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PurposeFedratinib (SAR302503, TG101348) is an orally administered Janus kinase (JAK) 2-selective inhibitor that is being developed for the treatment of patients with myelofibrosis (MF). The objectives of this analysis were to develop a population pharmacokinetic (PK) model to characterize fedratinib concentration-time profiles in patients with MF, polycythemia vera (PV) and essential thrombocythemia (ET) following oral fedratinib administration; and to investigate the effects of selected covariates on fedratinib PK parameters.MethodsNonlinear mixed effects modeling was employed in developing a population PK model for fedratinib. Intensive or sparse fedratinib concentration data collected in adult subjects with MF, PV or ET from six studies were pooled, and a total of 452 subjects and 3442 plasma concentration observations were included in the final model.ResultsFedratinib PK in patients with MF/PV/ET was adequately described by a two-compartment structural PK model with first-order absorption incorporating a lag time and first-order elimination. Following oral administration, fedratinib undergoes biphasic disposition and exhibits linear, time-invariant PK at doses of 200 mg and above. Compared to MF/ET patients, PV patients had higher apparent clearance (CL/F) and apparent central volume of distribution. Creatinine clearance was a statistically significant covariate on CL/F, and patients with mild and moderate renal impairment had 10% and 37% increases in fedratinib exposure as compared to patients with normal renal function. No clinically meaningful effect on fedratinib exposure was observed regarding age, body weight, sex, race and liver function.ConclusionsThese results should serve as the basis for dose adjustment of fedratinib for special populations.

Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and is characterized by gradual cyst growth and expansion, increase in kidney volume with an ultimate decline in kidney function leading to end stage renal disease (ESRD). Given the decades long period of stable kidney function while cyst growth occurs, it is important to identify those patients who will progress to ESRD. Recent data from our and other laboratories have demonstrated that metabolic reprogramming may play a key role in cystic epithelial proliferation resulting in cyst growth in ADPKD. Height corrected total kidney volume (ht-TKV) accurately reflects cyst burden and predicts future loss of kidney function. We hypothesize that specific plasma metabolites will correlate with eGFR and ht-TKV early in ADPKD, both predictors of disease progression, potentially indicative of early physiologic derangements of renal disease severity. Methods To investigate the predictive role of plasma metabolites on eGFR and/or ht-TKV, we used a non-targeted GC-TOF/MS-based metabolomics approach on hypertensive ADPKD patients in the early course of their disease. Patient data was obtained from the HALT-A randomized clinical trial at baseline including estimated glomerular filtration rate (eGFR) and measured ht-TKV. To identify individual metabolites whose intensities are significantly correlated with eGFR and ht-TKV, association analyses were performed using linear regression with each metabolite signal level as the primary predictor variable and baseline eGFR and ht-TKV as the continuous outcomes of interest, while adjusting for covariates. Significance was determined by Storey’s false discovery rate (FDR) q-values to correct for multiple testing. Results Twelve metabolites significantly correlated with eGFR and two triglycerides significantly correlated with baseline ht-TKV at FDR q-value < 0.05. Specific significant metabolites, including pseudo-uridine, indole-3-lactate, uric acid, isothreonic acid, and creatinine, have been previously shown to accumulate in plasma and/or urine in both diabetic and cystic renal diseases with advanced renal insufficiency. Conclusions This study identifies metabolic derangements in early ADPKD which may be prognostic for ADPKD disease progression. Clinical trial HALT Progression of Polycystic Kidney Disease (HALT PKD) Study A; Clinical www.clinicaltrials.gov identifier: NCT00283686; first posted January 30, 2006, last update posted March 19, 2015.

In randomized clinical trials (RCTs) of nonvitamin K antagonist oral anticoagulants (NOACs) for acute venous thromboembolism (VTE), ~ 12–13% of patients were elderly and ~ 26% had mild-to-moderate renal impairment. Observational studies are not restricted by the selection and treatment criteria of RCTs. In this ancillary analysis of the RE-COVERY DVT/PE global observational study, we aimed to describe patient characteristics, comorbidities, and anticoagulant therapy for subgroups of age (< or ≥ 75 years) and renal impairment (creatinine clearance [CrCl; estimated with Cockcroft–Gault formula] < 30 [severe], 30 to < 50 [moderate], 50 to < 80 [mild], ≥ 80 [normal] mL/min). Of 6095 eligible patients, 25.3% were aged ≥ 75 years; 38.2% (1605/4203 with CrCl values) had mild-to-moderate renal impairment. Comorbidities were more common in older patients (73.9% aged ≥ 75 vs. 58.1% < 75 years) and in those with mild or moderate versus no renal impairment (75.9%, 80.9%, and 59.3%, respectively). At hospital discharge or 14 days after diagnosis (whichever was later), most patients (53.7% and 55.1%, respectively) in both age groups received NOACs; 20.8% and 23.4%, respectively, received vitamin K antagonists, 19.0% and 21.8% parenteral therapy, 2.3% and 3.8% other anticoagulant treatments. Use of NOACs decreased with worsening renal impairment (none 58.5%, moderate 49.6%, severe 25.7%) and, in younger versus older patients with moderate renal impairment (33.1% vs. 56.1%). In routine practice, there are more elderly and renally impaired patients with VTE than represented in RCTs. Decreasing renal function, but not older age, was associated with less NOAC use. Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT02596230.Graphic abstractDecreasing renal function, particularly in the subgroup with CrCl < 30 mL/min, but not older age, was associated with less use of nonvitamin K antagonist oral anticoagulants (NOACs). Nevertheless, more than half of the older patients with moderate renal impairment received a NOAC as their oral anticoagulant.

Background Patients with infective endocarditis (IE) have an elevated risk of renal dysfunction because of extensive systemic inflammation and use of nephrotoxic antibiotics. In this randomized, placebo-controlled trial, we investigated whether perioperative sodium bicarbonate administration could attenuate postoperative renal dysfunction in patients with IE undergoing cardiac surgery. Methods Seventy patients randomly received sodium chloride ( n  = 35) or sodium bicarbonate ( n  = 35). Sodium bicarbonate was administered as a 0.5 mmol/kg loading dose for 1 h commencing with anesthetic induction, followed by a 0.15 mmol/kg/h infusion for 23 h. The primary outcome was peak serum creatinine (SCr) level during the first 48 h postoperatively. The incidence of acute kidney injury, SCr level, estimated glomerular filtration rate, and major morbidity endpoints were assessed postoperatively. Results The peak SCr during the first 48 h postoperatively (bicarbonate vs. control: 1.01 (0.74, 1.37) mg/dl vs. 0.88 (0.76, 1.27) mg/dl, P  = 0.474) and the incidence of acute kidney injury (bicarbonate vs. control: 29% vs. 23%, P  = 0.584) were similar in both groups. The postoperative increase in SCr above baseline was greater in the bicarbonate group than in the control group on postoperative day 2 (0.21 (0.07, 0.33) mg/dl vs. 0.06 (0.00, 0.23) mg/dl, P  = 0.028) and postoperative day 5 (0.23 (0.08, 0.36) mg/dl vs. 0.06 (0.00, 0.23) mg/dl, P  = 0.017). Conclusions Perioperative sodium bicarbonate administration had no favorable impact on postoperative renal function and outcomes in patients with IE undergoing cardiac surgery. Instead, it was associated with possibly harmful renal effects, illustrated by a greater increase in SCr postoperatively, compared to control. Trial registration ClinicalTrials.gov, NCT01920126 . Registered on 31 July 2013.

To establish equations for the estimation of glomerular filtration rates (eGFRs) based on serum creatinine (SCr) and/or serum cystatin C (SCysC) in Chinese patients with chronic kidney disease (CKD), and to compare the new equations with both the reference GFR (rGFR) and the literature equations to evaluate their applicability. The 788 Chinese CKD patients were randomly divided into two groups, the training group and the testing group, to establish new eGFR-formulas based on serum CysC and to validate the established formulas, respectively. (99m)Tc-DTPA clearance (as the rGFR), serum Cr, and serum CysC were determined for all patients, and GFR was calculated using the Cockcroft-Gault equation (eGFR1), the MDRD formula (eGFR2), the CKD-EPI formulas (eGFR3, eGFR4), and the Chinese eGFR Investigation Collaboration formulas (eGFR5, eGFR6). The accuracy of each eGFR was compared with the rGFR. The training and testing groups' mean GFRs were 50.84±31.36 mL/min/1.73 m(2) and 54.16±29.45 mL/min/1.73 m(2), respectively. The two newly developed eGFR formulas were fitted using iterative computation: [Formula: see text] and [Formula: see text]. Significant correlation was observed between each eGFR and the rGFR. However, proportional errors and constant errors were observed between rGFR and eGFR1, eGFR2, eGFR4, eGFR5 or eGFR6, and constant errors were observed between eGFR3 and rGFR, as revealed by the Passing & Bablok plot analysis. The Bland-Altman analysis illustrated that the 95% limits of agreement of all equations exceeded the previously accepted limits of <60 mL/min •1.73 m(2), except the equations of eGFR7 and eGFR8. The newly developed formulas, eGFR7 and eGFR8, provide precise and accurate GFR estimation using serum CysC detection alone or in combination with serum Cr detection. Differences in detection methods should be carefully considered when choosing literature eGFR equations to avoid misdiagnosis and mistreatment.

AimPredicting progression in diabetic kidney disease (DKD) is critical to improving outcomes. We sought to develop/validate a machine-learned, prognostic risk score (KidneyIntelX™) combining electronic health records (EHR) and biomarkers.MethodsThis is an observational cohort study of patients with prevalent DKD/banked plasma from two EHR-linked biobanks. A random forest model was trained, and performance (AUC, positive and negative predictive values [PPV/NPV], and net reclassification index [NRI]) was compared with that of a clinical model and Kidney Disease: Improving Global Outcomes (KDIGO) categories for predicting a composite outcome of eGFR decline of ≥5 ml/min per year, ≥40% sustained decline, or kidney failure within 5 years.ResultsIn 1146 patients, the median age was 63 years, 51% were female, the baseline eGFR was 54 ml min−1 [1.73 m]−2, the urine albumin to creatinine ratio (uACR) was 6.9 mg/mmol, follow-up was 4.3 years and 21% had the composite endpoint. On cross-validation in derivation (n = 686), KidneyIntelX had an AUC of 0.77 (95% CI 0.74, 0.79). In validation (n = 460), the AUC was 0.77 (95% CI 0.76, 0.79). By comparison, the AUC for the clinical model was 0.62 (95% CI 0.61, 0.63) in derivation and 0.61 (95% CI 0.60, 0.63) in validation. Using derivation cut-offs, KidneyIntelX stratified 46%, 37% and 17% of the validation cohort into low-, intermediate- and high-risk groups for the composite kidney endpoint, respectively. The PPV for progressive decline in kidney function in the high-risk group was 61% for KidneyIntelX vs 40% for the highest risk strata by KDIGO categorisation (p < 0.001). Only 10% of those scored as low risk by KidneyIntelX experienced progression (i.e., NPV of 90%). The NRIevent for the high-risk group was 41% (p < 0.05).ConclusionsKidneyIntelX improved prediction of kidney outcomes over KDIGO and clinical models in individuals with early stages of DKD.

Background Low 24-hour urine volume (24UV) may be a significant risk factor for decline in kidney function. We therefore aimed to study associated markers and possible determinants of 24UV in a sample of the Swiss population. Methods The cross-sectional Swiss Salt Study included a population-based sample of 1535 (746 men and 789 women) individuals from three linguistic regions of Switzerland. Data from 1300 subjects were available for the present analysis. 24UV was measured using 24-hour urine collection. Determinants of 24UV were identified using multivariable linear regression models. Results In bivariate analysis, 24UV was higher in women compared to men (2000 ml/24 h [interquartile range (IQR): 1354, 2562] versus 1780 ml/24 h [IQR: 1244, 2360], p = 0.002). In multivariable regression analyses, independent associated markers of 24UV were female sex (β = 280, 95% confidence interval [CI]: 174, 386, p < 0.0001), fluid intake (β = 604, 95% CI: 539, 670, p < 0.0001), sodium excretion (β = 4.2, 95% CI: 3.4, 4.9, p < 0.0001) age (β = 6.6, CI: 3.4, 9.7, p < .0001), creatinine clearance (β = 2.4, CI: 0.2, 4.6, p = 0.04), living in the German-speaking part of Switzerland (β = 124, CI: 29, 219, p = 0.01), alcohol consumption (β = 41, CI: 9, 73, p = 0.01 for increasing categories of alcohol consumption), body mass index (β = −32, CI: -45, -18, p < 0.0001), current smoking (β = −146, CI: -265, -26, p = 0.02), and consumption of meat and cold cut (β = −56, CI: -108, -5, p = 0.03). Conclusion In this large population-based, cross-sectional study, we found several strong and independent correlates for 24UV. These findings may be important to improve our understanding in the development of chronic kidney disease.

Chronic kidney disease (CKD) is serious and common, yet recognition and public health responses are limited. To describe clinical features of, prevalence of, major risk factors for, and care for CKD among patients treated in 2 large US health care systems. This cohort study collected data from the Center for Kidney Disease Research, Education, and Hope (CURE-CKD) registry, an electronic health record-based registry jointly curated and sponsored by Providence St Joseph Health and the University of California, Los Angeles. Patients were adults and children with CKD (excluding end-stage kidney disease) and adults at risk of CKD (ie, with diabetes, hypertension, or prediabetes) identified by laboratory values, vital signs, prescriptions, and administrative codes. Data were collected from January 2006 through December 2017, with analyses performed from March 2019 through November 2019. Diabetes, hypertension, and prediabetes. Clinical and demographic characteristics, prevalence, and prescribed medications. Of 2 625 963 adults and children in the sample, 606 064 adults (23.1%) with CKD had a median (interquartile range [IQR]) age of 70 (59-81) years, with 338 785 women (55.9%) and 434 474 non-Latino white individuals (71.7%). A total of 12 591 children (0.4%) with CKD had a median (IQR) age of 6 (1-13) years, with 7079 girls (56.2%) and 6653 non-Latino white children (52.8%). Median (IQR) estimated glomerular filtration rate was 53 (41-61) mL/min/1.73 m2 among adults and 70 (50-95) mL/min/1.73 m2 in children. Prevalence rates for CKD in adults were 4.8% overall (606 064 of 12 669 700) with 1.6% (93 644 of 6 011 129) during 2006 to 2009, 5.7% (393 455 of 6 903 084) during 2010 to 2013, and 8.4% (683 574 of 8 179 860) during 2014 to 2017 (P < .001). A total of 226 693 patients (37.4%) had category 3a CKD; 100 239 (16.5%), category 3b CKD; 39 125 (6.5%), category 4 CKD; and 20 328 (3.4%), category 5 CKD. Among adults with CKD, albuminuria and proteinuria assessments were available in 52 551 (8.7%) and 25 035 (4.1%) patients, respectively. A renin-angiotensin system inhibitor was prescribed to 124 575 patients (20.6%), and 204 307 (33.7%) received nonsteroidal anti-inflammatory drugs or proton pump inhibitors. Of 1 973 258 adults (75.1%) at risk, one-quarter had diabetes or prediabetes (512 299 [26.0%]), nearly half had hypertension (955 812 [48.4%]), and one-quarter had both hypertension and diabetes or prediabetes (505 147 [25.6%]). This registry-based cohort study revealed a burgeoning number of patients with CKD and its major risk factors. Rates of identification and use of kidney protective agents were low, while potential nephrotoxin use was widespread, underscoring the pressing need for practice-based improvements in CKD prevention, recognition, and treatment.

To characterize the use of cystatin C (cysC) across and within hospitals. This 2-part study first evaluated access to cysC testing across 129 hospitals in the state of Minnesota, using a telephone-based survey. Second, granular data from a single center (Mayo Clinic) with on-site, rapid-turnaround testing (<1 day) and automated estimated glomerular filtration rate (eGFR) reporting was used to describe temporal patterns. The characteristics of hospitals that offered cysC testing and of patients who underwent rapid cysC testing at Mayo Clinic between January 1, 2011, and March 31, 2018, were described. Poisson regression analyzed temporal trends in cysC testing. Of the 114 hospitals (88%) that responded to the statewide survey, cysC was available in 91 (80%), but only 3 of 91 (3%) reported a turnaround time of <1 day. At Mayo Clinic, cysC use increased from 0.74 tests per 1000 patient-days in 2011 to 14 tests per 1000 patient-days in 2018 (P=.004). Of the 3774 patients with cysC tests, the mean first available eGFR was 46 mL/min per 1.73 m2 using cysC and 59 mL/min per 1.73 m2 using serum creatinine (P<.001). CysC testing was used across all intensities of care and was ordered by a variety of specialties. Nephrology was consulted in only 42% of cases. In the hospital, rapid-turnaround cysC testing is necessary for practical use but was not widely available in Minnesota. When available, a marked increase in cysC testing was observed over the study timeframe. Additional research is needed to determine optimal strategies for implementation of cysC within hospitals.

The reliability of serum 1,5-anhydroglucitol (1,5-AG) in patients with type 2 diabetes and renal insufficiency remains controversial. To evaluate the relationship between renal function and serum 1,5-AG and to assess the extent to which renal function influences 1,5-AG. A total of 5337 participants with type 2 diabetes were enrolled. The measured glomerular filtration rate (mGFR) was assayed using 99mTc-DTPA dynamic renal scintigraphy. All subjects were stratified into 5 groups based on mGFR (≥120 [n = 507], 90-120 [n = 2015], 60-90 [n = 2178], 30-60 [n = 604], and <30 mL/min/1.73 m2 [n = 33]). Overall, the serum 1,5-AG and mGFR levels were 3.3 (1.7-7.0) μg/mL and 88.6 ± 24.1 mL/min/1.73 m2, respectively. mGFR was found to be negatively correlated with 1,5-AG levels (r = -0.189, P < .001). Multiple linear regression revealed that mGFR was independently and negatively related to serum 1,5-AG after adjusting for covariates including hemoglobin A1c (HbA1c; P < .001). In subgroups with mGFR ≥ 30 mL/min/1.73 m2, the correlation coefficients between 1,5-AG and HbA1c, fasting plasma glucose, postprandial plasma glucose, and the differences between postprandial and fasting plasma glucose remained significant (range, -0.126 to -0.743, all P < .01). However, the link between 1,5-AG and traditional glycemic markers was attenuated in individuals with mGFR < 30 mL/min/1.73 m2. Sensitivity analysis after excluding anemic patients showed similar results regarding the relationship between serum 1,5-AG and HbA1c across the mGFR subgroups. Although we observed a weak inverse correlation (r = -0.189) between mGFR and serum 1,5-AG in type 2 diabetes, 1,5-AG remains a valid marker for assessing glucose control in subjects with mild or moderate renal dysfunction.