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Background: If the GFR falls far enough, uremic symptoms such as anorexia and nausea prompt the initiation of dialysis. Thrice weekly hemodialysis can prevent recurrence of these symptoms even when patients become anuric. To accomplish this it must maintain the plasma levels of the uremic solutes which cause these symptoms lower than they were when dialysis was initiated. This study examined kinetic properties that solutes must possess for hemodialysis to accomplish this. We also sought to identify uremic solutes that possess these properties.

Methods: Mathematical modeling analyzed how a solute's kinetic properties would determine the relation of its level in an anuric dialysis patients to its level when uremic symptoms prompt dialysis initiation. The previously unstudied solute methylurea was assayed by liquid chromatography tandem mass spectrometry (LC/MS/MS) in 13 participants on hemodialysis, 9 participants with advanced CKD, and 10 participants without kidney disease.

Results: Mathematical modeling showed that conventional dialysis can effectively control the plasma levels better than the failing native kidneys only of solutes which have a high dialytic clearance relative to their native kidney clearance and a large volume of distribution. LC/MS/MS measurements showed that methylurea has these properties. The dialytic clearance of methylurea was 255 ± 32 ml/min and its volume of distribution was 1.09 ± 0.25 times the body water volume in hemodialysis patients. The methylurea clearance was lower than the GFR in patients without kidney disease (fractional clearance 0.44 ± 0.19) and patients with advanced CKD (fractional clearance 0.53 ± 0.10). Literature review revealed that urea was the only solute previously known to possess these properties.

Conclusions: A further search for solutes whose properties include a high dialytic clearance, a relatively low native kidney clearance, and a high volume of distribution could help identify solutes that contribute to uremic symptoms.

Background: Cognition is a research priority for people living with chronic kidney disease (CKD), but identification of critical research questions is lacking. This study aimed to determine which cognition-related research questions are most important to CKD stakeholders.

Methods: A modified Delphi technique with 3 survey rounds was used. The study sample included 3 panels (People with lived CKD experience, Researchers, and Clinicians) recruited through international patient and kidney research networks, kidney societies, and snowball sampling with email invitations. Survey rounds were distributed electronically through REDCap. In Round 1 (October 2021-May 2022), respondents contributed three important research questions regarding cognition in CKD (free text). After deduplication and qualitative synthesis, respondents ranked the importance of these questions on a nine-point Likert scale in Round 2 (Feb-April 2023). Questions with mean and median ratings of >7 by at least two respondent panels or rated critically important by the 'lived experience' panel were re-ranked in Round 3 ( Aug-Sept 2023) and assessed for consensus to identify the final list of priority research questions.

Results: Respondents (n=152) identified 125 and 44 discrete questions after Rounds 1 and 2, respectively. The final shortlist included 27 questions in 8 categories. The most critical research question identified was "What factors prevent cognitive impairment in people receiving dialysis?" Overall, respondents prioritized questions focusing on prevention and treatment of cognitive impairment. Scores between the panels were significantly different for 16 questions. Those with lived CKD experience prioritized quality of life, researchers emphasized developing interventions to mitigate cognitive impairment, and clinicians prioritized the effect of CKD treatment on cognitive impairment.

Conclusions: Through an established consensus methodology involving key stakeholder groups, we identified 27 critical research questions about cognition in CKD. These questions should guide future study design and outcome selection.

Background: Water retention, ultrafiltration insufficiency, and metabolic complications due to abnormally high glucose concentrations are still common problems in patients treated with peritoneal dialysis. Phloretin, a nonselective inhibitor of facilitative glucose transporter channels (GLUT), has shown to improve water transport and lower glucose absorption in experimental peritoneal dialysis. However, the dose-response relationship remains unknown, and we therefore performed a dose-response study to elucidate the pharmacodynamic properties of intra-peritoneal phloretin therapy.

Methods: Experimental peritoneal dialysis was performed in fifty healthy Sprague-Dawley rats, using glucose-based dialysis fluid containing five different concentrations of phloretin. We utilized radiolabeled 18F-deoxyglucose (18-FDG) to determine the plasma-to-dialysate transport. The data was then analyzed to determine the dose-response relationship of phloretin according to the Hill-model equation.

Results: Intraperitoneal phloretin therapy followed a dose-response relationship where higher concentrations of phloretin lowered the diffusion capacity of 18-FDG and conventional glucose, while enhancing ultrafiltration. Phloretin showed high potency for water removal and diffusion outcomes, requiring low concentrations to achieve substantial effects.

Conclusions: Intraperitoneal phloretin therapy followed a distinct dose-response relationship, showing high potency in improving ultrafiltration and reducing glucose absorption in experimental PD. These findings support the therapeutic potential of GLUT-inhibitors like phloretin and support future clinical studies to evaluate efficacy and optimal dosing in patients undergoing PD.

Background: This study evaluated the combined effects of oxylanthanum carbonate (OLC), an investigational phosphate binder, and tenapanor, an approved sodium/hydrogen exchanger 3 (NHE3) inhibitor that reduces paracellular phosphate absorption, on urinary phosphate excretion in rats on a high phosphorus diet.

Methods: Sixty-four male Sprague Dawley rats were randomized into eight groups: vehicle; tenapanor (0.15 mg/kg) only; OLC (0.75%, 1.5%, and 3%) only; and combination OLC (0.75%, 1.5%, and 3%) + tenapanor (0.15 mg/kg). Vehicle and tenapanor were dosed orally twice/day whereas OLC was incorporated into diets. We collected 24-hour urine samples to measure urinary phosphate excretion, a proxy for intestinal phosphate absorption efficiency. Primary analyses compared pooled results in the three OLC dose groups.

Results: In the tenapanor 0.15 mg/kg group, mean urinary phosphate excretion from Days 9 to 11 was 8.5 mg/day (12.5%) lower compared to the vehicle group. In the OLC alone groups, mean urinary phosphate excretion (pooled across the 0.75, 1.5, and 3% OLC dose groups) was 12 mg/day (17.7%) lower compared to the vehicle group. Compared to vehicle, urinary phosphate excretion was 28.0 mg/day (41.3%) lower in the combination OLC + tenapanor groups (p=0.016). Bliss model of independence assessing the statistical significance between observed and predicted results indicated that combination OLC + tenapanor was synergistic (p=0.009 for 0.75% OLC + tenapanor and p=0.010 for 1.5% OLC + tenapanor).

Conclusions: In summary, we demonstrated sizeable reductions in urinary phosphate excretion in response to OLC monotherapy and the most pronounced reductions in urinary phosphate excretion when using OLC in combination with tenapanor.

Background: 'Life Years from Transplant' (LYFT) is a measure of the predicted difference between the expected lifespan with and without a kidney transplant. The metric was originally proposed in 1999; since then, demographics of the kidney transplant candidate population have materially changed.

Methods: Using contemporary SRTR data, we propose more sophisticated methods for estimating LYFT with a focus on older kidney transplant candidates, a growing sector of the current candidate pool. We examine trends in predicted LYFT from 1995 to 2020.

Results: We show that among older patients on the deceased donor waitlist, transplant remains a better option compared with dialysis (overall LYFT=5 years). LYFT trends have diminished modestly (by <1 life year) over time, in part related to efforts to enhance access to transplantation through intercurrent policy changes.

Conclusions: Updated LYFT estimates remain informative clinical measures that can support patient-centered decision making. However less homogenous metrics with meaningful disaggregation are needed to inform institutional evaluation and policy change. Models should be repeatedly evaluated as demographics of the candidate pool evolve.

Background: Individuals with end-stage renal disease may be at increased risk of sudden cardiac arrest (SCA) associated with dialysis therapy. However, community-based studies with comprehensive adjudication of SCA are lacking.

Methods: We conducted a community-based study using a case-case study design in a US population of ≈1 million. All SCA cases with chronic kidney disease (CKD) were ascertained prospectively (2002-2020). We reviewed EMS narratives and archived medical records from regional hospitals to capture patients dialysis history, schedules, and the timing of SCA events in relation to dialysis sessions. Among those on regular hemodialysis, individuals who suffered SCA during hemodialysis or within an hour after completing hemodialysis (Intradialytic/immediate post-HD [IIHD]) were compared to cases with SCA at other times (non-IIHD). Non-compliant individuals or those intolerant of dialysis were excluded.

Results: Out of 1,023 SCA cases with CKD, 195 (19.1%) were undergoing regular scheduled hemodialysis. Among these cases, 24.1% were IIHD SCA, while 75.9% occurred non-IIHD. The incidence of SCA during dialysis was 2.9 times higher than expected by chance. SCA events were more likely to occur on dialysis days (65.3% of events) vs. 34.7% events on the 4 off dialysis days (p<0.001). IIHD SCA had higher serum sodium (138.9±4.8 vs. 135.5±5.5 mmol/L, p=0.005), lower serum potassium (3.6±0.7 vs. 5.6±1.6 mmol/L, p<0.001), and higher bicarbonate levels (25.9±6.6 vs. 20.2±5.5 mmol/L, p<0.001) compared to their non-IIHD SCA counterparts. Regarding resuscitation details, IIHD SCA had a higher percentage of shockable rhythm (46.5 vs. 32.4%, p=0.09), witnessed collapse (85.1 vs. 53.4%, p<0.001), bystander CPR (72.3 vs. 37.9%, p<0.001), return of spontaneous circulation (66.0 vs. 42.5%, p=0.005), and survival to hospital discharge (30.4 vs. 5.4%, p<0.001) compared to non-IIHD SCA.

Conclusions: In patients undergoing dialysis, SCA events were significantly more common on dialysis days, and 3-fold higher than expected by chance. We identified potential risk factors and survival outcome differences between IIHD vs. non-IIHD SCA groups that warrant future investigation.

Background: Glucocorticoids are central to vasculitis treatment but increase vertebral fracture risk. This study assessed whether vasculitis as the cause of ESRD is associated with incident vertebral fracture, controlling for corticosteroid use.

Methods: A retrospective cohort study was conducted from 2006-2019 on adults in the U.S. Renal Data System initiating dialysis between 2006 and 2017, surviving ≥1 year, with continuous Medicare Part D coverage during the first year of dialysis. Primary exposure was vasculitis as the cause of ESRD determined from form Centers for Medicare & Medicaid Services (CMS)-2728, completed by a physician at dialysis initiation. A granulomatosis with polyangiitis (GPA) subgroup had ≥1 International Classification of Diseases (ICD)-9/10 code for GPA in the first dialysis year. One inpatient or two outpatient ICD-9/10 codes within 90 days defined incident vertebral fracture. Clinical covariates were ascertained from form CMS-2728 and ICD-9/10 codes and pharmacy claims over the first dialysis year. Multivariable logistic regression examined the association of ESRD secondary to vasculitis with incident vertebral fracture, and in GPA in a secondary analysis.

Results: Among 633,543 individuals with ESRD, vertebral fracture occurred in 6.18% with and 3.23% without ESRD from vasculitis. After multivariable adjustment including corticosteroid daily dose in the first dialysis year, ESRD secondary to vasculitis was associated with vertebral fracture (relative risk (RR):1.33, 95% confidence interval (CI):1.17-1.52), and similarly in those with GPA (RR:1.47, 95% CI:1.23-1.75).

Conclusions: ESRD from vasculitis, and from GPA specifically, increases vertebral fracture risk among individuals with ESRD after accounting for first dialysis year corticosteroid dose.

Background: Patient involvement in research can help to ensure that the evidence generated aligns with their needs and priorities. In the Establishing Meaningful Patient-Centered Outcomes With Relevance for Patients with Polycystic Kidney Disease (EMPOWER PKD) project we aimed to identify patient-important outcomes and discuss the impact of PKD on patients.

Methods: Nine focus groups were held with adult patients with PKD, caregivers, and clinical or research experts in PKD. We used a nominal, multi-vote technique to rank patient-important outcomes to be prioritized by future PKD research. We conducted a thematic analysis of verbatim transcriptions to identify themes regarding the impact of PKD on their daily lives. Other focus group topics included insurability and patient engagement.

Results: Ninety patients and/or caregivers and eight clinicians and/or researchers participated in the focus groups. Nine focus groups yielded 35 outcomes important to patients which were grouped into six categories, ranked in order of importance: kidney health, comorbidities, lifestyle, psychological impact, family and awareness, and mortality. Regarding the impact of PKD on the patient's daily lives, we identified 5 themes, listed in order of importance: psychological impact, effect on daily living, issues affecting decision-making, healthcare-related issues, and PKD-specific testing dilemmas.

Conclusions: This study of stakeholder engagement in patients with PKD revealed important priorities and values that should be considered for future research and when caring for patients with PKD. Future research should focus on kidney health and managing comorbidities in patients with PKD. This will help to bridge the knowledge gap and develop meaningful comparative effectiveness research (CER) in PKD.