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Clinical Journal of the American... Aug 2023Sodium-glucose cotransporter 2 (SGLT2) inhibitors attenuate incident cardiovascular outcomes, irrespective of baseline GFR, in conservatively managed CKD. As this...
BACKGROUND
Sodium-glucose cotransporter 2 (SGLT2) inhibitors attenuate incident cardiovascular outcomes, irrespective of baseline GFR, in conservatively managed CKD. As this condition inexorably progresses to demanding KRT, drug withdrawal is supported by the current lack of evidence of safety of SGLT2 inhibitors in dialysis.
METHODS
This study was a prospective, single-center, open-label trial ( ClinicalTrials.gov identifier: NCT05343078 ) aimed at assessing the pharmacokinetic properties and safety of dapagliflozin in patients with kidney failure on regular dialysis regimens compared with those with type 2 diabetes and age- and sex-matched controls with normal kidney function. Peripheral blood samples were collected from both groups every 30 minutes for 4 hours and again after 48 hours after ingestion of dapagliflozin 10 mg, which occurred immediately before dialysis session initiation in the kidney failure group. This protocol occurred in drug-naïve patients and again after six daily doses of dapagliflozin to assess whether the drug had accumulated. The plasma and dialysate levels of dapagliflozin at each time point were determined by liquid chromatography and used to calculate pharmacokinetics parameters (peak concentration [C max ] and area under the plasma concentration-versus-time curve) for each participant.
RESULTS
Dapagliflozin C max was 117 and 97.6 ng/ml in the kidney failure and control groups, respectively, whereas the corresponding accumulation ratios were 26.7% and 9.5%. No serious adverse events were reported for either group. Dapagliflozin recovered from dialysate corresponded to 0.10% of the administered dose.
CONCLUSIONS
In patients with kidney failure on dialysis, dapagliflozin was well tolerated, was slightly dialyzable, and had nonaccumulating pharmacokinetic properties.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Pharmacokinetics and Dialyzability of Dapagliflozin in Dialysis Patients (DARE-ESKD 1), NCT05343078.
Topics: Humans; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Prospective Studies; Peritoneal Dialysis; Renal Dialysis; Renal Insufficiency; Dialysis Solutions
PubMed: 37227937
DOI: 10.2215/CJN.0000000000000196 -
Journal of the American Society of... May 2024Patients with CKD face meaningful risk of heart failure hospitalization. Daprodustat compared with darbepoetin was associated with a nonsignificantly greater number of...
KEY POINTS
Patients with CKD face meaningful risk of heart failure hospitalization. Daprodustat compared with darbepoetin was associated with a nonsignificantly greater number of heart failure hospitalizations in non-dialysis patients.
BACKGROUND
Patients with CKD are at higher risk of heart failure. The hypoxia-inducible factor prolyl hydroxylase inhibitor daprodustat is an orally acting alternative to conventional injectable erythropoietin-stimulating agents (ESAs) for the treatment of anemia in patients with CKD. Whether daprodustat affects the risk of heart failure hospitalization is unknown.
METHODS
The Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Dialysis (ASCEND-D; =2964) and Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat–Non-Dialysis (ASCEND-ND; =3872) trials compared daprodustat with conventional ESA in patients with anemia of CKD who did or did not require dialysis, respectively. We identified risk factors of heart failure hospitalization and assessed the effect of daprodustat compared with conventional ESA on heart failure hospitalizations.
RESULTS
History of heart failure, diabetes, and higher systolic BP were independently associated with heart failure hospitalization in both trials, irrespective of treatment assignment. The number of first heart failure hospitalizations was greater in the daprodustat arm in patients not receiving dialysis (hazard ratio [HR], 1.22 [95% confidence interval (CI), 0.95 to 1.56], = 0.12) and in patients receiving dialysis (HR, 1.10 [95% CI, 0.84 to 1.45], = 0.47), although these differences were not statistically significant. HRs in patients with and without history of heart failure were 1.37 (95% CI, 0.89 to 2.11) versus 1.08 (95% CI, 0.79 to 1.46) (-interaction=0.36) in the ASCEND-ND trial and 1.52 (95% CI, 0.97 to 2.38) versus 0.93 (95% CI, 0.66 to 1.30) (-interaction=0.09) in the ASCEND-D trial, respectively. In analyses, daprodustat increased total (first and recurrent) heart failure hospitalizations in participants not receiving dialysis (rate ratio, 1.46 [95% CI, 1.11 to 1.92], = 0.007) but not in participants receiving dialysis (rate ratio, 1.01 [95% CI, 0.74 to 1.39], = 0.93). Daprodustat did not significantly affect the risk of a composite outcome of first heart failure hospitalization or death.
CONCLUSIONS
A greater number of first heart failure hospitalization events occurred in patients treated with daprodustat compared with conventional ESA, but this difference did not reach statistical significance. Differences in the number of heart failure hospitalization events were most apparent in patients not receiving dialysis and in patients with history of heart failure.
PODCAST
This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_04_10_ASN0000000000000321.mp3
Topics: Humans; Heart Failure; Renal Insufficiency, Chronic; Glycine; Benzhydryl Compounds; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 38383961
DOI: 10.1681/ASN.0000000000000321 -
Nature Reviews. Nephrology Aug 2023Haemodialysis is life sustaining but expensive, provides limited removal of uraemic solutes, is associated with poor patient quality of life and has a large carbon... (Review)
Review
Haemodialysis is life sustaining but expensive, provides limited removal of uraemic solutes, is associated with poor patient quality of life and has a large carbon footprint. Innovative dialysis technologies such as portable, wearable and implantable artificial kidney systems are being developed with the aim of addressing these issues and improving patient care. An important challenge for these technologies is the need for continuous regeneration of a small volume of dialysate. Dialysate recycling systems based on sorbents have great potential for such regeneration. Novel dialysis membranes composed of polymeric or inorganic materials are being developed to improve the removal of a broad range of uraemic toxins, with low levels of membrane fouling compared with currently available synthetic membranes. To achieve more complete therapy and provide important biological functions, these novel membranes could be combined with bioartificial kidneys, which consist of artificial membranes combined with kidney cells. Implementation of these systems will require robust cell sourcing; cell culture facilities annexed to dialysis centres; large-scale, low-cost production; and quality control measures. These challenges are not trivial, and global initiatives involving all relevant stakeholders, including academics, industrialists, medical professionals and patients with kidney disease, are required to achieve important technological breakthroughs.
Topics: Humans; Kidneys, Artificial; Quality of Life; Renal Dialysis; Dialysis Solutions; Wearable Electronic Devices
PubMed: 37277461
DOI: 10.1038/s41581-023-00726-9 -
Lancet (London, England) Jul 2023Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF.
METHODS
BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488).
FINDINGS
Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48).
INTERPRETATION
Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation.
FUNDING
Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.
Topics: Adult; Child; Humans; Male; Female; Kidney Transplantation; Chlorides; Australia; Crystalloid Solutions; Double-Blind Method
PubMed: 37343576
DOI: 10.1016/S0140-6736(23)00642-6 -
Cureus Aug 2023Sepsis is a life-threatening organ failure caused by a dysregulated response to infection. Fluid resuscitation and vasopressors are used to maintain systolic blood... (Review)
Review
Sepsis is a life-threatening organ failure caused by a dysregulated response to infection. Fluid resuscitation and vasopressors are used to maintain systolic blood pressure and organ perfusion. Fluid resuscitation can be done with liberal or restricted fluids as well as colloids or crystalloid fluids. This review analyses the evidence for the use of liberal or restrictive fluids and colloids or crystalloids for the management of sepsis. A methodical search was conducted across PubMed, Cochrane Library, and ScienceDirect, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines were followed for this study. Randomized controlled trials and retrospective observational studies were included in this study. Liberal and restrictive fluid strategies were found to be comparable in efficacy, but restrictive fluid regimens had the added benefit of a lower incidence of fluid overload. Balanced crystalloids were safer and more effective when compared to normal saline. Albumin replacement was found to be safe and showed efficacy in reducing mortality in patients with sepsis and septic shock.
PubMed: 37779759
DOI: 10.7759/cureus.44317 -
JAMA Dec 2023Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial... (Clinical Trial)
Clinical Trial
IMPORTANCE
Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival.
OBJECTIVE
To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia.
DESIGN, SETTING, AND PARTICIPANTS
Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies.
EXPOSURE
Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age.
MAIN OUTCOMES AND MEASURES
The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement.
RESULTS
The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks).
CONCLUSIONS AND RELEVANCE
Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03101891.
Topics: Female; Humans; Infant; Infant, Newborn; Pregnancy; Fetal Therapies; Gestational Age; Kidney; Kidney Diseases; Prospective Studies; Infusions, Parenteral; Oligohydramnios; Fetal Diseases; Lung Diseases; Isotonic Solutions; Ultrasonography, Interventional; Pregnancy Outcome; Treatment Outcome; Premature Birth
PubMed: 38051327
DOI: 10.1001/jama.2023.21153 -
Clinical Journal of the American... Jan 2024
PubMed: 38214917
DOI: 10.2215/CJN.0000000000000433 -
Nutrients Jul 2023Hyperphosphatemia is a common complication in advanced chronic kidney disease and contributes to cardiovascular morbidity and mortality. The present narrative review... (Review)
Review
Hyperphosphatemia is a common complication in advanced chronic kidney disease and contributes to cardiovascular morbidity and mortality. The present narrative review focuses on the management of phosphatemia in uremic patients receiving peritoneal dialysis. These patients frequently develop hyperphosphatemia since phosphate anion behaves as a middle-size molecule despite its low molecular weight. Accordingly, patient transporter characteristics and peritoneal dialysis modalities and prescriptions remarkably influence serum phosphate control. Given that phosphate peritoneal removal is often insufficient, especially in lower transporters, patients are often prescribed phosphate binders whose use in peritoneal dialysis is primarily based on clinical trials conducted in hemodialysis because very few studies have been performed solely in peritoneal dialysis populations. A crucial role in phosphate control among peritoneal dialysis patients is played by diet, which must help in reducing phosphorous intake while preventing malnutrition. Moreover, residual renal function, which is preserved in most peritoneal dialysis patients, significantly contributes to maintaining phosphate balance. The inadequate serum phosphate control observed in many patients on peritoneal dialysis highlights the need for large and well-designed clinical trials including exclusively peritoneal dialysis patients to evaluate the effects of a multiple therapeutic approach on serum phosphate control and on hard clinical outcomes in this high-risk population.
Topics: Humans; Phosphates; Hyperphosphatemia; Peritoneal Dialysis; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 37513579
DOI: 10.3390/nu15143161 -
Nature Reviews. Nephrology Oct 2023Patients with kidney disease, especially those with kidney failure, are particularly susceptible to the adverse effects of disasters because their survival depends on... (Review)
Review
Patients with kidney disease, especially those with kidney failure, are particularly susceptible to the adverse effects of disasters because their survival depends on functional infrastructure, advanced technology, the availability of specific drugs and well-trained medical personnel. The risk of poor outcomes across the entire spectrum of patients with kidney diseases (acute kidney injury, chronic kidney disease and kidney failure on dialysis or with a functioning transplant) increases as a result of disaster-related logistical challenges. Patients who are displaced face even more complex problems owing to additional threats that arise during travel and after reaching their new location. Overall, risks may be mitigated by pre-disaster preparedness and training. Emergency kidney disaster responses depend on the type and severity of the disaster and include medical and/or surgical treatment of injuries, treatment of mental health conditions, appropriate diet and logistical interventions. After a disaster, patients should be evaluated for problems that were not detected during the event, including those that may have developed as a result of the disaster. A retrospective review of the disaster response is vital to prevent future mistakes. Important ethical concerns include fair distribution of limited resources and limiting harm. Patients with kidney disease, their care-givers, health-care providers and authorities should be trained to respond to the medical and logistical problems that occur during disasters to improve outcomes.
Topics: Humans; Renal Dialysis; Kidney; Acute Kidney Injury; Disasters; Drug-Related Side Effects and Adverse Reactions
PubMed: 37479903
DOI: 10.1038/s41581-023-00743-8