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Acute kidney injury (AKI) is a rare but life-threatening complication of the administration of methotrexate (MTX) at high doses (≥1 g/m2) for treatment of solid or hematological malignancies. MTX overexposure can lead to MTX-AKI, and subsequent higher risk of extra-kidney toxicities, morbidity and mortality. MTX-AKI can also lead to secondary chronic kidney disease requiring a reduced dose or contraindication for subsequent MTX infusions, thus worsening the cancer-related prognosis. Treatment of MTX-AKI is mainly preventive, combining alkaline hyperhydration, withdrawal of all nephrotoxic agents and drugs that modulate the metabolism of MTX, metabolic salvage using leucovorin (folinic acid), and close monitoring of serum MTX and creatinine concentrations. Glucarpidase (carboxypeptidase-G2), a recombinant bacterial enzyme that hydrolyzes MTX into two non-cytotoxic metabolites, should be considered for patients with MTX overexposure to prevent and lessen AKI and other potential toxicities. This article provides a comprehensive review of MTX metabolism, mechanisms and prevention of MTX-AKI, and its management.

Background: Patients on hemodialysis (HD) have a high burden of emotional and physical symptoms. These symptoms are often under-recognized. NLP can be used to identify patient symptoms from the EHR. However, whether symptom documentation matches patient reported burden is unclear.

Methods: We conducted a prospective study of patients seen at an ambulatory nephrology practice from September 2020 to April 2021. We collected symptom surveys from patients, nurses, and physicians. We then developed a natural language processing (NLP) algorithm to identify symptoms from the patients' electronic health records (EHR) and validated the performance of this algorithm using manual chart review and patient surveys as a reference standard. Using patient surveys as the reference standard, we compared symptom identification by 1) physicians, 2) nurses, 3) physicians or nurses, and 4) NLP.

Results: We enrolled 97 patients into our study, 63% were female, 49% were Non-Hispanic Black, and 41% were Hispanic. The most common symptoms reported by patients were fatigue (61%), cramping (59%), dry skin (53%), muscle soreness (43%), and itching (41%). Physicians and nurses significantly under-recognized patients' symptoms (sensitivity 0.51 (95% CI 0.40-0.61) and 0.63 (95% CI 0.52-0.72) respectively). Nurses were better at identifying symptoms when patients reported more severe symptoms. There was no difference in results by patients' sex or ethnicity. NLP had a sensitivity of 0.92, specificity of 0.95, PPV of 0.75, and NPV of 0.99 with manual EHR review as the reference standard, and a sensitivity of 0.58 (95% CI 0.47-0.68), specificity of 0.73 (95% CI 0.48-0.89), PPV of 0.92 (95% CI 0.82-0.97), and NPV of 0.24 (95% CI 0.14-0.38) compared with patient surveys.

Conclusions: While patients on HD report high prevalence of symptoms, symptoms are under-recognized and under-documented. NLP was accurate at identifying symptoms when they were documented. Larger studies in representative populations are needed to assess the generalizability of the results of the study.

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.