Renal Function Group Research Articles

Effect of Renal Impairment on the Pharmacokinetics of a Single Oral Dose of Danuglipron in Participants With Type 2 Diabetes.

Danuglipron (PF-06882961) is an oral, small-molecule glucagon-like peptide-1 receptor agonist in development for the treatment of type 2 diabetes (T2D) and obesity. Impaired renal function is prevalent in patients with T2D. This Phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of danuglipron (20 mg) in healthy participants with normal renal function (estimated glomerular filtration rate [eGFR] unnormalized for body surface area: ≥90 mL/min), in participants with T2D and normal renal function (eGFR ≥90 mL/min), and in participants with T2D and mild (eGFR 60-89 mL/min), moderate (eGFR 30-59 mL/min), or severe (eGFR <30 mL/min) renal impairment (N = 39). Log-linear regression analyses and analyses of variance showed no evidence of a clinically significant effect of reduced renal function on danuglipron pharmacokinetics. Renal clearance of unchanged danuglipron was minimal (<1% across all renal function groups). Danuglipron pharmacokinetics were similar between healthy participants and participants with T2D and normal renal function. A single 20-mg oral dose of danuglipron was generally safe and well tolerated in all participant groups. In participants with T2D, renal impairment had no clinically meaningful effect on the pharmacokinetic, safety, and tolerability profiles of danuglipron, indicating that dose adjustment of danuglipron will not be required when administered to patients with T2D and reduced renal function.

Renal Function Parameters in Distinctive Molecular Subtypes of Prostate Cancer.

Prostate cancer is a prevalent malignancy in male patients, having diverse clinical outcomes. The follow-up of patients diagnosed with prostate cancer involves the evaluation of renal function, because its impairment reduces patient survival rates and adds complexity to their treatment and clinical care. This study aimed to investigate the relationship between renal function parameters and distinctive molecular subtypes of prostate adenocarcinomas, defined by the immunoexpression of the SPINK1, ERG, HOXB13, and TFF3 markers. The study group comprised 72 patients with prostate cancer and associated chronic kidney disease (CKD) who underwent radical prostatectomy. Histopathological, molecular, and renal parameters were analyzed. Patients were categorized based on ERG/SPINK1 and HOXB13/TFF3 status, and correlations with renal function and prognostic grade groups were assessed. The ERG+/SPINK1+ subgroup exhibited significantly higher postoperative CKD stages and serum creatinine levels compared to the ERG+/SPINK1- subgroup. This suggests an intricate relationship between SPINK1 overexpression and renal function dynamics. The HOXB13-/TFF3+ subgroup displayed higher preoperative serum creatinine levels and CKD stages than the HOXB13-/TFF3- subgroup, aligning with TFF3's potential role in renal function. Furthermore, the study revealed associations between CKD stages and prognostic grade groups in different molecular subtypes, pointing out an intricate interplay between renal function and tumor behavior. Although the molecular classification of prostate acinar ADK is not yet implemented, this research underscores the variability of renal function parameters in different molecular subtypes, offering potential insights into patient prognosis.

Efficacy and safety of axitinib for metastatic renal cell carcinoma: Real-world data on patients with renal impairment

ObjectivesLimited information is currently available on the efficacy and safety of axitinib for metastatic renal cell carcinoma (mRCC) patients with renal impairment. Therefore, the present study investigated the efficacy and toxicity of axitinib in patients with chronic kidney disease. MethodsPost-hoc analyses were performed on a Japanese multicenter cohort study of 477 mRCC patients who received axitinib followed by 1 or 2 regimens of systemic antiangiogenic therapy between January 2012 and December 2016. Differences in clinical characteristics and the efficacy and safety of axitinib were assessed based on pretreatment renal function. ResultsPatients were categorized into the following 5 renal function groups according to baseline renal function: estimated glomerular filtration rate (eGFR) ≥60 ml/min (n = 133), 45 ml/min ≤eGFR <60 ml/min (n = 153), 30 ml/min ≤eGFR< 45 ml/min (n = 130), eGFR <30 ml/min (n = 45), and dialysis (n = 16). Median progression-free survival (PFS) (95% confidence interval [CI]) in the 5 groups was 11 (8−16), 14 (11−19), 14 (10–19), 12 (8−24), and 6 (3-NR) months, respectively (p = 0.781). After adjustments for treatment-related confounders, the renal function group was not a significant prognostic factor for PFS. Objective response rates in the 5 groups were 22%, 23%, 23%, 18%, 20%, and 38%, respectively (p = 0.468). Regarding adverse events of all grades, hypertension (p = 0.0006) and renal and urinary disorders (p < 0.0001) were more frequently observed in the eGFR <30 ml/min group than in the other groups. ConclusionsSince renal function at the initiation of treatment with axitinib does not adversely affect the efficacy of VEGF-TKI therapy, clinicians do not need to avoid its administration to mRCC patients with impaired renal function in consideration of the risk of progression to end-stage renal disease.

Effect Of Urinary Kidney Injury Molecule-1 Levels On Short-Term Prognosis Of Chronic Heart Failure.

To explore the influential elements of urinary kidney injury molecule-1 levels in chronic heart failure, and to judge its ability to predict 90-day rehospitalisation. The cross-sectional case-control study was conducted from November 2020 to April 2021, at Hanzhong Central Hospital, China, and comprised adult patients having chronic heart failure with normal renal function in group A and healthy subjects in control group B. Patients in group A received anti-heart failure therapy for 1 week in hospital and were followed up for 90 days after discharge. Blood pressure (BP), kidney injury molecule-1, creatinine and serum pro- B-type natriuretic peptide levels were evaluated at baseline and 1 week after treatment in group A, while the samples were collected only at baseline in the control group B. Data was analysed using SPSS 22. Of the 102 subjects, 68(66.6%) were in group A; 44(64.7%) males and 24 (35.3%) females with mean age 62.38±9.51 years. The remaining 34(33.3%) subjects were in group B; 21(61.7%) males and 13(38.2%) females with mean age vs. 58.82±8.11 years. The urinary kidney injury molecule-1 level in group A was essentially on the increase compared to group B (p<0.05). After 1 week of treatment, the kidney injury molecule-1 level decreased compared to the baseline value in group A (p<0.05). Diastolic blood pressure and pro-B-type natriuretic peptide were the determinants of urinary kidney injury molecule-1 level, and urinary kidney injury molecule-1 level before discharge was significantly associated with rehospitalisation within 90 days (p<0.05). Urinary kidney injury molecule-1 level before discharge was a significant predictor of rehospitalisation within 90 days, and diastolic blood pressure and pro-B-type natriuretic peptide levels were the influencing factors of urinary kidney injury molecule-1. Also, urinary kidney injury molecule-1 levels were significantly raised in chronic heart failure.

The impact of renal function on the three-year outcomes in patients with myocardial infarction with nonobstructive coronary arteries

BackgroundDue to limited data availability, we compared the 3-year outcomes of patients with acute myocardial infarction (AMI) and nonobstructive coronary arteries (MINOCA) and those with obstructive coronary arteries (MIOCA) according to renal function. MethodsFrom a final cohort of 10,774 patients with AMI were classified into 2 groups: the chronic kidney disease (CKD) group (estimated glomerular filtration rate <60 mL/min/1.73 m2, 2,854 patients; MINOCA, 123; MIOCA, 2,731) and the non-CKD group (7,920 patients; MINOCA, 256; MIOCA, 7,664). The primary outcome was the 3-year all-cause death rate, and the secondary outcomes included cardiac death (CD), non-CD death (NCD), recurrent myocardial infarction (MI), and any revascularization. ResultsIn both the CKD and non-CKD groups, the adjusted in-hospital mortality, 3-year all-cause death, CD, and recurrent MI rates were similar between the MINOCA and MIOCA groups, but the adjusted 3-year any revascularization rates were significantly higher in the MIOCA group than in the MINOCA group. Characteristically, in the CKD group, the adjusted 3-year NCD rate (P = 0.032) was higher in the MINOCA group than in the MIOCA group, and sepsis was the main cause of NCD in this group. In both the MINOCA and MIOCA groups, all-cause death and NCD were significantly higher in the CKD group than in the non-CKD group. ConclusionsRegardless of renal function, the MINOCA and MIOCA groups had comparable mortality rates. However, patients with MINOCA and CKD had higher NCD rates. Close monitoring of renal function and enhanced strategies are required to reduce mortality in patients with MINOCA.

An HPLC-MS/MS method for determination of sulbactam in human plasma and its pharmacokinetic application in critically ill patients with augmented renal clearance.

A simple, rapid, and specific method has been developed and validated to measure sulbactam in human plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The pharmacokinetic characteristics of sulbactam in critically ill patients with augmented renal clearance were investigated after the repeated administration of cefoperazone-sulbactam (3 g, q8, IV drip, combination ratio of 2:1). Sulbactam plasma concentration was determined using LC-MS/MS with tazobactam used as an internal standard (IS). The method was fully validated with a sensitivity of 0.20 μg/mL, the linear concentration was ranged from 0.20 to 30.0 μg/mL. The intra-batch precision (RSD%) was less than 4.9%, and the accuracy deviation (RE%) ranged from -9.9 to 1.0%; the inter-batch precision (RSD%) was less than 6.2%, and the accuracy deviation (RE%) ranged from -9.2% to 3.7%. The value of the mean matrix factor at the low and high quality control (QC) concentration was 96.8 and 101.0%, respectively. The extraction recovery for QCL and QCH of sulbactam were 92.5 and 87.5%, respectively. Plasma samples and clinical data were collected at 0 (pre dose), 0.25, 0.5, 1, 2, 3, 6, and 8 hours (post dose) from 11 critically ill patients. Pharmacokinetic parameters were determined by non-compartmental analysis (NCA) using Phoenix WinNonlin software. This method was successfully applied to study the pharmacokinetics of sulbactam for critically ill patients. The main pharmacokinetic parameters of sulbactam in augmented renal function and normal renal function groups were summarized as follows: half-life, 1.45 ± 0.66 and 1.72 ± 0.58 hours, area under the concentration-time curve from 0 to 8 hours, 59.1 ± 20.1 and 111.4 ± 23.2 μg × h/mL, drug plasma clearance at steady state, 18.9 ± 7.5 and 9.32 ± 2 .03 L/h, respectively. These results suggested that a higher dose of sulbactam should be used in critically ill patients with augmented renal clearance.

Genome-wide association study of dilated cardiomyopathy-induced heart failure associated with renal insufficiency in a Chinese population

BackgroundAs it is unclear whether there is genetic susceptibility to cardiorenal syndrome (CRS), we conducted a genome-wide association study of dilated cardiomyopathy (DCM)-induced heart failure (HF) associated with renal insufficiency (RI) in a Chinese population to identify putative susceptibility variants and culprit genes.MethodsA total of 99 Han Chinese patients with DCM-induced chronic HF were selected and divided into one of three groups, namely, HF with normal renal function (Group 1), HF with mild RI (Group 2) and HF with moderate to severe RI (Group 3). Genomic DNA was extracted from each subject for genotyping.ResultsAccording to Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, top 10 lists of molecular function, cell composition and biological process of differential target genes and 15 signalling pathways were discriminated among the three groups. Additionally, sequencing results identified 26 significantly different single-nucleotide polymorphisms (SNPs) in the 15 signalling pathways, including three SNPs (rs57938337, rs6683225 and rs6692782) in ryanodine receptor 2 (RYR2) and two SNPs (rs12439006 and rs16958069) in RYR3. The genotype and allele frequencies of the five SNPs in RYR2 and RYR3 were significantly differential between HF (Group 1) and CRS (Group 2 + 3) patients.ConclusionTwenty-six significantly different SNP loci in 17 genes of the 15 KEGG pathways were found in the three patient groups. Among these variants, rs57938337, rs6683225 and rs6692782 in RYR2 and rs12439006 and rs16958069 in RYR3 are associated with RI in Han Chinese patients with heart failure, suggesting that these variants may be used to identify patients susceptible to CRS in the future.

Association between worsening renal function severity during hospitalization and low physical function at discharge: a retrospective cohort study of older patients with heart failure and chronic kidney disease from Japan.

The number of hospitalized older patients with chronic heart failure, chronic kidney disease, and worsening renal function is rising in Japan. This study aimed to clarify the impact of the severity of worsening renal function during hospitalization on low physical function at discharge of these patients. We included 573 consecutive heart failure patients who underwent phase I cardiac rehabilitation. Worsening renal function severity was defined according to elevation during hospitalization of baseline serum creatinine on admission: non-worsening renal function, serum creatinine < 0.2mg/dL; worsening renal function II/I, serum creatinine ≥ 0.2 to < 0.5mg/dL; worsening renal function III, and serum creatinine ≥ 0.5mL/dL. Physical function was measured with the Short Performance Physical Battery. We compared background factors, clinical parameters, pre-hospitalization walking levels, Functional Independence Measure score, and physical function in the three renal function groups. Multiple regression analysis was performed with the Short Performance Physical Battery at discharge as the dependent variable. The final analysis included 196 patients (mean age 82.7years, male 51.5%) categorized into three groups based on worsening renal function: worsening renal function grade III group (n = 55), worsening renal function grade II/I group (n = 36), and non-worsening renal function group (n = 105). There is no significant difference in walking levels before hospitalization between the three groups, but physical function at discharge was significantly lower in the worsening renal function III group. Moreover, worsening renal function III was an independent factor for low physical function at discharge. Worsening of renal function during hospitalization in older patients with heart failure and chronic kidney disease was strongly associated with low physical function at discharge, even after adjusting for other potentially confounding factors, such as pre-hospitalization walking levels, walking start day, and Geriatric Nutrition Risk Index at discharge. Notably, worsening renal function of mild or moderate severity (grade II/I) did not show a significant association with low physical function.

#4061 PHARMACOKINETICS OF SETMELANOTIDE IN INDIVIDUALS WITH RENAL IMPAIRMENT: RESULTS FROM A PHASE 1, OPEN-LABEL, SINGLE-DOSE STUDY

Abstract Background and Aims Setmelanotide is an approved treatment for chronic weight management and control of hunger in patients aged ≥6 years with specific forms of obesity including Bardet-Biedl syndrome (BBS). Setmelanotide may be considered for patients with renal impairment, including those with BBS, who often experience impaired renal function as a primary feature of the syndrome. This study evaluated the pharmacokinetics (PK) and safety of a single dose of setmelanotide in individuals without BBS who have renal impairment. Method This Phase 1, open-label study (NCT04348175) was conducted in 3 centers in the United States. Eligible individuals were aged 18-83 years and had general obesity with a body mass index (BMI) of 22-40 kg/m2. Individuals were assigned to a study cohort according to renal function, determined by estimated glomerular filtration rate (normal renal function [healthy volunteers]: ≥90 mL/min/1.73 m2; mild renal impairment: 60-89 mL/min/1.73 m2; moderate renal impairment: 30-59 mL/min/1.73 m2; severe renal impairment: 15-29 mL/min/1.73 m2). A single dose of 2.0 mg of setmelanotide was administered subcutaneously; however, 1.0 or 0.5 mg was administered to most patients with severe renal impairment following safety review of the patient cohorts with mild and moderate renal impairment because of the potential impacts of nausea and vomiting, and consequential dehydration, on renal function. Blood samples were collected for PK analysis from hour 0 up to hour 96 after setmelanotide administration. Patients with renal impairment and healthy volunteers were matched according to sex, age, and BMI. PK parameters in individuals who received &amp;lt;2.0 mg setmelanotide were dose normalized for comparisons across renal function groups. Safety and tolerability were monitored and evaluated. Results In total, 32 individuals were included. Age, sex, and BMI were generally similar across cohorts. Setmelanotide PK parameters were comparable regardless of renal function (Table 1). Mean area under the concentration-time curve was higher in individuals with renal impairment compared with healthy volunteers and increased with worsening renal function. Mean clearance was lower in individuals with renal impairment compared with healthy volunteers and decreased with worsening renal function. Thirty individuals (94%) experienced a treatment-emergent adverse event (TEAE), with gastrointestinal disorders (n=22; 69%) having the highest incidence. There were no severe, serious, or fatal TEAEs and no TEAEs leading to withdrawal. There were no meaningful differences in incidence of the most common TEAEs across cohorts. Conclusion Minimal differences in PK parameters were observed in individuals with mild and moderate renal impairment compared with healthy volunteers. Findings from this study are consistent with current setmelanotide dosing recommendations, which suggest a modified dosing regimen in patients with severe renal impairment.

The use of high-sensitivity cardiac troponin T and creatinine kinase-MB as a prognostic markers in patients with acute myocardial infarction and chronic kidney disease

Background High-sensitivity cardiac troponin T (hs-cTnT) and creatine kinase (CK)-MB are the most commonly used biomarkers for the diagnosis and prognosis of acute myocardial infarction (AMI). Chronic kidney disease (CKD) often leads to elevated hs-cTnT levels in non-AMI patients. However, studies comparing the prognostic value of both hs-cTnT and CK-MB in patients with AMI and CKD are lacking. Methods We conducted a retrospective study on AMI patients diagnosed between January 2015 and October 2020. Patients were categorized based on renal function as normal or CKD. Peak hs-cTnT and CK-MB levels during hospitalization were collected, and their diagnostic value was evaluated using receiver operating characteristic (ROC) curves. The impact on in-hospital mortality was analyzed using multivariate logistic regression. The relationship between the hs-cTnT/CK-MB ratio and in-hospital death was examined using a restricted cubic spline (RCS) curve. Results The study included 5022 AMI patients, of whom 797 (15.9%) had CKD. The AUCs of Hs-cTnT and CK-MB were higher in the CKD group [0.842 (95% CI: 0.789–0.894) and 0.821 (95% CI: 0.760–0.882)] than in the normal renal function group [0.695 (95% CI: 0.604-0.790) and 0.708 (95% CI: 0.624-0.793)]. After full adjustment for all risk factors, hs-cTnT (OR, 2.82; 95% CI, 1.03–9.86; p = 0.038) and CK-MB (OR, 4.91; 95% CI, 1.54–14.68; p = 0.007) above the cutoff values were independent predictors of in-hospital mortality in patients with CKD. However, in patients with normal renal function, only CK-MB above the cutoff (OR, 2.45; 95% CI, 1.02–8.24; p = 0.046) was a predictor of in-hospital mortality, whereas hs-cTnT was not. There was an inverted V-shaped relationship between the hs-cTnT/CK-MB ratio and in-hospital mortality, with an inflection point of 19.61. The ratio within the second quartile (9.63-19.6) was an independent predictor of in-hospital mortality in patients with CKD (OR 5.3, 95% CI 1.66–16.86, p = 0.005). Conclusions Hs-cTnT independently predicted in-hospital mortality in AMI patients with CKD, whereas its predictive value was not observed in patients with normal renal function. CK-MB was an independent predictor of in-hospital mortality regardless of renal function. Moreover, the hs-cTnT/CK-MB ratio may aid in risk stratification of AMI patients with CKD.

Meropenem Pharmacokinetics and Target Attainment in Critically Ill Patients.

This study aimed to investigate the pharmacokinetics and target attainment of meropenem and compare the effect of meropenem dosing regimens in critically ill patients. Thirty-seven critically ill patients who were administered meropenem in intensive care units were analyzed. Patients were classified according to their renal function. Pharmacokinetic parameters were assessed based on Bayesian estimation. The target attainment of 40%fT > MIC (fraction time that the free concentration exceeds the minimum inhibitory concentration) and 100%fT > MIC with the pathogen MIC of 2 mg/L and 8 mg/L were specially focused. Furthermore, the effects of standard dosing (1g meropenem, 30 min intravenous infusion every 8h) and non-standard dosing (dosage regimens except standard dosing) were compared. The results showed that the values of meropenem clearance (CL), central volume of distribution (V1), intercompartmental clearance (Q), and peripheral volume of distribution (V2) were 3.3 L/h, 9.2 L, 20.1 L/h and 12.8 L, respectively. The CL of the patients among renal function groups was significantly different (p < 0.001). The tow targets attainment for the pathogen MIC of 2 mg/L and 8 mg/L were 89%, 73%, 49% and 27%, respectively. The severe renal impairment group has higher fraction of target attainment than the other group. The standard dosing achieved the target of 40%fT > 2/8 mg/L (85.7% and 81%, respectively) and patients with severe renal impairment achieved the target fraction of 100% for 40%fT > MIC. Additionally, there was no significant difference between standard and non-standard dosing group in target attainment. Our findings indicate that renal function is an important covariate for both meropenem pharmacokinetics parameters and target attainment. The target attainment between standard and non-standard dosing group was not comparable. Therefore, therapeutic drug monitoring is indispensable in the dosing adjustment for critically ill patients if it is available.

Comparative preoperative sonological assessment of gastric contents in patients with chronic kidney disease versus those with normal renal function - A prospective observational study.

Though the role of fasting preoperative gastric ultrasound has been validated in different patient populations, namely, obese, pregnant and diabetics, it has not been explored in patients with chronic kidney disease (CKD). This prospective, observational study compared the fasting sonological assessment of gastric contents in patients with CKD versus those with normal renal function scheduled for elective surgery. After ethical approval and trial registration were obtained, preoperative gastric ultrasound was done in 115 CKD patients and 115 with normal renal function. Qualitative and quantitative assessment of residual gastric volume was done. Also, the patients were administered the Porto Alegre Dyspeptic Symptoms Questionnaire (PADYQ) to evaluate gastroparesis objectively. The researcher was not blinded to the patient groups. Data analyses were done using the Statistical Package for Social Sciences (SPSS) for Windows software (version 22.0). Gastric volumes exceeding 1.5 ml/kg or particulate or solid contents were found in 57 patients with CKD and 36 patients with normal renal function (P = 0.004). The PADYQ scores were 6.54 ± 8.49 for CKD and 2.15 ± 5.71 for normal renal function (P < 0.0001) groups. CKD patients had a higher age (P < 0.001), lower body mass index (P = 0.005) and higher incidence of diabetes mellitus (P < 0.001). There were no incidents of gastric aspiration. Renal dysfunction contributes to delayed gastric emptying. PADYQ can also help identify those at high risk of gastroparesis. Combining the questionnaire and preoperative gastric ultrasound must be considered in these patients to ensure optimum safety.

Recommendation of pharmacokinetics/pharmacodynamics target of ethambutol to suppress tuberculosis resistance: A population pharmacokinetics study on a large prospective cohort

The ability of ethambutol (EMB) to suppress bacterial resistance has been demonstrated in a time-dependent manner. Through the development of a population pharmacokinetics (PK) model, this study aimed to suggest the PK/pharmacodynamics (PD) target and identify the significant covariates that influence interindividual variability (IIV) in the PK of EMB. In total, 837 patients from 20 medical centres across Korea were enrolled in this study. The non-linear mixed-effect method was used to establish and validate the population PK model. A two-compartment model with transit compartment absorption was sufficient to describe the PK of EMB. Body weight and renal function were identified as significant covariates that affect IIV of the apparent clearance (CL/F) of EMB. Patients with moderate renal function showed 35% and 55% lower CL/F (CL/F 89.9 L/h) compared with those with mild and normal renal function, respectively. All the renal function groups with simulated doses ranging from 800 to 1200 mg achieved area under the curve over minimum inhibitory concentration (MIC) >119, and maintained T>MIC for >23 h for MIC of 0.5 µg/mL. Based on our simulation result, it is suggested that doses of 800, 1000, and 1200 mg should obtain the T>MIC target of 4, 6, and 8 h, respectively. This model was validated internally and externally. This study provides insight into the PK/PD indexes of EMB for three different renal function groups and T>MIC targets for different doses. The results could be used to provide optimal-dose suggestions for EMB.

Pharmacokinetics and Safety of Cotadutide, a GLP-1 and Glucagon Receptor Dual Agonist, in Individuals with Renal Impairment: A Single-Dose, Phase I, Bridging Study.

Cotadutide is a balanced glucagon-like peptide-1 and glucagon receptor dual agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes with chronic kidney disease. We evaluated the pharmacokinetics (PK), safety and immunogenicity of a single dose of cotadutide in individuals with varying degrees of renal impairment. In this phase I bridging study, individuals 18-85 years of age, with a body mass index of 17-40 kg/m2 and varying degrees of renal function {end-stage renal disease (ESRD; creatinine clearance [CrCl] < 20mL/min); severe renal impairment (CrCl ≥ 20 to < 30 mL/min); lower moderate renal impairment (CrCl ≥ 30 to < 44 mL/min); upper moderate renal impairment (CrCl ≥ 45 to < 60 mL/min); normal renal function (CrCl ≥ 90 mL/min)} were treated with a single dose of subcutaneous cotadutide 100 µg under fasted conditions in the lower abdomen. The co-primary endpoints were area under the plasma concentration-time curve from time zero to 48h (AUC48) and the maximum observed plasma concentration (Cmax) for cotadutide. Safety and immunogenicity were secondary endpoints. This trial is registered with ClinicalTrials.gov (NCT03235375). A total of 37 individuals were enrolled in the study (only three enrolled in the ESRD group, therefore this group was excluded from the primary PK analysis). AUC48 and Cmax values for cotadutide were similar across all renal function groups {severe renal impairment vs. normal renal function: AUC48 geometric mean ratio (GMR) 0.99 (90% confidence interval [CI] 0.76-1.29); lower moderate renal impairment versus normal renal function: AUC48 GMR 1.01 (90% CI 0.79-1.30); upper moderate renal impairment versus normal renal function: AUC48 GMR 1.09 (90% CI 0.82-1.43)}. A sensitivity analysis that combined the ESRD and severe renal impairment groups did not show notable changes in the AUC48 and Cmax GMRs. The incidences of treatment-emergent adverse events (TEAE) ranged from 42.9 to 72.7% across all groups and were mostly mild to moderate in severity. Only one patient had a grade III or worse TEAE during the study period. No positive antidrug antibody results were observed. These results suggest that the PK and tolerability of cotadutide are unaffected by renal function and that dose adjustments may not be required in individuals with renal impairment.

Machine learning-based multimodal MRI texture analysis for assessing renal function and fibrosis in diabetic nephropathy: a retrospective study.

Diabetic nephropathy (DN) has become a major public health burden in China. A more stable method is needed to reflect the different stages of renal function impairment. We aimed to determine the possible practicability of machine learning (ML)-based multimodal MRI texture analysis (mMRI-TA) for assessing renal function in DN. For this retrospective study, 70 patients (between 1 January 2013 and 1 January 2020) were included and randomly assigned to the training cohort (n1 = 49) and the testing cohort (n2 = 21). According to the estimated glomerular filtration rate (eGFR), patients were assigned into the normal renal function (normal-RF) group, the non-severe renal function impairment (non-sRI) group, and the severe renal function impairment (sRI) group. Based on the largest coronal image of T2WI, the speeded up robust features (SURF) algorithm was used for texture feature extraction. Analysis of variance (ANOVA) and relief and recursive feature elimination (RFE) were applied to select the important features and then support vector machine (SVM), logistic regression (LR), and random forest (RF) algorithms were used for the model construction. The values of area under the curve (AUC) on receiver operating characteristic (ROC) curve analysis were used to assess their performance. The robust T2WI model was selected to construct a multimodal MRI model by combining the measured BOLD (blood oxygenation level-dependent) and diffusion-weighted imaging (DWI) values. The mMRI-TA model achieved robust and excellent performance in classifying the sRI group, non-sRI group, and normal-RF group, with an AUC of 0.978 (95% confidence interval [CI]: 0.963, 0.993), 0.852 (95% CI: 0.798, 0.902), and 0.972 (95% CI: 0.995, 1.000), respectively, in the training cohort and 0.961 (95% CI: 0.853, 1.000), 0.809 (95% CI: 0.600, 0.980), and 0.850 (95% CI: 0.638, 0.988), respectively, in the testing cohort. The model built from multimodal MRI on DN outperformed other models in assessing renal function and fibrosis. Compared to the single T2WI sequence, mMRI-TA can improve the performance in assessing renal function.

Pharmacokinetics and Safety of Imeglimin in Japanese Patients With Impaired Renal Function.

Imeglimin is a diabetic drug excreted mainly in the urine; therefore, the impact of renal impairment on its pharmacokinetics (PK) is of interest. We assessed the PK and safety of imeglimin in Japanese patients with impaired renal function. This was an uncontrolled, open-label, single-dose, phase 1 study. Participants were classified into 4 groups by their estimated glomerular filtration rate (mL/min/1.73m2 ) as follows: ≥90, normal renal function; and 60 to <90, mild; 30 to <60, moderate; and 15 to <30, severe renal impairment. All participants received imeglimin 1000 mg except those with severe renal impairment, who received imeglimin 500 mg. PK parameters were estimated using noncompartmental analysis, and those after multiple administrations were projected using a noncompartmental superposition method. In total, 24 Japanese participants (6 in each group) were enrolled and completed the study. The mean plasma imeglimin concentration reached the maximum at 2-4 hours after administration and then rapidly decreased. The geometric mean maximum observed plasma concentration and area under the plasma concentration-time curve values were higher in the impaired renal function groups versus normal renal function group. Most imeglimin was excreted in urine by 24 hours after administration. Renal clearance decreased with decreasing renal function. Projected maximum observed plasma concentration and area under the plasma concentration-time curve over the dosing interval after multiple dosing were greater in the renal impairment groups versus normal renal function group. No adverse events were observed. Considering increased plasma exposure along with decreased renal clearance, dose adjustment is required in patients with moderate and severe renal impairment with estimated glomerular filtration rate of 15 to <45 mL/min/1.73 m2 .

Long-term renal outcomes comparison between patients with chronic kidney disease and hepatorenal syndrome after living donor liver transplantation.

Hepatorenal syndrome (HRS) is a disastrous renal complication of advanced liver disease with a poor prognosis. Restoring normal liver function through liver transplantation (LT) is a standardized treatment with favorable short-term survival. However, the long-term renal outcomes in patients with HRS receiving living donor LT (LDLT) are controversial. This study aimed to investigate the prognostic impact of LDLT in patients with HRS. We reviewed adult patients who underwent LDLT between July 2008 and September 2017. Recipients were classified into 1) HRS type 1 (HRS1, N = 11), 2) HRS type 2 (HRS2, N = 19), 3) non-HRS recipients with pre-existing chronic kidney disease (CKD, N = 43), and 4) matched normal renal function (N = 67). Postoperative complications and 30-day surgical mortality were comparable among the HRS1, HRS2, CKD, and normal renal function groups. The 5-year survival rate was >90% and estimated glomerular filtration rate (eGFR) transiently improved and peaked at 4 weeks post-transplantation in patients with HRS. However, renal function deteriorated and resulted in CKD stage ≥ III in 72.7% of HRS1 and 78.9% of HRS2 patients (eGFR <60 ml/min/1.73 m2). The incidence of developing CKD and end-stage renal disease (ESRD) was similar between the HRS1, HRS2, and CKD groups, but significantly higher than that in the normal renal function group (both P < 0.001). In multivariate logistic regression, pre-LDLT eGFR <46.4 ml/min/1.73 m2 predicted the development of post-LDLT CKD stage ≥ III in patients with HRS (AUC = 0.807, 95% CI = 0.617-0.997, P = 0.011). LDLT provides a significant survival benefit for patients with HRS. However, the risk of CKD stage ≥ III and ESRD among patients with HRS was similar to that in pre-transplant CKD recipients. An early preventative renal-sparing strategy in patients with HRS is recommended.

Effect of renal function on the diagnostic performance of plasma biomarkers for Alzheimer's disease.

Several blood-based biomarkers are promising to be used in the diagnosis of Alzheimer's disease (AD) including Aβ42/40, p-tau181, and neurofilament light (NfL). The kidney is associated with the clearance of proteins. It is crucial to evaluate the effect of renal function on the diagnostic performance of these biomarkers before clinical implementation, which is important for the establishment of reference ranges and the interpretation of results. This study is a cross-sectional analysis based on ADNI cohort. Renal function was determined by the estimated glomerular filtration rate (eGFR). Plasma Aβ42/40 was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma p-tau181 and NfL were analyzed by Single Molecule array (Simoa) technique. [18F] florbetapir-PET (Aβ-PET) was used as a reference standard to estimate the brain amyloid load. The cutoff of Aβ-PET positivity was defined as ≥1.11. Linear regression models were used to investigate the associations of continuous eGFR with each plasma biomarker separately. The diagnostic accuracies of plasma biomarkers for positive brain amyloid across different renal function groups were analyzed by Receiver operating characteristic (ROC) curve. Youden-Index was used to determine the cutoff levels. A total of 645 participants were included in this study. The levels and diagnostic performance of Aβ42/40 were not affected by renal function. eGFR was only found negatively associated with p-tau181 levels in Aβ-PET negetive sample (β = -0.09, p = 0.039). eGFR was found negatively associated with NfL levels both in whole sample and Aβ-PET stratified groups (β = -0.27, p < 0.001 in whole sample; β = -0.28, p = 0.004 in A-; β = -0.27, p < 0.001 in A+). The diagnostic accuracies of p-tau181 and NfL were not affected by renal function. But the cutoff values of p-tau181 and NfL changed in participants with mild to moderate eGFR decline compared to participants with normal eGFR. Plasma Aβ42/40 was a robust biomarker for AD which was not affected by renal function. Plasma p-tau181 and NfL levels were affected by renal function, specific reference values of them should be considered in populations with different renal function stages.

Justifying Ribociclib Dose in Patients with Advanced Breast Cancer with Renal Impairment Based on PK, Safety, and Efficacy Data: An Innovative Approach Integrating Data from a Dedicated Renal Impairment Study and Oncology Clinical Trials.

Renal impairment is common in patients with cancer and can alter the PK and thus the safety and efficacy of drugs. We assessed the impact of renal impairment during treatment with ribociclib, a cyclin-dependent kinase 4/6 inhibitor, and determined dose recommendations for patients with advanced breast cancer with renal impairment. A comprehensive assessment integrating pharmacokinetic, safety, and efficacy data from a phase I dedicated renal impairment study in non-cancer subjects and six phase I-III trials in patients with cancer was performed. Ribociclib showed higher pharmacokinetic exposure in subjects with renal impairment than those with normal renal function following a single 400-mg dose in the dedicated renal impairment study. However, in patient trials, both single-dose and steady‑state ribociclib exposure was comparable between patients with cancer with mild/moderate renal impairment and those with normal renal function following the recommended starting dose of 600 mg. Model-predicted steady‑state exposure in patients with advanced breast cancer was also similar across the renal function groups. Progression-free survival was similar and safety profiles were generally consistent across the renal cohorts (normal/mild/moderate) in patients with advanced breast cancer, with low-grade and manageable adverse events, demonstrating a positive benefit-risk profile. From the collective evidence and considering a real-world clinical setting, no dose adjustment is recommended for patients with mild/moderate renal impairment, whereas a reduced dose is recommended for patients with severe renal impairment. This report presented a holistic and innovative strategy to determine dose in patients with renal impairment and demonstrated the effectiveness of integrating the data of both a clinical pharmacology study and patient trials to justify doses in patients with renal impairment. Clinicaltrials.gov identifiers: NCT02431481, NCT01958021, NCT02422615, NCT02278120, NCT01237236, NCT01898845, NCT01872260.

Estimation of differential renal function on routine abdominal imaging employing compressed-sensed contrast-enhanced MR: a feasibility study referenced against dynamic renal scintigraphy in patients with deteriorating renal retention parameters

PurposeTo assess whether high temporal/spatial resolution GRASP MRI acquired during routine clinical imaging can identify several degrees of renal function impairment referenced against renal dynamic scintigraphy.MethodsThis retrospective study consists of method development and method verification parts. During method development, patients subject to renal imaging using gadoterate meglumine and GRASP post-contrast MRI technique (TR/TE 3.3/1.6 ms; FoV320 × 320 mm; FA12°; Voxel1.1 × 1.1x2.5 mm) were matched into four equally-sized renal function groups (no-mild-moderate-severe impairment) according to their laboratory-determined estimated glomerular filtration rates (eGFR); 60|120 patients|kidneys were included. Regions-of-interest (ROIs) were placed on cortices, medullary pyramids and collecting systems of bilateral kidneys. Cortical perfusion, tubular concentration and collecting system excretion were determined as TimeCortex=Pyramid(sec), SlopeTubuli (sec−1), and TimeCollecting System (sec), respectively, and were measured by a combination of extraction of time intensity curves and respective quantitative parameters. For method verification, patients subject to GRASP MRI and renal dynamic scintigraphy (99mTc-MAG3, 100 MBq/patient) were matched into three renal function groups (no-mild/moderate-severe impairment). Split renal function parameters post 1.5–2.5 min as well as MAG3 TER were correlated with time intensity parameters retrieved using GRASP technique; 15|30 patients|kidneys were included.ResultsMethod development showed differing values for TimeCortex=Pyramid(71|75|93|122 s), SlopeTubuli(2.6|2.1|1.3|0.5 s−1) and TimeCollecting System(90|111|129|139 s) for the four renal function groups with partial significant tendencies (several p-values < 0.001). In method verification, 29/30 kidneys (96.7%) were assigned to the correct renal function group.ConclusionHigh temporal and spatial resolution GRASP MR imaging allows to identify several degrees of renal function impairment using routine clinical imaging with a high degree of accuracy.