Managing diabetic kidney disease (DKD) is inherently complex, requiring clinicians to synthesize patient history, fluctuating biomarkers, and evolving treatment guidelines. While large language models (LLMs) show promise in medical decision support, their clinical adoption is hindered by factual inaccuracies and a lack of specific reasoning required for individualized patient management. To address this, we developed a hierarchical multi-agent system that integrates a locally deployed retrieval-augmented generation (RAG) framework with a cloud-based advanced reasoning engine, grounding responses in a curated corpus of clinical guidelines. We conducted a multi-center retrospective validation using 267 patient cases. The system's performance was evaluated against baseline models through a blinded review by twelve independent physicians across clinical dimensions including accuracy, safety, and factuality. Our evaluation reveals that the RAG-enhanced system significantly outperforms unaugmented models in providing accurate, guideline-compliant recommendations. Notably, it substantially reduced safety-critical errors, particularly in identifying medication contraindications related to renal function stages, while achieving high inter-rater reliability. This study demonstrates that anchoring LLMs with authoritative knowledge effectively mitigates hallucination risks and enhances clinical reliability. The proposed framework functions as a reliable on-demand assistant for DKD management, providing guideline-grounded decision support for primary care providers.

The efficacy of epcoritamab in refractory diffuse large B-cell lymphoma (DLBCL) has been established. However, its safety in dialysis-dependent patients is unclear. A 53-year-old man with refractory DLBCL who had received a series of different chemotherapies became dependent on dialysis because of worsening preexisting chronic kidney disease. Epcoritamab was initiated at a standard dose, and a complete response was achieved after the third cycle. However, it was discontinued after the seventh cycle because of the development of lower leg necrosis due to pre-existing arteriosclerosis. Epcoritamab may therefore be feasible with careful monitoring, even in dialysis-dependent patients with refractory DLBCL.

A primigravida in her 20s presented to the emergency department at 30 weeks gestation with acute onset, sharp right lower abdominal pain with associated nausea and emesis. Symptoms were refractory to intravenous antiemetics and multimodal pain regimen. Laboratory work-up was unremarkable. Abdominal ultrasound showed mild right hydronephrosis with perinephric oedema and complex fluid collection. Follow-up MRI revealed a large fluid collection in the right retroperitoneum, consistent with a right renal forniceal rupture. A right double-J ureteral stent was placed with resolution of symptoms. The remainder of the pregnancy was uncomplicated. The patient had a spontaneous vaginal delivery at 38 weeks. The ureteral stent was removed 4 weeks postpartum. Renal forniceal rupture is a rare manifestation of obstructive uropathy. Several of the renal and endocrine physiologic changes in pregnancy make pregnancy itself a risk factor. It can mimic common pregnancy complications, requiring a broad differential diagnosis and prompt imaging.

Recent advances in Blood-Based Biomarkers (BBMs) are transforming the diagnostic landscape of Alzheimer Disease (AD), with plasma p-tau217 emerging as a highly accurate and scalable diagnostic marker of AD pathology. Across multiple analytical platforms, plasma p-tau217 has demonstrated consistently strong diagnostic performance for the detection of amyloid pathology. The interpretation of BBMs in older adults presents unique challenges due to the high prevalence of multimorbidity, chronic kidney disease, polypharmacy and frailty. Although these factors may influence absolute biomarker concentrations, current evidence suggests the diagnostic performance of p-tau217 remains largely preserved across diverse older populations when interpreted appropriately. Frailty may modify the relationship between AD pathology and clinical expression of mild cognitive impairment/dementia and may influence the absolute concentration of BBMs underscoring the importance of contextualising test results within a comprehensive assessment. Importantly, these factors should not preclude a clinical-biological diagnosis of AD. The clinical value of BBMs such as p-tau217 in older adults lies not in their use in isolation, but in their integration with a gerontologically attuned diagnostic pathway. Current evidence and international guidelines support the use of BBMs only in symptomatic older adults presenting to specialist services and not in asymptomatic individuals. This commentary reviews recent advances in BBM performance, emerging clinical guidelines, real-world evidence and potential diagnostic pitfalls relevant to older adults. We propose that incorporating BBMs within a Comprehensive Geriatric Assessment framework offers a pragmatic approach to achieving timely, accurate and equitable clinical-biological diagnosis whilst preserving the holistic, person centred principles of geriatric medicine.

Cancer cachexia is a debilitating systemic syndrome that affects a substantial proportion of patients with advanced malignancy and is associated with impaired treatment tolerance, reduced quality of life, and increased mortality. While skeletal muscle wasting is a defining clinical feature, cachexia involves coordinated dysfunction across multiple organs, yet it remains unclear whether cachexia imposes a unified, body-wide transcriptional program or primarily induces organ-specific responses. Here, we leveraged an isogenic xenograft model derived from human duodenal neuroendocrine carcinoma in which the cachexia-inducing subline AkuNEC was established through in vivo serial passaging from the parental, largely non-cachexia-inducing line TCC-NECT-2. We performed bulk RNA sequencing of skeletal muscle, liver, kidney, and heart from cachectic AkuNEC-bearing mice, non-cachectic TCC-NECT-2-bearing mice, and uninoculated controls. Differential expression analyses identified organ-dependent sets of transcripts associated with cachexia. However, unsupervised analyses of global expression patterns consistently showed that tissue identity dominated transcriptome structure and samples did not segregate by cachexia status. In addition, comparisons of tumor-bearing vs uninoculated controls revealed broadly similar transcriptional shifts for AkuNEC and TCC-NECT-2 within each organ. Together, these data indicate that cachexia-associated transcriptional changes are present but remain modest relative to dominant tissue-specific programs at the whole-transcriptome level. The AkuNEC/TCC-NECT-2 system provides a controlled platform for future studies incorporating cell-type-resolved, spatial, and multi-omic approaches to delineate the mechanisms linking tumor evolution to multi-organ remodeling in cancer cachexia.

Acute heart failure (AHF) is a leading cause of hospitalization worldwide, with congestion as its central pathophysiologic feature. Loop diuretics, particularly furosemide, remain the cornerstone of decongestive therapy, yet the optimal administration strategy, continuous infusion versus bolus dosing, remains debated. Furthermore, sequential nephron blockade through the addition of distal tubule-acting diuretics or sodium-glucose cotransporter-2 (SGLT2) inhibitors has emerged as a strategy to overcome diuretic resistance. This systematic review had two primary objectives: first, to compare continuous infusion versus bolus dosing of furosemide; second, to evaluate the efficacy and safety of adjunctive sequential nephron blockade (SGLT2 inhibitors, thiazides, and acetazolamide) added to loop diuretics within the context of the ongoing debate over optimal decongestion in AHF. A systematic literature search was conducted in PubMed, Scopus, Web of Science, the Cochrane Library, and ClinicalTrials.gov for studies published between 2021 and 2025. Eligible studies included randomized controlled trials (RCTs) and prospective observational studies evaluating either continuous furosemide infusion versus bolus furosemide or adjunctive sequential nephron blockade (added to loop diuretics) versus placebo, usual care, or, in one case, an active diuretic comparator. The Cochrane Risk of Bias 2 (RoB 2) tool was used for RCTs, and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool was used for the nonrandomized study. A narrative synthesis was performed because of substantial clinical and methodological heterogeneity. Ten studies (nine RCTs and one prospective observational study) comprising 2,972 patients were included. Continuous furosemide infusion consistently improved surrogate measures of decongestion (urine output and weight loss) compared with bolus dosing. However, these benefits did not reliably translate into improved symptoms or shorter hospital stays, and one large study reported increased renal injury and adverse events, highlighting a potential efficacy-safety trade-off. Sequential nephron blockade with SGLT2 inhibitors enhanced diuresis with favorable renal and electrolyte safety profiles and a nonsignificant trend toward lower mortality (the studies were not powered for mortality). Thiazide-based strategies achieved potent diuresis but significantly increased the risks of acute kidney injury and electrolyte disturbances without a mortality benefit. Acetazolamide improved decongestion safely but did not reduce mortality or readmissions. No single decongestive strategy is universally superior. However, direct comparisons across strategies are limited by substantial heterogeneity in study design, patient populations (e.g., renal function and congestion severity), and outcome definitions. Continuous furosemide infusion offers enhanced diuresis but inconsistent clinical benefits and potential renal harm. Based largely on surrogate outcomes from heterogeneous studies not designed to detect differences in mortality or readmissions, definitive clinical recommendations remain limited. SGLT2 inhibitors represent a promising but not yet proven adjunct in AHF, pending larger, adequately powered trials. Thiazide-based sequential blockade should be reserved for refractory cases with close monitoring. Treatment should be individualized based on baseline renal function, congestion severity, and electrolyte status.

Antibody-mediated rejection (AMR) is a major cause of kidney transplant failure. The CD38 antibody felzartamab has been shown to reduce AMR activity, but recurrence after stopping treatment suggested a need for sustained therapy. We extended a placebo-controlled phase 2 trial (NCT05021484) to assess the feasibility and durability of prolonged, biomarker-guided treatment.

Tubulointerstitial fibrosis (TIF) is a crucial pathological feature and inevitable consequence of progressive diabetic kidney disease (DKD). Transfer RNA-derived fragments (tRFs), a novel class of small non-coding RNA by cleavage of tRNAs, have recently attracted attention due to their functional significance in diverse biological processes. However, the role of tRFs in TIF is largely elusive. In the present study, we found that a tRF, tRF‑1:30‑Gln‑CTG‑4, was markedly decreased in proximal renal tubules and highly correlated with TIF in DKD mice. The overexpression of tRF‑1:30‑Gln‑CTG‑4 revealed a therapeutic effect against TIF. Further, RNA pull-down and RNA-immunoprecipitation assay were performed to identify that FBXO7, an adaptor protein in the SCF E3 ligase complex, was the targeted protein of tRF‑1:30‑Gln‑CTG‑4. Mass spectrometry and co-immunoprecipitation experiments revealed that PINK1, a master mitophagy-regulating protein, acted as the substrate of FBXO7 in tubular epithelial cells. Mechanistically, elevated FBXO7 promoted mitophagy defect through mediating PINK1 ubiquitylation and proteasomal degradation. The overexpression of tRF‑1:30‑Gln‑CTG‑4 alleviated defective mitophagy. Taken together, this study not only represents a novel insight into the pathogenesis of TIF but also provides a promising therapeutic targeting for the delaying the progression of DKD.