression of Nrf2, enhanced the activity of antioxidant enzymes, reduced apoptosis, protected against renal I/R injury, and prevented AKI from transforming into CKD. These findings suggest that AS-IV is a promising drug for treating kidney injury.

Clinical Study on Anesthesia with Remifentanil and Propofol in Patients with High Hemodynamics.

Objective: To study the effect of remifentanil and propofol as an anesthesia regimen in patients with high hemodynamics. Methods: From January 2019 to October 2020, 200 patients with high hemodynamics undergoing surgery at the First Affiliated Hospital of Nanchang University in China were selected as study participants, including 100 patients anesthetized with remifentanil and propofol (research group), and 100 patients anesthetized with fentanyl and propofol (control group). Vital signs, hemodynamic changes and recovery time after anesthesia were compared in the 2 groups and any adverse events while under anesthesia were recorded. Results: Both groups had significant fluctuations in vital signs and hemodynamics during anesthesia (P > .05), but the research group showed smaller changes with more stable vital signs and hemodynamics (P < .05). In addition, postoperative recovery time from anesthesia was shorter and the incidence of adverse events was lower in the research group than in the control group (P < .05). Conclusion: Remifentanil-propofol anesthesia is simple, convenient, safe and reliable in patients with high hemodynamics, and can integrate narcotic drugs with blood pressure control.

The Effects of Oral Energy-Dense Supplements on Nutritional Status in Nondiabetic Maintenance Hemodialysis Patients: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Fat-based energy-dense nutritional supplements may offer benefits over protein- or carbohydrate-dense supplements for patients receiving dialysis because of the adverse metabolic consequences of the latter. We conducted a randomized controlled trial to assess the effects of the short-term use of a fat-based nutritional supplement on various measures of nutritional status in patients receiving maintenance hemodialysis who have low dietary energy intake. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We enrolled nondiabetic patients receiving hemodialysis for >3 months who had inadequate dietary energy intake (<30 kcal/kg per day). The participants were randomly assigned in a 1:1 ratio to receive an oral fat-based energy-dense supplement (300 kcal daily) or routine care for 12 weeks (n=120 per group). The primary outcome was the change in phase angle measured by bioelectrical impedance analysis, a marker of cell integrity and body cell mass, from the baseline to week 12. The secondary outcomes were changes in quality of life. Other outcomes included laboratory nutritional indicators and physical examinations. RESULTS: The average age of the total population was 47 (SD: 12) years, and 55% were men. The median of dialysis vintage was 43.4 (22.5-76.3) months; 240 participants were randomly assigned to the intervention (n=120) or control group (n=120). In total, 228 (95%) participants completed the trial. The change in phase angle did not differ significantly between the intervention and control groups (estimate, 0.0; 95% confidence interval, -0.1 to 0.1 versus estimate, 0.0; 95% confidence interval, -0.1 to 0.1; estimated difference, 0.0; 95% confidence interval -0.2 to 0.2; P=0.99). None of the 19 domains of quality of life differed between the groups. Adverse events were reported in 23 (19%) participants in the control group and 40 (33%) participants in the intervention group. CONCLUSIONS: In nondiabetic patients on maintenance hemodialysis, short-term administration of fat-based energy-dense nutritional supplement has no clinically significant effect on nutritional status as measured by phase angle. PODCAST: This article contains a podcast at https://https://www.asn-online.org/media/podcast/CJASN/2021_08_03_CJN16821020.mp3.

Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways.

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (Cmax), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children.

Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients.

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.

The association between dietary energy intake and the risk of mortality in maintenance haemodialysis patients: a multi-centre prospective cohort study.

Maintenance haemodialysis (MHD) is the use of a machine to filter wastes, salts and fluid from blood for at least 3 months to prolong the life of patients with advanced kidney failure. Although low dietary energy intake (DEI) has been observed in MHD patients, few studies have related DEI to the risk of mortality. To explore this relationship, a study included 1039 MHD patients from eight centres was conducted. DEI was assessed by three 24-h diet recalls and was normalised to ideal body weight (IBW). All-cause mortality and CVD mortality were the primary and secondary outcomes, respectively. During a median follow-up of 28 months, a U-shaped relationship was observed between DEI and all-cause or CVD mortality. The risk of all-cause mortality decreased significantly with the increase of DEI in participants with DEI <167·4 kJ/kg IBW per d (hazard ratio (HR) 0·98; 95 % CI 0·96, 1·00) and increased significantly with the increase of DEI in those with DEI ≥167·4 kJ/kg IBW per d (HR 1·12; 95 % CI 1·04, 1·20). Similarly, the risk of CVD mortality decreased with the increase of DEI in participants with DEI <152·7 kJ/kg IBW per d (HR 0·96; 95 % CI 0·93, 0·99) and increased with the increase of DEI in participants with DEI ≥152·7 kJ/kg IBW per d (HR 1·11; 95 % CI 1·04, 1·18). In summary, there was a U-shaped association between DEI and all-cause or CVD mortality, with a turning point at about 167·4 and 152·7 kJ/kg IBW per d, respectively, in MHD patients.

Comparison of three nutritional screening tools for predicting mortality in maintenance hemodialysis patients.

OBJECTIVES: The aim of this study was to compare the effect of different nutritional screening tools on predicting the risk for mortality in patients on maintenance hemodialysis (MHD). METHODS: A cohort of 1025 patients on MHD were enrolled from eight hospitals. The malnutrition-inflammation score (MIS), objective score of nutrition on dialysis (OSND), and geriatric nutritional risk index (GNRI) were measured at baseline. All-cause mortality and cardiovascular (CV) mortality were the major study outcomes. RESULTS: The median follow-up duration was 28.1 mo. The MIS (per SD increase, hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.18-1.55), the OSND (per SD decrease, HR, 1.24; 95% CI, 1.09-1.42), and the GNRI (per SD decrease, HR, 1.26; 95% CI, 1.10-1.43) were significantly associated with the risk for all-cause mortality. More importantly, the mortality predictability of the MIS appears similar to the GNRI (P = 0.182) and greater than the OSND (MIS versus OSND: P = 0.001; GNRI versus OSND: P = 0.045). Similar results were found for CV mortality. CONCLUSIONS: Each of the three nutritional screening tools was significantly associated with an increased risk for all-cause and CV mortality. The mortality predictability of the MIS was similar to the GNRI and greater than the OSND.