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The Medical Clinics of North America Jul 2023Diabetes is a major public health challenge and diabetic kidney disease (DKD), a broader diagnostic term than diabetic nephropathy, is the leading cause of chronic... (Review)
Review
Diabetes is a major public health challenge and diabetic kidney disease (DKD), a broader diagnostic term than diabetic nephropathy, is the leading cause of chronic kidney disease and end-stage kidney disease in the United States and worldwide. A better understanding of the underlying pathophysiological mechanisms of DKD, and recent clinical trials testing new therapeutic interventions, have shown promising results to curb this epidemic. Given the global health burden of DKD, it is extremely important to prioritize prevention, early recognition, referral, and aggressive management of DKD in the primary care setting.
Topics: Humans; Diabetic Nephropathies; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Diabetes Mellitus, Type 2
PubMed: 37258007
DOI: 10.1016/j.mcna.2023.03.004 -
Cardiovascular Diabetology Jul 2023Type 2 diabetes (T2D), cardiovascular disease (CVD) and chronic kidney disease (CKD), are recognized among the most disruptive public health issues of the current... (Review)
Review
Type 2 diabetes (T2D), cardiovascular disease (CVD) and chronic kidney disease (CKD), are recognized among the most disruptive public health issues of the current century. A large body of evidence from epidemiological and clinical research supports the existence of a strong interconnection between these conditions, such that the unifying term cardio-metabolic-renal (CMR) disease has been defined. This coexistence has remarkable epidemiological, pathophysiologic, and prognostic implications. The mechanisms of hyperglycemia-induced damage to the cardio-renal system are well validated, as are those that tie cardiac and renal disease together. Yet, it remains controversial how and to what extent CVD and CKD can promote metabolic dysregulation. The aim of this review is to recapitulate the epidemiology of the CMR connections; to discuss the well-established, as well as the putative and emerging mechanisms implicated in the interplay among these three entities; and to provide a pathophysiological background for an integrated therapeutic intervention aiming at interrupting this vicious crosstalks.
Topics: Humans; Diabetes Mellitus, Type 2; Cardio-Renal Syndrome; Kidney; Cardiovascular Diseases; Renal Insufficiency, Chronic; Metabolic Diseases
PubMed: 37525273
DOI: 10.1186/s12933-023-01937-x -
Kidney International Apr 2024
Topics: Humans; Renal Insufficiency, Chronic
PubMed: 38490803
DOI: 10.1016/j.kint.2023.10.018 -
Physiological Reviews Oct 2023The kidneys play a key role in maintaining total body homeostasis. The complexity of this task is reflected in the unique architecture of the organ. Ureteral obstruction... (Review)
Review
The kidneys play a key role in maintaining total body homeostasis. The complexity of this task is reflected in the unique architecture of the organ. Ureteral obstruction greatly affects renal physiology by altering hemodynamics, changing glomerular filtration and renal metabolism, and inducing architectural malformations of the kidney parenchyma, most importantly renal fibrosis. Persisting pathological changes lead to chronic kidney disease, which currently affects ∼10% of the global population and is one of the major causes of death worldwide. Studies on the consequences of ureteral obstruction date back to the 1800s. Even today, experimental unilateral ureteral obstruction (UUO) remains the standard model for tubulointerstitial fibrosis. However, the model has certain limitations when it comes to studying tubular injury and repair, as well as a limited potential for human translation. Nevertheless, ureteral obstruction has provided the scientific community with a wealth of knowledge on renal (patho)physiology. With the introduction of advanced omics techniques, the classical UUO model has remained relevant to this day and has been instrumental in understanding renal fibrosis at the molecular, genomic, and cellular levels. This review details key concepts and recent advances in the understanding of obstructive nephropathy, highlighting the pathophysiological hallmarks responsible for the functional and architectural changes induced by ureteral obstruction, with a special emphasis on renal fibrosis.
Topics: Humans; Animals; Ureteral Obstruction; Kidney; Renal Insufficiency, Chronic; Hemodynamics; Fibrosis; Disease Models, Animal
PubMed: 37440209
DOI: 10.1152/physrev.00027.2022 -
Cardiovascular Research Sep 2023Chronic kidney disease (CKD) is classified into five stages with kidney failure being the most severe stage (stage G5). CKD conveys a high risk for coronary artery... (Review)
Review
Chronic kidney disease (CKD) is classified into five stages with kidney failure being the most severe stage (stage G5). CKD conveys a high risk for coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Cardiovascular complications are the most common causes of death in patients with kidney failure (stage G5) who are maintained on regular dialysis treatment. Because of the high death rate attributable to cardiovascular (CV) disease, most patients with progressive CKD die before reaching kidney failure. Classical risk factors implicated in CV disease are involved in the early stages of CKD. In intermediate and late stages, non-traditional risk factors, including iso-osmotic and non-osmotic sodium retention, volume expansion, anaemia, inflammation, malnutrition, sympathetic overactivity, mineral bone disorders, accumulation of a class of endogenous compounds called 'uremic toxins', and a variety of hormonal disorders are the main factors that accelerate the progression of CV disease in these patients. Arterial disease in CKD patients is characterized by an almost unique propensity to calcification and vascular stiffness. Left ventricular hypertrophy, a major risk factor for heart failure, occurs early in CKD and reaches a prevalence of 70-80% in patients with kidney failure. Recent clinical trials have shown the potential benefits of hypoxia-inducible factor prolyl hydroxylase inhibitors, especially as an oral agent in CKD patients. Likewise, the value of proactively administered intravenous iron for safely treating anaemia in dialysis patients has been shown. Sodium/glucose cotransporter-2 inhibitors are now fully emerged as a class of drugs that substantially reduces the risk for CV complications in patients who are already being treated with adequate doses of inhibitors of the renin-angiotensin system. Concerted efforts are being made by major scientific societies to advance basic and clinical research on CV disease in patients with CKD, a research area that remains insufficiently explored.
Topics: Humans; Renal Insufficiency, Chronic; Cardiovascular Diseases; Heart Failure; Renal Dialysis; Sodium
PubMed: 37249051
DOI: 10.1093/cvr/cvad083 -
Advances in Therapy Oct 2023Atrial fibrillation (AF) and renal insufficiency often coexist and are increasingly prevalent with advancing age. Both the risk of thromboembolic events and bleeding... (Review)
Review
Atrial fibrillation (AF) and renal insufficiency often coexist and are increasingly prevalent with advancing age. Both the risk of thromboembolic events and bleeding propensity are higher in patients with AF and impaired renal function versus those with good renal health. Direct oral anticoagulants (DOACs) are being increasingly preferred over vitamin K antagonists (VKAs) in the treatment of patients with AF and impaired renal function as VKAs may accelerate progression of chronic kidney disease. DOACs, however, are eliminated by the kidneys to varying degrees, and their dosages must be adapted in accordance with renal function. Since creatinine clearance (CrCl) monitoring is recommended in patients with AF receiving DOAC therapy, CrCl must be routinely monitored in patients at the start and during the course of anticoagulation to avoid deviation from Summary of Product Characteristics dosage specifications. This review article provides an overview of current knowledge on the selection and dose of DOACs including apixaban, dabigatran, edoxaban and rivaroxaban in AF patients at different stages of renal insufficiency, with a special focus on elderly patients with comorbidities and receiving multiple medications. The groups discussed in this review include patients with varying levels of CrCl including hyperfiltration or CrCl > 90 ml/min, CrCl < 90-50 ml/min, CrCl < 50-30 ml/min, CrCl < 30-15 ml/min and end-stage renal disease or on dialysis.
Topics: Aged; Humans; Atrial Fibrillation; Renal Insufficiency; Kidney; Renal Insufficiency, Chronic; Prescriptions; Anticoagulants; Fibrinolytic Agents
PubMed: 37594666
DOI: 10.1007/s12325-023-02544-8 -
JAMA Apr 2024Hemodialysis requires reliable vascular access to the patient's blood circulation, such as an arteriovenous access in the form of an autogenous arteriovenous fistula or... (Review)
Review
IMPORTANCE
Hemodialysis requires reliable vascular access to the patient's blood circulation, such as an arteriovenous access in the form of an autogenous arteriovenous fistula or nonautogenous arteriovenous graft. This Review addresses key issues associated with the construction and maintenance of hemodialysis arteriovenous access.
OBSERVATIONS
All patients with kidney failure should have an individualized strategy (known as Patient Life-Plan, Access Needs, or PLAN) for kidney replacement therapy and dialysis access, including contingency plans for access failure. Patients should be referred for hemodialysis access when their estimated glomerular filtration rate progressively decreases to 15 to 20 mL/min, or when their peritoneal dialysis, kidney transplant, or current vascular access is failing. Patients with chronic kidney disease should limit or avoid vascular procedures that may complicate future arteriovenous access, such as antecubital venipuncture or peripheral insertion of central catheters. Autogenous arteriovenous fistulas require 3 to 6 months to mature, whereas standard arteriovenous grafts can be used 2 to 4 weeks after being established, and "early-cannulation" grafts can be used within 24 to 72 hours of creation. The prime pathologic lesion of flow-related complications of arteriovenous access is intimal hyperplasia within the arteriovenous access that can lead to stenosis, maturation failure (33%-62% at 6 months), or poor patency (60%-63% at 2 years) and suboptimal dialysis. Nonflow complications such as access-related hand ischemia ("steal syndrome"; 1%-8% of patients) and arteriovenous access infection require timely identification and treatment. An arteriovenous access at high risk of hemorrhaging is a surgical emergency.
CONCLUSIONS AND RELEVANCE
The selection, creation, and maintenance of arteriovenous access for hemodialysis vascular access is critical for patients with kidney failure. Generalist clinicians play an important role in protecting current and future arteriovenous access; identifying arteriovenous access complications such as infection, steal syndrome, and high-output cardiac failure; and making timely referrals to facilitate arteriovenous access creation and treatment of arteriovenous access complications.
Topics: Humans; Arteriovenous Shunt, Surgical; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Renal Insufficiency; Renal Replacement Therapy; Retrospective Studies; Treatment Outcome; Referral and Consultation; Clinical Protocols
PubMed: 38497953
DOI: 10.1001/jama.2024.0535 -
Critical Reviews in Clinical Laboratory... Jan 2024Acute kidney injury (AKI) is a commonly encountered clinical syndrome. Although it often complicates community acquired illness, it is more common in hospitalized... (Review)
Review
Acute kidney injury (AKI) is a commonly encountered clinical syndrome. Although it often complicates community acquired illness, it is more common in hospitalized patients, particularly those who are critically ill or who have undergone major surgery. Approximately 20% of hospitalized adult patients develop an AKI during their hospital care, and this rises to nearly 60% in the critically ill, depending on the population being considered. In general, AKI is more common in older adults, in those with preexisting chronic kidney disease and in those with known risk factors for AKI (including diabetes and hypertension). The development of AKI is associated with an increase in both mortality and morbidity, including the development of post-AKI chronic kidney disease. Currently, AKI is defined by a rise in serum creatinine from either a known or derived baseline value and/or oliguria or anuria. However, clinicians may fail to recognize the initial development of AKI because of a delay in the rise of serum creatinine or because of inaccurate urine output monitoring. This, in turn, delays any putative measures to treat AKI or to limit its degree. Consequently, efforts have focused on new biomarkers associated with AKI that may allow early recognition of this syndrome with the intent that this will translate into improved patient outcomes. Here we outline current biomarkers associated with AKI and explore their potential in aiding diagnosis, understanding the pathophysiology and directing therapy.
Topics: Humans; Aged; Critical Illness; Creatinine; Biomarkers; Acute Kidney Injury; Renal Insufficiency, Chronic
PubMed: 37668397
DOI: 10.1080/10408363.2023.2242481 -
Redox Biology Dec 2023Acute kidney injury (AKI) progression to chronic kidney disease (CKD) represents a unique renal disease setting characterized by early renal cellular injury and...
Acute kidney injury (AKI) progression to chronic kidney disease (CKD) represents a unique renal disease setting characterized by early renal cellular injury and regulated cell death, and later renal fibrosis, of which the critical role and nature of ferroptosis are only partially understood. Here, we report that renal tubular epithelial ferroptosis caused by HDAC3 (histone deacetylase 3) aberration and the resultant GPX4 suppression drives AKI-CKD progression. In mouse models of AKI-CKD transition induced by nephrotoxic aristolochic acid (AA) and folic acid (FA), renal tubular epithelial ferroptosis occurred early that coincided with preferential HDAC3 elevation and marked suppression of a core anti-ferroptosis enzyme GPX4 (glutathione peroxidase 4). Intriguingly, genetic Hdac3 knockout or administration of a HDAC3-selective inhibitor RGFP966 effectively mitigated the GPX4 suppression, ferroptosis and the fibrosis-associated renal functional loss. In cultured tubular epithelial cells, HDAC3 over-expression or inhibition inversely affected GPX4 abundances. Further analysis revealed that Gpx4 promoter contains a typical binding motif of transcription factor KLF5 (Kruppel-like factor 5). HDAC3 and KLF5 inducibly associated and bound to Gpx4 promoter upon AA treatment, leading to local histone hypoacetylation and GPX4 transactivation inhibition, which was blocked by RGFP966 and a KLF5 inhibitor ML264, respectively, suggesting that KLF5 co-regulated the HDAC3-incurred Gpx4 transcription inhibition. More importantly, in AKI-CKD mice receiving a GPX4 inactivator RSL3, the anti-ferroptosis and renoprotective effects of RGFP966 were largely abrogated, indicating that GPX4 is an essential downstream mediator of the HDAC3 aberration and renal ferroptosis during AKI-CKD transition. Together, our study identified a critical epigenetic pathway of ferroptosis during AKI-CKD transition and suggested that the strategies preserving GPX4 by HDAC3 inhibition are potentially effective to reduce renal ferroptosis and slow AKI-CKD progression.
Topics: Animals; Mice; Acute Kidney Injury; Ferroptosis; Kidney; Renal Insufficiency, Chronic; Disease Progression
PubMed: 37890360
DOI: 10.1016/j.redox.2023.102939 -
Journal of Renal Nutrition : the... Nov 2023While dialysis has been the prevailing treatment paradigm for patients with advanced chronic kidney disease (CKD), emphasis on conservative and preservative management... (Review)
Review
While dialysis has been the prevailing treatment paradigm for patients with advanced chronic kidney disease (CKD), emphasis on conservative and preservative management in which dietary interventions are a major cornerstone have emerged. Based on high-quality evidence, international guidelines support the utilization of low-protein diets as an intervention to reduce CKD progression and mortality risk, although the precise thresholds (if any) for dietary protein intake vary across recommendations. There is also increasing evidence demonstrating that plant-dominant low-protein diets reduce the risk of developing incident CKD, CKD progression, and its related complications including cardiometabolic disease, metabolic acidosis, mineral and bone disorders, and uremic toxin generation. In this review, we discuss the premise for conservative and preservative dietary interventions, specific dietary approaches used in conservative and preservative care, potential benefits of a plant-dominant low-protein diet, and practical implementation of these nutritional strategies without dialysis.
Topics: Humans; Renal Dialysis; Dietary Proteins; Disease Progression; Renal Insufficiency, Chronic; Kidney; Diet, Protein-Restricted
PubMed: 37394104
DOI: 10.1053/j.jrn.2023.06.010