Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional health care team providing diabetes care in the U.S. and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the health care system, and physical activity behaviors, including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycaemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional healthcare team providing diabetes care in the USA and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the healthcare system and physical activity behaviours including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided. Graphical abstract Supplementary Information The online version of this article (10.1007/s00125-022-05787-2) contains peer-reviewed but unedited supplementary material.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) encompasses laboratory and bone abnormalities and vascular calcification and has deleterious effects on clinical outcomes. KDOQI (Kidney Disease Outcomes Quality Initiative), an initiative of the National Kidney Foundation, addressed this issue with the publication of a clinical practice guideline for bone metabolism and disease in CKD in 2003, and 2 years later, a new definition and classification scheme for CKD-MBD was developed following a KDIGO (Kidney Disease: Improving Global Outcomes) Controversies Conference. The initial KDIGO guideline on CKD-MBD was then published in 2009. New evidence was subsequently reviewed at the 2013 KDIGO Controversies Conference, and in 2017, KDIGO issued a clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. This commentary presents the views of the KDOQI CKD-MBD work group convened by the National Kidney Foundation. The KDOQI work group agrees with most of the KDIGO guideline update recommendations, particularly the suggestions regarding bone mineral density testing, joint assessments of longitudinal trends in mineral metabolism markers, and dietary phosphate counseling focused on phosphate additives. However, the KDOQI work group has some concerns about the suggestions related to hypocalcemia and hypercalcemia, phosphate-binder choice, and treatment of abnormal parathyroid hormone concentrations. The overall goal of this commentary is to provide a broad discussion for the US nephrology community regarding CKD-MBD and its diagnosis, prevention, and treatment.

Importance Coronary artery calcification (CAC) is highly prevalent in patients with pre-dialysis chronic kidney disease (CKD). However, there are sparse data on the association of CAC with subsequent risk of cardiovascular disease (CVD) and all-cause mortality in this population. Objectives To study the prospective association of CAC with risk of CVD and all-cause mortality among patients with pre-dialysis CKD. Design, Setting, and Participants Chronic Renal Insufficiency Cohort study recruited adults aged 21–74 years with an estimated-glomerular filtration rate (eGFR) of 20–70 mL/min/1.73 m2 from seven clinical centers in the US. Of them, 1,541 participants without CVD at baseline who had CAC measures were included in current analyses. Exposure CAC was assessed by electron-beam computed tomography or multi-detector computed tomography. Main Outcomes and Measures Incidence of CVD (including myocardial infarction, heart failure, and stroke) and all-cause mortality were reported every six months and confirmed by medical record adjudication. Results During an average of 5.9 years of follow-up, we observed 188 CVD (60 myocardial infarction, 120 heart failure, and 27 stroke) and 137 deaths. In Cox proportional hazards models adjusted for age, gender, race, clinical site, education, physical activity, total cholesterol, HDL-cholesterol, systolic blood pressure, antihypertensive treatment, current cigarette smoking, diabetes, body-mass index, C-reactive protein, hemoglobin A1c, phosphate, troponin T, log-N-terminal pro-B-type natriuretic peptide, fibroblast growth factor-23, eGFR, and proteinuria, the hazard ratios (95% confidence interval [CI]) associated with one standard deviation of CAC were 1.40 (1.16 to 1.69, p<.001) for CVD, 1.44 (1.02 to 2.02, p=.04) for myocardial infarction, 1.39 (1.10 to 1.76, p=.006) for heart failure, and 1.19 (0.94 to 1.51, p=.15) for all-cause mortality. In addition, inclusion of CAC score led to significant increase in c-statistic 0.02 (95% CI 0.00 to 0.09, p<.001) for predicting CVD over all above-mentioned established and novel CVD risk factors. Conclusion and Relevance CAC is independently and significantly related to the risks of CVD, myocardial infarction, and heart failure in CKD patients. In addition, CAC improves risk prediction for CVD, myocardial infarction, and heart failure over established and novel CVD risk factors among CKD patients, although the change in c-statistics is small.

Heart failure is a common consequence of CKD, and it portends high risk for mortality. However, among patients without known heart failure, the associations of different stages of estimated GFR (eGFR) with changes in cardiac structure and function are not well described. Here, we performed a cross-sectional analysis to study these associations among 3487 participants of the Chronic Renal Insufficiency Cohort Study. We estimated GFR using cystatin C. The prevalence of left ventricular hypertrophy (LVH) assessed by echocardiography was 32%, 48%, 57%, and 75% for eGFR categories $60, 45-59, 30-44, and ,30 ml/ min per 1.73 m 2 , respectively. In fully adjusted multivariable analyses, subjects with eGFR levels of ,30 ml/ min per 1.73 m 2 had twofold higher odds of LVH (OR=2.20, 95% CI=1.40-3.40; P,0.001) relative to subjects with eGFR$60 ml/min per 1.73 m 2 . This reduction in kidney function also significantly associated with abnormal LV geometry but not diastolic or systolic dysfunction. An eGFR of 30-44 ml/min per 1.73 m 2 also significantly associated with LVH and abnormal LV geometry compared with eGFR$60 ml/min per 1.73 m 2 . In summary, in this large CKD cohort, reduced kidney function associated with abnormal cardiac structure. We did not detect significant associations between kidney function and systolic or diastolic function after adjusting for potential confounding variables.

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