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BACKGROUND: Distal diuretics are considered less effective than loop diuretics in CKD. However, data to support this perception are limited. METHODS: To investigate whether distal diuretics are noninferior to dietary sodium restriction in reducing BP in patients with CKD stage G3 or G4 and hypertension, we conducted a 6-week, randomized, open-label crossover trial comparing amiloride/hydrochlorothiazide (5 mg/50 mg daily) with dietary sodium restriction (60 mmol per day). Antihypertension medication was discontinued for a 2-week period before randomization. We analyzed effects on BP, kidney function, and fluid balance and related this to renal clearance of diuretics. RESULTS: A total of 26 patients (with a mean eGFR of 39 ml/min per 1.73 m(2)) completed both treatments. Dietary sodium restriction reduced sodium excretion from 160 to 64 mmol per day. Diuretics produced a greater reduction in 24-hour systolic BP (SBP; from 138 to 124 mm Hg) compared with sodium restriction (from 134 to 129 mm Hg), as well as a significantly greater effect on extracellular water, eGFR, plasma renin, and aldosterone. Both interventions resulted in a similar decrease in body weight and NT-proBNP. Neither approaches decreased albuminuria significantly, whereas diuretics did significantly reduce urinary angiotensinogen and β2-microglobulin excretion. Although lower eGFR and higher plasma indoxyl sulfate correlated with lower diuretic clearance, the diuretic effects on body weight and BP at lower eGFR were maintained. During diuretic treatment, higher PGE2 excretion correlated with lower free water clearance, and four patients developed mild hyponatremia. CONCLUSIONS: Distal diuretics are noninferior to dietary sodium restriction in reducing BP and extracellular volume in CKD. Diuretic sensitivity in CKD is maintained despite lower diuretic clearance. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: DD-study: Diet or Diuretics for Salt-sensitivity in Chronic Kidney Disease (DD), NCT02875886

Clinical guidance is often sought when prescribing drugs for patients with primary mitochondrial disease. Theoretical considerations concerning drug safety in patients with mitochondrial disease may lead to unnecessary withholding of a drug in a situation of clinical need. The aim of this study was to develop consensus on safe medication use in patients with a primary mitochondrial disease. A panel of 16 experts in mitochondrial medicine, pharmacology, and basic science from six different countries was established. A modified Delphi technique was used to allow the panellists to consider draft recommendations anonymously in two Delphi rounds with predetermined levels of agreement. This process was supported by a review of the available literature and a consensus conference that included the panellists and representatives of patient advocacy groups. A high level of consensus was reached regarding the safety of all 46 reviewed drugs, with the knowledge that the risk of adverse events is influenced both by individual patient risk factors and choice of drug or drug class. This paper details the consensus guidelines of an expert panel and provides an important update of previously established guidelines in safe medication use in patients with primary mitochondrial disease. Specific drugs, drug groups, and clinical or genetic conditions are described separately as they require special attention. It is important to emphasise that consensus-based information is useful to provide guidance, but that decisions related to drug prescribing should always be tailored to the specific needs and risks of each individual patient. We aim to present what is current knowledge and plan to update this regularly both to include new drugs and to review those currently included. European Molecular Biology OrganizationEuropean Molecular Biology Organization (EMBO) [ALTF 268-2016]; Fondazione TelethonFondazione Telethon [GUP09004, GSP16001]; Instituto de salud carlosInstituto de Salud Carlos III [ISCIII-FIS PI17/00109]; Medical Research Council (GB) [MR/S002065/1]; National Institute Food and AgricultureUnited States Department of Agriculture (USDA)National Institute of Food and Agriculture [1017927]; UK Medical Research CouncilMedical Research Council UK (MRC) [13/NE/0326]; Wellcome TrustWellcome Trust [203105/Z/16/Z, 204709/Z/16/Z]; European Molecular Biology Organisation; Prinses Beatrix Spierfonds [WO.R17-19]; National Institute for Health ResearchNational Institute for Health Research (NIHR) [CL2016-01-003]; Newcastle upon Tyne Hospitals NHS Foundation Trust; Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC); Newcastle University; Wellcome; European UnionEuropean Union (EU); Instituto de Salud Carlos IIIInstituto de Salud Carlos III; Virginia Tech; National Institute of Food and AgricultureUnited States Department of Agriculture (USDA)National Institute of Food and Agriculture; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [HL123647]; Medical Research CouncilMedical Research Council UK (MRC) [L016354]; Action Medical Research; Biomedical Research Centre; Muscular Dystrophy UK European Molecular Biology Organization, Grant/Award Number: ALTF 268-2016; Fondazione Telethon, Grant/Award Numbers: GUP09004, GSP16001; Instituto de salud carlos, Grant/Award Number: ISCIII-FIS PI17/00109; Medical Research Council (GB), Grant/Award Number: MR/S002065/1; National Institute Food and Agriculture, Grant/Award Number: 1017927; UK Medical Research Council, Grant/Award Number: 13/NE/0326; Wellcome Trust, Grant/Award Numbers: 203105/Z/16/Z, 204709/Z/16/Z; European Molecular Biology Organisation; Prinses Beatrix Spierfonds, Grant/Award Number: WO.R17-19; National Institute for Health Research, Grant/Award Number: CL2016-01-003; Newcastle upon Tyne Hospitals NHS Foundation Trust; Biotechnology and Biological Sciences Research Council; Newcastle University; Wellcome; European Union; Instituto de Salud Carlos III; Virginia Tech; National Institute of Food and Agriculture; National Institutes of Health, Grant/Award Number: HL123647; Medical Research Council, Grant/Award Number: L016354; Action Medical Research; Biomedical Research Centre; Muscular Dystrophy UK