Function Decline In Adults Research Articles

Causal evidence of healthy diets, long-term PM2.5 exposure, and kidney function decline in adults: An observational study

BackgroundEvidence of a causal relationship between long-term PM2.5 exposure and reduced kidney function is lacking in developing countries, and the potential moderating role and mechanisms of healthy dietary patterns remain unexplored. MethodsParticipants in this study were drawn from a national cohort from China. We used high-resolution, near real-time data to calculate PM2.5 exposure, blood biomarker data to assess kidney function, and detailed food surveillance data to assess dietary patterns. We used rigorously tested instrumental variable models to examine the causal effects of air pollution and the moderating role of healthy diet, and causal mediation models to explore potential mechanisms. ResultsThis study included 4447 adults with an average eGFRmdrd(CN) of 82.13 mL/min/1.73 m2. Each unit increase in PM2.5 was associated with a decrease in eGFRmdrd(CN) of -0.7 mL/min/1.73 m2 (95% confidential interval: -1.1– -0.3). Healthy dietary patterns was found able to mitigate the harm of PM2.5. Males are more susceptible to the effects of PM2.5 than females. PM2.5-related lipoprotein cholesterol variation was found one of the pathways in which PM2.5 impair kidney function. ConclusionsThe findings reveal that PM2.5 exposure would impair kidney function, especially for males. Embracing healthy dietary patterns can help alleviate the harm. Long-term exposure to PM2.5 may impair kidney function by causing variations in lipoprotein cholesterol.

FRI619 Kidney Magnetic Resonance Imaging Reveals Altered Tissue Architecture In Young Persons With Type 1 And 2 Diabetes

Abstract Disclosure: S. Poon: None. K. Nash: None. Y. Choi: None. L. Li: None. P. Prasad: None. D. Raalte: Other; Self; consulting relationships with Boehringer Ingelheim, Eli Lilly, Merck and Sanofi, and receives research operating funding from AstraZeneca, Boehringer Ingelheim-Eli Lilly Diabetes Alliance, MSD. A. Karihaloo: Employee; Self; Novo Nordisk. A. Sawyer: None. P. Bjornstad: Advisory Board Member; Self; AstraZeneca, Bayer, Lilly, Boehringer Ingelheim, Novo Nordisk, and XORTX. Other; Self; PB reports serving or having served as a consultant for AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, LG Chemistry, Sanofi, Novo Nordisk, and Horizon Pharma. Background: Apparent diffusion coefficient (ADC) by magnetic resonance imaging (MRI) provides information about the microstructure and cellular organization of the kidney, and has been linked with kidney function decline in adults with chronic kidney disease. However, it is unclear whether alterations in tissue architecture or cellular density are also present in young persons with type 1 and 2 diabetes. Accordingly, the objective of this analysis was to determine early changes in ADC among young persons with and without diabetes. Materials and Method: Kidney MRIs were performed in 37 lean controls (age: 18±6 years, 54% female, eGFR: 106±19 ml/min/1.73m2), 28 participants with youth-onset T1D (age: 20±4 years, 50% female, diabetes duration: 9±6 years, HbA1c: 8.3±1.3%, eGFR: 110±19 ml/min/1.73m2) and 30 participants with youth-onset T2D (age: 17±4 years, 62% female, diabetes duration: 2±2 years, HbA1c: 7.4±2.2%, eGFR: 127±24 ml/min/1.73m2). All scans were performed on 3T whole-body scanners. A single reader at The NorthShore University HealthSystem analyzed all images while blinded to participants’ clinical information. Lower values of cortical ADC on diffusion-weighted MRI may indicate increased cellular density and are often used to estimate fibrosis. Estimated GFR (eGFR) were calculated by Full Age Spectrum serum creatinine equation. We performed multivariable linear regression models adjusted for age and sex. Results: Compared to lean controls (age and sex-adjusted means ± standard errors (SE): (1722±22 × 10−6 mm2/s), young persons with T1D (1636±28 × 10−6 mm2/s, p=0.02) and T2D (1612±27 × 10−6 mm2/s, p=0.002) exhibited lower cortical ADC. Despite younger age and shorter diabetes duration, young persons with T2D had numerically lower cortical ADC compared to those with T1D, although the difference did not reach statistical significance. Higher age and male sex were associated with lower cortical ADC (β±SE: −7.5±2.8 x 10−6 mm2/s per 1 year of age, p=0.009; β±SE: −71.1±28.5 x 10−6 mm2/s per 1 year for male sex, p=0.008) in multivariable models. Lower eGFR was associated with lower cortical ADC (β±SE: 2.3±0.8 x 10−6 mm2/s per 1 ml/min/1.73m2 increment eGFR, p=0.005). HbA1c and urine albumin-to-creatinine ratio did not associate significantly with cortical ADC in multivariable models. Conclusion: Young persons with diabetes exhibit lower cortical ADC compared to healthy lean controls, suggesting alternations in microstructure and cellular density and potentially early signs of fibrosis. Additionally, despite shorter duration of disease and younger age, participants with T2D had the lowest cortical ADC values among the 3 groups. Further research is needed to investigate the role of cortical ADC in predicting kidney function decline in young individuals with diabetes, as well as molecular determinants of the alterations in microstructure and cellular density. Presentation: Friday, June 16, 2023

Inverse Association Between Baseline Plasma Selenium Concentrations and Risks of Renal Function Decline in Hypertensive Adults

The kidney has the highest level of selenium (Se) in the body, but the role of plasma Se in chronic kidney disease is uncertain. We aimed to investigate the longitudinal association between baseline plasma Se and renal function decline in adults with hypertension and to explore possible effect modifiers. This was a post hoc analysis of 935 men and women with hypertension aged 40 to 75 years from a folic-acid intervention trial (the China Stroke Primary Prevention Trial) in China. The baseline plasma Se was analyzed both as a continuous variable and as tertiles. The primary outcome was a rapid decline in renal function, defined as a mean decline in the estimated glomerular filtration rate of ≥ 5 mL/(min × 1.73 m2) per year. The median follow-up duration from baseline to outcome was 4.4 years. After multivariate adjustment, there was an inverse association between plasma Se and a rapid decline in renal function (per 10-unit increment; OR: 0.85; 95% CI: 0.73, 0.99). When the baseline plasma Se was assessed as tertiles, compared to the lowest tertile (<74.5 μg/L), a lower trend of the primary outcome was found in the second tertile (74.5 to < 89.4 μg/L; OR: 0.60; 95% CI: 0.34, 1.07) and the highest tertile (89.4 to <150 μg/L; OR: 0.42; 95% CI: 0.22, 0.80; Ptrend = 0.006). Furthermore, the Se-renal association was more pronounced among participants with folic acid treatment or with a higher baseline folate concentration (both Pinteraction values < 0.05). In this sample of Chinese adults with hypertension, baseline plasma Se concentrations were inversely associated with the risk of renal function decline. The China Stroke Primary Prevention Trial was registered at clinicaltrials.gov as NCT00794885.

Biomarkers of asthma relapse and lung function decline in adults with spontaneous asthma remission: A population-based cohort study.

The extent to which biomarkers of asthma activity persist in spontaneous asthma remission and whether such markers are associated with future respiratory outcomes remained unclear. We investigated the association between sub-clinical inflammation in adults with spontaneous asthma remission and future asthma relapse and lung function decline. The Tasmanian Longitudinal Health Study is a population-based cohort (n=8583). Biomarkers of systemic inflammation were measured on participants at age 45, and latent profile analysis was used to identify cytokine profiles. Bronchial hyperresponsiveness (BHR) and nitric oxide products in exhaled breath condensate (EBC NOx) were measured at age 50. Participants with spontaneous asthma remission at ages 45 (n=466) and 50 (n=318) were re-evaluated at age 53, and associations between baseline inflammatory biomarkers and subsequent asthma relapse and lung function decline were assessed. We identified three cytokine profiles in adults with spontaneous asthma remission: average (34%), Th2-high (42%) and Th2-low (24%). Compared to the average profile, a Th2-high profile was associated with accelerated decline in post-BD FEV1 /FVC (MD -0.18% predicted per-year; 95% CI -0.33, -0.02), while a Th2-low profile was associated with accelerated decline in both post-BD FEV1 (-0.41%; -0.75, -0.06) and post-BD FVC (-0.31%; -0.62, 0.01). BHR and high TNF-α during spontaneous remission were associated with an increased risk of asthma relapse. In contrast, we found no evidence of association between EBC NOx and either asthma relapse or lung function decline. BHR and serum inflammatory cytokines have prognostic value in adults with spontaneous asthma remission. At-risk individuals with BHR, Th2-high or Th2-low cytokine profiles may benefit from closer monitoring and on-going follow-up.

Perspectives on Drug Development in Early ADPKD.

Perspectives on Drug Development in Early ADPKD.

Estimated GFR in autosomal dominant polycystic kidney disease: errors of an unpredictable method

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) causes about 10% of cases of end stage renal disease. Disease progression rate is heterogeneous. Tolvaptan is presently the only specific therapeutic option to slow kidney function decline in adults at risk of rapidly progressing ADPKD with chronic kidney disease (CKD) stages 1–4. Thus, a reliable evaluation of kidney function in patients with ADPKD is needed.MethodsWe evaluated the agreement between measured (mGFR) and estimated glomerular filtration rate (eGFR) by 61 formulas based on creatinine and/or cystatin-C (eGFR) in 226 ADPKD patients with diverse GFR values, from predialysis to glomerular hyperfiltration. Also, we evaluated whether incorrect categorization of CKD using eGFR may interfere with the indication and/or reimbursement of Tolvaptan treatment.ResultsNo formula showed acceptable agreement with mGFR. Total Deviation Index averaged about 50% for eGFR based on creatinine and/or cystatin-C, indicating that 90% of the estimations of GFR showed bounds of error of 50% when compared with mGFR. In 1 out of 4 cases with mGFR < 30 ml/min, eGFR provided estimations above this threshold. Also, in half of the cases with mGFR between 30 and 40 ml/min, formulas estimated values < 30 ml/min.ConclusionsThe evaluation of renal function with formulas in ADPKD patients is unreliable. Extreme deviation from real renal function is quite frequent. The consequences of this error deserve attention, especially in rapid progressors who may benefit from starting treatment with tolvaptan and in whom specific GFR thresholds are needed for the indication or reimbursement. Whenever possible, mGFR is recommended.Graphic abstract

Clinical practice recommendations for prehabilitation and post-operative rehabilitation for arthroplasty: A scoping review.

The rising need for arthroplasty (joint replacement) has resulted in a significant increase in wait-times. Longer surgical wait-times may further exacerbate functional decline in adults with osteoarthritis as well as delay postoperative functional recovery. This review aims to better inform rehabilitation care provision before (prehabilitation) and after (post-rehabilitation) hip or knee arthroplasty based on recommendations from clinical practice guidelines (CPGs). This scoping review used a three-stage process to screen and extract articles, which resulted in 123 articles reviewed for analysis. Included CPGs were in the English language and focussed on rehabilitation interventions or practices involving adult patients preparing for or recuperating from hip and knee arthroplasty (published 2009-2020). Patient assessments, use of assistive devices, as well as self-management and education programs were recommended before and after arthroplasty. Physiotherapy was recommended to support post-operative rehabilitation. Conversely, there was limited evidence supporting recommendations for or against physiotherapy during the prehabilitation phase of the arthroplasty care journey. The findings from this review highlight the current gap in high-quality evidence supporting hip and knee arthroplasty rehabilitation CPGs before and after surgery. Findings warrant additional research to ensure patients are best prepared for surgery and supported for optimal recovery.

The relationship between regional amyloid deposition and executive function decline in adults with Down syndrome

AbstractBackgroundAn increase in global deposition of amyloid is known to be related to declines in a variety of cognitive domains among people with Down syndrome (DS). Less known is the correspondence between increased regional amyloid load and declines in specific functions. Since a decline in frontal lobe functions (e.g., attention, inhibitory control, shifting, motivation) is considered by many to be a key early indicator of AD dementia in adults with DS, the current study aims to identify regional amyloid changes that are associated with executive function (EF) decline in both pre‐symptomatic and symptomatic adults with DS.MethodLongitudinal data from participants of the Biomarkers of Alzheimer’s Disease in Adults with Down Syndrome (ADDS) consortium, at all stages of AD (pre‐clinical, prodromal, and clinical dementia), were examined. Forty‐two participants received amyloid PET and MRI scans and extensive neuropsychological testing of select cognitive functions at two time points, approximately 16 months apart. Changes in amyloid accumulation in the anterior and posterior cingulate, frontal lobe, superior temporal lobe, and parietal lobe were hypothesized to be related to performance on three measures of EF: Rapid Assessment of Developmental Disabilities (RADD) Digit Span Forward and Stroop Cats and Dogs Naming and Switching. PET data were co‐registered with T1‐weighted MRIs, converted to SUVR units using the cerebellum cortex reference region, and spatially normalized using a DS MRI template in MNI space. We modeled relationships between amyloid SUVR and EF using multiple regression in SPM12 with covariates accounting for time difference between the scans and neurocognitive assessment acquisition and sex.ResultsConsistent with our hypothesis, we found clear associations between increased amyloid deposition and decline in EF in people with DS in approximately the same regions as found in neurotypical populations without AD (Figure 1). Frontal lobe amyloid deposition disrupts dorsal and ventral attention network processes.ConclusionsWe found amyloid deposition in specific functional networks correspond to EF decline in a population with lifelong amyloid production and cognitive impairments. These findings bring us one step closer to validating biomarkers of early AD in DS.

Executive Functioning in Adults with Down Syndrome: Machine-Learning-Based Prediction of Inhibitory Capacity.

The study of executive function decline in adults with Down syndrome (DS) is important, because it supports independent functioning in real-world settings. Inhibitory control is posited to be essential for self-regulation and adaptation to daily life activities. However, cognitive domains that most predict the capacity for inhibition in adults with DS have not been identified. The aim of this study was to identify cognitive domains that predict the capacity for inhibition, using novel data-driven techniques in a sample of adults with DS (n = 188; 49.47% men; 33.6 ± 8.8 years old), with low and moderate levels of intellectual disability. Neuropsychological tests, including assessment of memory, attention, language, executive functions, and praxis, were submitted to Random Forest, support vector machine, and logistic regression algorithms for the purpose of predicting inhibition capacity, assessed with the Cats-and-Dogs test. Convergent results from the three algorithms show that the best predictors for inhibition capacity were constructive praxis, verbal memory, immediate memory, planning, and written verbal comprehension. These results suggest the minimum set of neuropsychological assessments and potential intervention targets for individuals with DS and ID, which may optimize potential for independent living.

Association of Depressive Symptoms with Rapid Kidney Function Decline in Adults with Normal Kidney Function.

The relationship of depressive symptoms with kidney function remains poorly investigated. We aimed to evaluate the prospective association between depressive symptoms and rapid decline in kidney function in Chinese adults with normal kidney function. A total of 4763 participants with eGFR≥60 ml/min per 1.73 m2 at baseline were enrolled from the China Health and Retirement Longitudinal Study. Baseline depressive symptoms were determined using a ten-item Center for Epidemiologic Studies Depression scale with a cutoff score of greater than or equal to ten to define high depressive symptoms. The GFR was estimated by a combination of serum creatinine and cystatin C. The primary outcome was rapid decline in kidney function, defined as an annualized decline in eGFR of ≥5 ml/min per 1.73 m2. Secondary outcome was defined as an annualized decline in eGFR of ≥5 ml/min per 1.73 m2 and to a level of <60 ml/min per 1.73 m2 at the exit visit. During a median follow-up of 4 years (interquartile range, 3.92-4.00), 260 (6%) participants developed rapid decline in kidney function. Overall, there was a significant positive association between baseline depressive symptoms and rapid decline in kidney function (per five-scores increment; adjusted odds ratio, 1.15; 95% confidence interval, 1.03 to 1.28) after adjustments for major demographic, clinical, or psychosocial covariates. Consistently, compared with participants with low depressive symptoms (total Center for Epidemiologic Studies Depression scale score less than ten), a significantly higher risk of rapid decline in kidney function was found among those with high depressive symptoms (total Center for Epidemiologic Studies Depression scale score greater than or equal to ten; adjusted odds ratio, 1.39; 95% confidence interval, 1.03 to 1.88). Similar results were found for the secondary outcome (per five-scores increment; adjusted odds ratio, 1.26; 95% confidence interval, 1.06 to 1.51). High depressive symptoms were significantly associated with a higher risk of rapid kidney function decline among Chinese adults with normal kidney function.

FC 130RANDOMIZED, PLACEBO-CONTROLLED, PHASE 3B TRIAL OF TOLVAPTAN IN THE TREATMENT OF CHILDREN AND ADOLESCENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): 1-YEAR DATA

Abstract Background and Aims Tolvaptan (TOL) is a vasopressin V2 receptor antagonist that inhibits total kidney volume (TKV) growth and kidney function decline in adults with rapidly progressing ADPKD. The therapeutic potential of TOL in pediatric patients at risk of early disease progression has not been previously reported. We conducted a clinical trial of TOL in children and adolescents with early manifesting ADPKD to evaluate pharmacodynamic properties and preliminary efficacy and safety information in this age group. Method This was a Phase 3b, 2-part trial (EudraCT: 2016-000187-42; ClinicalTrials.gov: NCT02964273). Phase A (reported here) was a 1-year, randomized, double-blind, placebo (PBO)-controlled, multicenter trial; Phase B is an ongoing, 2-year, open-label extension. Subjects had to be diagnosed with ADPKD (presence of renal cysts with family history and/or genetic diagnosis), with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and body weight ≥20 kg. The target population was aged 12-17 years; subjects aged 4-11 years were also allowed to enter if eligibility criteria were met. Starting and maintenance TOL/PBO doses were based on body weight. The co-primary endpoints were changes from baseline in spot urine osmolality (Uosm) and specific gravity at Week 1; additional endpoints were the 12-month changes in TKV and eGFR. Safety and tolerability were monitored. In this exploratory trial, outcomes were summarized descriptively, with no statistical comparisons planned between groups. Results Of 91 subjects enrolled (66 aged 12–17 years and 25 aged &amp;lt;12 years), 48 were randomized to TOL and 43 to PBO. Among enrolled subjects, there was a history of hypertension in 23.1%, proteinuria 15.4%, kidney pain 12.1%, and hepatic cysts 6.6%. Mean changes (±SD) from baseline in spot Uosm and specific gravity at Week 1 were greater with TOL vs PBO: -386 (284) vs -93 (332) mOsm/kg and -0.009 (0.007) vs -0.002 (0.008), respectively. In subjects aged 12–17 years (1 subject with tuberous sclerosis and ADPKD excluded as an outlier), the mean % TKV change (±SD) from baseline to Month 12 was 4.6% (9.1) for TOL and 7.7% (9.3) for PBO (Figure 1). Mean change (±SD) in eGFR from Day 7 to Month 12 in subjects ages 12–17 years was 0.4 (10.3) mL/min/1.73 m2 for TOL and -3.5 (10.9) mL/min/1.73 m2 for PBO (Figure 2). The most frequent treatment-emergent adverse events during Phase A were (TOL vs PBO): polyuria (25.0% vs 2.3%), blood creatinine increased (18.8% vs 4.7%), pollakiuria (18.8% vs 0.0%), cough (14.6% vs 11.6%), nocturia (14.6% vs 4. 7%), thirst (14.6% vs 2.3%), abdominal pain (12.5% vs 7.0%), constipation (10.4% vs 2.3%), and orthostatic hypotension (10.4% vs 0.0%). Potentially clinically significant increases in creatinine (&amp;gt;1.5 x baseline) occurred in 4 TOL subjects and no PBO subject. No subject had elevated transaminases or drug-induced liver injury. Serious adverse events were reported in 1 TOL subject (viral pericarditis) and 6 PBO, none considered related to treatment. One subject discontinued due to pollakiuria (TOL) and 1 due to dizziness (PBO). Conclusion TOL demonstrated activity indicative of effective V2 receptor antagonism in children and adolescents with ADPKD. In addition, our trial yielded preliminary results suggestive of efficacy in slowing TKV growth and eGFR decline with acceptable tolerability, warranting further investigation in pediatric patients with ADPKD. The 2-year, Phase B extension to this trial is ongoing. Sponsored by OPDC, Inc.

DMD – THERAPY: P.294 Does steroid therapy influence pulmonary function decline in adults with Duchenne muscular dystrophy after loss of ambulation?

Data from longitudinal paediatric Duchenne Muscular Dystrophy (DMD) cohorts has shown significant benefits of corticosteroids (CS) in patient treatment and management. Additionally, current scientific literature suggests that CS therapy delays the onset of pulmonary decline by approximately two years. However, there is limited data on the effects of CS in patients after loss of ambulation. Despite the updated in 2018 standards of care for DMD, there is still inconsistency in clinical care for non-ambulant patients across the UK.

WS23.3 The average rate of lung function decline in adults with cystic fibrosis in the United Kingdom: data from the UK Cystic Fibrosis Registry

WS23.3 The average rate of lung function decline in adults with cystic fibrosis in the United Kingdom: data from the UK Cystic Fibrosis Registry

Average rate of lung function decline in adults with cystic fibrosis in the United Kingdom: Data from the UK CF registry

BackgroundRate of change in lung function is used as a measure of disease progression and a predictor of mortality in individuals with cystic fibrosis (CF). The aim of this study was to determine the national rate of decline in percent predicted Forced Expiratory Volume in 1 second (ppFEV1) in adults in the UK accounting for age, sex and pancreatic status. MethodsData on ppFEV1 for adults with CF, excluding those post lung transplantation, was extracted from the UK CF registry between 2015 and 2017. Multilevel modelling was conducted to calculate the annual rate of change in ppFEV1 accounting for age, sex and pancreatic status. ResultsOverall annual ppFEV1 decline was -1.52% (95% CI: -1.66 to -1.38%) and -0.55% (95% CI: -0.86 to -0.23%) in pancreatic insufficient (PI) and sufficient (PS) adults respectively. In PI individuals, females had a greater rate of decline in ppFEV1. There were differences between age groups. The fastest rate of decline was observed in the 18–28 years group, declining -1.76% (95% CI: -2.06 to -1.46) and -1.61% (95% CI: -1.91 to -1.31) per year in PI females and males respectively. The pattern between the sexes and age categories was more inconsistent in the PS group. ConclusionsThe average annual rates of decline in lung function in adults with CF in the UK are similar to reports from other large international cohorts. Pancreatic status has a marked impact on average rate of decline. Younger adults, especially females, have a faster rate of decline and need close monitoring.

A Post Hoc Analysis of Statin Use in Tolvaptan Autosomal Dominant Polycystic Kidney Disease Pivotal Trials.

Tolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl-CoA reductase inhibitors (statins). This post hoc analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use. The trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (n=1644) or placebo (n=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone. No differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (e.g., musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference -2.4%; 95% confidence interval, -11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; -7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3× upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; -2.0% to 4.7%). Tolvaptan has been used safely in combination with statins in clinical trials. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3.

Rapid lung function decline in adults with early-stage cystic fibrosis lung disease

RationaleThe prevalence of adults living with cystic fibrosis (CF) who have early-stage lung disease is increasing. ObjectivesDescribe the prevalence and evaluate spirometric risk factors associated with the subgroup of patients with early-stage lung disease and FEV1 decline of ≥5% predicted/year. MethodsRetrospective cohort study of patients ≥18 years with FEV1% predicted ≥80% included in the US CF Foundation Patient Registry from 2010–2013. Regression models were developed to estimate FEV1 rate of decline. Multivariable logistic analysis was used to assess if spirometric risk factors were associated with FEV1 decline. Measurements and main results3,029 subjects were in the study cohort. Approximately 15% of the cohort had a substantial decline in lung function ≥5% predicted/year. In multivariable models adjusted for confounders, FEV1/FVC ratio <0.8 (Odds Ratio (OR) 1.63, 95% confidence interval (CI) 1.31 to 2.02) and history of FEV1% predicted variability (OR 2.35,95%CI 1.74 to 3.18) were associated with rapid lung function decline. ConclusionsEven among adults with early-stage lung disease, approximately 15% are shown to progress and experience a large decline in lung function. This reinforces the concept that lung function in early-stage CF is not normal or mild. Rather, lung function decline may be delayed, but not avoided, in these individuals. Variability in FEV1% predicted and airway obstruction as measured by FEV1/FVC ratio may identify individuals at increased risk of decline. Adults with early-stage lung disease should be followed in clinic to monitor for onset of decline.

The Association between Obesity Phenotypes and Early Renal Function Decline in Adults without Hypertension, Dyslipidemia, and Diabetes.

BackgroundThe prevalence of chronic kidney disease is increasing worldwide. Several studies have suggested that obesity is associated with early renal dysfunction. However, little is known about the relationship between obesity phenotypes and early renal function decline. Therefore, this study aimed to identify the relationship between obesity phenotypes and early renal function decline in adults without hypertension, dyslipidemia, and diabetes.MethodsWe conducted a cross-sectional analysis of clinical and anthropometric data from 1,219 patients who underwent a routine health checkup in 2014. We excluded adults with cardiovascular disease, renal disease, diabetes, hypertension, dyslipidemia, or low glomerular filtration rate (<60 mL/min/1.73 m2). Renal function was determined according to the estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C equation.ResultsAge, sex, body mass index, waist circumference, triglyceride, low-density lipoprotein, and fasting glucose had an association with the estimated glomerular filtration rate. After adjusting for age, sex, smoking status, and alcohol intake, the odds ratios of the metabolically abnormal normal weight and metabolically abnormal obese phenotypes for the presence of low estimated glomerular filtration rates were 1.807 (95% confidence interval, 1.009– 3.236) and 1.834 (95% confidence interval, 1.162–2.895), compared with the metabolically healthy normal weight phenotype. However, the metabolically healthy obese phenotype did not show a significant association with early renal function decline.ConclusionIn this cross-sectional study, we confirmed the association between the metabolically abnormal normal weight and metabolically abnormal obese phenotypes and early kidney function decline in adults without hypertension, dyslipidemia, and diabetes.

Population Pharmacokinetic Analyses and Model Validation of Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease.

Tolvaptan is the first approved drug treatment to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). The objective is to develop (1091 subjects, 7335 observations) and validate (678 subjects, 3012 observations) a population pharmacokinetic model to describe tolvaptan pharmacokinetics in ADPKD subjects. The final model was evaluated with a bootstrapping method. The final model was internally and externally evaluated using visual predictive checks (VPC). Pharmacokinetics was best described by a 1‐compartmental model with 0‐order absorption, nonlinear relative bioavailability (F1), and first‐order elimination. Accounting for changes in F1 significantly improved the model: as the dose increased from 15 mg to 120 mg, F1 decreased by 36%. Population estimates for clearance/F (CL/F), volume of distribution/F (Vd/F), duration of absorption (D1), the highest dose at which F1 is lowest, and the amount of dose at which F1 is 50% were 12.6 L·h‐1, 110 L, 0.58 hour, 182 mg, and 166 mg, respectively. The interindividual variability was 64% in CL/F, 70% in Vd/F, and 238% in D1. Residual variability was described by a combined‐error model. The VPC (500 data sets simulated) showed that 76% to 92% of the observed data fell within the 90% prediction intervals. The model stability assessed by a 1000‐run bootstrap analysis showed that the mean parameter estimates of data were within 10% of those obtained with the final model. The developed model is robust and stable. Internal and external validation confirmed the model ability to describe the data optimally.

A Practical Guide for Treatment of Rapidly Progressive ADPKD with Tolvaptan.

In the past, the treatment of autosomal dominant polycystic kidney disease (ADPKD) has been limited to the management of its symptoms and complications. Recently, the US Food and Drug Administration (FDA) approved tolvaptan as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing ADPKD. Full prescribing information approved by the FDA provides helpful guidelines but does not address practical questions that are being raised by nephrologists, internists, and general practitioners taking care of patients with ADPKD, and by the patients themselves. In this review, we provide practical guidance and discuss steps that require consideration before and after prescribing tolvaptan to patients with ADPKD to ensure that this treatment is implemented safely and effectively. These steps include confirmation of diagnosis; identification of rapidly progressive disease; implementation of basic renal protective measures; counseling of patients on potential benefits and harms; exclusions to use; education of patients on aquaresis and its expected consequences; initiation, titration, and optimization of tolvaptan treatment; prevention of aquaresis-related complications; evaluation and management of liver enzyme elevations; and monitoring of treatment efficacy. Our recommendations are made on the basis of published evidence and our collective experiences during the randomized, clinical trials and open-label extension studies of tolvaptan in ADPKD.

Effect of Coaching to Increase Water Intake on Kidney Function Decline in Adults With Chronic Kidney Disease

In observational studies, increased water intake is associated with better kidney function. To determine the effect of coaching to increase water intake on kidney function in adults with chronic kidney disease. The CKD WIT (Chronic Kidney Disease Water Intake Trial) randomized clinical trial was conducted in 9 centers in Ontario, Canada, from 2013 until 2017 (last day of follow-up, May 25, 2017). Patients had stage 3 chronic kidney disease (estimated glomerular filtration rate [eGFR] 30-60 mL/min/1.73 m2 and microalbuminuria or macroalbuminuria) and a 24-hour urine volume of less than 3.0 L. Patients in the hydration group (n = 316) were coached to drink more water, and those in the control group (n = 315) were coached to maintain usual intake. The primary outcome was change in kidney function (eGFR from baseline to 12 months). Secondary outcomes included 1-year change in plasma copeptin concentration, creatinine clearance, 24-hour urine albumin, and patient-reported overall quality of health (0 [worst possible] to 10 [best possible]). Of 631 randomized patients (mean age, 65.0 years; men, 63.4%; mean eGFR, 43 mL/min/1.73 m2; median urine albumin, 123 mg/d), 12 died (hydration group [n = 5]; control group [n = 7]). Among 590 survivors with 1-year follow-up measurements (95% of 619), the mean change in 24-hour urine volume was 0.6 L per day higher in the hydration group (95% CI, 0.5 to 0.7; P < .001). The mean change in eGFR was -2.2 mL/min/1.73 m2 in the hydration group and -1.9 mL/min/1.73 m2 in the control group (adjusted between-group difference, -0.3 mL/min/1.73 m2 [95% CI, -1.8 to 1.2; P = .74]). The mean between-group differences (hydration vs control) in secondary outcomes were as follows: plasma copeptin, -2.2 pmol/L (95% CI, -3.9 to -0.5; P = .01); creatinine clearance, 3.6 mL/min/1.73 m2 (95% CI, 0.8 to 6.4; P = .01); urine albumin, 7 mg per day (95% CI, -4 to 51; P = .11); and quality of health, 0.2 points (95% CI, -0.3 to 0.3; P = .22). Among adults with chronic kidney disease, coaching to increase water intake compared with coaching to maintain the same water intake did not significantly slow the decline in kidney function after 1 year. However, the study may have been underpowered to detect a clinically important difference. clinicaltrials.gov Identifier: NCT01766687.