Garovic, Vesna D

This study is the first to investigate cytokine profiles in women with advanced CKD and low sexual function. We found that lower levels of soluble CD40 ligand were independently linked to higher odds of having low sexual function. Principal component analysis demonstrated that a broader immune activation pattern was associated with higher odds of having low sexual function. Together, these findings suggest that immune signaling patterns may be relevant to sexual health in women with CKD.

Background: Hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), and preterm delivery are associated with higher long-term cardiovascular, metabolic, and kidney disease risk. Their implications for living kidney donation remain uncertain. Methods: We conducted a retrospective cohort study of 498 female living kidney donors (2000–2017) from the Mayo Clinic Living Donor Program with documented pregnancy histories, pre-donation CT angiography, implantation kidney biopsy, and measured GFR. Donors with prior HDP (n=45), GDM (n=18), or preterm delivery (n=65) were compared with donors without adverse pregnancy outcomes (APO; n=385). Kidney morphometry, histology, and function were analyzed with adjustment for age at donation and first pregnancy, parity, and hypertension. Post-donation kidney outcomes were assessed using surveys and medical record review. Results: Donors with prior HDP and GDM had higher BMI at donation (+7.9% and +8.9%; p=0.006 and 0.04), whereas donors with preterm delivery had lower BMI (−4.8%; p=0.03) compared with donors with no APO. After adjustment, donors with HDP showed no differences in kidney volumes, biopsy features, or kidney function at donation or during follow-up. Donors with GDM had larger total and cortical kidney volumes (9.5–10%), less arterial luminal stenosis, and higher 5-year post-donation eGFR (+15%; p=0.03). Donors with preterm delivery had a lower risk of eGFR <45 mL/min/1.73 m 2 (HR 0.28; p=0.03). Conclusions: Prior adverse pregnancy outcomes were not associated with adverse kidney structure at donation or accelerated kidney function decline post-donation. These findings support that APO history alone should not preclude living kidney donation when other eligibility criteria are met.

ABSTRACT Biological aging greatly impacts the body’s ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell–resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20–80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34–69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A ⁺ senescent cells (SnCs) exhibit loss of β-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A ⁺ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive ( CDKN2A ⁺) from a maladaptive ( CDKN1A ⁺) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.

Circulating extracellular vesicles, proinflammatory/pro-oxidant metabolites, and history of preeclampsia may be used as biomarkers for diagnosis of early CAC in postmenopausal women.

BACKGROUND: Hypertension, the leading cause of cardiovascular mortality, remains suboptimally controlled. Large language models (LLMs) could improve hypertension control by augmenting clinical decision-making, but their reliability for guideline-driven tasks is unverified. This study evaluated the accuracy and safety of hypertension management recommendations generated by 3 LLMs. METHODS: Fifty-one vignettes were constructed and submitted to the LLMs (GPT-4, Gemini, Medical Large Language Model [by Google; MedLM]) and a hypertension expert to generate the responses. Three blinded reviewers rated each response on a 4-point accuracy scale, a binary safety (safe/unsafe) scale, and attempted to identify the source (LLM versus expert) providing the response. RESULTS: GPT-4 had the highest accuracy (83%) and safety (86%) scores among LLMs but remained inferior to expert responses (92% accuracy, 93% safety). Gemini and MedLM performed significantly worse (accuracy: 64% and 35%; safety: 73% and 39%, respectively). GPT-4 generated the most guideline-concordant responses (46%) among the 3 LLMs (Gemini 35%, MedLM 14%) but was lower than expert responses (68%). Interrater reliability for accuracy ratings was higher for LLM-generated responses (GPT-4 [intraclass correlation coefficient, 0.30], Gemini [intraclass correlation coefficient, 0.61], and MedLM [intraclass correlation coefficient, 0.58]), with lower agreement for expert responses (intraclass correlation coefficient, 0.23). A similar pattern was observed for safety and source discrimination ratings. The agreement was strongest for safety assessments and weakest for source discrimination. CONCLUSIONS: Among the 3 tested LLMs, GPT-4 demonstrated closer agreement to expert decisions, thereby showing greater potential for supporting hypertension management. Despite their potential, current LLM versions are inferior to expert recommendations. Human-in-the-loop supervision remains essential when deploying LLMs for clinical decision-making.

Background We aimed to assess the longitudinal changes of glycocalyx, a proteoglycan/glycoprotein layer that lines and protects endothelial cells in normotensive pregnancies (NPs); to correlate glycocalyx parameters with kidney injury markers (podocin‐positive to nephrin‐positive [P/N] ratio); and to explore changes in P/N ratio in preeclampsia. Methods Plasma and urine samples and glycocalyx measurements using side‐stream darkfield imaging were collected at each trimester from pregnant women (n=31). Plasma glycocalyx components were measured by ELISA, and urinary P/N‐positive extracellular vesicles by flow cytometry. Results In NPs (n=26), glycocalyx degradation increased from the first to the second trimester ( P =0.008) and returned to first‐trimester values in the third trimester ( P =0.008). Microvascular perfusion decreased from the first to the second trimester ( P =0.006) and increased back to first‐trimester values by the third trimester ( P =0.039). Plasma syndecan 1 level showed a steady increase from the first to the second trimester ( P <0.001) and further in the third trimester ( P <0.001); hyaluronic acid increased from the first to the second trimester ( P =0.016) without further changes. Glycocalyx degradation was associated with an increase in P/N ratio from the first to the second trimester of NPs and remained stable through the third trimester. P/N ratio strongly correlated with elevated syndecan 1 and hyaluronic acid levels in the third trimester. Comparison of P/N ratios between NP and preeclampsia (n=5) showed higher values in preeclampsia across all trimesters ( P =0.028). Conclusions Glycocalyx changes during NPs are associated with elevated urinary podocyte markers. Increase in P/N ratio across NPs, and further in preeclampsia, suggests that podocyte injury in preeclampsia is extension of physiological changes in pregnancy, which may predate its clinical presentation.

BACKGROUND: Senescence, a mechanism of cellular aging, which is characterized by irreversible proliferation arrest and a proinflammatory secretory phenotype, has been documented in women with preeclampsia. As cellular senescence can persist and progress, we postulated that it is associated with accelerated aging phenotype and accumulation of comorbidities in women with a history of preeclampsia. METHODS: We included a cohort of women with a history of preeclampsia (n=40) age- and parity-matched to a group of referent women with normotensive pregnancies (n=40). Women with prior major cardiovascular events, neurological, or autoimmune conditions were excluded. We collected urine and blood samples to study markers of aging, data on multimorbidity at the time of enrollment, and prospectively followed them for events over the course of 6 years, on average. RESULTS: Women with a history of preeclampsia exhibited unfavorable aging profiles compared with referent women, including decreased urinary α-Klotho ( P =0.018); increased leptin ( P =0.016) and leptin/adiponectin ratio ( P =0.027), and increased extracellular vesicles positive for tissue factor ( P =0.025). Women with a history of preeclampsia likewise had a higher rate of comorbidities at the time of enrollment ( P =0.003) and had a 4× higher risk of developing major cardiovascular events compared with referent women ( P =0.003). CONCLUSIONS: Our data suggest that a history of preeclampsia is associated with accelerated aging as indicated by senescence marker differences and the accumulation of multimorbidity later in life. Targeting cellular senescence may offer novel, mechanism-based approaches for the diagnosis and treatment of adverse health outcomes in women with a history of preeclampsia.

Key Points In heme protein–mediated AKI (HP-AKI), a senescence phenotype promptly occurs, and increased expression of p16 Ink4a contributes to HP-AKI. Renal p16 Ink4a expression is induced by hemoglobin, myoglobin, and heme in vivo and in renal epithelial cells exposed to heme in vitro . Impairing the binding or degradation of heme by hemopexin deficiency or heme oxygenase-1 deficiency, respectively, further upregulates p16 Ink4a . Background Understanding the pathogenetic basis for AKI involves the study of ischemic and nephrotoxic models of AKI, the latter including heme protein–mediated AKI (HP-AKI). Recently, interest has grown regarding the role of senescence as a mechanism of kidney injury, including AKI. We examined whether senescence occurs in HP-AKI and potential inducers of and the role of a key driver of senescence, namely, p16 Ink4a , in HP-AKI. Methods The long-established murine glycerol model of HP-AKI was used, and indices of senescence were examined. To evaluate the interaction of heme and p16 Ink4a expression, murine models of genetic deficiency of hemopexin ( HPX ) and heme oxygenase-1 ( HO-1 ) were used. To determine the involvement of p16 Ink4a in HP-AKI, the population of p16 Ink4a -expressing cells was reduced using the INK-ATTAC model. Results Using multiple indices, a senescence phenotype appears in the kidney within hours after the induction of HP-AKI. This phenotype includes significant upregulation of p16 Ink4a . p16 Ink4a is upregulated in the kidney after the individual administration of myoglobin, hemoglobin, and heme, as well as in renal epithelial cells exposed to heme in vitro . Genetic deficiencies of HPX and HO-1 , which, independently, are expected to increase heme content in the kidney, exaggerate induction of p16 Ink4a in the kidney and exacerbate HP-AKI, the latter shown in the present studies involving HPX −/− mice and in previous studies involving HO-1 −/− mice. Finally, reduction in the population of p16 Ink4a -expressing cells in the kidney improves renal function in HP-AKI even within 24 hours. Conclusions The pathogenesis of HP-AKI involves senescence and the induction of p16 Ink4a , the latter driven, in part, by hemoglobin, myoglobin, and heme.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) have been associated with an increased risk of chronic hypertension for both mothers and offspring. We sought to quantify the incidence of chronic hypertension in offspring from HDP-affected pregnancies in a large, population-based cohort study. Furthermore, we evaluate the association of HDP exposure in utero and maternal chronic hypertension in offspring. METHODS: We performed a population-based cohort study of 8755 individuals born during 1976 to 1982 to 7544 women who all resided in the same community at the time of delivery. HDP were identified using a previously validated algorithm. Diagnosis of chronic hypertension in mothers and their offspring was determined using diagnostic codes. Cox proportional hazards regression was used to assess the association between HDP and chronic hypertension. RESULTS: HDP exposure (hazard ratio, 1.50 [95% CI, 1.18–1.90]) and maternal chronic hypertension (hazard ratio, 1.73 [95% CI, 1.48–2.02]) were both associated with a significant increased risk for chronic hypertension in offspring. Both risk factors remained significantly associated with increased risk of hypertension in offspring when included together in a multivariate model. Having both exposures was associated with a 2.4-fold increase in the risk of hypertension in offspring, suggesting a synergistic additive interaction. CONCLUSIONS: HDP exposure in gestation and maternal hypertension are both independently associated with an increased risk of chronic hypertension in offspring. Our results suggest that HDP exposure in utero, in addition to maternal chronic hypertension, may lead to a greater risk for the development of hypertension in offspring.

Beyond conventional risk factors for cardiovascular disease, women face an additional burden of sex-specific risk factors. Key stages of a woman’s reproductive history may influence or reveal short- and long-term cardiometabolic and cardiovascular trajectories. Early and late menarche, polycystic ovary syndrome, infertility, adverse pregnancy outcomes (eg, hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, and intrauterine growth restriction), and absence of breastfeeding are all associated with increased future cardiovascular disease risk. The menopause transition additionally represents a period of accelerated cardiovascular disease risk, with timing (eg, premature menopause), mechanism, and symptoms of menopause, as well as treatment of menopause symptoms, each contributing to this risk. Differences in conventional cardiovascular disease risk factors appear to explain some, but not all, of the observed associations between reproductive history and later-life cardiovascular disease; further research is needed to elucidate hormonal effects and unique sex-specific disease mechanisms. A history of reproductive risk factors represents an opportunity for comprehensive risk factor screening, refinement of cardiovascular disease risk assessment, and implementation of primordial and primary prevention to optimize long-term cardiometabolic health in women.