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Background: Diabetic patients on haemodialysis have a higher risk of mortality than non-diabetic patients. The aim of this COSMOS (Current management of secondary hyperparathyroidism: a multicentre observational study) analysis was to assess whether bone and mineral laboratory values [calcium, phosphorus and parathyroid hormone (PTH)] contribute to this risk., Methods: COSMOS is a multicentre, open-cohort, 3-year prospective study, which includes 6797 patients from 227 randomly selected dialysis centres in 20 European countries. The association between mortality and calcium, phosphate or PTH was assessed using Cox proportional hazard regression models using both penalized splines smoothing and categorization according to KDIGO guidelines. The effect modification of the association between the relative risk of mortality and serum calcium, phosphate or PTH by diabetes was assessed., Results: There was a statistically significant effect modification of the association between the relative risk of mortality and serum PTH by diabetes (P = .011). The slope of the curve of the association between increasing values of PTH and relative risk of mortality was steeper for diabetic compared with non-diabetic patients, mainly for high levels of PTH. In addition, high serum PTH (>9 times the normal values) was significantly associated with a higher relative risk of mortality in diabetic patients but not in non-diabetic patients [1.53 (95% confidence interval 1.07-2.19) and 1.17 (95% confidence interval 0.91-1.52)]. No significant effect modification of the association between the relative risk of mortality and serum calcium or phosphate by diabetes was found (P = .2 and P = .059, respectively)., Conclusion: The results show a different association of PTH with the relative risk of mortality in diabetic and non-diabetic patients. These findings could have relevant implications for the diagnosis and treatment of chronic kidney disease-mineral and bone disorders., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend. The new approaches should go beyond the current therapy focussed on the control of traditional risk factors such as hyperglycaemia and hypertension. In this scenario, drug repurposing constitutes an economic and feasible approach based on the discovery of useful activities for old drugs. Pentoxifylline is a nonselective phosphodiesterase inhibitor currently indicated for peripheral artery disease. Clinical trials and meta-analyses have shown renoprotection secondary to anti-inflammatory and antifibrotic effects in diabetic patients treated with this old known drug, which makes pentoxifylline a candidate for repurposing in diabetic kidney disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Cardiorenal syndromes (CRS) are broadly defined as disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. CRS are currently classified into five categories, mostly based on disease-initiating events and their acuity or chronicity. CRS types 3 and 4 (also called renocardiac syndromes) refer to acute and chronic kidney dysfunction resulting in acute and chronic heart dysfunction, respectively. The notion of renocardiac syndromes has broadened interest in kidney-heart interactions but uncertainty remains in the nephrological community's understanding of the clinical diversity, pathophysiological mechanisms and optimal management approaches of these syndromes. This triple challenge that renocardiac syndromes (and likely other cardiorenal syndromes) pose to the nephrologist can only be faced through a specific and demanding training plan to enhance his/her cardiological scientific knowledge and through an appropriate clinical environment to develop his/her cardiological clinical skills. The first must be the objective of the subspecialty of cardionephrology (or nephrocardiology) and the second must be the result of collaboration with cardiologists (and other specialists) in cardiorenal care units. This review will first consider various aspects of the challenges that renocardiac syndromes pose to nephrologists and, then, will discuss those aspects of cardionephrology and cardiorenal units that can facilitate an effective response to the challenges., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Despite the high prevalence of chronic kidney disease (CKD) and its high cardiovascular risk, patients with CKD, especially those with advanced CKD (stages 4-5 and patients on kidney replacement therapy), are excluded from most cardiovascular clinical trials. It is particularly relevant in patients with advanced CKD and heart failure (HF) who have been underrepresented in many pivotal randomized trials that have modified the management of HF. For this reason, there is little or no direct evidence for HF therapies in patients with advanced CKD and treatment is extrapolated from patients without CKD or patients with earlier CKD stages. The major consequence of the lack of direct evidence is the under-prescription of HF drugs to this patient population. As patients with advanced CKD and HF represent probably the highest cardiovascular risk population, the exclusion of these patients from HF trials is a serious deontological fault that must be solved. There is an urgent need to generate evidence on how to treat HF in patients with advanced CKD. This article briefly reviews the management challenges posed by HF in patients with CKD and proposes a road map to address them., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Background: Kidney fibrosis has been reported to be a prognostic factor in chronic kidney disease (CKD) progression. Previous studies have shown that the assessment of urinary Dickkopf-3 (uDKK3), a stress-induced tubular epithelial-derived profibrotic glycoprotein, might be a potential tubulointerstitial fibrosis biomarker and might identify patients at short-term risk of glomerular filtration rate loss. We aim to evaluate uDKK3 as a potential biomarker for progression of CKD in a cohort with various aetiologies of CKD and subsequently in an overt diabetic nephropathy cohort., Methods: We prospectively studied two independent cohorts comprising a total of 351 patients with Stages 2 and 3 CKD. Combined primary outcome consisted of a 50% increase in serum creatinine, end-stage kidney disease or death. The Progreser cohort included patients with heterogeneous aetiologies and the Pronedi cohort (101 patients) with overt diabetic nephropathy. The median follow-up time was 36 months [interquartile range (IQR) 30-39] and 36 (16-48), respectively., Results: At baseline, median uDKK3 was 2200 pg/mg (IQR 671-7617) in the Progreser cohort and 3042 pg/mg (IQR 661-9747) in the Pronedi cohort. There were no statistically significant differences in the uDKK3 ratio between both cohorts nor between CKD aetiologies. Baseline uDKK3 was significantly higher in patients who reached the primary outcome. In the Cox proportional hazards model, the highest levels of uDKK3 were found to be an independent factor for renal progression in the Progreser cohort {hazard ratio [HR] 1.91 [95% confidence interval (CI) 1.04-3.52]} and in the Pronedi cohort [HR 3.03 (95% CI 1.03-8.92)]. uDKK3 gradually increased in the following months, especially in patients with higher proteinuria. Treatment with renin-angiotensin-aldosterone system blockers did not modify uDKK3 after 4 or 12 months of treatment., Conclusions: uDKK3 identifies patients at high risk of CKD progression regardless of the cause of kidney injury. uDKK3 might serve as a useful biomarker for kidney disease progression and therefore could be used by clinicians to optimize staging for renal progression and monitor the response to potential treatments., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: The efficacy and safety of sucroferric oxyhydroxide (SO) have been reported in clinical trials. However, real-life data are scarce. This study presents data on the use, efficacy and safety of SO in real clinical practice., Methods: We performed a retrospective multicentre study, without any influence on the prescription decisions, that included 220 patients from 11 Spanish centres. Demographic, treatment, analytical and nutritional parameters and adherence, side effects and dropout rates were collected during 6 months., Results: SO was initiated due to inadequate control of serum phosphate (P) in 70% of participants and in 24.5% to reduce the number of tablets. Monotherapy with SO increased from 44% to 74.1%, with a reduction in the average daily number of sachets/tablets from six to two. Serum P decreased by 20% (4.6 ± 1.2 versus 5.8 ± 1.3 mg/dL; P < 0.001), with a significant reduction in intact parathyroid hormone levels (P < 0.01). The percentage of patients with adequate serum P control at threshold levels of 5 and 4.5 mg/dL increased by 45.4% and 35.9%, respectively. Serum ferritin was not modified, while the transferrin saturation index increased significantly (P = 0.04). Serum albumin and normalized protein catabolic rate, when normalized by serum P, increased, averaging 37% and 39%, respectively (P < 0.001). Adherent patients increased from 28.2% to 52.7%. Adverse effects were reported by 14.1% of participants, with abandonment of treatment in 9.5%., Conclusions: The use of SO in real-life results in better control of serum P, a reduction in the number of tablets and an improvement in therapeutic adherence. In addition, it may be beneficial with regards to secondary hyperparathyroidism and nutritional status., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Objective: Asymptomatic hyperuricaemia (AHU) is associated with inflammatory disorders, including cardiovascular disease. Uric acid (UA) lowering therapies may reduce the risk of appearance or the progression of these comorbidities. In this work, we investigated the relationship between serum UA levels and inflammation in subjects with AHU., Methods: Serum levels of high-sensitivity CRP (hsCRP), TNF-α and IL-6, and mRNA expression of TNFa and IL6 in peripheral blood mononuclear cells were measured in individuals with AHU and without comorbid conditions and in a control group with similar characteristics and normal serum UA levels. Additionally, we determined the variations in the inflammatory profile in a subgroup of subjects after 6 months of treatment with allopurinol., Results: Subjects at higher tertiles of serum UA presented higher levels of hsCRP and increased serum and mRNA expression levels of both cytokines (P < 0.001). UA levels constituted an independent predictor of increased levels of inflammatory parameters in multiple regression models (P < 0.001) and a risk factor for the presence of a subclinical inflammation in multivariate logistic regression (P < 0.001). Allopurinol reduced UA and serum and mRNA expression of inflammatory cytokines (P < 0.001). There was a significant correlation between the variations in serum UA and the variations in serum TNF-α (P < 0.01) and IL-6 (P < 0.05), and mRNA expression of these cytokines (P < 0.05). This association remained significant and independent (P < 0.01)., Conclusion: In subjects with AHU, serum UA may be an inductor of subclinical inflammation. Therapeutic reduction of serum UA was associated with a modulation of the inflammatory profile., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chronic kidney disease (CKD) significantly increases cardiovascular risk. In advanced CKD stages, accumulation of toxic circulating metabolites and mineral metabolism alterations triggers vascular calcification, characterized by vascular smooth muscle cell (VSMC) transdifferentiation and loss of the contractile phenotype. Phenotypic modulation of VSMC occurs with significant changes in gene expression. Even though ion channels are an integral component of VSMC function, the effects of uremia on ion channel remodeling has not been explored. We used an in vitro model of uremia-induced calcification of human aorta smooth muscle cells (HASMCs) to study the expression of 92 ion channel subunit genes. Uremic serum-induced extensive remodeling of ion channel expression consistent with loss of excitability but different from the one previously associated with transition from contractile to proliferative phenotypes. Among the ion channels tested, we found increased abundance and activity of voltage-dependent K + channel Kv1.3. Enhanced Kv1.3 expression was also detected in aorta from a mouse model of CKD. Pharmacological inhibition or genetic ablation of Kv1.3 decreased the amount of calcium phosphate deposition induced by uremia, supporting an important role for this channel on uremia-induced VSMC calcification., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Physiological Society.)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated their beneficial effect in diabetic kidney disease (DKD) on top of the standard of care [blood glucose control, renin-angiotensin system blockade, smoking cessation and blood pressure (BP) control], even in patients with overt DKD. However, the indication of this drug class is still blood glucose lowering in type 2 diabetic patients with estimated glomerular filtration rate >45 mL/min/1.73 m2. Based on the new evidence, several scientific societies have emphasized the preferential prescription of SGLT2i for patients at risk of heart failure or kidney disease, but still within the limits set by health authorities. A rapid positioning of both the European Medicines Agency and the US Food and Drug Administration will allow patients with overt DKD to benefit from SGLT2i. Clinical experience suggests that SGLT2i safety management may in part mirror renin-angiotensin blockade safety management in patients with overt DKD. This review focuses on the rationale for an indication of SGTL2i in DKD. We further propose clinical steps for maximizing the safety of SGLT2i in DKD patients on other antidiabetic, BP or diuretic medication., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Prevalence of atherosclerotic cardiovascular disease and its rate of progression are higher in patients with chronic kidney disease (CKD) compared with the general population. Mineral metabolism parameters have been shown to be involved in the increased velocity of atheromatosis progression. The aim of this study is to determine the role of 11 single-nucleotide polymorphisms (SNPs) of the Klotho gene on the rate of atherosclerosis progression in CKD., Methods: This was a multicentre, prospective, observational study of 1439 CKD patients from the NEFRONA cohort. Carotid and femoral ultrasounds were performed at baseline and after 24 months in 10 arterial territories. Progression of atheromatosis was defined as an increase in the number of territories with plaque. Genotyping of 11 SNPs of the Klotho gene was performed and its association with atheromatosis progression was determined by multivariate logistic regression., Results: Bivariate analysis showed that none of the 11 SNPs was associated with atheroma plaque prevalence, but 3 of them (rs495392, rs562020 and rs567170) showed association with atheromatosis progression. The multivariate analysis revealed that only rs495392 showed a statistically significant association with atheromatosis progression, after adjustment for several parameters known to affect it in CKD patients. Thus, the presence of one allele T was associated with a reduction of 30% of the odds of progression, whereas the presence of the two T alleles was associated with a decrease close to 50%., Conclusions: The presence of the allele T of the SNP rs495392 of the Klotho gene is associated with a decrease in the odds of progression of atheromatosis in CKD patients., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

In April 2019, two major Phase 3 randomized clinical trials were published that assessed primary renal outcomes in diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) tested an already available antidiabetic drug, canagliflozin, and the Study of Diabetic Nephropathy with Atrasentan (SONAR) tested a novel molecule, the endothelin-1 receptor blocker atrasentan, both on top of renin-angiotensin system blockade. Both trials demonstrated significant nephroprotection in patients with overt DKD (albuminuria >300 mg/g urinary creatinine) for combined primary endpoints of end-stage kidney disease (ESKD), doubling of serum creatinine or death from renal or cardiovascular causes in CREDENCE {hazard ratio [HR] 0.70 [95% confidence interval (CI) 0.59-0.82]} and ESKD and doubling of serum creatinine in SONAR [HR 0.65 (95% CI 0.49-0.88)]. Canagliflozin also decreased the secondary renal endpoint ESKD, doubling of serum creatinine or renal death [HR 0.66 (95% CI 0.53-0.81)], which was similar in nature and impact to the primary endpoint in SONAR. In addition, canagliflozin decreased a secondary endpoint of cardiovascular death or hospitalization for heart failure [HR 0.69 (95% CI 0.57-0.83)], whereas atrasentan had no significant impact on a secondary cardiovascular composite endpoint or on hospital admissions for heart failure and, despite restrictive exclusion criteria, there was a non-significant trend towards more frequent episodes of heart failure. Based on these results, canagliflozin will likely be approved for the indication of treating DKD in T2DM and the estimated glomerular filtration rate threshold for prescribing it will be lifted, whereas the future and place of atrasentan in the treatment of DKD remain unclear.

Many of the deadliest bacterial diseases that plague humanity in the modern age are caused by bacterial biofilms that produce chronic infections. However, most of our knowledge of the host immune response comes from the study of planktonic pathogens. While there are similarities in the host response to planktonic and biofilm bacteria, specific immune responses toward biofilms have not been well studied; the only apparent difference is the inability to clear the bacteria allowing the biofilm infection to become chronic. In some cases, the biofilms skew T-cell response toward a balance that allows a stalemate between the host and the pathogen, in which the infection can become persistent. In this minireview, we will summarize well-known examples of this phenomena as well as some emerging studies that may indicate that this situation is much more common than initially thought.

Background: Fibroblast growth factor-23 (FGF-23) and Klotho constitute the main regulatory system of phosphorus homeostasis. Beyond this physiological role, there is growing evidence suggesting that this system has relevant pathophysiological implications in different clinical processes., Content: In this review we discuss the pathophysiological implications of the FGF-23/Klotho system and the potential utility that measurements of its components may have as clinical biomarkers in different clinical settings, such as progression of chronic kidney disease, acute renal failure, and secondary hyperparathyroidism, as well as vascular dysfunction, atherosclerosis, and cardiovascular morbidity and mortality. We outline and discuss the current commercially available assays for determination of FGF-23 and Klotho and the assay limitations that must be overcome to translate these biomarkers into reliable indicators in clinical practice., Summary: In addition to its physiological role, the FGF-23/Klotho system appears to provide important information regarding the pathophysiology of several clinical conditions. Although there has been increasing study of the components of this new biological system and their potential use as clinical biomarkers, the ultimate value of this system in clinical practice will not be known until remaining assay limitations can be overcome and adequately designed studies have been conducted to demonstrate its clinical utility., (© 2013 The American Association for Clinical Chemistry.)

Background: The interest on magnesium (Mg) has grown since clinical studies have shown the efficacy of Mg-containing phosphate binders. However, some concern has arisen for the potential effect of increased serum Mg on parathyroid hormone (PTH) secretion. Our objective was to evaluate the direct effect of Mg in the regulation of the parathyroid function; specifically, PTH secretion and the expression of parathyroid cell receptors: CaR, the vitamin D receptor (VDR) and FGFR1/Klotho., Methods: The work was performed in vitro by incubating intact rat parathyroid glands in different calcium (Ca) and Mg concentrations., Results: Increasing Mg concentrations from 0.5 to 2 mM produced a left shift of PTH-Ca curves. With Mg 5 mM, the secretory response was practically abolished. Mg was able to reduce PTH only if parathyroid glands were exposed to moderately low Ca concentrations; with normal-high Ca concentrations, the effect of Mg on PTH inhibition was minor or absent. After 6-h incubation at a Ca concentration of 1.0 mM, the expression of parathyroid CaR, VDR, FGFR1 and Klotho (at mRNA and protein levels) was increased with a Mg concentration of 2.0 when compared with 0.5 mM., Conclusions: Mg reduces PTH secretion mainly when a moderate low calcium concentration is present; Mg also modulates parathyroid glands function through upregulation of the key cellular receptors CaR, VDR and FGF23/Klotho system.