CYP3A4 and CYP3A5 are the most abundant and important enzymes of the CYP3A subfamily, distributed in the liver, intestinal mucosa and kidney, and involved in tacrolimus metabolism. Here, we report a case of tacrolimus dosage refractoriness due to a genetic polymorphism of CYP3A5.

Individualized tacrolimus therapy: Insights from CYP3A5 polymorphisms and intestinal metabolism.

Clinical Case Reports

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus (DM). With the increasing prevalence of DM worldwide, the incidence of DKD remains high. If DKD is not well controlled, it can develop into chronic kidney disease or end-stage renal disease (ESRD), which places considerable economic pressure on society. Traditional therapies, including glycemic control, blood pressure control, blood lipid control, the use of renin-angiotensin system blockers and novel drugs, such as sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor inhibitors and glucagon-like peptide-1 receptor agonists, have been used in DKD patients. Although the above treatment strategies can delay the progression of DKD, most DKD patients still ultimately progress to ESRD. Therefore, new and multimodal treatment methods need to be explored. In recent years, researchers have continuously developed new treatment methods and targets to delay the progression of DKD, including miRNA therapy, stem cell therapy, gene therapy, gut microbiota-targeted therapy and lifestyle intervention. These new molecular therapy methods constitute opportunities to better understand and treat DKD. In this review, we summarize the progress of molecular therapeutics for DKD, leading to new treatment strategies.

Molecular Therapeutics for Diabetic Kidney Disease: An Update.

International Journal of Molecular Sciences

What is the impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on survival and on cardiovascular and kidneyoutcomes for adults living with chronic kidney disease (CKD)?

Few therapies slow kidney disease progression and improve long term prognosis for adults living with CKD. SGLT-2 inhibitors have demonstrated cardiovascular and kidney benefits in adults with CKD with and without type 2 diabetes. Existing guidance for SGLT-2 inhibitors does not account for the totality of current best evidence for adults with CKD and does not provide fully stratified treatment effects and recommendations across all risk groups based on risk of CKD progression and complications.

The guideline panel considered evidence regarding benefits and harms of SGLT-2 inhibitor therapy for adults with CKD over a five year period, along with contextual factors, and provided the following recommendations:1. For adults at low risk of CKD progression and complications, we suggest administering SGLT-2 inhibitors (weak recommendation in favour)2. For adults at moderate risk of CKD progression and complications, we suggest administering SGLT-2 inhibitors (weak recommendation in favour)3. For adults at high risk of CKD progression and complications, we recommend administering SGLT-2 inhibitors (strong recommendation in favour)4. For adults at very high risk of CKD progression and complications, we recommend administering SGLT-2 inhibitors (strong recommendation in favour).Recommendations are applicable to all adults with CKD, irrespective of type 2 diabetes status.

An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified typical risk strata of adults with CKD (from low to very high risk of CKD progression and related complications) using the classification system developed by Kidney Disease Improving Global Outcomes (KDIGO), and applied an individual patient perspective in moving from evidence to recommendations. Effects of SGLT-2 inhibitors were interpreted in absolute terms applicable to different risk strata with varying baseline risks for outcomes of benefit over a five year period. The panel explicitly considered the balance of benefits, harms, and burdens of starting an SGLT-2 inhibitor, incorporating the values and preferences of adults with different risk profiles. Interactive evidence summaries and decision aids accompany multilayered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that allows reuse and adaptation.

A linked systematic review and pairwise meta-analysis (13 trials including 29&#x2009;614 participants) of benefits and harms associated with SGLT-2 inhibitors in adults with CKD with or without type 2 diabetes informed guidance. Among individuals at very high risk of CKD progression and complications, moderate to high certainty evidence shows SGLT-2 inhibitors (relative to placebo or standard care without SGLT-2 inhibitors) decrease all-cause and cardiovascular mortality, hospitalisation for heart failure, kidney failure, non-fatal myocardial infarction, and non-fatal stroke. Among individuals at high risk, moderate to high certainty evidence shows SGLT-2 inhibitors result in similar benefits across outcomes except demonstrating little or no effect on hospitalisation for heart failure and kidney failure. Among individuals at moderate and low risk, moderate to high certainty evidence shows SGLT-2 inhibitors probably reduce all-cause mortality and non-fatal stroke, with little or no effect for other outcomes of benefit. Risk-stratified estimates were unavailable for outcomes of harm; the panel therefore considered absolute effects summarised across risk strata. SGLT-2 inhibitors are associated with little or no effect on acute kidney injury requiring dialysis, bone fractures, lower limb amputations, ketoacidosis, genital infections, or symptomatic hypovolaemia, although a residual possibility of harms at the individual patient level remains.

In order to apply recommendations, clinicians must appropriately identify adults with CKD, consider the underlying aetiology, and risk stratify them based on glomerular filtration rate (estimated or measured) and degree of albuminuria. In addition to classifying individuals into risk strata, further estimation of a given patient's risk based on the extent of their kidney disease and other comorbidities may be warranted to inform individual-level decisions and shared decision making. Available risk calculators may help estimate a given patient's risk of CKD progression and complications.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors for adults with chronic kidney disease: a clinical practice guideline.

BMJ : British Medical Journal

Venous thromboembolism (VTE), particularly portal vein thrombosis, is common in patients with cirrhosis. Misconceptions around the increased bleeding risk in this patient group may lead to delayed and/or inadequate anticoagulation. This nutshell review focusses on the approach to management including the role of direct oral anticoagulants in the treatment of VTE in patients with cirrhosis.

Prevention and management of venous thrombosis in patients with cirrhosis.

British Journal of Haematology

Agents That Came in From the Cold: Enflurane, Isoflurane, Desflurane, and Sevoflurane.

Anesthesia and Analgesia

Acute coronary syndrome (ACS) is associated with high mortality rates. Although the goal was to achieve a missed diagnosis rate of <mml:math xmlns:mml="https://www.w3.org/1998/Math/MathML"><mml:mo>&lt;</mml:mo></mml:math> 1%, the actual data showed a rate of <mml:math xmlns:mml="https://www.w3.org/1998/Math/MathML"><mml:mo>&gt;</mml:mo></mml:math> 2%. Chest pain diagnosis has remained unchanged over the years and is based on medical interviews and electrocardiograms (ECG), with biomarkers playing complementary roles. We aimed to summarize the key points of medical interviews, ECG clinics, use of biomarkers, and clinical scores, identify problems, and provide directions for future research. Medical interviews should focus on the character and location of chest pain (is it accompanied by radiating pain?) and the duration, induction, and ameliorating factors. An ECG should be recorded within 10 minutes of the presentation. The serial performance of an ECG is recommended for emergency department (ED) evaluation of suspected ACS. Characteristic ECG traces, such as Wellens syndrome and De Winter T-waves, should be understood. Therefore, troponin levels in all patients with suspected ischemic heart disease should be examined using a highly sensitive assay system. Depending on the ED facility, the patient should be risk stratified by serial measurements of cardiac troponin levels (re-testing at one hour would be preferred) to determine the appropriate time to perform an invasive strategy for a definitive diagnosis. The diagnostics should be based on Bayes' theorem; however, care should be taken to avoid the influence of heuristic bias.

Individualized tacrolimus therapy: Insights from CYP3A5 polymorphisms and intestinal metabolism.

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Individualized tacrolimus therapy: Insights from CYP3A5 polymorphisms and intestinal metabolism.

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