A Cohort Study

[Posted 29/Feb/2024]

AUDIENCE: Internal Medicine

KEY FINDINGS: Patients achieving surgical remission of CD have higher incidence of autoimmune disease than age- and sex-matched patients with NFPAs. Family history of autoimmune disease is a potential risk factor. Adrenal insufficiency may be a trigger.

BACKGROUND: Glucocorticoids suppress inflammation. Autoimmune disease may occur after remission of Cushing’s disease (CD). However, the development of autoimmune disease in this context is not well described. Purpose of this study is to determine 1) the incidence of autoimmune disease in patients with CD after surgical remission compared with patients with nonfunctioning pituitary adenomas (NFPAs) and 2) the clinical presentation of and risk factors for development of autoimmune disease in CD after remission.

DETAILS: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery. Assessment for hypercortisolemia included late-night salivary cortisol levels, 24-hour urine free cortisol (UFC) ratio (UFC value divided by the upper limit of the normal range for the assay), and dexamethasone suppression tests. Cumulative incidence of new-onset autoimmune disease at 3 years after surgery was higher in patients with CD (10.4% [95% CI, 5.7% to 15.1%]) than in those with NFPAs (1.6% [CI, 0% to 4.6%]) (hazard ratio, 7.80 [CI, 2.88 to 21.10]). Patients with CD showed higher prevalence of postoperative adrenal insufficiency (93.8% vs. 16.5%) and lower postoperative nadir serum cortisol levels (63.8 vs. 282.3 nmol/L) than patients with NFPAs. Compared with patients with CD without autoimmune disease, those who developed autoimmune disease had a lower preoperative 24-hour UFC ratio (2.7 vs. 6.3) and a higher prevalence of family history of autoimmune disease (41.2% vs. 20.9%).

Copyright © American College of Physicians. All Rights Reserved.

Source: Nyanyo, D. D., Mikamoto, M., Galbiati, F., et al. (2024). Autoimmune Disorders Associated With Surgical Remission of Cushing's Disease: A Cohort Study. Annals of Internal Medicine. Published: February 20, 2024. DOI: 10.7326/M23-2024.

[Posted 11/Dec/2025]

AUDIENCE: Hematology

KEY FINDINGS: Together with other published data, these findings suggest a model whereby BMP2 and BMP6 can signal to hepcidin induction independently of HJV and HFE and vice versa. In contrast, BMP5, HJV, and HFE are all required for iron-mediated hepcidin regulation in the absence of BMP2 and BMP6.

BACKGROUND: The bone morphogenetic protein (BMP)-SMAD signaling pathway is central to regulating hepcidin, the master regulator of systemic iron homeostasis. Authors have previously demonstrated that BMP6, BMP2, and, to a lesser extent, BMP5 are the major ligands contributing to hepcidin and iron homeostasis regulation in vivo.

DETAILS: Hemojuvelin (HJV) and homeostatic iron regulator (HFE) are hepcidin modulators that are mutated in hereditary hemochromatosis. Although both HJV and HFE regulate hepcidin, at least partly, by functionally interacting with the BMP–SMAD pathway, the mechanisms are incompletely understood. Notably, both HJV and HFE can regulate hepcidin in a BMP6-independent manner. To understand whether HJV and HFE influence hepcidin regulation by BMP2 and/or BMP5, authors investigated the iron phenotype of mice with combined mutations in endothelial Bmp2/Hjv and Bmp5/Hfe. Authors found that endothelial Bmp2/Hjv double knockout (KO) mice exhibit more severe hepcidin deficiency and iron overload than single endothelial Bmp2 or Hjv KO mice, similar to previous findings in mice with double endothelial Bmp2/Hfe KO and Bmp6/Hjv KO, or a functional loss of both Bmp6 and Hfe. Moreover, authors found that iron completely fails to induce hepcidin in both endothelial Bmp2/Hjv and Bmp2/Hfe double KO mice. In contrast, a functional loss of BMP5 does not worsen hemochromatosis in Hfe KO mice.

Copyright © Wiley Periodicals LLC. All rights reserved.

Source: Xiao, X., Moschetta, G. A., Chowdhury, S. B., et al. Hemochromatosis Proteins Hemojuvelin and Homeostatic Iron Regulator in Bone Morphogenetic Protein-Mediated Hepcidin Regulation and Iron Homeostasis. American Journal of Hematology. 2025; 100(12): 2175-2184. Published: December, 2025. DOI: 10.1002/ajh.70055.

[Posted 10/Dec/2025]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: The study underlies a role of renal tubular epithelial cells in the development and progression of kidney fibrosis and CKD induced by telomere dysfunction.

BACKGROUND: Renal tubular epithelial cells are the critical mediators of kidney fibrogenesis. Telomere dysfunction has been associated with kidney injury and fibrosis. However, the role of telomere dysfunction specifically in renal tubular epithelial cells in the onset and progression of kidney fibrosis remains poorly understood. TRF1 is a critical component of the telomeric protective complex known as shelterin, and its deficiency results in telomere dysfunction.

DETAILS: To investigate the impact of telomere dysfunction on kidney injury and fibrosis, authors generated mice depleted for the shelterin component TRF1 specifically in renal tubular epithelial cells.vGenetic ablation of Trf1 caused decline in kidney function accompanied by increased tubular injury and tubulointerstitial fibrosis 8 weeks after TRF1 depletion, concomitant with excessive accumulation of extracellular matrix, cell cycle arrest at G2/M phase, and telomeric damage. Trf1^Δ/Δ mice activated regenerative repair mechanisms, supporting proliferation-mediated telomere shortening in renal tubular epithelial cells. At humane end point, Trf1^Δ/Δ mice displayed elevated urinary albumin-to-creatinine ratio (UACR), associated with augmented interstitial fibrosis and tubular atrophy eventually leading to CKD. At the mechanistic level, authors reported the unprecedented finding that Trf1 deletion upregulates the Ras–Raf–Mek–Erk, PI3k/Akt/mammalian target of rapamycin, and p38 pathways.

Copyright © American Society of Nephrology. All rights reserved.

Source: Saraswati, S., Martínez, P., Serrano, R., et al. Telomere Dysfunction in Renal Tubular Epithelial Cells Leads to Kidney Fibrosis. Journal of the American Society of Nephrology. 2025; 36(12): 2348-2363. Published: December, 2025. DOI: 10.1681/ASN.0000000771.

[Posted 10/Dec/2025]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: TRE effectively reduces hepatic steatosis in MASLD, with comparable benefits on weight loss, body composition, and metabolic parameters as CR. This approach may serve as a practical dietary strategy for MASLD management.

BACKGROUND: Time-restricted eating (TRE) may improve weight loss, insulin resistance, and body composition, which are key factors in the pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD). However, evidence on the efficacy of TRE in patients with MASLD is limited. This study aimed to evaluate the potential benefits of TRE in patients with overweight or obesity and MASLD.

DETAILS: In this 16-week randomized controlled trial, patients with overweight or obesity and MASLD were randomized into three groups in a 1:1:1 ratio: standard of care (SOC), calorie restriction (CR), and TRE. The primary endpoint was an improvement in hepatic steatosis, measured using MRI-proton density fat fraction. Changes in liver fibrosis, body composition, lipid profiles, glucose homeostasis, and sleep quality were also analyzed. Among the 337 participants randomized, 333 were included in the full analysis set (113 in SOC, 110 in CR, and 110 in TRE). After the 16-week intervention, hepatic steatosis significantly decreased in the TRE group (-25.8%) compared to the SOC group (0.7%, p <0.001), with no significant difference between TRE and CR (-24.7%, p >0.999). The TRE group also showed greater reductions in body weight, waist circumference, and body fat mass compared to the SOC group, while changes were comparable between TRE and CR. Liver stiffness, glucose homeostasis, and sleep quality were similar between the TRE and CR groups. No serious adverse events were reported.

Copyright © Elsevier Inc. All rights reserved.

Source: Oh, J. H., Yoon, E. L., Park, H., et al. Efficacy and Safety of Time-Restricted Eating in Metabolic Dysfunction-Associated Steatotic Liver Disease. Journal of Hepatology. 2025; 83(6): 1256-1265. Published: December, 2025. DOI: 10.1016/j.jhep.2025.06.005.

A Meta-Analysis

[Posted 9/Dec/2025]

AUDIENCE: Endocrinology, Nephrology

KEY FINDINGS: Within the studied participants, there were clear absolute benefits of SGLT2 inhibitors on kidney, hospitalization, and mortality outcomes irrespective of diabetes status and level of UACR.

BACKGROUND: There is uncertainty about the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in participants with chronic kidney disease, with guidelines offering different strengths of recommendation based on diabetes status and urine albumin to creatinine ratio (UACR). Study was conducted to assess the relative and absolute effects of SGLT2 inhibitor use across efficacy and serious safety outcomes in participants stratified by diabetes status and UACR (>=200 mg/g or <200 mg/g). Included 8 randomized clinical trials that studied an SGLT2 inhibitor with a label indication for use in kidney disease and recorded longitudinal kidney outcomes and baseline data on albuminuria. Assessed the effects of SGLT2 inhibitor use on clinical efficacy and safety outcomes. Heterogeneity by baseline level of UACR was assessed separately by diabetes status.

DETAILS: A total of 58,816 participants (mean age, 64 [SD, 10] years; 35% were female; 48,946 with diabetes and 9870 without diabetes) were included from trials comparing an SGLT2 inhibitor vs placebo. Allocation to an SGLT2 inhibitor produced a lower rate of kidney disease progression (33 vs 48 for placebo per 1000 patient-years; hazard ratio [HR], 0.65 [95% CI, 0.60-0.70] in those with diabetes and 32 vs 46 per 1000; HR, 0.74 [95% CI, 0.63-0.85] in those without diabetes), a lower rate of acute kidney injury (14 vs 18 per 1000 [HR, 0.77; 95% CI, 0.69-0.87] with diabetes and 13 vs 18 per 1000 [HR, 0.72; 95% CI, 0.56-0.92] without diabetes), a lower rate of any hospitalization (202 vs 231 per 1000 [HR, 0.90; 95% CI, 0.87-0.92] with diabetes and 203 vs 237 per 1000 [HR, 0.89; 95% CI, 0.83-0.95] without diabetes), and a lower rate of any death (42 vs 47 per 1000 [HR, 0.86; 95% CI, 0.80-0.91] with diabetes and 42 vs 48 per 1000 [HR, 0.91; 95% CI, 0.78-1.05] without diabetes). Diabetes-specific HRs were similar in participants (with a UACR >=200 mg/g vs with a UACR <200 mg/g) considered separately. Higher absolute risk at a UACR of 200 mg/g or greater meant larger estimated absolute benefits on kidney disease progression were evident in this subgroup. Clear absolute benefits were evident for other efficacy outcomes, and particularly hospitalization, in participants with a UACR less than 200 mg/g. Net absolute benefits remained in the analyses of non–heart failure populations and when estimated glomerular filtration rate was less than 60 mL/min/1.73 m2.

Copyright © American Medical Association. All Rights Reserved.

Source: Staplin, N., Roddick, A. J., Neuen, B. L., et al. Effects of Sodium Glucose Cotransporter 2 Inhibitors by Diabetes Status and Level of Albuminuria: A Meta-Analysis. JAMA. . 2025; Published online: November 7, 2025. DOI: 10.1001/jama.2025.20835.

[Posted 12/Nov/2025]

AUDIENCE: Nephrology, Cardiology, Internal Medicine

KEY FINDINGS: The rate of serious cardiovascular events among participants receiving maintenance hemodialysis was lower with daily supplementation with n-3 fatty acids than with placebo.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients receiving hemodialysis, yet effective preventive therapies remain limited. Supplementation with n-3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have cardiovascular benefits in the general population, but efficacy among patients receiving hemodialysis is uncertain.

DETAILS: In a double-blind, randomized, placebo-controlled trial conducted at 26 sites in Canada and Australia, we assigned adult patients receiving maintenance hemodialysis to daily supplementation with fish oil (4 g of n-3 polyunsaturated fatty acids [1.6 g of EPA and 0.8 g of DHA]) or corn-oil placebo. The primary end point was a composite of all serious cardiovascular events including sudden and nonsudden cardiac death, fatal and nonfatal myocardial infarction, peripheral vascular disease leading to amputation, and fatal and nonfatal stroke. Secondary end points included extension of the primary end point to include noncardiac causes of death, the individual components of the primary end point, and a first cardiovascular event or death from any cause. In a double-blind, randomized, placebo-controlled trial conducted at 26 sites in Canada and Australia, we assigned adult patients receiving maintenance hemodialysis to daily supplementation with fish oil (4 g of n-3 polyunsaturated fatty acids [1.6 g of EPA and 0.8 g of DHA]) or corn-oil placebo. The primary end point was a composite of all serious cardiovascular events including sudden and nonsudden cardiac death, fatal and nonfatal myocardial infarction, peripheral vascular disease leading to amputation, and fatal and nonfatal stroke. Secondary end points included extension of the primary end point to include noncardiac causes of death, the individual components of the primary end point, and a first cardiovascular event or death from any cause.

Copyright © Massachusetts Medical Society. All rights reserved.

Source: Lok, C. E., Farkouh, M., Hemmelgam, B. R., et al. Fish-Oil Supplementation and Cardiovascular Events in Patients Receiving Hemodialysis. NEJM. 2025; Published: November 7, 2025. DOI: 10.1056/NEJMoa2513032.