Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure and has few treatment options. Metformin is well tolerated and safe in other patient populations. The primary objective of this clinical trial was to determine the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus. STUDY DESIGN: Prospective randomized controlled double-blind clinical trial. SETTING & PARTICIPANTS: 51 adults aged 30-60 years with ADPKD, without diabetes, and an estimated glomerular filtration rate (eGFR) 50-80 mL/min/1.73 m2. EXPOSURE: Metformin (maximum dose 2,000 mg/d) or placebo for 12 months. OUTCOME: Coprimary end points were the percentage of participants in each group prescribed at the end of the 12-month period: (1) the full randomized dose or (2) at least 50% of the randomized dose. Secondary and exploratory outcomes were the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in eGFR over a 12-month period. RESULTS: The participants' mean age was 48 ± 8 (SD) years, and eGFR was 70 ± 14 mL/min/1.73 m2. The metformin group had no cases of lactic acidosis, and there was 1 episode of mild hypoglycemia in each group. Participants in the metformin group reported more adverse symptoms, mostly related to the gastrointestinal tract. Eleven of 22 metformin-treated participants (50%) completed the treatment phase on the full dose compared with 23 of 23 in the placebo group (100%). In the metformin group, 82% of participants tolerated at least 50% of the dose, compared with 100% in the placebo group. In exploratory analyses, changes in htTKV or eGFR were not significantly different between the groups. LIMITATIONS: Short study duration. CONCLUSIONS: We found that 50% or more of the maximal metformin dose was safe and well tolerated over 12 months in patients with ADPKD. Safety of other preparations of metformin as well as its efficacy should be tested in future clinical trials. FUNDING: Government and philanthropic grants (NIDDK and the Zell Foundation). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02903511.

Mineral bone disease in autosomal dominant polycystic kidney disease.

Mice with disruption of Pkd1 in osteoblasts demonstrate reduced bone mineral density, trabecular bone volume and cortical thickness. To date, the bone phenotype in adult patients with autosomal dominant polycystic kidney disease (ADPKD) with stage I and II chronic kidney disease has not been investigated. To examine this, we characterized biochemical markers of mineral metabolism, examined bone turnover and biology, and estimated risk of fracture in patients with ADPKD. Markers of mineral metabolism were measured in 944 patients with ADPKD and other causes of kidney disease. Histomorphometry and immunohistochemistry were compared on bone biopsies from 20 patients with ADPKD with a mean eGFR of 97 ml/min/1.73m2 and 17 healthy individuals. Furthermore, adults with end stage kidney disease (ESKD) initiating hemodialysis between 2002-2013 and estimated the risk of bone fracture associated with ADPKD as compared to other etiologies of kidney disease were examined. Intact fibroblast growth factor 23 was higher and total alkaline phosphatase lower in patients with compared to patients without ADPKD with chronic kidney disease. Compared to healthy individuals, patients with ADPKD demonstrated significantly lower osteoid volume/bone volume (0.61 vs. 1.21%) and bone formation rate/bone surface (0.012 vs. 0.026 µm3/µm2/day). ESKD due to ADPKD was not associated with a higher risk of fracture as compared to ESKD due to diabetes (age adjusted incidence rate ratio: 0.53 (95% confidence interval 0.31, 0.74) or compared to other etiologies of kidney disease. Thus, individuals with ADPKD have lower alkaline phosphatase, higher circulating intact fibroblast growth factor 23 and decreased bone formation rate. However, ADPKD is not associated with higher rates of bone fracture in ESKD.

Mineralocorticoid Antagonism and Vascular Function in Early Autosomal Dominant Polycystic Kidney Disease: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Vascular dysfunction, characterized by impaired vascular endothelial function and increased large-elastic artery stiffness, is evident early in autosomal dominant polycystic kidney disease (ADPKD) and is an important predictor of cardiovascular events and mortality. Aldosterone excess has been implicated in the development of endothelial dysfunction and arterial stiffness, in part by causing increased oxidative stress and inflammation. We hypothesized that aldosterone antagonism would reduce vascular dysfunction in patients with early-stage ADPKD. STUDY DESIGN: Prospective, randomized, controlled, double-blind, clinical trial. SETTING & PARTICIPANTS: 61 adults aged 20 to 55 years with ADPKD, estimated glomerular filtration rate ≥ 60mL/min/1.73m2, and receiving a renin-angiotensin-aldosterone system inhibitor. INTERVENTION: Spironolactone (maximum dose, 50mg/d) or placebo for 24 weeks. OUTCOMES: Change in brachial artery flow-mediated dilation (FMDBA) was the primary end point and change in carotid-femoral pulse-wave velocity (CFPWV) was the secondary end point. RESULTS: 60 participants completed the trial. Participants had a mean age of 34±10 (SD) years, 54% were women, and 84% were non-Hispanic white. Spironolactone did not change FMDBA (8.0% ± 5.5% and 7.8% ± 4.3% at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 8.4% ± 6.2% and 8.0% ± 4.6%; P=0.9for comparison of change between groups) or CFPWV (640±127 and 603±101cm/s at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 659±138 and 658±131cm/s; P=0.1). Brachial systolic blood pressure was reduced with spironolactone (median change, -6 [IQR, -15, 1] vs -2 [IQR, -7, 10] mm Hg in the placebo group; P=0.04). Spironolactone did not change the majority of circulating and/or endothelial cell markers of oxidative stress/inflammation and did not change vascular oxidative stress. LIMITATIONS: Low level of baseline vascular dysfunction; lack of aldosterone measurements. CONCLUSIONS: 24 weeks of aldosterone antagonism reduced systolic blood pressure without changing vascular function in patients with early-stage ADPKD. FUNDING: NIDDK, NIH National Center for Advancing Translational Sciences, and the Zell Family Foundation. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01853553.

Value of an aggregate index in describing the impact of trends in antimicrobial resistance for Escherichia coli.

BACKGROUND: Drug resistance indexes (DRIs) quantify the cumulative impact of antimicrobial resistance on the likelihood that a given pathogen will be susceptible to antimicrobial therapy. OBJECTIVE: To derive a DRI for community urinary tract infections caused by Escherichia coli in British Columbia for the years 2007 to 2010, and to examine trends over time and across patient characteristics. METHODS: Indication-specific utilization data were obtained from BC PharmaNet for outpatient antimicrobial prescriptions linked to diagnostic information from physician payment files. Resistance data for E coli urinary isolates were obtained from BC Biomedical Laboratories (now part of LifeLabs Medical Laboratory Services). DRIs were derived by multiplying the rate of resistance to a specific antimicrobial by the proportional rate of utilization for that drug class and aggregating across drug classes. Higher index values indicate more resistance. RESULTS: Adaptive-use DRIs remained stable over time at approximately 18% (95% CI 17% to 18%) among adults ≥15 years of age and approximately 28% (95% CI 26% to 31%) among children <15 years of age. Similar results were observed when proportional drug use was restricted to the baseline year (ie, a static-use model). Trends according to age group suggest a U-shaped distribution, with the highest DRIs occurring among children <10 years of age and adults ≥65 years of age. Males had consistently higher DRIs than females for all age groups. CONCLUSIONS: The stable trend in adaptive-use DRIs over time suggests that clinicians are adapting their prescribing practices for urinary tract infections to local resistance patterns. Results according to age group reveal a higher probability of resistance to initial therapy among young children and elderly individuals.

HISTORIQUE: Les indices de pharmacorésistance (IPR) quantifient l'effet cumulatif de la résistance antimicrobienne sur la probabilité qu'un pathogène donné soit susceptible à un traitement antimicrobien. OBJECTIF: Dériver l'IPR des infections urinaires d'origine non nosocomiale causées par l'Escherichia coli en Colombie-Britannique entre 2007 et 2010 et examiner les tendances au fil du temps et selon les caractéristiques des patients. MÉTHODOLOGIE: Les données sur les indications d'utilisation, tirées du système PharmaNet de la Colombie-Britannique relativement aux prescriptions d'antimicrobiens, étaient liées à l'information diagnostique prélevée dans les dossiers d'honoraires des médecins. Les données de résistance reliées aux isolats urinaires d'E coli provenaient des BC Biomedical Laboratories (qui font désormais partie des LifeLabs Medical Laboratory Services). Les IPR étaient dérivés en multipliant le taux de résistance à un antimicrobien précis au taux proportionnel d'utilisation de cette classe de médicament et en les regroupant entre les classes de médicaments. Des indices de valeur plus élevés indiquaient une plus forte résistance. RÉSULTATS: Les IPR à utilisation adaptée demeuraient stables au fil du temps, à environ 18 % (95 % IC 17 % à 18 %) chez les adultes de 15 ans et plus, et à environ 28 % (95 % IC 26 % à 31 %) chez les enfants de moins de 15 ans. Les chercheurs ont observé des résultats similaires lorsque l'utilisation proportionnelle des médicaments était restreinte à l'année de référence (modèle à utilisation statique). Les tendances en fonction des groupes d'âge laissent supposer une répartition en U, les IPR les plus élevés se produisant chez les enfants de moins de dix ans et les adultes de 65 ans et plus. Dans tous les groupes d'âge, les hommes présentaient un IPR plus élevé que les femmes. CONCLUSIONS: D'après la tendance stable des IPR à utilisation adaptée au fil du temps, les cliniciens adaptent leurs pratiques de prescription pour le traitement des infections urinaires aux profils de résistance locaux. Les résultats en fonction des groupes d'âge révèlent une plus forte probabilité de résistance à la thérapie initiale chez les jeunes enfants et les personnes âgées.

Statin therapy in patients with early-stage autosomal dominant polycystic kidney disease: Design and baseline characteristics.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort. AIMS: The aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD. METHODS: One hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m2 will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years. OUTCOMES: The primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress. CONCLUSION: This study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing. REGISTRATION: This study is registered on Clinicaltrials.gov # NCT03273413.

Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a randomized, placebo-controlled, double-blind trial, 68 children/young adults 6-25 years of age with ADPKD and eGFR>80 ml/min per 1.73 m2 were randomized to either curcumin supplementation (25 mg/kg body weight per day) or placebo administered in powder form for 12 months. The coprimary outcomes were brachial artery flow-mediated dilation and aortic pulse-wave velocity. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume) by magnetic resonance imaging. In a subgroup of participants ≥18 years, vascular oxidative stress was measured as the change in brachial artery flow-mediated dilation following an acute infusion of ascorbic acid. RESULTS: Enrolled participants were 18±5 (mean ± SD) years, 54% were girls, baseline brachial artery flow-mediated dilation was 9.3±4.1% change, and baseline aortic pulse-wave velocity was 512±94 cm/s. Fifty-seven participants completed the trial. Neither coprimary end point changed with curcumin (estimated change [95% confidence interval] for brachial artery flow-mediated dilation [percentage change]: curcumin: 1.14; 95% confidence interval, -0.84 to 3.13; placebo: 0.33; 95% confidence interval, -1.34 to 2.00; estimated difference for change: 0.81; 95% confidence interval, -1.21 to 2.84; P=0.48; aortic pulse-wave velocity [centimeters per second]: curcumin: 0.6; 95% confidence interval, -25.7 to 26.9; placebo: 6.5; 95% confidence interval, -20.4 to 33.5; estimated difference for change: -5.9; 95% confidence interval, -35.8 to 24.0; P=0.67; intent to treat). There was no curcumin-specific reduction in vascular oxidative stress or changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared with placebo. CONCLUSIONS: Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD, NCT02494141. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_07_CJN08950621.mp3.

Curcumin therapy to treat vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease: Design and baseline characteristics of participants.

Although often considered to be a disease of adults, complications of autosomal dominant polycystic kidney disease (ADPKD) begin in childhood. While the hallmark of ADPKD is the development and continued growth of multiple renal cysts that ultimately result in loss of kidney function, cardiovascular complications are the leading cause of death among affected patients. Vascular dysfunction (endothelial dysfunction and large elastic artery stiffness) is evident very early in the course of the disease and appears to involve increased oxidative stress and inflammation. Treatment options to prevent cardiovascular disease in adults with ADPKD are limited, thus childhood may represent a key therapeutic window. Curcumin is a safe, naturally occurring polyphenol found in the Indian spice turmeric. This spice has a unique ability to activate transcription of key antioxidants, suppress inflammation, and reduce proliferation. Here we describe our ongoing randomized, placebo-controlled, double-blind clinical trial to assess the effect of curcumin therapy on vascular function and kidney growth in 68 children and young adults age 6-25 years with ADPKD. Baseline demographic, vascular, and kidney volume data are provided. This study has the potential to establish a novel, safe, and facile therapy for the treatment of arterial dysfunction, and possibly renal cystic disease, in an understudied population of children and young adults with ADPKD.

At-a-glance - The impact of poisoning-related mortality on life expectancy at birth in Canada, 2000 to 2016. / Aperçu - Incidence de la mortalité par intoxication sur l'espérance de vie à la naissance au Canada (2000-2016).

Increases in opioid-related mortality have contributed to declines in life expectancy at birth in the United States and British Columbia. Canadian national mortality data from 2000 to 2016 were analyzed to determine the contribution of poisoning-related mortality to changes in life expectancy at birth by age group and sex. From 2000 to 2016, life expectancy at birth increased by almost three years; however, mortality due to unintentional poisonings, including those involving opioids, curbed this increase by 0.16 years. Although a national decrease in life expectancy at birth has not been observed in Canada during this period, current trends suggest that the national opioid overdose crisis will continue to attenuate gains to life expectancy.

RÉSUMÉ: L'augmentation de la mortalité liée aux opioïdes a contribué à des baisses de l'espérance de vie à la naissance aux États-Unis et en Colombie-Britannique. Nous avons analysé les données nationales sur la mortalité au Canada entre 2000 et 2016 afin de déterminer dans quelle mesure les décès liés aux intoxications avaient influencé l'espérance de vie à la naissance selon le groupe d'âge et le sexe. Entre 2000 et 2016, l'espérance de vie à la naissance a augmenté de presque trois ans, mais la mortalité attribuable aux intoxications accidentelles, dont celles par opioïdes, a réduit cette hausse de 0,16 an. Même si l'espérance de vie à la naissance n'a pas globalement diminué au Canada pendant cette période, les tendances actuelles laissent présager que la crise nationale des surdoses d'opioïdes va continuer à amoindrir les gains relatifs à l'espérance de vie.

Antibiotic prescribing by dentists has increased: Why?

BACKGROUND: Although the overall rate of antibiotic prescribing has been declining in British Columbia, Canada, the authors conducted a study to explain the increased rate of prescribing by dentists. METHODS: The authors obtained anonymized, line-listed data on outpatient prescriptions from 1996 to 2013 from a centralized, population-based prescription database, including a variable coding prescriber licensing body. Analyses used Anatomical Therapeutic Classification standard codes and defined daily dose (DDD) values. The authors normalized prescribing rates to the population and expressed the rates in DDDs per 1,000 inhabitants per day (DID). The Canadian Dental Association released a webinar that invited correspondence from dentists about the drivers of the trend. RESULTS: From 1996 to 2013, overall antibiotic use declined from 18.24 DID to 15.91 DID, and physician prescribing declined 18.2%, from 17.25 DID to 14.11 DID. However, dental prescribing increased 62.2%, from 0.98 DID to 1.59 DID, and its proportionate contribution increased from 6.7% to 11.3% of antibiotic prescriptions. The rate of prescribing increased the most for dental patients 60 years or older. Communication from dentists in Canada and the United States identified the following explanatory themes: unnecessary prescriptions for periapical abscess and irreversible pulpitis; increased prescribing associated with dental implants and their complications; slow adoption of guidelines calling for less perioperative antibiotic coverage for patients with valvular heart disease and prosthetic joints; emphasis on cosmetic practices reducing the surgical skill set of average dentists; underinsurance practices driving antibiotics to be a substitute for surgery; the aging population; and more dental registrants per capita. CONCLUSIONS: Emerging themes for dental prescribing should be explored further in future studies; however, themes already identified may guide priorities in antibiotic stewardship for continuing dental education sessions. PRACTICAL IMPLICATIONS: Antibiotic prescribing should be reviewed to make sure that we are compliant with guidelines. Most practitioners will find opportunities to prescribe less often and for shorter durations.

Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease.

BACKGROUND AND OBJECTIVES: In autosomal dominant polycystic kidney disease (ADPKD), progressive kidney cyst formation commonly leads to ESRD. Because important manifestations of ADPKD may be evident in childhood, early intervention may have the largest effect on long-term outcome. Statins are known to slow progressive nephropathy in animal models of ADPKD. This randomized double-blind placebo-controlled phase III clinical trial was conducted from 2007 to 2012 to assess the effect of pravastatin on height-corrected total kidney volume (HtTKV) and left ventricular mass index (LVMI) by magnetic resonance imaging (MRI) and urine microalbumin excretion (UAE) in children and young adults with ADPKD. DESIGNS, SETTING, PARTICIPANTS, & MEASUREMENTS: There were 110 pediatric participants with ADPKD and normal kidney function receiving lisinopril who were randomized to treatment with pravastatin or placebo for a 3-year period with evaluation at 0, 18, and 36 months. The primary outcome variable was a ≥ 20% change in HtTKV, LVMI, or UAE over the study period. RESULTS: Ninety-one participants completed the 3-year study (83%). Fewer participants receiving pravastatin achieved the primary endpoint compared with participants receiving placebo (69% versus 88%; P=0.03). This was due primarily to a lower proportion reaching the increase in HtTKV (46% versus 68%; P=0.03), with similar findings observed between study groups for LVMI (25% versus 38%; P=0.18) and UAE (47% versus 39%; P=0.50). The percent change in HtTKV adjusted for age, sex, and hypertension status over the 3-year period was significantly decreased with pravastatin (23% ± 3% versus 31% ± 3%; P=0.02). CONCLUSIONS: Pravastatin is an effective agent to slow progression of structural kidney disease in children and young adults with ADPKD. These findings support a role for early intervention with pravastatin in this condition.

Removable silicon insertion stiffeners for neural probes using polyethylene glycol as a biodissolvable adhesive.

Flexible polymer probes are expected to enable extended interaction with neural tissue by minimizing damage from micromotion and reducing inflammatory tissue response. However, their flexibility prevents them from being easily inserted into the tissue. This paper describes an approach for temporarily attaching a silicon stiffener with biodissolvable polyethylene glycol (PEG) so that the stiffener can be released from the probe and extracted shortly after probe placement. A novel stiffener design with wicking channels, along with flip-chip technology, enable accurate alignment of the probe to the stiffener, as well as uniform distribution of the PEG adhesive. Insertion, extraction, and electrode function were tested in both agarose gel and a rat brain. Several geometric and material parameters were tested to minimize probe displacement during stiffener extraction. We demonstrated average probe displacement of 28 ± 9 µm.

Effect of statin therapy on disease progression in pediatric ADPKD: design and baseline characteristics of participants.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney condition and is associated with important renal and cardiovascular manifestations in childhood. Renal cystic disease can be documented in some cases as early as in utero. Early intervention is critical if the long-term complications of this condition, including end-stage renal disease, are to be ameliorated. Here we describe our ongoing randomized double-blind placebo-controlled phase III clinical trial to assess the effect of pravastatin treatment on renal and cardiovascular disease progression in 107 children and young adults age 8-22 years with ADPKD who are receiving the angiotensin converting enzyme inhibitor lisinopril. Baseline demographic and laboratory data are provided. Results of this study could markedly impact the standard of care for evaluation and treatment of ADPKD in this population.