Diabetic kidney disease remains a leading cause of end-stage renal disease despite contemporary RAAS blockade and SGLT2 inhibition, underscoring the need for complementary therapies. This review critically evaluates the mechanistic basis for semaglutide’s cardio-renal protection, a GLP-1 receptor agonist with emerging nephroprotective effects. The FLOW trial demonstrated a 24% reduction (HR 0.76) in the primary composite kidney outcome and slowed annual eGFR decline by 1.16 mL/min/1.73m 2 in type 2 diabetes with chronic kidney disease. The SELECT trial demonstrated a 20% reduction in major cardiovascular events in non-diabetic individuals with obesity and established atherosclerotic disease, a benefit preserved in a normoglycemic subgroup, with pre-specified secondary evidence supporting renal benefit. Despite this clinical outcome data, key mechanisms remain incompletely understood: natriuresis is reproducible, yet proximal tubular GLP-1 receptor expression is uncertain, and no proposed pathway has been confirmed in human tissue. To address this gap, we present an evidence-tier framework separating clinical from mechanistic evidence and ranking pathways by evidentiary strength across organ systems. Using this framework, hemodynamic mechanisms are identified as the best-supported explanation for renal protection based on current clinical evidence, though direct confirmation in human renal tissue remains lacking for the NHE3 pathway and competing natriuretic mechanisms. SELECT’s normoglycemic subgroup provides one of the strongest clinical constraints on proposed mechanisms: any proposed pathway must be capable of operating without overt hyperglycemia, though not necessarily of broader metabolic change. Closing the gap between clinical outcome data and mechanistic understanding represents a major unresolved question in cardio-renal pharmacology.
Background Long-term serologic and ophthalmic outcomes after total thyroidectomy in Graves’ disease (GD) with thyroid eye disease (TED) remain incompletely characterized. Objectives To characterize 3-year postoperative TSH receptor antibody (TRAb) trajectories and identify factors associated with persistent elevation. Design Retrospective cohort study. Methods We included 289 patients with ophthalmologist-confirmed TED who underwent total thyroidectomy from 2011 to 2022 at a tertiary center. Thyroid function, TBII-measured TRAb, thyroid-stimulating antibody, and ophthalmic outcomes were assessed preoperatively and at 3 months and at 1, 2, and 3 years. Patients were classified as immediate decline (ID), delayed decline (DD), or no decline (ND). Results Median TRAb decreased from 33.1 (IQR, 15.2-40.0) IU/L preoperatively to 7.15 (2.66-20.82) IU/L at 3 months and 2.29 (1.28-10.07) IU/L at 3 years (all q < 0.001). Mean CAS decreased from 0.6 ± 1.3 to 0.1 ± 0.5 at 3 months and remained near zero. Among 32 patients with active TED, mean CAS decreased from 3.8 ± 1.0 to 0.4 ± 0.9 at 3 months, and all achieved inactive TED by 1 year. Greater thyroid weight was associated with ND in the primary model (OR per 50-g increase, 1.50; 95% CI, 1.04-2.16; p = 0.031) and after additional adjustment for systemic corticosteroid exposure (OR, 1.49; 95% CI, 1.03-2.15; p = 0.036). However, this association was not robust in sensitivity analyses excluding patients with TRAb values above the assay reporting limit. Conclusion Postoperative TRAb levels generally declined but followed heterogeneous trajectories that may reflect persistent systemic TSH receptor autoimmunity; however, these trajectories appear to have limited utility for predicting ophthalmic outcomes in patients with predominantly longstanding, low-activity TED.
Background Diabetes mellitus (DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) share insulin resistance, chronic inflammation, and dysregulated lipid metabolism. However, associations of composite immune-inflammatory indices with prevalent MASLD in DM remain incompletely characterized. Objectives To assess 13 immune-inflammatory indices in relation to United States Fatty Liver Index (USFLI)-defined prevalent MASLD in adults with DM and their contributions to an interpretable classification framework. Design Cross-sectional analysis of 2007-2018 National Health and Nutrition Examination Survey data. Methods We included 951 adults with DM. Survey-weighted logistic regression, false-discovery-rate-corrected quartile analyses, and restricted cubic splines were performed; propensity score matching (PSM) served as a sensitivity analysis. Exploratory unweighted classification compared generalized linear model, random forest, support vector machine, and extreme gradient boosting (XGBoost). The final XGBoost model was interpreted using Shapley additive explanations (SHAP), and a simplified nomogram was internally evaluated. Results Neutrophil-to-high-density lipoprotein cholesterol ratio (NHR), monocyte-to-high-density lipoprotein cholesterol ratio (MHR), lymphocyte-to-high-density lipoprotein cholesterol ratio (LHR), and platelet-to-high-density lipoprotein cholesterol ratio (PHR) showed the most consistent evidence, with odds ratios of 1.921, 1.926, 1.930, and 1.811, respectively. NHR and LHR showed nonlinear associations, whereas MHR and PHR were consistent with linear relationships. PSM yielded 247 matched pairs with directionally consistent associations. XGBoost showed the highest mean cross-validated discrimination; in the held-out test set, in which MASLD prevalence was 72.0%, the areas under the receiver operating characteristic and precision-recall curves were 0.801 and 0.905, respectively. SHAP identified body mass index (BMI) and triglycerides as the largest contributors, with BMI × NHR and BMI × MHR as leading candidate non-additive patterns within the fitted model. The nomogram achieved corresponding values of 0.828 and 0.921 and positive net benefit across a broad range of thresholds. Conclusion NHR, MHR, LHR, and PHR were consistently associated with USFLI-defined prevalent MASLD among adults with DM. These accessible indices and interpretable tools may complement characterization and identification of MASLD.
We report a case of moderate-to-severe euthyroid thyroid eye disease (TED) with persistently negative thyrotropin receptor antibodies (TRAb) followed for three years, and review the literature on similar cases. The patient was a 60-year-old man with moderate-to-severe TED manifestations but no thyroid dysfunction and persistently negative thyroid antibodies. Diagnostic evaluation included thyroid function and antibody tests, thyroid ultrasonography and scintigraphy, and orbital magnetic resonance imaging. Treatment included intravenous methylprednisolone and orbital radiotherapy. A literature review was conducted on PubMed to identify similar cases of TRAb-negative euthyroid TED. The patient achieved significant improvement in proptosis and clinical activity score after intravenous methylprednisolone, and diplopia and restricted ocular motility were greatly alleviated after orbital radiotherapy. The literature review identified 46 TRAb-negative euthyroid TED patients from 10 articles: most presented with mild, unilateral or asymmetrical orbital involvement, while a minority, including our patient, had bilateral moderate-to-severe manifestations; treatment mainly included oral or intravenous glucocorticoids and orbital radiotherapy, with 6 achieving a response and 4 achieving a partial response among 10 documented patients. Thyroid stimulating immunoglobulin (TSI) was positive in most patients tested with a cell-based functional bioassay, but negative in a minority. This case and literature review highlight the diagnostic and therapeutic challenges in TRAb-negative euthyroid TED. These findings highlight the importance of recognizing this entity for timely diagnosis and support the use of standardized TED treatment protocols. In cases where TRAb is negative yet clinical features strongly suggest TED, a sensitive TSI bioassay may offer additional diagnostic clarity. However, some patients remain negative with both tests. In our patient, only a binding-type TSI assay was available, and the diagnosis rested on clinical and radiological grounds. Further study of its pathogenesis is needed.
Medullary thyroid carcinoma (MTC) is a rare pediatric tumor arising from the parafollicular C cells of the thyroid. The majority of childhood MTC cases are associated with germline mutations in the RET proto-oncogene. Although the American Thyroid Association (ATA) has classified most of these mutations according to their risk level, some rare or unclassified variants may also be identified. These variants pose significant challenges for clinicians in both diagnosis and treatment. This report presents the case of a 6-year-old girl who was admitted with growth retardation. Her medical history included intestinal neuronal dysplasia (IND), vesicoureteral reflux, and chronic kidney disease (CKD). Physical examination revealed maxillofacial anomalies. Laboratory tests demonstrated significantly elevated serum calcitonin and parathyroid hormone (PTH) levels. Thyroid ultrasonography identified bilateral nodular lesions, and a fine-needle aspiration biopsy was consistent with MTC. Genetic analysis revealed a heterozygous c.1894_1899del p. (Glu632_Leu633del) mutation in exon 11 of the RET gene. This specific mutation is not included in the ATA risk classification guidelines. The patient underwent total thyroidectomy and central-lateral lymph node dissection. Pathological evaluation confirmed MTC and revealed additional parathyroid hyperplasia. Postoperatively, calcitonin levels normalized, but PTH levels remained high due to secondary hyperparathyroidism related to CKD. This case highlights the clinical implications of an unclassified RET mutation and illustrates how rare comorbid conditions such as IND and CKD can complicate the diagnostic process. Reporting similar cases will significantly contribute to a more comprehensive understanding of the genotype-phenotype relationship and to the refinement of risk classification and management strategies for pediatric MTC.
