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Lung congestion is a risk factor for all-cause and cardiovascular mortality in patients on chronic hemodialysis, and its estimation by ultrasound may be useful to guide ultrafiltration and drug therapy in this population. In an international, multi-center randomized controlled trial (NCT02310061) we investigated whether a lung ultrasound-guided treatment strategy improved a composite end point (all-cause death, non-fatal myocardial infarction, decompensated heart failure) vs usual care in patients receiving chronic hemodialysis with high cardiovascular risk. Patient-Reported Outcomes (Depression and the Standard Form 36 Quality of Life Questionnaire, SF36) were assessed as secondary outcomes. A total of 367 patients were enrolled: 183 in the active arm and 180 in the control arm. In the active arm, the pre-dialysis lung scan was used to titrate ultrafiltration during dialysis and drug treatment. Three hundred and seven patients completed the study: 152 in the active arm and 155 in the control arm. During a mean follow-up of 1.49 years, lung congestion was significantly more frequently relieved in the active (78%) than in the control (56%) arm and the intervention was safe. The primary composite end point did not significantly differ between the two study arms (Hazard Ratio 0.88; 95% Confidence Interval: 0.63-1.24). The risk for all-cause and cardiovascular hospitalization and the changes of left ventricular mass and function did not differ among the two groups. A post hoc analysis for recurrent episodes of decompensated heart failure (0.37; 0.15-0.93) and cardiovascular events (0.63; 0.41-0.97) showed a risk reduction for these outcomes in the active arm. There were no differences in patient-reported outcomes between groups. Thus, in patients on chronic hemodialysis with high cardiovascular risk, a treatment strategy guided by lung ultrasound effectively relieved lung congestion but was not more effective than usual care in improving the primary or secondary end points of the trial.

Diabetis mellitus; Malaltia renal diabètica; Atenció multidisciplinària Diabetes mellitus; Diabetic kidney disease; Multidisciplinary care Diabetes mellitus; Enfermedad renal diabética; Atención multidisciplinaria Age-standardized rates of diabetes mellitus (DM)-related complications, such as acute myocardial infarction, stroke or amputations, have decreased in recent years, but this was not associated with a clear reduction of the incidence of advanced chronic kidney disease (CKD) requiring renal replacement therapy. The early detection of diabetic kidney disease (DKD) is a key to reduce complications, morbidity and mortality. Consensus documents and clinical practice guidelines recommend referral of DM patients to nephrology when the estimated glomerular filtration rate falls below 30 mL/min/1.73 m2 or when albuminuria exceeds 300 mg/g urinary creatinine. Conceptually, it strikes as odd that patients with CKD are referred to the specialist caring for the prevention and treatment of CKD only when >70% of the functioning kidney mass has been lost. The increasing global health burden of CKD, driven in large part by DKD, the suboptimal impact of routine care on DKD outcomes as compared with other DM complications, the realization that successful therapy of CKD requires early diagnosis and intervention, the advances in earlier diagnosis of kidney injury and the recent availability of antidiabetic drugs with a renal mechanism of action and lack of hypoglycaemia risk, which additionally are cardio- and nephroprotective, all point towards a paradigm shift in the care for DM patients in which they should be referred earlier to nephrology as part of a coordinated and integrated care approach. Sources of support: FIS/Fondos FEDER PI18/01386, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM.

Introduction Since infammation alters vascular permeability, including vascular permeability in the lung, we hypothesized that it can be an amplifer of lung congestion in a category of patients at high risk for pulmonary oedema like end stage kidney disease (ESKD) patients. Objective and methods We investigated the efect modifcation by systemic infammation (serum CRP) on the relationship between a surrogate of the flling pressure of the LV [left atrial volume indexed to the body surface area (LAVI)] and lung water in a series of 220 ESKD patients. Lung water was quantifed by the number of ultrasound B lines (US-B) on lung US. Six-hundred and three recordings were performed during a 2-year follow up. Longitudinal data analysis was made by the Mixed Linear Model. Results At baseline, 88 had absent, 101 had mild to moderate lung congestion and 31 severe congestion. The number of US B lines associated with LAVI (r=0.23, P

Background and Aims Kidney fibrosis has been reported to be a key progression hallmark of chronic kidney disease (CKD). It seems likely that a precise biomarker of renal fibrosis extension would contribute to predict accurately the risk of a decline in glomerular filtration rate (eGFR). 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 eGFR loss. We aim to evaluate uDKK3 as a potential biomarker for long-term CKD progression in a cohort with various etiologies of CKD, and subsequently in an overt diabetic nephropathy cohort. We also tested the role of treatment with RAAS blockers on the uDKK3 levels and if the treatment could modify them. Method We prospectively studied two independent cohorts consisted of 356 patients with stage 2-3 CKD. Progreser cohort comprised 255 patients with heterogeneous etiologies of CKD and Pronedi cohort 101 patients with overt diabetic nephropathy. The primary outcome was the time to the first event of the composite endpoint (>50% increase in serum creatinine concentration, end-stage kidney disease [ESKD], or death). We divided patients into tertiles according to their baseline uDKK3 levels: less than 1092 pg/mg (Tertile 1, T1), between 1092-5050 pg/mg (Tertile 2, T2) and higher than 5050 pg/mg (Tertile 3, T3). We used the cut point of T3 as an exploratory cut-off. Cox regression models were used to adjust for potential effects of confounders or modifiers: age, gender, mean arterial pressure, body mass index (BMI), urine albumin/creatinine ratio, urine protein/creatinine ratio and serum creatinine. Mixed-effects models were adjusted to study longitudinal data. Results Progreser cohort and Pronedi cohort did not differ in their clinical baseline characteristics except in proteinuria. At baseline, uDKK3 levels were not different between different etiologies or both cohorts, median uDKK3 was 2199 (IQR: 658-7618) pg/mg in the Progreser cohort and 3041 (IQR: 653-9777) pg/mg in the Pronedi cohort (p:0.56). Median time of follow-up was 36 months. Forty-nine patients (19 %) in Progreser cohort and 31 patients (31%) in Pronedi cohort reached the primary composite outcome. Baseline uDKK3 was significantly higher in patients who reached primary outcome. In Cox multivariate model, after adjustment for potential confounders, the highest levels of uDKK3 were found to be an independent factor for renal progression in Progreser cohort (HR 1.83, CI95% 1.11-3.31) and in Pronedi cohort (HR 2.74, CI95% 1.09-6.98). Both in the Progreser and the Pronedi cohorts, uDKK3 levels above 5050 pg/mg, were associated with a lower eGFR, higher proteinuria and were independently associated with a worse renal survival. uDKK3 gradually increased in the following months, especially in patients with higher proteinuria. Treatment with RAAS-blockers did not modify uDKK3 after 4 or 12 months of treatment. Conclusion In this study, uDKK3 ratio identified patients at high risk for long-term kidney disease progression regardless of the etiology of CKD. The hypothesis was generated in a cohort of patients with CKD of heterogeneous etiologies and was further confirmed in a cohort with overt diabetic nephropathy. The predictive role of uDKK3 persisted after adjusting by eGFR and proteinuria. uDKK3 is the first non-invasive biomarker of renal fibrosis and might serve as a useful biomarker for kidney disease progression. Therefore uDKK3 could be used by clinicians to optimize staging for renal progression and monitor therapeutic efficacy of different measures to halt CKD progression.

AimTo examine international time trends in the incidence of renal replacement therapy (RRT) for end‐stage renal disease (ESRD) by primary renal disease (PRD).MethodsRenal registries reporting on patients starting RRT per million population for ESRD by PRD from 2005 to 2014, were identified by internet search and literature review. The average annual percentage change (AAPC) with a 95% confidence interval (CI) of the time trends was computed using Joinpoint regression.ResultsThere was a significant decrease in the incidence of RRT for ESRD due to diabetes mellitus (DM) in Europe (AAPC=‐0.9; 95%CI‐1.3;‐0.5) and to hypertension/renal vascular disease (HT/RVD) in Australia (AAPC=‐1.8; 95%CI‐3.3;‐0.3), Canada (AAPC=‐2.9; 95%CI‐4.4;‐1.5) and Europe (AAPC=‐1.1; 95%CI‐2.1;‐0.0). A decrease or stabilization was observed for glomerulonephritis in all regions and for autosomal dominant polycystic kidney disease (ADPKD) in all regions except for Malaysia and the Republic of Korea. An increase of 5.2% to 16.3% was observed for DM, HT/RVD and ADPKD in Malaysia and the Republic of Korea.ConclusionLarge international differences exist in the trends in incidence of RRT by primary renal disease. Mapping of these international trends is the first step in defining the causes and successful preventative measures of CKD.

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.

Background. Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with noncardiovascular death in CKD populations are lacking. Methods. The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (n ¼ 2185 CKD patients). Results. After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG þ rs2283368 CC/CT þ rs2320762 GG). Among the patients with the three SNPs genotyped (n ¼ 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA þ rs2283368 TT þ rs2320762 GT/TT). All the other combinations [n ¼ 846 (83.3%)] were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher fhazard ratio [HR] 3.28 [confidence interval (CI) 1.51-7.12]g and lower [HR 6 × 10-6 (95% CI 3.3 × 10-7-1.1 × 10-5)] risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination. Conclusions. Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD. © The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

Type 2 diabetes mellitus (T2DM) represents the main cause of chronic kidney disease (CKD) and end-stage renal disease (ESKD), and diabetic kidney disease (DKD) is a major cause of morbidity and mortality in diabetes. Despite advances in the nephroprotective treatment of T2DM, DKD remains the most common complication, driving the need for renal replacement therapies (RRT) worldwide, and its incidence is increasing. Until recently, prevention of DKD progression was based around strict blood pressure (BP) control, using renin–angiotensin system blockers that simultaneously reduce BP and proteinuria, adequate glycemic control and control of cardiovascular risk factors. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are a new class of anti-hyperglycemic drugs shown to improve cardiovascular and renal events in DKD. In this regard, GLP-1RA o er the potential for adequate glycemic control in multiple stages of DKD without an increased risk of hypoglycemia, preventing the onset of macroalbuminuria and slowing the decline of glomerular filtration rate (GFR) in diabetic patients, also bringing additional benefit in weight reduction, cardiovascular and other kidney outcomes. Results from ongoing trials are pending to assess the impact of GLP-1RA treatments on primary kidney endpoints in DKD

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 >45mL/min/1.73m2. 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, FIS/Fondos FEDER (PI16/02057, PI17/00257, ISCIIIRETIC REDinREN RD016/0009), FRIAT, Sociedad Española de Nefrología, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM, and CIBER CV 16/11/00420

Resumen Introduccion y objetivos Los individuos con tasa de filtrado glomerular estimada (TFGe) disminuida tienen mayor riesgo de muerte por todas las causas (MT) y cardiovascular; se debate si los sujetos mayores con TFGe entre 45 y 59 ml/min/1,73 m2 tambien tienen un riesgo aumentado. Se evaluo la asociacion entre la TFGe y la MT y los eventos cardiovasculares (ECV) en individuos de edad 60-74 y ≥ 75 anos en un area de baja incidencia de enfermedad coronaria. Metodos Se realizo un estudio retrospectivo de cohortes utilizando registros electronicos de atencion primaria y hospital. Se incluyo a 130.233 individuos de 60 o mas anos con una determinacion de creatinina entre el 1 de enero de 2010 y el 31 de diciembre de 2011 y una TFGe segun la formula de la Chronic Kidney Disease Epidemiology Collaboration. Las asociaciones independientes entre la TFGe y la MT y el ingreso por ECV se evaluaron mediante modelos de regresion de Cox y Fine-Gray respectivamente. Resultados Media de edad, 70 anos; el 56,1% eran mujeres. El 13,5% tenia una TFGe Conclusiones En un area de baja incidencia de enfermedad coronaria, el riesgo de muerte y ECV fue de mayor a menor TFGe. A edades ≥ 75 anos, la categoria de TFGe 45-59, en el limite significativo de ECV, incluyo a muchos individuos sin riesgo adicional significativo.

Introduction: Variations in the use of healthcare services can be defined as systematic variations of adjusted rates for certain aggregation levels of the population. The study analyses how renal replacement therapy (RRT) is used, identifying RRT variability in Catalonia from 2002 to 2012. Material and methods: Ecological study by health area using data from the Catalan renal registry. We present incident rates, standardised incidence ratios and prevalence, while variability was calculated through direct and indirect standardisation methods. Results: From 2002 until 31/12/2012, 10,784 patients initiated RRT in Catalonia: 9238 on haemodialysis (HD) (50 treatments per 100,000 people 2010/2012), 1076 on peritoneal dialysis (PD) (8.2 treatments per 100,000 people 2010/2012) and 470 received an early kidney transplant (KT) (4.4 treatments per 100,000 people 2010/2012). Over the 10 years, the HD cumulative incidence rate fell (7%), while the PD and KT incidence rates increased (63% and 177%, respectively); both are higher in young patients (

Albuminuria; Atrasentan; Canagliflozin Albuminuria; Atrasentan; Canagliflozina Albuminúria; Atrasentan; Canagliflozina 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. Funded by FIS/Fondos FEDER (PI16/02057, PI16/01814. PI17/00257, ISCIII-RETIC REDinREN RD016/0009), Sociedad Espanola de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. E.P. is a researcher in the Ramón y Cajal Program.