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Morten Baltzer Houlind,1–4 Esben Iversen,1 Baker Nawfal Jawad,1 Thomas Kallemose,1 Mads Hornum5,6 1Department of Clinical Research, Copenhagen University Hospital – Amager and Hvidovre, Hvidovre, Denmark; 2The Capital Region Pharmacy, Herlev, Denmark; 3Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark; 4Emergency Department, Copenhagen University Hospital – Amager & Hvidovre, Hvidovre, Denmark; 5Department of Nephrology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark; 6Department of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Morten Baltzer Houlind, Tel +45 28838563, Email morten.baltzer.houlind@regionh.dk View the original paper by Dr Kaas-Hansen and colleagues A Response to Letter has been published for this article

The effect of 10 min of high-intensity cycling exercise on circulating growth hormone (GH), insulin-like growth factors I and II (IGF-I and -II), and insulin-like growth factor binding protein 3 (IGF BP-3) was studied in nine eumenorrheic women (age 19-48 yr) at two different phases of the menstrual cycle. Tests were performed on separate mornings corresponding to the follicular phase and to the periovulatory phase of the menstrual cycle, during which plasma levels of endogenous estradiol (E2) were relatively low (272 +/- 59 pmol/l) and high (1,112 +/- 407 pmol/l), respectively. GH increased significantly in response to exercise under both E2 conditions. Plasma GH before exercise (2.73 +/- 2.48 vs. 1.71 +/- 2.09 micrograms/l) and total GH over 10 min of exercise and 1-h recovery (324 +/- 199 vs. 197 +/- 163 ng) were both significantly greater for periovulatory phase than for follicular phase studies. IGF-I, but not IGF-II, increased acutely after exercise. IGF BP-3, assayed by radioimmunoassay, was not significantly different at preexercise, and exercise, or at 30-min recovery time points and was not different between the two study days. When assayed by Western blot, however, there was a significant increase in IGF BP-3 30 min after exercise for the periovulatory study. These findings indicate that the modulation of GH secretion associated with menstrual cycle variations in circulating E2 affects GH measured after exercise, at least in part, by an increase in baseline levels. The acute increase in IGF-I induced by exercise appears to be independent of the GH response and is not affected by menstrual cycle timing.

It is not completely clear which organs are responsible for glucagon elimination in humans, and disturbances in the elimination of glucagon could contribute to the hyperglucagonemia observed in chronic liver disease and chronic kidney disease (CKD). Here, we evaluated kinetics and metabolic effects of exogenous glucagon in individuals with stage 4 CKD (n = 16), individuals with Child-Pugh A-C cirrhosis (n = 16), and matched control individuals (n = 16), before, during, and after a 60-min glucagon infusion (4 ng/kg/min). Individuals with CKD exhibited a significantly lower mean metabolic clearance rate of glucagon (14.0 [95% CI 12.2;15.7] mL/kg/min) compared with both individuals with cirrhosis (19.7 [18.1;21.3] mL/kg/min, P < 0.001) and control individuals (20.4 [18.1;22.7] mL/kg/min, P < 0.001). Glucagon half-life was significantly prolonged in the CKD group (7.5 [6.9;8.2] min) compared with individuals with cirrhosis (5.7 [5.2;6.3] min, P = 0.002) and control individuals (5.7 [5.2;6.3] min, P < 0.001). No difference in the effects of exogenous glucagon on plasma glucose, amino acids, or triglycerides was observed between groups. In conclusion, CKD, but not liver cirrhosis, leads to a significant reduction in glucagon clearance, supporting the kidneys as a primary site for human glucagon elimination., (© 2024 by the American Diabetes Association.)

Background: Estimated GFR (eGFR) has shown poor agreement with measured GFR (mGFR) in several populations. We investigated the impact of age and body composition on the accuracy and precision of eGFR in heart transplant (HTx) recipients., Methods: In a longitudinal, observational, retrospective study design, patients receiving first-time HTx with at least one registered mGFR value within 15 months after HTx and a corresponding plasma creatinine were included. GFR was measured by 51Cr-EDTA and eGFR calculated by creatinine-based CKD-EPI formula., Results: A total of 150 patients with a total of 723 mGFR measurements were included. During the first year after HTx, mean weight increased by 4.2 kg (CI: 3.2 to 5.1) followed by an annual decrease of 0.35 kg/year (Cl: -0.05 to 0.74). mGFR increased by 7.5 mL/min (Cl: 3.2 to 11.8) the first year but was stable hereafter (0.0 mL/min/year; CI: -1.0 to 1.0). The initial weigh gain and increase in mGFR were most pronounced in patients &lt;45 years. Neither eGFR adjusted nor unadjusted for BSA detected the initial increase in mGFR. At 1 year after HTx, limits of agreement on the Bland-Altman plot were -37.2 to 33.1 mL/min with a bias of -2.1 mL/min (Cl: -5.0 to 0.9). In patients &lt;45 years, eGFR significantly overestimated mGFR by 7.1 mL/min (Cl: 1.0 to 13.2) and showed a significant lower precision than patients &gt;45 years. There was no effect of BMI class, weight, BSA, or change in BMI class on the difference between eGFR and mGFR., Conclusion: eGFR is, on average, accurate but imprecise in HTx patients. The agreement is affected by age but not body composition., (© 2024 S. Karger AG, Basel.)

Background: This study validates the application of Systematized Nomenclature of Medicine second edition (SNOMED II) codes used to describe medical kidney biopsies in Denmark in encoded form, aiming to support robust epidemiological research on the causes, treatments and prognosis of kidney diseases., Methods: Kidney biopsy reports from 1 January 1998 to 31 December 2018 were randomly extracted from the Danish National Patobank, using SNOMED codes. A 5% sample was selected, and nephrologists assessed the corresponding medical records, assigning each case the applied clinical diagnoses. Sensitivity, specificity, positive predictive values (PPV), negative predictive values and Cohen's kappa coefficient for the retrieved SNOMED codes were calculated., Results: A total of 613 kidney biopsies were included. The primary clinical disease groups were glomerular disease ( n  = 368), tubulointerstitial disease ( n  = 67), renal vascular disease ( n  = 51), diabetic nephropathy ( n  = 51) and various renal disorders ( n  = 40). Several SNOMED codes were used to describe each clinical disease group and PPV for the combined SNOMED codes were high for glomerular disease (94%), diabetic nephropathy (85%) and systemic diseases affecting the kidney (96%). Conversely, tubulointerstitial disease (62%), renal vascular disease (60%) and other renal disorders (17%) showed lower PPV., Conclusions: SNOMED codes have a high PPV for glomerular diseases, diabetic nephropathy and systemic diseases affecting the kidney, in which they could be applied for future epidemiological research., Competing Interests: No potential conflicts of interest were reported by M.M., I.B., H.D., J.W.G., H.H., K.H., P.I., K.H.R., M.B.J., D.K., F.H.M., P.R., K.E.O., F.P. and K.D.S. T.K. reports honoraria for education and consultancy from AstraZeneca. R.B. reports honoraria for education and consultancy from AstraZeneca, Bayer, Mundipharma, Vifor and Boehringer Ingelheim. M.H. reports honoraria for advisory boards for AstraZeneca, Bayer, Boeringer Ingelheim, Vifor, GSK and Novo Nordisk A/S, and education for AstraZeneca, Boeringer Ingelheim and Novo Nordisk A/S outside the scope of this manuscript. D.H. reports research grant from Vifor Pharma and Gedeon Richter, and consultancy fees and lecture fees from UCB Nordic, GSK and AstraZeneca., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Subcellular membranes have complex lipid and protein compositions, which give rise to organelle-specific membrane packing, fluidity, and permeability. Due to its exquisite solvent sensitivity, the lipophilic fluorescence dye Nile Red has been used extensively to study membrane packing and polarity. Further improvement of Nile Red can be achieved by introducing electron-donating or withdrawing functional groups. Here, we compare the potential of derivatives of Nile Red with such functional substitutions for super-resolution fluorescence microscopy of lipid packing in model membranes and living cells. All studied Nile Red derivatives exhibit cholesterol-dependent fluorescence changes in model membranes, as shown by spectrally resolved stimulated emission depletion (STED) microscopy. STED imaging of Nile Red probes in cells reveals lower membrane packing in fibroblasts from healthy subjects compared to those from patients suffering from Niemann Pick type C1 (NPC1) disease, a lysosomal storage disorder with accumulation of cholesterol and sphingolipids in late endosomes and lysosomes. We also find small but consistent changes in the fluorescence lifetime of the Nile Red derivatives in NPC1 cells, suggesting altered hydrogen-bonding capacity in their membranes. All Nile Red derivatives are essentially non-fluorescent in water but increase their brightness in membranes, allowing for their use in MINFLUX single molecule tracking experiments. Our study uncovers the potential of Nile Red probes with functional substitutions for nanoscopic membrane imaging., (© 2024. The Author(s).)

Background: Although kidney insufficiency has been shown to be associated with increased risk of myocardial injury, benefit of coronary angiography (CAG) and revascularization remains uncertain, with implications on management strategies and outcomes. We aimed to compare rates of CAG and revascularization and subsequent risk of cardiovascular and kidney outcomes in hospitalized patients with myocardial injury and kidney dysfunction., Methods: Retrospective cohort study encompassing hospitalized patients with myocardial injury i.e. elevated troponin I or T and an eGFR ≤60 ml/min/1.73 m 2 identified between 2011 and 2021 in Danish national registers. 30-day odds for CAG were computed across granular eGFR-categories based on multiple logistic regression. Standardized one-year risks of cardiovascular and kidney outcomes including mortality were determined based on hazards obtained in multiple Cox regression., Results: A total of 52,798 patients with myocardial injury were identified. CAG was performed in 14.3 % (n = 7549). 30-day odds ratios for CAG were 0.64 [0.60-0.68], 0.38 [0.34-0.42], 0.18 [0.14-0.22], and 0.35 [0.30-0.40] in patients with eGFR 31-45 ml/min/1.73 m 2 , eGFR 15-30 ml/min/1.73 m 2 for eGFR<15 ml/min/1.73 m 2 and chronic dialysis, respectively (eGFR 46-60 ml/min/1.73 m 2 as reference). Median follow-up was 4.1 years. One-year mortality risk differences associated with CAG and revascularization (no CAG as reference) were -7.8 [-7.0; -8.7] and -9.1 [-8.4; -9.9] for eGFR 46-60 ml/min/1.73 m 2 ; -7.0 [-5.7;-8-3] and -8.0 [-6.6; -9.5] for eGFR 31-45 ml/min/1.73 m 2 ; -5.4 [-3.0; -7.2] and -5.2 [-2.2; -8.3] for eGFR 15-30 ml/min/1.73 m 2 ; -8.8 [-3.1; -13.7] and -5.4 [3.1; -13.4] for eGFR<15 ml/min/1.73 m 2 ; and -4.9 [-0.1; -9.7] and -4.2 [1.5; -9.2] for chronic dialysis, respectively., Conclusion: Probability of CAG following myocardial injury declined with progressive kidney dysfunction. Overall, CAG was associated with lower mortality irrespective of kidney function and subsequent revascularization., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Post-transplantation diabetes mellitus (PTDM) remains a leading complication after solid organ transplantation. Previous international PTDM consensus meetings in 2003 and 2013 provided standardized frameworks to reduce heterogeneity in diagnosis, risk stratification and management. However, the last decade has seen significant advancements in our PTDM knowledge complemented by rapidly changing treatment algorithms for management of diabetes in the general population. In view of these developments, and to ensure reduced variation in clinical practice, a 3rd international PTDM Consensus Meeting was planned and held from 6-8 May 2022 in Vienna, Austria involving global delegates with PTDM expertise to update the previous reports. This update includes opinion statements concerning optimal diagnostic tools, recognition of prediabetes (impaired fasting glucose and/or impaired glucose tolerance), new mechanistic insights, immunosuppression modification, evidence-based strategies to prevent PTDM, treatment hierarchy for incorporating novel glucose-lowering agents and suggestions for the future direction of PTDM research to address unmet needs. Due to the paucity of good quality evidence, consensus meeting participants agreed that making GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) recommendations would be flawed. Although kidney-allograft centric, we suggest that these opinion statements can be appraised by the transplantation community for implementation across different solid organ transplant cohorts. Acknowledging the paucity of published literature, this report reflects consensus expert opinion. Attaining evidence is desirable to ensure establishment of optimized care for any solid organ transplant recipient at risk of, or who develops, PTDM as we strive to improve long-term outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Introduction: Atrial fibrillation is highly prevalent in patients on chronic dialysis. It is unclear whether anticoagulant therapy for stroke prevention is beneficial in these patients. Vitamin K-antagonists (VKA) remain the predominant anticoagulant choice. Importantly, anticoagulation remains inconsistently used and a possible benefit remains untested in randomised clinical trials comparing oral anticoagulation with no treatment in patients on chronic dialysis. The Danish Warfarin-Dialysis (DANWARD) trial aims to investigate the safety and efficacy of VKAs in patients with atrial fibrillation on chronic dialysis. The hypothesis is that VKA treatment compared with no treatment is associated with stroke risk reduction and overall benefit., Methods and Analysis: The DANWARD trial is an investigator-initiated trial at 13 Danish dialysis centres. In an open-label randomised clinical trial study design, a total of 718 patients with atrial fibrillation on chronic dialysis will be randomised in a 1:1 ratio to receive either standard dose VKA targeting an international normalised ratio of 2.0-3.0 or no oral anticoagulation. Principal analyses will compare the risk of a primary efficacy endpoint, stroke or transient ischaemic attack and a primary safety endpoint, major bleeding, in patients allocated to VKA treatment and no treatment, respectively. The first patient was randomised in October 2019. Patients will be followed until 1 year after the inclusion of the last patient., Ethics and Dissemination: The study protocol was approved by the Regional Research Ethics Committee (journal number H-18050839) and the Danish Medicines Agency (case number 2018101877). The trial is conducted in accordance with the Helsinki declaration and standards of Good Clinical Practice. Study results will be disseminated to participating sites, at research conferences and in peer-reviewed journals., Trial Registration Numbers: NCT03862859, EUDRA-CT 2018-000484-86 and CTIS ID 2022-502500-75-00., Competing Interests: Competing interests: CDP has received speaker honoraria or consultancy fees from AstraZeneca and Astellas. Support for attending meetings and travel from Boehringer Ingelheim. CDP also has an ongoing collaboration with Vifor Pharma including donation of a research grant unrelated to this study. DH has received speaker and consultancy fees from AstraZeneca, GlaxoSmithKline and UCB Nordic. ELFB has received a donation of a research grant from AstraZeneca unrelated to this study. ELG has received speaker honoraria or consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Novo Nordisk, MSD, Lundbeck Pharma and Organon. He is an investigator in clinical studies sponsored by AstraZeneca, Idorsia or Bayer and has received unrestricted research grants from Boehringer Ingelheim. IB has received speaker honoraria from Amgen and Bayer. JBO has received speaker honoraria or consultancy fees from Bayer, Bristol-Myers Squibb, Organon and Pfizer. LB has received consultancy fees from AstraZeneca, Astellas, Vifor Pharma, Pfizer and Novartis. LK has received speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis and Novo Nordisk. MH has received speaker and consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Vifor and GSK within the last 3 years. ML has received speaker and consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk and GlaxoSmithKline. NC has received speaker honoraria from AstraZeneca and Bristol-Myers Squibb. RB has received speaker honoraria or consultancy fees from AstraZeneca, Bayer and Boehringer Ingelheim. She is an investigator in clinical studies sponsored by Boehringer Ingelheim, AstraZeneca or Bayer and has received unrestricted research grants from Boehringer Ingelheim., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The pathogenesis of renal disease in obesity and metabolic syndrome (MS) is mostly unknown. This is in part because of the limited information about renal morphological changes in these conditions. We evaluated renal histology in subjects with MS and those without MS, who are participants in the European Nephrectomy Biobank (ENBiBA) project., Methods: MS was defined with at least 3 of the following criteria: (i) body mass index (BMI) ≥27 kg/m 2 ; (ii) prediabetes: fasting glucose of 100-125 mg/dl or HbA1c >5.7%; (iii) systolic or diastolic blood pressure >140/90 mm Hg or the use of medications; and (iv) triglycerides >150 mg/dl or high-density lipoprotein cholesterol <40 (in men) or 50 mg/dl (in women). The absence of these criteria defined patients without MS. Exclusion criteria were diabetes or known causes of renal disease., Results: A total of 157 cases were evaluated: 49 without and 108 with MS. Those with MS were older (54 ± 16 vs. 66 ± 11, P  < 0.0001), had more prevalent chronic kidney disease (CKD, estimated glomerular filtration rate [eGFR] <60 ml/min): 24% (23%) versus 4% (8%) ( P  = 0.02), and had higher albumin-to-creatinine ratio (10 [4-68] vs. 4.45 [0-27], P  = 0.05) than those without MS. Global sclerosis (3% [1-7] vs. 7% [3-13], P  < 0.0001), nodular sclerosis, mesangial expansion, glomerulomegaly; moderate + severe hyalinosis, and arteriosclerosis were more frequent in those with MS than in those without (88 [82] vs. 29 [59]; 83 [77] vs. 30 [61]; P  < 0.05). These vascular changes were independent of differences in age., Conclusion: In MS, ischemic renal disease may play a role in renal disease. In addition, some patients may develop lesions compatible with diabetic nephropathy such as increased mesangial expansion and nodular sclerosis. Further analyses are needed to study the consequences of the pandemic of obesity on renal health., (© 2024 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a kidney protective effect in patients with diabetic kidney disease. Several mechanisms have been proposed, but why precisely SGLT2 inhibition has a kidney protective effect is incompletely understood. Clinical trials using SGLT2 inhibitors have found them to induce a rapid weight loss likely due to loss of sodium and subsequently fluid. While SGLT2 inhibitors are reported to increase hematocrit, it remains unknown whether the natriuretic and aquaretic effect reduces patient's blood volume and whether this could partly explain its kidney protective effects. A blood volume reduction could induce several beneficial effects with reduction in arterial and venous blood pressure as two central mechanisms. The aim of this paper was to review current techniques for assessing patient blood volume that could enhance our understanding of SGLT2 inhibitors' physiological effects., Summary: Changes induced by SGLT2 inhibitors on erythrocyte volume and plasma volume can be assessed by tracer dilution techniques that include radioisotopes, indocyanine green (ICG) dye, or carbon monoxide (CO). Techniques with radioisotopes can provide direct estimates of both erythrocyte volume and plasma volume but are cumbersome procedures and the radiation exposure is a limitation for repeated measures in clinical studies. Methods more suitable for repeated assessment of erythrocyte and plasma volume include dilution of injected ICG dye or dilution of inhaled CO. ICG dye requires higher precision with timed blood samples and provides only a direct estimate of plasma volume wherefrom erythrocyte volume is estimated. Inhalation of CO is a time-effective and automated method that provides measure of the total hemoglobin mass wherefrom erythrocyte and plasma volumes are estimated., Key Messages: A kidney protective effect has been observed in clinical trials with SGLT2 inhibitors, but the underlying mechanisms are not fully understood. Significant weight loss within weeks has been reported in the SGLT2 inhibitor trials and could be related to a reduction in blood volume secondary to increased natriuresis and aquaresis. Alterations in blood volume compartments can be quantified by tracer dilution techniques and further improve our understanding of kidney protection from SGLT2 inhibitors., (© 2023 S. Karger AG, Basel.)