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Deutsches Arzteblatt International Jul 2024Chronic renal insufficiency (CRI) is becoming more common and has an increasing impact on public health. In Germany, approximately one in ten adults has CRI. Its most... (Review)
Review
BACKGROUND
Chronic renal insufficiency (CRI) is becoming more common and has an increasing impact on public health. In Germany, approximately one in ten adults has CRI. Its most serious consequence is generally not the development of end-stage renal failure, but rather the markedly increased cardiovascular risk as kidney function declines.
METHODS
This review is based on the findings of a selective search in PubMed for literature about the treatment options for CRI, and on our overview of the existing guideline recommendations on diagnostic testing.
RESULTS
Patients with diabetes mellitus and arterial hypertension are at especially high risk of developing CRI. For these patients, some of the guidelines recommend regular testing for albuminuria and measurement of the glomerular filtration rate (GFR), though sometimes only when specific risk constellations are present. The treatment of CRI has evolved in recent years. At first, aside from general measures, only RAS inhibitors were available as a specific therapy for CRI. With the extension of the approval of SGLT-2 inhibitors to non-diabetic CRI patients, the options for treatment have become wider. Two randomized controlled trials have revealed the benefit of SGLT-2 inhibitors with respect to their respective primary endpoints: time to a specified eGFR reduction and renal/cardiovascular death (HR 0.61 [0.51; 0.72] and 0.72 [0.64; 0.82]). The potential side effects and contraindications of SGLT-2 inhibitors must be taken into account. A further treatment option for diabetics with CRI has become available with the approval of the non-steroidal mineralocorticoid receptor antagonist finerenone.
CONCLUSION
In patients with risk factors, renal function should be regularly tested.
PubMed: 38814568
DOI: 10.3238/arztebl.m2024.0072 -
Frontiers in Endocrinology 2024Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by... (Review)
Review
Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in , resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the ; copy number variants in , , , , , and , and sequence variants in , , , , , , and . Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.
Topics: Humans; Adrenal Hyperplasia, Congenital; 46, XX Disorders of Sex Development; Female; Male; Disorders of Sex Development
PubMed: 38812815
DOI: 10.3389/fendo.2024.1354759 -
ESC Heart Failure May 2024In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations... (Review)
Review
In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium-glucose co-transporter-2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up-titration along with a close follow-up with frequent clinical and laboratory re-assessment after an episode of acute HF (the so-called 'high-intensity care' strategy) was associated with better outcomes in the STRONG-HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP-HFpEF-DM and STEP-HFpEF trials, semaglutide 2.4 mg once weekly administered for 1 year decreased body weight and significantly improved quality of life and the 6 min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH-AHF supported the use of natriuresis-guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.
PubMed: 38806171
DOI: 10.1002/ehf2.14857 -
BMJ Open Quality May 2024Clinical practice guidelines recommend screening for primary hyperaldosteronism (PH) in patients with resistant hypertension. However, screening rates are low in the...
Clinical practice guidelines recommend screening for primary hyperaldosteronism (PH) in patients with resistant hypertension. However, screening rates are low in the outpatient setting. We sought to increase screening rates for PH in patients with resistant hypertension in our Veterans Affairs (VA) outpatient resident physician clinic, with the goal of improving blood pressure control. Patients with possible resistant hypertension were identified through a VA Primary Care Almanac Metric query, with subsequent chart review for resistant hypertension criteria. Three sequential patient-directed cycles were implemented using rapid cycle improvement methodology during a weekly dedicated resident quality improvement half-day. In the first cycle, patients with resistant hypertension had preclinic PH screening labs ordered and were scheduled in the clinic for hypertension follow-up. In the second cycle, patients without screening labs completed were called to confirm medication adherence and counselled to screen for PH. In the third cycle, patients with positive screening labs were called to discuss mineralocorticoid receptor antagonist (MRA) initiation and possible endocrinology referral. Of 97 patients initially identified, 58 (60%) were found to have resistant hypertension while 39 had pseudoresistant hypertension from medication non-adherence. Of the 58 with resistant hypertension, 44 had not previously been screened for PH while 14 (24%) had already been screened or were already taking an MRA. Our screening rate for PH in resistant hypertension patients increased from 24% at the start of the project to 84% (37/44) after two cycles. Of the 37 tested, 24% (9/37) screened positive for PH, and 5 patients were started on MRAs. This resident-led quality improvement project demonstrated that a focused intervention process can improve PH identification and treatment.
Topics: Humans; Hyperaldosteronism; Quality Improvement; Hypertension; Mass Screening; Female; Male; Middle Aged; Ambulatory Care Facilities; Aged; United States; Internship and Residency; United States Department of Veterans Affairs
PubMed: 38802267
DOI: 10.1136/bmjoq-2023-002611 -
Frontiers in Pharmacology 2024The renin-angiotensin-aldosterone system (RAAS) members, especially Ang II and aldosterone, play key roles in the pathogenesis of diabetic cardiomyopathy (DCM)....
BACKGROUND
The renin-angiotensin-aldosterone system (RAAS) members, especially Ang II and aldosterone, play key roles in the pathogenesis of diabetic cardiomyopathy (DCM). Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers combined with aldosterone receptor antagonists (mineralocorticoid receptor antagonists) have substantially improved clinical outcomes in patients with DCM. However, the use of the combination has been limited due to its high risk of inducing hyperkalemia.
METHODS
Type 1 diabetes was induced in 8-week-old male C57BL/6J mice by intraperitoneal injection of streptozotocin at a dose of 55 mg/kg for 5 consecutive days. Adeno-associated virus 9-mediated short-hairpin RNA (shRNA) was used to knock down the expression of ADAM17 in mice hearts. Eplerenone was administered via gavage at 200 mg/kg daily for 4 weeks. Primary cardiac fibroblasts were exposed to high glucose (HG) for 24 h to examine the cardiac fibroblasts to myofibroblasts transformation (CMT).
RESULTS
Cardiac collagen deposition and CMT increased in diabetic mice, leading to cardiac fibrosis and dysfunction. In addition, ADAM17 expression and activity increased in the hearts of diabetic mice. ADAM17 inhibition and eplerenone treatment both improved diabetes-induced cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction, ADAM17 deficiency combined with eplerenone further reduced the effects of cardiac fibrosis, cardiac hypertrophy and cardiac dysfunction compared with single therapy . High-glucose stimulation promotes CMT and leads to increased ADAM17 expression and activity. ADAM17 knockdown and eplerenone pretreatment can reduce the CMT of fibroblasts that is induced by high glucose levels by inhibiting TGFβ1/Smad3 activation; the combination of the two can further reduce CMT compared with single therapy .
CONCLUSION
Our findings indicated that ADAM17 knockout could improve diabetes-induced cardiac dysfunction and remodeling through the inhibition of RAAS overactivation when combined with eplerenone treatment, which reduced TGF-β1/Smad3 pathway activation-mediated CMT. The combined intervention of ADAM17 deficiency and eplerenone therapy provided additional cardiac protection compared with a single therapy alone without disturbing potassium level. Therefore, the combination of ADAM17 inhibition and eplerenone is a potential therapeutic strategy for human DCM.
PubMed: 38799171
DOI: 10.3389/fphar.2024.1364827 -
JCEM Case Reports Jun 2024We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite...
We present the case of a 20-year-old woman with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, with uncontrolled hyperandrogenemia despite supraphysiological glucocorticoid therapy. We used abiraterone acetate, an inhibitor of the 17-hydroxylase/17,20-lyase enzyme, to suppress adrenal androgen synthesis and allow physiological glucocorticoid and mineralocorticoid therapy, as a proof-of-concept, before proceeding to bilateral adrenalectomy. We report the patient's clinical course, the changes in adrenal steroids, and the immunohistochemistry of the adrenals.
PubMed: 38798742
DOI: 10.1210/jcemcr/luae077 -
Drug Metabolism and Pharmacokinetics May 2024The quantitative systems pharmacology (QSP) approach is widely applied to address various essential questions in drug discovery and development, such as identification...
Insights into drug development with quantitative systems pharmacology: A prospective case study of uncovering hyperkalemia risk in diabetic nephropathy with virtual clinical trials.
The quantitative systems pharmacology (QSP) approach is widely applied to address various essential questions in drug discovery and development, such as identification of the mechanism of action of a therapeutic agent, patient stratification, and the mechanistic understanding of the progression of disease. In this review article, we show the current landscape of the application of QSP modeling using a survey of QSP publications over 10 years from 2013 to 2022. We also present a use case for the risk assessment of hyperkalemia in patients with diabetic nephropathy treated with mineralocorticoid receptor antagonists (MRAs, renin-angiotensin-aldosterone system inhibitors), as a prospective simulation of late clinical development. A QSP model for generating virtual patients with diabetic nephropathy was used to quantitatively assess that the nonsteroidal MRAs, finerenone and apararenone, have a lower risk of hyperkalemia than the steroidal MRA, eplerenone. Prospective simulation studies using a QSP model are useful to prioritize pharmaceutical candidates in clinical development and validate mechanism-based pharmacological concepts related to the risk-benefit, before conducting large-scale clinical trials.
PubMed: 38797092
DOI: 10.1016/j.dmpk.2024.101019 -
International Journal of Molecular... May 2024Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adverse foetal...
Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adverse foetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on foetal HPA axis function and postnatal offspring development. Hence, this study investigated the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone, were measured in all dams and pups. Glucose tolerance, insulin and gene expressions of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase basal ACTH and corticosterone concentrations, disturbed MR and GR gene expression, glucose intolerance and insulin resistance assessed via the Homeostasis Model Assessment (HOMA) indices in the pups born from the PD group compared to NPD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.
Topics: Animals; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Female; Pregnancy; Prediabetic State; Rats; Adrenocorticotropic Hormone; Rats, Sprague-Dawley; Corticosterone; Male; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Prenatal Exposure Delayed Effects; Diabetes Mellitus, Type 2; Insulin Resistance
PubMed: 38791468
DOI: 10.3390/ijms25105431 -
Biomedicines May 2024In chronic kidney disease (CKD) patients, several risk factors contribute to the development of endothelial dysfunction (ED), which can be described as an alteration in... (Review)
Review
In chronic kidney disease (CKD) patients, several risk factors contribute to the development of endothelial dysfunction (ED), which can be described as an alteration in the cell structure or in the function of the endothelium. Among the well-known CKD-related risk factors capable of altering the production of endothelium-derived relaxing factors, we include asymmetric dimethylarginine increase, reduced dimethylarginine dimethylamine hydrolase enzyme activity, low-grade chronic systemic inflammation, hyperhomocysteinemia, oxidative stress, insulin resistance, alteration of calcium phosphorus metabolism, and early aging. In this review, we also examined the most important techniques useful for studying ED in humans, which are divided into indirect and direct methods. The direct study of coronary endothelial function is considered the gold standard technique to evaluate if ED is present. In addition to the discussion of the main pharmacological treatments useful to counteract ED in CKD patients (namely sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonist), we elucidate innovative non-pharmacological treatments that are successful in accompanying the pharmacological ones. Among them, the most important are the consumption of extra virgin olive oil with high intake of minor polar compounds, adherence to a plant-dominant, low-protein diet (LPD), an adaptive physical activity program and, finally, ketoanalogue administration in combination with the LPD or the very low-protein diet.
PubMed: 38791047
DOI: 10.3390/biomedicines12051085 -
Biomolecules May 2024Urine free cortisol measurements are routinely performed to evaluate hypercortisolism. Despite their analytical inaccuracy, immunoassay-based methods are frequently...
INTRODUCTION
Urine free cortisol measurements are routinely performed to evaluate hypercortisolism. Despite their analytical inaccuracy, immunoassay-based methods are frequently used. Advances in liquid chromatography-high-resolution mass spectrometry (LC-HRMS) facilitate the incorporation of powerful diagnostic tools into clinical laboratories. In addition to its high analytical specificity and simultaneous analysis of different metabolites, accurate mass measurement allows for untargeted compound identification, which may help to identify clinically relevant metabolites or drugs.
METHODS
The present study aimed to validate a simple routine LC-HRMS method to quantify cortisol, cortisone, 6β-hydroxycortisol, and 18-hydroxycortisol simultaneously in human urine. Additionally, the study also validated a GC-MS method for the same steroids, evaluated their cross-reactivity with commercial cortisol immunoassays, and quantified the 24 h urine excretion in patients under clinical suspicion or follow-up for hypercortisolism.
RESULTS
The LC-HRMS method involved liquid-liquid extraction using dichloromethane, micro-LC for chromatographic separation and detection using the accurate masses of the steroids, and simultaneous high-resolution full scan acquisition. The method presented acceptable linearity, precision, and accuracy. Significant interference from 6β-hydroxycortisol and cortisone was demonstrated in the cortisol immunoassays, which impacted their reliability in the follow-up of patients with hypercortisolism and significant changes in these cortisol metabolites (i.e., due to drug-induced changes in CYP3A4 activity).
CONCLUSION
A rapid and accurate routine LC-HRMS method was validated, which is useful for the evaluation of hypercortisolism and other disorders of glucocorticoid and mineralocorticoid metabolism.
Topics: Humans; Hydrocortisone; Cortisone; Gas Chromatography-Mass Spectrometry; Chromatography, Liquid; Glucocorticoids; Cushing Syndrome; Male; Female
PubMed: 38785966
DOI: 10.3390/biom14050558