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Spironolactone is effective at reducing blood pressure in patients with uncontrolled resistant hypertension. However, the use of spironolactone in patients with chronic kidney disease can be restricted by hyperkalaemia. We evaluated use of the potassium binder patiromer to allow more persistent use of spironolactone in patients with chronic kidney disease and resistant hypertension. In this phase 2 multicentre, randomised, double-blind, placebo-controlled study, we enrolled participants aged 18 years and older with chronic kidney disease (estimated glomerular filtration rate 25 to ≤45 mL/min per 1·73 m2) and uncontrolled resistant hypertension from 62 outpatient centres in ten countries (Bulgaria, Croatia, Georgia, Hungary, Ukraine, France, Germany, South Africa, the UK, and the USA). Patients meeting all eligibility criteria at the final screening visit were stratified by local serum potassium measurement (4·3 to <4·7 mmol/L vs 4·7 to 5·1 mmol/L) and history of diabetes. Participants were randomly assigned (1:1) with an interactive web response system to receive either placebo or patiromer (8·4 g once daily), in addition to open-label spironolactone (starting at 25 mg once daily) and their baseline blood pressure medications. Participants, the study team that administered treatments and measured blood pressure, and the investigators were masked to assigned treatment groups. Dose titrations were permitted after 1 week (patiromer) and 3 weeks (spironolactone). The primary endpoint was the between-group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomised patients (intention to treat). The study was registered with Clinicaltrials.gov, NCT03071263. Between Feb 13, 2017, and Aug 20, 2018, we screened 574 patients. 295 (51%) of 574 patients met all inclusion criteria and were randomly assigned to spironolactone in addition to double-blind treatment with either placebo (n=148) or patiromer (n=147). At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0–29·0; p<0·0001). Adverse events were mostly mild or moderate in severity and occurred in 79 (53%) of 148 patients in the placebo group and 82 (56%) of 147 patients in the patiromer group. In patients with resistant hypertension and chronic kidney disease, patiromer enabled more patients to continue treatment with spironolactone with less hyperkalaemia. Persistent spironolactone enablement in this population of patients has clinical relevance for the treatment of resistant hypertension. Relypsa, a Vifor Pharma Group Company.

Background Clinical decision support systems (CDSSs) enable the automated, real-time detection of situations associated with a risk of adverse drug events (ADEs). However, the effectiveness of CDSS in reducing ADEs has yet to be demonstrated. We have chosen to focus on the detection of ADE such as hyperkalemia and/or acute kidney injury (AKI), which are common among hospitalized older adults. The present study’s primary objective is to use a CDSS to reduce the number of ADEs (such as AKI and/or hyperkalemia) that occur in hospitalized older adults. Methods This is a multicenter, stepped-wedge, cluster-randomized study involving five hospitals. Each hospital will start with a control period (i.e., routine care, during which each center’s CDSS is deactivated) and then switch to an intervention period (during which the CDSS is activated). The intervention will be the use of a CDSS and a strategy for managing and transmitting alerts to clinical pharmacists. The rules concerning AKI and hyperkalemia have been drafted and reviewed by a multidisciplinary group. Each rule created in the CDSS is associated with a standardized procedure, based on a review of the literature. Older patients (aged 65 or over) admitted to a participating general medicine ward, a surgical ward, or obstetrics ward will be eligible for inclusion after the provision of verbal informed consent. Discussion This study will assess the effectiveness of the CDSS in reducing the incidence of AKI and hyperkalemia. The implementation of the CDSS can assist clinical pharmacists in their daily work and is expected to prevent ADEs. Trial registration ClinicalTrials.gov Identifier: NCT05923983. Registered February 02, 2023.

Background/Objectives: Whole-food plant-based diets (WFPBDs) are beneficial in managing hypertension in the general population but have not been well studied in chronic kidney disease (CKD), potentially due to concerns about hyperkalemia. We hypothesized that individuals with CKD 3 or 4 attending a 15-day WFPBD education program would achieve lower blood pressure compared to those who did not, without an increased risk of hyperkalemia. Methods: This was a pilot trial of 40 subjects with mild-to-moderate CKD and hypertension but without diabetes or proteinuria from a single academic center. The subjects were randomized to the 15-day education program or the control group. The changes in blood pressure, serum potassium, and other anthropometric and biochemical values were assessed. Results: Systolic blood pressure decreased from the baseline to day 15 in the intervention group by 8 mm Hg and increased in the control group by 2.7 mm Hg, although the difference in the blood pressure change did not reach statistical significance (p = 0.12). Diastolic blood pressure was not different between the two groups. Potassium changed by 0.01 mEq/L in the intervention group and −0.07 mEq/L in the control group (p = 0.52). The intervention subjects had significant decreases in body mass (−3.0 vs. −0.12 kg, p < 0.0001), total cholesterol (−39.4 vs. −5.0 mg/dL, p < 0.0001), low-density lipoprotein (−28.4 vs. −0.6 mg/dL, p < 0.0001), and high-density lipoprotein (−8.6 vs. −0.4 mg/dL, p = 0.006) compared to the controls. The changes in albumin and phosphorus were not different between the two groups. Conclusions: The subjects with mild-to-moderate CKD attending a 15-day WFPBD education program had a non-statistically significant reduction in systolic blood pressure without an increased risk of hyperkalemia compared to those who did not attend. The intervention subjects achieved significantly greater reductions in body mass and cholesterol without adverse effects on albumin or phosphorus. Larger and longer-duration trials using this approach in a diverse group of CKD patients are warranted.

Abstract Aims Hyperkalaemia risk precludes optimal renin–angiotensin–aldosterone system inhibitor use in patients with heart failure (HF), particularly those with chronic kidney disease (CKD). Patiromer is a sodium-free, non-absorbed potassium (K+)-binding polymer approved for the treatment of hyperkalaemia. In PEARL-HF, patiromer 25.2 g (fixed dose) prevented hyperkalaemia in HF patients with or without CKD initiating spironolactone. The current study evaluated the effectiveness of a lower starting dose of patiromer (16.4 g/day) followed by individualized titration in preventing hyperkalaemia and hypokalaemia when initiating spironolactone. Methods and results This open-label 8-week study enrolled 63 patients with CKD, serum K+ 4.3–5.1 mEq/L, and chronic HF, who, based on investigator opinion, should receive spironolactone. Eligible patients started spironolactone 25 mg/day and patiromer 16.8 g/day (divided into two doses), with patiromer titrated to maintain serum K+ 4.0–5.1 mEq/L. Mean (standard deviation) serum K+ was 4.78 (0.51) mEq/L at baseline; weekly values were 4.48–4.70 mEq/L during treatment. Serum K+ of 3.5–5.5 mEq/L at the end of study treatment (primary endpoint) was achieved by 57 (90.5%) patients; 53 (84.1%) had serum K+ 4.0–5.1 mEq/L. One patient (1.6%) developed hypokalaemia, and two patients (3.2%) developed hypomagnesaemia. Spironolactone was increased to 50 mg/day in all patients; 43 (68%) patients required one or more patiromer dose titration. Adverse events (AEs) occurred in 36 (57.1%) patients, with a low rate of discontinuations [four (6.3%) patients]. The most common AE was mild to moderate abdominal discomfort [four (6.3%) patients]. Conclusions In this open-label study, patiromer 16.8 g/day followed by individualized titration maintained serum K+ within the target range in the majority of patients with HF and CKD, all of whom were uptitrated to spironolactone 50 mg/day, patiromer was well tolerated, with a low incidence of hyperkalaemia, hypokalaemia, and hypomagnesaemia.

Background CKD is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is a potassium-binding medication that has been shown to reduce incidence of hyperkalaemia in CKD, non-CKD, and HF populations, which we propose will support maximisation of RAASi therapy. Methods We propose a 1:1 randomised, double-blind, placebo-controlled trial in which participants will receive either SZC or placebo. We will up-titrate participants’ RAASi therapy while monitoring their serum potassium levels and adjusting their SZC dose if necessary. Participants with CKD and HF will be recruited from CKD and HF clinics at St George’s Hospital. The total study period will be 18 months; 130 participants will be enrolled for approximately two months each following screening. Our primary outcome will be the proportion of participants who achieve maximum RAASi dose while maintaining normokalaemia. Secondary outcomes include participants reaching maximum RAASi dose without severe hyperkalaemia; time from randomisation to hyperkalaemia; time from randomisation to severe hyperkalaemia; number of RAASi dose escalations per participant; final doses of RAASi therapy; changes in quality of life score, eGFR, ACR, serum sodium, troponin T; number and duration of hospital admissions; and within-participant change in serum potassium compared to baseline. Discussion This trial will be the first to examine the use of SZC for the maximisation of RAASi dosing in patients with advanced CKD and HF. We will assess the impact of achieving target RAASi dosing on hospital admission rates and duration of stay, with the hope that optimum RAASi treatment will translate into reduced morbidity and improved QoL. If clinical benefit is demonstrated, we hope that the joint multidisciplinary CKD-HF approach will be expanded. Trial registration EudraCT number 2020–002946-18. Registered on 08 June 2020. Online record pending.

Background/Objectives: Recent guidelines for preterm parenteral nutrition (PN) recommend an earlier and higher intake of amino acids (AA) and energy to avoid postnatal catabolism and approximate normal fetal growth. Few investigations explored how early PN may affect electrolyte and water homeostasis. We performed a prospective observational trial to assess the effect of nutrient intake on electrolyte homeostasis and balance. Subjects/Methods: During 16 months, all infants ⩽32 weeks were eligible. In the first week of life, we recorded the following daily: electrolytes (plasma and 8-h urine collection), nutritional intake, urine output, body weight, and we calculated sodium (Na) and potassium (K) balance. Infants were divided, for analysis, into three groups of AA intake: low <1.5 g/kg/day (LAA), medium 1.5–2 g/kg/day (MAA) and high >2 g/kg/day (HAA). Results: A total of 154 infants were included. HAA group presented lower weight loss. Na balance was influenced by urine output and postnatal age, with little contribution of nutrition. Kalemia and K balance were mainly influenced by AA intake. K balance differed among groups: LAA, −2.3 mmol/kg/week; MAA, 1.1 mmol/kg/week; and HAA 2.6 mmol/kg/week ( P <0.0001). In the HAA group, plasma and urine K were significantly lower and non-oliguric hyperkalemia was reduced. Conclusions: Na homeostasis was very slightly modified by early nutrition, suggesting that a negative Na balance is obligatory after birth. We showed that AA intake strongly affects K balance, minimize hyperkalemia and reduces weight loss. As K balance is strictly linked to cellular metabolism, we speculate that early nutrition may inhibit cellular catabolism and reduce the contraction of intracellular water compartment.

As scintigraphy with [(111)In-DTPA(0)]octreotide has become a standard technique in analysing somatostatin receptor-receptor positive lesions such as neuroendocrine tumours, a logical next step is peptide receptor radionuclide therapy (PRRT). Initial studies on PRRT were performed with high doses of [(111)In-DTPA(0)]octreotide, and recently other radionuclides coupled to other somatostatin analogues have been used for this purpose. However, the dose delivered to the kidney is a major dose-limiting factor. Amino acid solutions have previously been used to reduce renal uptake of radioactivity, but these solutions have some disadvantages, i.e. their hyperosmolarity and their propensity to cause vomiting and metabolic changes. In this study we tested various amino acid solutions in patients receiving [(111)In-DTPA(0)]octreotide PRRT in order to assess their safety and their capacity to inhibit the renal uptake of radioactivity. Patients served as their own non-infused control. Renal radioactivity at 24 h following the injection of [(111)In-DTPA(0)]octreotide was inhibited by (1) a commercially available amino acid solution (AA) (21%+/-14%, P<0.02), (2) by 25 g (17%+/-9%, P<0.04), 50 g (15%+/-13%, P<0.04) or 75 g of lysine (44%+/-11%, P<0.001) and (3) by a combination of 25 g of lysine plus 25 g of arginine (LysArg) (33%+/-23%, P<0.01). Fluid infusion alone (500, 1,000 or 2,000 ml of saline/glucose) did not change renal uptake of radioactivity. In patients studied with 75 g of lysine (Lys75) and LysArg, serum potassium levels rose significantly. Maximal potassium levels were within the toxic range (6.3, 6.7 and 6.8 mmol/l) in three out of six patients infused with Lys75, whereas with LysArg the highest concentration measured was 6.0 mmol/l. Electrocardiographic analysis did not reveal significant changes in any of the patients. Vomiting occurred in 50% of patients infused with AA, but in only 6% of patients receiving no amino acid infusion (controls) and 9% of patients receiving LysArg. We conclude that co-infusion of Lys75 or LysArg results in a significant inhibition of renal radioactivity in PRRT, allowing higher treatment doses and thus resulting in higher tumour radiation doses. Because Lys75 produced serious hyperkalaemia, it is not suitable for clinical use. LysArg, however, is effective in offering renal protection in PRRT and is safe.

Background: Parenteral nutrition is commonly given to premature infants. It has previously been suggested that standardized parenteral nutrition (SPN) may offer nutritional advantages compared to individualized parenteral nutrition (IPN). However, whether the same level of biochemical control is assured with SPN and with IPN remains uncertain. Objectives: To compare fluid and electrolyte balance in preterm infants receiving IPN versus SPN in the first week of life. Methods: 107 infants born at <33 weeks gestation were prospectively evaluated. Serum and urinary creatinine and electrolyte concentration, urine volume, body weight, fluid, electrolyte and energy intakes were recorded daily. Results: 40 infants received IPN and 67 SPN. Infants in IPN had significantly more water and less sodium intake than those receiving SPN. Energy and amino acid intakes were significantly lower in IPN than in SPN groups. Incidence of hypernatremia and hyponatremia was similar in both groups. Nonoliguric hyperkalemia (NOHK) was significantly more frequent in IPN than in SPN (20.0 vs. 2.9%) and mean serum K + peak over the first 3 days was higher in IPN than in SPN (5.63 ± 1.05 vs. 4.91 ± 0.78 mmol/l). Weight loss (% of birth weight) at day 7 was significantly higher in IPN than in SPN (7.7 ± 5.8 vs. 4.2 ± 6.5) without differences in urine output/input fluid intake ratio and glomerular renal function between the two groups. Conclusions: There were no significant differences in water and sodium balance in preterm infants who received IPN versus SPN. The risk of NOHK was higher in IPN. Also, SPN significantly increased amino acid and caloric intakes, and it reduced early weight loss.

Despite recent therapeutic advances, chronic kidney disease (CKD) is one of the fastest growing global causes of death. This illustrates limitations of current therapeutic approaches and, potentially, unidentified knowledge gaps. For decades, renin-angiotensin-aldosterone system (RAAS) blockers have been the mainstay of therapy for CKD. However, they favor the development of hyperkalemia, which is already common in CKD patients due to the CKD-associated decrease in urinary potassium (K + ) excretion and metabolic acidosis. Hyperkalemia may itself be life-threatening as it may trigger potentially lethal arrhythmia, and additionally may limit the prescription of RAAS blockers and lead to low-K + diets associated to low dietary fiber intake. Indeed, hyperkalemia is associated with adverse kidney, cardiovascular, and survival outcomes. Recently, novel kidney protective therapies, ranging from sodium/glucose cotransporter 2 (SGLT2) inhibitors to new mineralocorticoid receptor antagonists have shown efficacy in clinical trials. Herein, we review K + pathophysiology and the clinical impact and management of hyperkalemia considering these developments and the availability of the novel K + binders patiromer and sodium zirconium cyclosilicate, recent results from clinical trials targeting metabolic acidosis (sodium bicarbonate, veverimer), and an increasing understanding of the role of the gut microbiota in health and disease.

Dyskalemias are often seen in children with chronic kidney disease (CKD). While hyperkalemia is common, with an increasing prevalence as glomerular filtration rate declines, hypokalemia may also occur, particularly in children with renal tubular disorders and those on intensive dialysis regimens. Dietary assessment and adjustment of potassium intake is critically important in children with CKD as hyperkalemia can be life-threatening. Manipulation of dietary potassium can be challenging as it may affect the intake of other nutrients and reduce palatability. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, has developed clinical practice recommendations (CPRs) for the dietary management of potassium in children with CKD stages 2–5 and on dialysis (CKD2–5D). We describe the assessment of dietary potassium intake, requirements for potassium in healthy children, and the dietary management of hypo- and hyperkalemia in children with CKD2–5D. Common potassium containing foods are described and approaches to adjusting potassium intake that can be incorporated into everyday practice discussed. Given the poor quality of evidence available, a Delphi survey was conducted to seek consensus from international experts. Statements with a low grade or those that are opinion-based must be carefully considered and adapted to individual patient needs, based on the clinical judgment of the treating physician and dietitian. These CPRs will be regularly audited and updated by the PRNT.