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Basal insulin analogues in people with diabetes and chronic kidney disease.
León-Jiménez, D, Miramontes-González, JP, Márquez-López, L, Astudillo-Martín, F, Beltrán-Romero, LM, Moreno-Obregón, F, Escalada-San Martín, J
Diabetic medicine : a journal of the British Diabetic Association. 2022;(2):e14679
Abstract
BACKGROUND Diabetic kidney disease is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide. ESKD has a high prevalence in patients with diabetes mellitus (DM). CKD increases the chances of hypoglycaemia by different mechanisms, causes insulin resistance and a decrease in insulin metabolism. Both the "Kidney Disease: Improving Global Outcomes" (KDIGO) and "American Diabetes Association" (ADA) guidelines recommend the use of insulin as part of treatment, but the type of basal insulin is not specified. METHODS We reviewed the literature to determine whether first- and second-generation basal insulins are effective and safe in CKD patients. We reviewed specific pivotal studies conducted by pharmaceutical laboratories, as well as independent studies. CONCLUSIONS Basal insulins are safe and effective in patients with CKD and diabetes mellitus but we do not have specific studies. Given that CKD is one of the main complications of type 2 DM, and insulin specific treatment in the final stages, the absence of studies is striking. Real-life data are also important since trials such as pivotal studies do not fully represent actual patients. Treatment should be individualized until we have specific trials in this type of population.
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Stress Cardiac Biomarkers, Cardiovascular and Renal Outcomes, and Response to Canagliflozin.
Vaduganathan, M, Sattar, N, Xu, J, Butler, J, Mahaffey, KW, Neal, B, Shaw, W, Rosenthal, N, Pfeifer, M, Hansen, MK, et al
Journal of the American College of Cardiology. 2022;(5):432-444
Abstract
BACKGROUND Circulating biomarkers reflecting different mechanistic pathways may identify at-risk individuals with diabetes who may benefit from sodium-glucose cotransporter-2 (SGLT2) inhibitors. OBJECTIVES The purpose of this study was to determine if high-sensitivity cardiac troponin T (hs-cTnT), soluble suppression of tumorigenesis-2 (sST2), and insulin-like growth factor binding protein 7 (IGFBP7) levels, either alone or in combination, may modify the treatment benefits of canagliflozin. METHODS In the CANVAS (CANagliflozin cardioVascular Assessment Study) biomarker substudy, we evaluated the prognostic significance of baseline biomarker measurements, the long-term trajectory of each, and response to canagliflozin on key cardiovascular and kidney outcomes. RESULTS Among the 4,330 study participants, baseline hs-cTnT, sST2, and IGFBP7 were available in 3,503 (81%), 3,084 (71%), and 3,577 (83%). In total, 39% had elevated hs-cTnT ≥14 pg/mL, 6% had sST2 >35 ng/mL, and 49% had IGFBP7 >96.5 ng/mL. Canagliflozin significantly slowed increases of hs-cTnT (P = 0.027) and sST2 (P = 0.033) through 6 years. Each biomarker was significantly associated with cardiovascular and kidney outcomes, independent of clinical covariates. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Patients with hs-cTnT ≥14 ng/L and those with sST2 >35 ng/mL derived greater relative benefit for major adverse cardiovascular events (MACE) (both Pinteraction ≤0.05). A panel of all 3 biomarkers predicted each cardiac and kidney outcome evaluated; participants with an increasing number of abnormal circulating biomarkers appeared to have greater relative reductions in MACE from canagliflozin treatment (Pinteraction trend = 0.005). CONCLUSIONS Canagliflozin delays longitudinal rise in hs-cTnT and sST2 compared with placebo out to 6 years. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Elevated cardiovascular biomarkers, either alone or in combination, may identify individuals who may derive greater MACE benefit from SGLT2 inhibition. CANVAS (CANagliflozin cardioVascular Assessment Study; NCT01032629).
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[Clinical and genetic analysis of a newborn with hypoparathyroidism, sensorineural hearing loss, and renal dysplasia syndrome].
Shao, Q, Wu, P, Lin, B, Chen, S, Liu, J, Chen, S
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2022;(2):222-226
Abstract
OBJECTIVE To analyze the clinical phenotype and genetic basis for a male neonate featuring hypoparathyroidism, sensorineural hearing loss, and renal dysplasia (HDR) syndrome. METHODS The child was subjected to genome-wide copy number variation (CNVs) analysis and whole exome sequencing (WES). Clinical data of the patient was analyzed. A literature review was also carried out. RESULTS The patient, a male neonate, had presented with peculiar facial appearance, simian crease and sacrococcygeal mass. Blood test revealed hypocalcemia, hypoparathyroidism. Hearing test suggested bilateral sensorineural deafness. Doppler ultrasound showed absence of right kidney. Copy number variation sequencing revealed a 12.71 Mb deletion at 10p15.3-p13 (chr10: 105 001_12 815 001) region. WES confirmed haploinsufficiency of the GATA3 gene. With supplement of calcium and vitamin D, the condition of the child has improved. CONCLUSION The deletion of 10p15.3p13 probably underlay the HDR syndrome in this patient.
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Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors for cardiovascular and renal protection: A treatment approach far beyond their glucose-lowering effect.
Gómez-Huelgas, R, Sanz-Cánovas, J, Cobos-Palacios, L, López-Sampalo, A, Pérez-Belmonte, LM
European journal of internal medicine. 2022;:26-33
Abstract
Findings from cardiovascular outcome trials on certain newer glucose-lowering drugs have shown clear cardiovascular and renal benefits. In this review, we provide an updated overview of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT-2) inhibitors in terms of cardiovascular and renal protection. Both drugs have been described as diabetes/disease-modifying drugs. There is robust evidence on the benefits of GLP-1 receptor agonists in renal disease and atherosclerotic cardiovascular disease-especially in stroke-which are mainly explained by their antiproteinuric effect. However, this class of drugs has only shown neutral effects on heart failure and further studies are necessary in order to assess their role in this disease. SGLT-2 inhibitors have shown strong benefits in heart failure hospitalizations and renal outcomes, mainly through limiting glomerular filtration rate deterioration, regardless of the presence of diabetes. Nonetheless, their effect on the prevention of major adverse atherosclerotic cardiovascular events and cardiovascular mortality seems to be limited to patients with type 2 diabetes and established cardiovascular disease. Evidence on the cardiovascular and renal benefits of GLP-1 receptor agonists and SGLT-2 inhibitors have significantly modified management plans and treatment choices for patients with type 2 diabetes. There is now a focus on a multifactorial approach that goes beyond the glucose-lowering effect of these drugs, which are the preferred choice in routine clinical practice. According to the current evidence, a patient-focused approach that includes both individualized glycemic control and cardiorenal prevention using GLP-1 receptor agonists and SGLT-2 inhibitors with proven cardiovascular and renal benefits is believed to be the best strategy for achieving the treatment goals of patients with type 2 diabetes. Despite the strong cardiovascular and renal benefits of these drugs, further research is required in order to clarify questions that remain unanswered.
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Effect of an Intensive Weight-Loss Lifestyle Intervention on Kidney Function: A Randomized Controlled Trial.
Díaz-López, A, Becerra-Tomás, N, Ruiz, V, Toledo, E, Babio, N, Corella, D, Fitó, M, Romaguera, D, Vioque, J, Alonso-Gómez, ÁM, et al
American journal of nephrology. 2021;(1):45-58
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Abstract
INTRODUCTION Large randomized trials testing the effect of a multifactorial weight-loss lifestyle intervention including Mediterranean diet (MedDiet) on renal function are lacking. Here, we evaluated the 1-year efficacy of an intensive weight-loss intervention with an energy-reduced MedDiet (erMedDiet) plus increased physical activity (PA) on renal function. METHODS Randomized controlled "PREvención con DIeta MEDiterránea-Plus" (PREDIMED-Plus) trial is conducted in 23 Spanish centers comprising 208 primary care clinics. Overweight/obese (n = 6,719) adults aged 55-75 years with metabolic syndrome were randomly assigned (1:1) to an intensive weight-loss lifestyle intervention with an erMedDiet, PA promotion, and behavioral support (intervention) or usual-care advice to adhere to an energy-unrestricted MedDiet (control) between September 2013 and December 2016. The primary outcome was 1-year change in estimated glomerular filtration rate (eGFR). Secondary outcomes were changes in urine albumin-to-creatinine ratio (UACR), incidence of moderately/severely impaired eGFR (<60 mL/min/1.73 m2) and micro- to macroalbuminuria (UACR ≥30 mg/g), and reversion of moderately (45 to <60 mL/min/1.73 m2) to mildly impaired GFR (60 to <90 mL/min/1.73 m2) or micro- to macroalbuminuria. RESULTS After 1 year, eGFR declined by 0.66 and 1.25 mL/min/1.73 m2 in the intervention and control groups, respectively (mean difference, 0.58 mL/min/1.73 m2; 95% CI: 0.15-1.02). There were no between-group differences in mean UACR or micro- to macroalbuminuria changes. Moderately/severely impaired eGFR incidence and reversion of moderately to mildly impaired GFR were 40% lower (HR 0.60; 0.44-0.82) and 92% higher (HR 1.92; 1.35-2.73), respectively, in the intervention group. CONCLUSIONS The PREDIMED-Plus lifestyle intervention approach may preserve renal function and delay CKD progression in overweight/obese adults.
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Apixaban or Vitamin K Antagonists and Aspirin or Placebo According to Kidney Function in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial.
Hijazi, Z, Alexander, JH, Li, Z, Wojdyla, DM, Mehran, R, Granger, CB, Parkhomenko, A, Bahit, MC, Windecker, S, Aronson, R, et al
Circulation. 2021;(12):1215-1223
Abstract
BACKGROUND In the AUGUSTUS trial (An Open-Label, 2×2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y12 inhibitor. We evaluated the risk-benefit balance of antithrombotic therapy according to kidney function. METHODS In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearance <30 mL/min was an exclusion criterion in the AUGUSTUS trial. RESULTS Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL·min-1·1.73 m-2, respectively. At the 6-month follow-up, a total of 543 primary outcomes of bleeding, 1125 death or hospitalizations, and 282 ischemic events occurred. Compared with vitamin K antagonists, patients assigned apixaban had lower rates for all 3 outcomes across most eGFR categories without significant interaction. The absolute risk reduction with apixaban was most pronounced in those with an eGFR of 30 to 50 mL·min-1·1.73 m-2 for bleeding events with rates of 13.1% versus 21.3% (hazard ratio, 0.59; 95% CI, 0.41-0.84). Patients assigned aspirin had a higher risk of bleeding in all eGFR categories with an even greater increase among those with eGFR >80 mL·min-1·1.73 m-2: 16.6% versus 5.6% (hazard ratio, 3.22; 95% CI, 2.19-4.74; P for interaction=0.007). The risk of death or hospitalization and ischemic events were comparable to aspirin and placebo across eGFR categories with hazard ratios ranging from 0.97 (95% CI, 0.76-1.23) to 1.28 (95% CI, 1.02-1.59) and from 0.75 (95% CI, 0.48-1.17) to 1.34 (95% CI, 0.81-2.22), respectively. CONCLUSIONS The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400.
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Sodium/glucose cotransporter 2 and renoprotection: From the perspective of energy regulation and water conservation.
Kitada, K, Kidoguchi, S, Nakano, D, Nishiyama, A
Journal of pharmacological sciences. 2021;(3):245-250
Abstract
Sodium/glucose cotransporter 2 (SGLT2) is a renal low-affinity high-capacity sodium/glucose cotransporter expressed in the apical membrane of the early segment of proximal tubules. SGLT2 reabsorbs filtered glucose in the kidney, and its inhibitors represent a new class of oral medications used for type 2 diabetes mellitus, which act by increasing glucose and sodium excretion in urine, thereby reducing blood glucose levels. However, clinical trials showed marked improvement of renal outcomes, even in nondiabetic kidney diseases, although the underlying mechanism of this renoprotective effect is unclear. We showed that long-term excretion of salt by the kidneys, which predisposes to osmotic diuresis and water loss, induces a systemic body response for water conservation. The energy-intensive nature of water conservation leads to a reprioritization of systemic body energy metabolism. According to current data, use of SGLT2 inhibitors may result in similar reprioritization of energy metabolism to prevent dehydration. In this review article, we discuss the beneficial effects of SGLT2 inhibition from the perspective of energy metabolism and water conservation.
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Reducing the Risk of Stroke in Patients with Impaired Renal Function: Nutritional Issues.
Spence, JD
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2021;(9):105376
Abstract
Patients with renal failure have extremely high cardiovascular risk; in dialysis patients the risk of stroke is increased approximately 10-fold over that in the general population. Reasons include not only a high prevalence of traditional risk factors such as diabetes, hypertension and dyslipidemia, but also the accumulation of toxic substances that are eliminated by the kidneys, so have very high levels in patients with renal failure. These include plasma total homocysteine, asymmetric dimethylarginine, thiocyanate, and toxic products of the intestinal microbiome (Gut-Derived Uremic Toxins; GDUT), which include trimethylamine N- oxide (TMAO), produced from phosphatidylcholine (largely from egg yolk) and carnitine (largely from red meat). Other GDUT are produced from amino acids, largely from meat consumption. Deficiency of vitamin B12 is very common, raises plasma tHcy, and is easily treated. However, cyanocobalamin is toxic in patients with renal failure. To reduce the risk of stroke in renal failure it is important to limit the intake of meat, avoid egg yolk, and use methylcobalamin instead of cyanocobalamin, in addition to folic acid.
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Metabolism of sugars: A window to the regulation of glucose and lipid homeostasis by splanchnic organs.
Tappy, L
Clinical nutrition (Edinburgh, Scotland). 2021;(4):1691-1698
Abstract
BACKGROUND &AIMS: Dietary sugars are absorbed in the hepatic portal circulation as glucose, fructose, or galactose. The gut and liver are required to process fructose and galactose into glucose, lactate, and fatty acids. A high sugar intake may favor the development of cardio-metabolic diseases by inducing Insulin resistance and increased concentrations of triglyceride-rich lipoproteins. METHODS A narrative review of the literature regarding the metabolic effects of fructose-containing sugars. RESULTS Sugars' metabolic effects differ from those of starch mainly due to the fructose component of sucrose. Fructose is metabolized in a set of fructolytic cells, which comprise small bowel enterocytes, hepatocytes, and kidney proximal tubule cells. Compared to glucose, fructose is readily metabolized in an insulin-independent way, even in subjects with diabetes mellitus, and produces minor increases in glycemia. It can be efficiently used for energy production, including during exercise. Unlike commonly thought, fructose when ingested in small amounts is mainly metabolized to glucose and organic acids in the gut, and this organ may thus shield the liver from potentially deleterious effects. CONCLUSIONS The metabolic functions of splanchnic organs must be performed with homeostatic constraints to avoid exaggerated blood glucose and lipid concentrations, and thus to prevent cellular damages leading to non-communicable diseases. Excess fructose intake can impair insulin-induced suppression of glucose production, stimulate de novo lipogenesis, and increase intrahepatic and blood triglyceride concentrations. With chronically high fructose intake, enterocyte can switch to lipid synthesis and accumulation of triglyceride, possibly causing an enterocyte dysfunction.
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Colonic dialysis can influence gut flora to protect renal function in patients with pre-dialysis chronic kidney disease.
Li, Y, Dai, M, Yan, J, Liu, F, Wang, X, Lin, L, Huang, M, Li, C, Wen, R, Qin, J, et al
Scientific reports. 2021;(1):12773
Abstract
Chronic kidney disease (CKD) is a major public health burden around the world. The gut microbiome may contribute to CKD progression and serve as a promising therapeutic target. Colonic dialysis has long been used in China to help remove gut-derived toxins to delay CKD progression. Since disturbances in the gut biome may influence disease progression, we wondered whether colonic dialysis may mitigate the condition by influencing the biome. We compared the gut microbiota, based on 16S rRNA gene sequencing, in fecal samples of 25 patients with CKD (stages 3-5) who were receiving colonic dialysis(group CD), 25 outpatients with CKD not receiving colonic dialysis(group OP), and 34 healthy subjects(group HS). Richness of gut microbiota was similar between patients on colonic dialysis and healthy subjects, and richness in these two groups was significantly higher than that in patients not on colonic dialysis. Colonic dialysis also altered the profile of microbes in the gut of CKD patients, bringing it closer to the profile in healthy subjects. Colonic dialysis may protect renal function in pre-dialysis CKD by mitigating dysbiosis of gut microbiota.