Background Although 98% of potassium (K+) resides intracellularly, current clinical diagnostics assess only extracellular K+ concentrations. Noninvasive imaging of tissue K+ distribution could provide novel insights into pathophysiologic processes in diseases such as primary aldosteronism (PA). PA is characterized by excessive aldosterone production, which leads to electrolyte imbalances, hypertension, and increased cardiovascular risk. Purpose To determine whether potassium 39 (39K) MRI combined with sodium 23 (23Na) MRI can help detect alterations in skeletal muscle K+ and Na+ distribution in participants with PA. Materials and Methods A prospective pre-post study in participants with PA and a cross-sectional case-control study in participants with PA and age- and sex-matched control participants were conducted between January 2019 and April 2024. Participants underwent 7-T 39K and 23Na MRI of the calf muscle before treatment and approximately 4 months after standard therapy (mineralocorticoid receptor antagonists or adrenalectomy). Control participants underwent a single scan. Apparent tissue K+ concentrations (aTPCs) and apparent tissue Na+ concentrations (aTSCs) were quantified; serum aldosterone and K+ were measured and correlated with imaging. Fifty-five male mice underwent sham surgery or deoxycorticosterone acetate-pellet implantation for translational chemical muscle K+ validation. Statistical tests included the Student t test or Mann-Whitney U test (between-group), Wilcoxon signed-rank test (within-participant), and Spearman correlation (two-sided α = .05). Results Forty-two participants were evaluated, including 21 participants with PA (mean age, 52 years ± 9 [SD]; 11 female participants) and 21 control participants (mean age, 53 years ± 9; 11 female participants). Participants with PA showed lower aTPC and higher aTSC than control participants (mean aTPC: 72.7 mmol/L ± 6.8 vs 79.1 mmol/L ± 10.0, P = .02; mean aTSC: 23.9 mmol/L ± 5.3 vs 19.0 mmol/L ± 3.0, P < .001). In within-participant comparisons, PA therapy increased aTPC (mean, 72.9 mmol/L ± 7.5 to 80.9 mmol/L ± 9.8; P = .001) but decreased aTSC (25.2 mmol/L ± 4.8 to 18.9 mmol/L ± 3.4; P < .001), with values approaching control participant values. Baseline aTPC did not correlate with serum K+ (r2 = .02, P = .54). Mouse muscle chemistry mirrored MRI-based K+ depletion. Conclusion Combined 39K and 23Na MRI enabled noninvasive detection of aldosterone-mediated tissue electrolyte shifts. ClinicalTrials.gov Identifier: NCT04251780 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Ellermann in this issue.

Background: The sodium-restricted rice diet (RD) was once the only effective treatment for malignant hypertension (MH); however, a modern, comprehensive data analysis is lacking. We determined patient survival and ocular improvements in 544 MH patients treated between 1942-1982. Methods: At entry, systolic blood pressure (SBP) was ≥170 mmHg and retinal hemorrhage (n = 312), hemorrhage with papilledema (n= 211) or papilledema alone (n = 21) were present. Dates of death were available for 454 patients; ocular data (at baseline and again before day 365) for 342 patients with hemorrhage and 143 with papilledema. We used actuarial analysis to determine survival and resolution of ocular findings. We used Cox proportional hazards to calculate mortality hazard ratio (HR), and period life tables to estimate loss of longevity. Results: Median initial SBP of 213.3 mmHg fell to 178.4 during year 1, and to ≈143 after 9 years. RD patients survived longer than untreated patients: 1890 vs 540 days for patients with hemorrhage alone; 510 vs 180 days with both hemorrhage and papilledema. Few patients reached their expected longevity; median loss of potential life was 15.4 years. Compared to patients whose SBP fell <15 mmHg by 4 weeks, those with a fall ≥ 37 mmHg had HR for mortality of 0.32. Retinal hemorrhages cleared in 260/342 patients; papilledema, in 133/143. Conclusion: With RD treatment blood pressure decreased, and ocular abnormalities largely resolved. Survival improved, but predicted longevity was not achieved. The RD helped MH and could still provide a useful adjunct to pharmacologic therapy. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NA ### Funding Statement This project was made possible through the generous gifts of anonymous donors to Duke Nephrology. We are grateful for the support. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Duke University Medical Center Institutional Review Board (Pro00105257) approved construction of the database and execution of the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Thee data files used in this manuscript will be posted in a Duke repository at time of publication.

Polyuria, defined as urine output exceeding 3 l per day, is common following living donor kidney transplantation, yet its frequency and mechanisms are unclear. This study investigates the pathophysiology and potential recipient- or donor-specific factors influencing post-transplantation polyuria. We retrospectively evaluated 35 consecutive living donor kidney transplantations performed at the University Medical Center Marburg between 2018 and 2024. Clinical and laboratory characteristics of recipients and donors as well as the daily routine blood tests and 24-hour urine collections of the first 10 days post-transplantation were analyzed. Polyuria occurred in 69.7% of recipients on the first day post-transplantation, independent of residual diuresis, ischemia time, or donor pre-transplantation urine volume. Urine output decreased to normal within 10 days, with no differences in serum creatinine or urinary kidney injury markers between polyuric and non-polyuric patients. Mechanistically, polyuria was driven by sodium-dependent osmotic diuresis, with sodium excretion being the sole decisive driver of early post-transplantation urine volume. Polyuria after living donor kidney transplantation occurred in nearly 70% of cases without affecting short-term graft function and is explained by sodium-dependent osmotic diuresis. No donor- or recipient-specific predictors could be identified. Careful volume management is crucial in managing this condition.

BACKGROUND:Muscle RING finger (MuRF) proteins are striated muscle-specific E3 ubiquitin ligases essential for muscle homeostasis. Whereas MuRF1 is well known for its role in muscle atrophy, MuRF2 and MuRF3 contribute to microtubule stabilization, influencing muscle differentiation and function. Their cooperative functions in regulating myogenesis are unclear. This study aimed to identify novel MuRF2 and MuRF3 interaction partners and investigate their function in myogenic differentiation. METHODS:Interaction partners of MuRF2 and MuRF3 were identified using stable isotope labelling with amino acids in cell culture (SILAC), followed by affinity purification and quantitative mass spectrometry (AP-MS). Mechanistic analyses included co-immunoprecipitation, domain mapping, ubiquitination assays, protein stability measurements and endosome isolation. Myogenic differentiation was evaluated by immunocytochemistry, qRT-PCR and western blotting. Functional effects were assessed using CRISPR-Cas9-mediated knockout and siRNA silencing. RESULTS:We identified sorting nexin 5 (SNX5), a BAR and PX domain-containing retromer component involved in retrograde vesicular transport, as a novel MuRF2 and MuRF3 binding partner. Both coiled-coil domains of MuRF3 were required for SNX5 binding, and the BAR domain of SNX5 mediated interaction with MuRF2 and MuRF3. Immunofluorescence staining demonstrated MuRF3-SNX5 interaction and colocalization on early endosomes along microtubules in myocytes. MuRF2 promoted ubiquitination of SNX5 at lysines 290 and 324, leading to proteasomal degradation, whereas MuRF3 counteracted this effect. Mass spectrometry revealed the protein kinase A regulatory subunit (PKA-RI-α) as cargo of SNX5-coated early endosomes in myocytes. SNX5 knockout (SNX5-KO) reduced RI-α stability in myocytes, enhanced PKA activity and increased HDAC5 degradation via the autophagy-lysosomal pathway, leading to MEF2-mediated upregulation of myostatin. SNX5-KO impaired myogenesis, with significant reductions in myogenin/Myog (p < 0.005), myomaker/Mymk (p < 0.01), myomerger/Mymx (p < 0.005) and MyHC isoforms Myh2 and Myh4 (p < 0.01). Myostatin treatment mimicked the SNX5-KO phenotype, reducing fast-twitch MyHC isoforms Myh1, Myh2, Myh3 and Myh4 (p < 0.05 for all) and significantly lowering Myomaker, Myomerger and MyHC expression throughout differentiation (p < 0.05 for all). Morphologically, myostatin-treated cells were shorter and thinner and had fewer nuclei. Quantification showed reduced differentiation and fusion indices (p < 0.001) and fewer nuclei per myosin-positive cell (p < 0.01). CONCLUSIONS:MuRF2 and MuRF3 exert opposing effects on SNX5-mediated retrograde transport, influencing PKA signalling and myogenic differentiation. SNX5 stabilizes RI-α within early endosomes, facilitating ordered myogenic differentiation. Our findings expand the known functions of MuRF proteins beyond proteasomal degradation and identify SNX5 as a key regulator of PKA activity in muscle cells. These insights may provide novel therapeutic targets for muscle-related disorders.

Objective To analyze the differences of free and esterified oxo-eicosatetraenoic acids(oxo-ETEs)in blood cells and plasma from arterial and venous blood in hemodialysis(HD)patients.Methods Arterial and venous blood samples from 12 patients with end-stage renal disease(ESRD)before and after HD treatment at Charité-Universitätsmedizin Berlin,Germany,from June to December 2020 were collected.The esterified and free oxo-ETEs derived from arachidonic acid in blood cells and plasma were measured by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).Results Neither esterified nor free oxo-ETEs in blood cells displayed significant arteriovenous differences before and after HD.HD predominantly affected the metabolic levels of esterified and free oxo-ETEs in plasma.HD reduced the arteriovenous differences of esterified 12-oxo-ETE,free 15-oxo-ETE,and free 5-oxo-ETE in plasma,while raised the arteriovenous differences of esterified 15-oxo-ETE.Conclusions The oxo-ETEs in blood cells are relatively well-stabilized responding to HD treatment,whereas arteriovenous differences of free and esterified oxo-ETEs in plasma are present and active in response to HD treatment,potentially contributing to the cardiovascular disease.

BACKGROUND:The rice diet (RD), a low-sodium (<200 mg/d), low-protein (≈20 g/d), and low-fat (<5 g/d) diet was used to treat patients with malignant hypertension beginning in the 1940s, before any effective antihypertensive drugs were available. We retrospectively analyzed a curated cohort of RD patients with malignant hypertension to assess factors, including dietary adherence, associated with blood pressure (BP) reduction. METHODS:From 17 487 RD charts, we identified 544 malignant hypertension patients (baseline systolic BP ≥170 mm Hg and with concurrent retinal hemorrhage or papilledema), excluding those with diabetes, brain tumor, or prior sympathectomy. Outcome data were censored after any 30-day break in consecutive data. Baseline features, BP changes from baseline to week 4, and diet adherence (assessed by urinary chloride, UCl) were evaluated using summary statistics, univariate, and multivariable analyses. RESULTS:Most patients participated in the RD program before antihypertensive drugs were available; only 48 (8.8%) received any antihypertensive medications in the first month. The cohort (68.9% male) had a median baseline BP of 213/128 mm Hg and body mass index of 23.6 kg/m2. Median time in the program before censoring was 109 days; median total time in the RD program was 333 days. BP declined significantly within the first week, reaching 179/108 mm Hg at week 4. UCl dropped from 217 to 21 mg/dL by week 4. Lower UCl, higher baseline BP, and female sex, but not retinal hemorrhage or papilledema, were associated with greater systolic BP reduction. CONCLUSIONS:The low-sodium, low-fat, low-protein RD effectively lowered BP in malignant hypertension patients in 4 weeks, independent of antihypertensive medications.

Background: The Rice Diet (RD), a low-sodium (<150mg/day), low-protein (20g/day), low-fat (<5g/day), diet was used to treat patients with malignant hypertension (MH) beginning in the 1940's, before any effective anti-hypertensive drugs were available. We retrospectively analyzed a curated cohort of RD patients with MH to assess factors, including dietary adherence, associated with blood pressure (BP) reduction. Methods: From 17,487 RD charts, we identified 544 MH patients (baseline systolic BP (SBP)>=170 mmHg and with concurrent retinal hemorrhage and/or papilledema), excluding those with diabetes, brain tumor, or prior sympathectomy. Outcome data were censored after any 30-day break in consecutive data. Baseline features, BP changes from baseline to Week 4, and adherence (assessed by urinary chloride, UCl) were evaluated using summary statistics, univariate and multivariable analyses. Results: Most patients participated in the RD program before antihypertensive drugs were available; only 48 (4.2%) received any anti-hypertensive medications in the first month. The cohort (68.9% male) had a median baseline BP of 213/128 mmHg and BMI of 23.6 kg/m2. Median time in the program before censoring was 109 days; median total amount of time in the RD program was 333 days. BP declined significantly within the first week, reaching 179/108 mmHg at Week 4. UCl dropped from 217 to 21 mg/dL by Week 4. Lower UCl, higher baseline BP and female gender, but not retinal hemorrhage and/or papilledema, were associated with greater SBP reduction. Conclusion: The low-sodium, low-fat, low-protein RD effectively lowered BP in patients with MH in four weeks, independent of antihypertensive medications. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial This is not a clinical trial. ### Funding Statement This project was made possible through the generous gifts of anonymous donors to Duke Nephrology. We are grateful for the support. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Execution of this study was approved by the Duke University Medical Center IRB (Pro00105257) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data can be made available upon written request.

Malignant hypertension (MH), severe arterial hypertension accompanied by retinal hemorrhage (Class III), papilledema (Class IV), or both was untreatable in 1942. Walter Kempner treated MH patients with a very low sodium (~200 mg/day), protein (~5% of calories), and fat (~5% of calories) diet with success in some patients. The scope and efficacy of this “Rice” Diet (RD) was not clear. We analyzed data from 563 non-diabetic MH patients treated from 1942-1988. The cohort, mostly male (69.4%) with a median age 51 years and median BMI 24.01 provided several interesting findings. First, the number of MH patients increased until the early 1950s, but then declined sharply by 1955, before effective pharmacotherapy was available. This sudden MH “disappearance” seems real, but is unexplained by therapy or other known events. Second, 341 MH patients showed that median survival more that doubled with RD treatment compared to untreated MH patients described by Keith-Wagner-Barker (KWB) in 1939. Third, the RD-diet survival benefit began after ~90-100 days into treatment. During the first ~90-100 RD days, survival closely tracks that of untreated MH patients described by KWB; thereafter, survival curves diverged substantially (e.g., calculated half-time survival for Class IV increased from 163.5 to 815.5 days, Figure ). Fourth, serial retinal photographs of 359 MH patients, showed that of 343 with initial hemorrhage, 36 of 177 patients surviving at 1 year (20%) still had hemorrhage; of 146 with initial papilledema, only 1 of 76 patients surviving at 1 year (1%) still had papilledema. Fifth, survival curves of MH patients with only hemorrhage or only papilledema were similar; however, survival was markedly shorter in those with both hemorrhage and papilledema, implying that the deleterious effects of vascular and neuropathic changes are independent of one another and additive. Remaining questions concern: why did MH “suddenly” disappear; how does RD impact vaculopathy; what factors impact survival trajectories.

AIM:To place the consequences of calcineurin inhibition in a cardiovascular context. METHODS:Literature review coupled with personal encounters. RESULTS:Calcineurin is a calcium-binding and calmodulin-binding protein that is conserved across evolution from yeast to mammals. The enzyme functions as a calcium-dependent, calmodulin-stimulated protein phosphatase. Its role in regulating physiology has largely been elucidated by observing calcineurin inhibition. Calcineurin inhibition transformed organ transplantation from an experiment into a therapy and made much of general immunotherapy possible. The function of this phosphatase and how its inhibition leads to toxicity concern us to this date. Initial research from patients and animal models implicated a panoply of factors contributing to hypertension and vasculopathy. Subsequently, the role of calcineurin in regulating the effective fluid volume, sodium reabsorption, and potassium and hydrogen ion excretion was elucidated by investigating calcineurin inhibition. Understanding the regulatory effects of calcineurin on endothelial and vascular smooth muscle cell function has also made substantial progress. However, precisely how the increase in systemic vascular resistance arises requires further mechanistic research. CONCLUSION:Calcineurin inhibition continues to save lives; however, options to counteract the negative effects of calcineurin inhibition should be vigorously pursued.

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64–65. ADAM-19 cleavage increased G q and decreased G s activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions.

Hypertension requires increased systemic vascular resistance. Thus far, Mendelian hypertension-related genes are related to salt retention, an indirect regulatory effect. With the identification of mutated, overactive, PDE3A (phosphodiesterase 3A), we have uncovered a more direct vasoconstrictive mechanism. The autosomal-dominant syndrome features another specific phenotype, brachydactyly type E. Hypertension and the bony phenotype invariably occur together. We distinguished between these phenotypes by examining individual pedigrees. We implicated the gene encoding the parathyroid hormone-related peptide in the brachydactyly. We identified the hypertensive mechanisms as involving regulatory-region, gain-of-function, exon 4 rare pathogenic variants, in the cAMP-cGMP-catabolizing enzyme, PDE3A. We generated rodent models that recapitulate all human phenotypes. Comparisons not only allowed pathogenic insights into the human condition but also provided intervention models. Moreover, we identified rare pathogenic variants in exon 13 encoding the enzymatic pocket. These patients had identical phenotypes, also corroborated in a rodent model, which produced the same human phenotypes. These data could allow the differentiation between a target organ and blood pressure phenotype. The research allows visualization of enzymatic processes at the intracellular nanodomain level. The scope of this project has elucidated genetic mechanisms important to cartilage development, possibly cancer metastases, and findings relevant to cardiovascular regulation via systemic vascular resistance. For our team, the project was an educational/scientific adventure over a professional lifetime.

Background and AimsHigh tissue sodium accumulation and intermuscular adipose tissue (IMAT) are associated with aging, type 2 diabetes, and chronic kidney disease. In this study, we aim to investigate whether high lower-extremity tissue sodium accumulation relates to IMAT quantity and whether systemic inflammatory mediators and adipocytokines contribute to such association.MethodsTissue sodium content and IMAT accumulation (percentage of IMAT area to muscle area) were measured in 83 healthy individuals using sodium imaging (23Na-MRI) and proton (1H-MRI) imaging of the calf. Insulin sensitivity was assessed by glucose disposal rate (GDR) measured with the hyperinsulinemic-euglycemic clamp.ResultsMedian (interquartile range) muscle and skin sodium contents were 16.6 (14.9, 19.0) and 12.6 (10.9, 16.7) mmol/L, respectively. Median IMAT was 3.69 (2.80, 5.37) %. In models adjusted for age, sex, BMI, GDR, adiponectin, and high-sensitivity C-reactive protein, increasing tissue sodium content was significantly associated with higher IMAT quantity (p = 0.018 and 0.032 for muscle and skin tissue sodium, respectively). In subgroup analysis stratified by sex, skin sodium was significantly associated with IMAT only among men. In interaction analysis, the association between skin sodium and IMAT was greater with increasing levels of high-sensitivity C-reactive protein and interleukin-6 (p for interaction = 0.022 and 0.006, respectively).ConclusionsLeg muscle and skin sodium are associated with IMAT quantity among healthy individuals. The relationship between skin sodium and IMAT may be mediated by systemic inflammation. Intermuscular adipose tissue and tissue sodium in healthy individuals.image

The isolated perfused kidney is a classic ex vivo preparation for studying renal physiology in general and vascular function. Here, we present a protocol for assessing myogenic tone in isolated mouse kidneys as well as vasodilatory and vasoconstrictive responses, expressed as perfusion pressure. We describe steps for pre-operative preparation, kidney and renal artery isolation, and connection of renal artery with glass cannula. We then detail how to measure pressure changes in perfused kidneys and the myogenic tone. For complete details on the use and execution of this protocol, please refer to Cui et al.1

BACKGROUND:Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. OBJECTIVES:The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. METHODS:DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. RESULTS:Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70). CONCLUSIONS:Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).

BackgroundIn the early 1940s, before antihypertensive drugs were available, the Rice Diet Programme (RDP) was developed to treat severe hypertension and, later, diabetes and obesity. Despite significant advancements in dietary management for these conditions since then, debates remain regarding the proper guidelines for sodium and macronutrients intakes. The patient care records of RDP offer a unique source of longitudinal examination of a very low sodium (<10 mmol/day), fat, cholesterol and protein diet on blood pressure (BP), other health markers and survival.MethodsIn 2019, the Rice Diet Database Project (RDDP) digitised handwritten patient care records and retinal photographs of 17 487 RDP participants, establishing a digital database for analyses. Manual transcription accuracy exceeded 97%. We used regression models to investigate the impact of dietary adherence on systolic BP (SBP) and body weight. Further, we performed Kaplan-Meier survival analysis to compare 5-year survival probability of participants defined by baseline level of SBP.ResultsThe database encompasses a wide array of health markers, including BP, weight, urine chloride (UCl) concentration and retinal features that offer a unique resource for studying the impact of the RDP on hypertension, diabetes and obesity. Initial analysis shows reductions in BP and weight as well as improved survival in participants with severe hypertension, underscoring the effectiveness of the diet. The data also permit examining the safety of extreme dietary sodium reduction.The database has numerous strengths (large patient population; extensive, long-term measurements and the use of UCl excretion to document dietary adherence) and limitations (missing data; temporal changes in methodologies over 50 years and lack of control subjects).ConclusionThe RDDP database allows exploration of the effects of a diet extremely low in sodium, protein, fat and cholesterol on health indicators and patient survival. This report highlights the database’s potential for detailed and intricate future analyses.

AIM:2,3-bisphosphoglycerate mutase (BPGM) is traditionally recognized for its role in modulating oxygen affinity to hemoglobin in erythrocytes. Recent transcriptomic analyses, however, have indicated a significant upregulation of BPGM in acutely injured murine and human kidneys, suggesting a potential renal function for this enzyme. Here we aim to explore the physiological role of BPGM in the kidney. METHODS:A tubular-specific, doxycycline-inducible Bpgm-knockout mouse model was generated. Histological, immunofluorescence, and proteomic analyses were conducted to examine the localization of BPGM expression and the impact of its knockout on kidney structure and function. In vitro studies were performed to investigate the metabolic consequences of Bpgm knockdown under osmotic stress. RESULTS:BPGM expression was localized to the distal nephron and was absent in proximal tubules. Inducible knockout of Bpgm resulted in rapid kidney injury within 4 days, characterized by proximal tubular damage and tubulointerstitial fibrosis. Proteomic analyses revealed involvement of BPGM in key metabolic pathways, including glycolysis, oxidative stress response, and inflammation. In vitro, Bpgm knockdown led to enhanced glycolysis, decreased reactive oxygen species elimination capacity under osmotic stress, and increased apoptosis. Furthermore, interactions between nephron segments and immune cells in the kidney suggested a mechanism for propagating stress signals from distal to proximal tubules. CONCLUSION:BPGM fulfills critical functions beyond the erythrocyte in maintaining glucose metabolism in the distal nephron. Its absence leads to metabolic imbalances, increased oxidative stress, inflammation, and ultimately kidney injury.

Oxylipins, the oxidative metabolites of polyunsaturated fatty acids (PUFAs), serve as key mediators of oxidative stress, inflammatory responses, and vasoactive reactions in vivo. Our previous work has established that hemodialysis affects both long chain fatty acids (LCFAs) and oxylipins in plasma and erythrocytes to varying degrees, which may be responsible for excess cardiovascular complications in end-stage renal disease. In this study, we aimed to determine changes in blood oxylipins during cardiopulmonary bypass (CPB) in patients undergoing cardiac surgery to identify novel biomarkers and potential metabolites of CPB-related complications. We tested the hypothesis that CPB would differentially affect plasma oxylipins and erythrocytes oxylipins. We conducted a prospective observational study of 12 patients undergoing elective cardiac surgery with expected CPB procedure. We collected venous and arterial blood samples before CPB, 15 and 45 min after the start of CPB, and 60 min after the end of CPB, respectively. Oxylipins profiling in plasma and erythrocytes was achieved using targeted HPLC‐MS mass spectrometry. Our results revealed that most venous plasma diols and hydroxy- oxylipins decreased after CPB initiation, with a continuous decline until the termination of CPB. Nevertheless, no statistically significant alterations were detected in erythrocytes oxylipins at all time points. CPB decreases numerous diols and hydroxy oxylipins in blood plasma, whereas no changes in erythrocytes oxylipins are observed during this procedure in patients undergoing cardiac surgery. As lipid mediators primarily responsive to CPB, plasma diols and hydroxy oxylipins may serve as potential key biomarkers for CPB-related complications.