Diabetes Mellitus and Diabetic Kidney Disease: The Future Is Already Here.

Diabetes mellitus (DM) is a metabolic systemic disease with a high rate of morbidity and mortality [...].

A randomized multicenter trial on a lung ultrasound-guided treatment strategy in patients on chronic hemodialysis with high cardiovascular risk.

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.

Urinary Dickkopf-3: a new biomarker for CKD progression and mortality.

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.

Optimizing the timing of nephrology referral for patients with diabetic kidney disease.

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.

GLP-1 Receptor Agonists and Diabetic Kidney Disease: A Call of Attention to Nephrologists.

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 offer 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 inhibition: towards an indication to treat diabetic kidney disease.

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.

Inflammation is an amplifier of lung congestion by high lv filling pressure in hemodialysis patients: a longitudinal study.

INTRODUCTION: Since inflammation alters vascular permeability, including vascular permeability in the lung, we hypothesized that it can be an amplifier 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 effect modification by systemic inflammation (serum CRP) on the relationship between a surrogate of the filling 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 quantified 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 < 0.001) and serum CRP was a robust modifier of this relationship (P < 0.001). Similarly, in fully adjusted longitudinal analyses US-B lines associated with simultaneous estimates of LAVI (P = 0.002) and again CRP was a strong modifier of this relationship in adjusted analyses (P ≤ 0.01). Overall, at comparable LAVI levels, lung congestion was more pronounced in inflamed than in non-inflamed patients. CONCLUSION: In ESKD systemic inflammation is a modifier of the relationship between LAVI, an integrate measure of LV filling pressure, and lung water. For any given pressure, lung water is increased with higher CRP levels, likely reflecting a higher permeability of the alveolar-capillary barrier.

Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation and Study of Diabetic Nephropathy with Atrasentan: what was learned about the treatment of diabetic kidney disease with canagliflozin and atrasentan?

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.

¿Serán las nuevas moléculas efectivas en protección renal y cardiovascular en la diabetes mellitus y la enfermedad renal diabética? / Will the new molecules be effective in renal and cardiovascular protection in diabetes mellitus and diabetic kidney disease?

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International comparison of trends in patients commencing renal replacement therapy by primary renal disease.

AIM: To examine international time trends in the incidence of renal replacement therapy (RRT) for end-stage renal disease (ESRD) by primary renal disease (PRD). METHODS: Renal 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. RESULTS: There 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 5.2-16.3% was observed for DM, HT/RVD and ADPKD in Malaysia and the Republic of Korea. CONCLUSION: Large 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.

Impact of immunosuppressive therapy on arterial stiffness in kidney transplantation: are all treatments the same?

Arterial stiffness is a biologic process related to ageing and its relationship with cardiovascular risk is well established. Several methods are currently available for non-invasive measurement of arterial stiffness that provide valuable information to further assess patients' vascular status in real time. In kidney transplantation recipients, several factors could accelerate the stiffness process, such as the use of calcineurin inhibitors (CNIs), the presence of chronic kidney disease and other classical cardiovascular factors, which would explain, at least in part, the high cardiovascular mortality and morbidity. Despite the importance of arterial stiffness as a biomarker of cardiovascular risk, and unlike other cardiovascular risk factors (e.g. left ventricular hypertrophy), only a few clinical trials or retrospective studies of kidney recipients have evaluated its impact. In this review we describe the clinical impact of arterial stiffness as a prognostic marker of cardiovascular disease and the effects of different immunosuppressive regimens on its progression, focusing on the potential benefits of CNI-sparing protocols and supporting the rationale for individualization of immunosuppression in patients with lower arterial elasticity. Among the immunosuppressive drugs, a belatacept-based regimen seems to offer better vascular protection compared with CNIs, although further studies are needed to confirm the preliminary positive results.

Effects of Pentoxifylline on Soluble Klotho Concentrations and Renal Tubular Cell Expression in Diabetic Kidney Disease.

OBJECTIVE: The effect of pentoxifylline on Klotho levels in patients with type 2 diabetes mellitus with chronic kidney disease (CKD) was assessed in a post hoc analysis of the Pentoxifylline for Renoprotection in Diabetic Nephropathy (PREDIAN) trial. RESEARCH DESIGN AND METHODS: Circulating and urinary tumor necrosis factor-α (TNF-α) and Klotho were measured before and after 1 year of pentoxifylline. The effect on Klotho expression was assessed in cultured renal tubular cells. RESULTS: Pentoxifylline administration resulted in decreased serum and urinary TNF-α, whereas serum and urinary Klotho increased significantly. Changes in urinary Klotho, urinary TNF-α, and phosphorus were associated with changes in serum Klotho; changes in estimated glomerular filtration rate, urinary TNF-α, and albuminuria were related to urinary Klotho variation. In renal tubular cells, pentoxifylline prevented the decrease in Klotho expression induced by inflammatory cytokines or albumin. CONCLUSIONS: Pentoxifylline increased Klotho levels in patients with diabetes with stage 3-4 CKD and prevented reduced Klotho expression in vitro. This beneficial effect may be related to anti-inflammatory and antialbuminuric activity.

Tasa de filtrado glomerular estimada, eventos cardiovasculares y mortalidad por grupos de edad en individuos de 60 o más años del sur de Europa / Estimated glomerular filtration rate, cardiovascular events and mortality across age groups among individuals older than 60 years in Southern Europe

Introducción 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 también tienen un riesgo aumentado. Se evaluó la asociación entre la TFGe y la MT y los eventos cardiovasculares (ECV) en individuos de edad 60-74 y ≥ 75 años en un área de baja incidencia de enfermedad coronaria. Métodos: Se realizó un estudio retrospectivo de cohortes utilizando registros electrónicos de atención primaria y hospital. Se incluyó a 130.233 individuos de 60 o más años con una determinación de creatinina entre el 1 de enero de 2010 y el 31 de diciembre de 2011 y una TFGe según la fórmula 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 regresión de Cox y Fine-Gray respectivamente. Resultados: Media de edad, 70 años; el 56,1% eran mujeres. El 13,5% tenía una TFGe < 60 (el 69,7%, TFGe 45-59). Durante una mediana de seguimiento de 38,2 meses, 6.474 participantes fallecieron y 3.746 presentaron ECV. Tanto para la MT como para los ECV, las HR ajustadas de los participantes de 75 o más años fueron significativas con TFGe < 60. Con TFGe 45-59, para MT fueron HR = 1,61; IC95%, 1,37-1,89 y HR = 1,19; IC95%, 1,10-1,28 en los grupos de edad de 60-74 y ≥ 75 años respectivamente, y para ECV, HR = 1,28; IC95%, 1,08-1,51 y HR = 1,12; IC95%, 0,99-1,26. Conclusiones: En un área de baja incidencia de enfermedad coronaria, el riesgo de muerte y ECV fue de mayor a menor TFGe. A edades ≥ 75 años, la categoría de TFGe 45-59, en el límite significativo de ECV, incluyó a muchos individuos sin riesgo adicional significativo

Introduction and objectives: Individuals with a decreased estimated glomerular filtration rate (eGFR) are at increased risk of all-cause (ACM) and cardiovascular mortality; there is ongoing debate about whether older individuals with eGFR 45 to 59 mL/min/1.73 m2 are also at increased risk. We evaluated the association between eGFR and ACM and cardiovascular events (CVE) in people aged 60 to 74 and ≥ 75 years in a population with a low coronary disease incidence. Methods: We conducted a retrospective cohort study by using primary care and hospital electronic records. We included 130 233 individuals aged ≥ 60 years with creatinine measurement between January 1, 2010 and December 31, 2011; eGFR was estimated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. The independent association between eGFR and the risk of ACM and hospital admission due to CVE were determined with Cox and Fine-Gray regressions, respectively. Results: The median was age 70 years, and 56.1% were women; 13.5% had eGFR < 60 (69.7% eGFR 45-59). During a median follow-up of 38.2 months, 6474 participants died and 3746 had a CVE. For ACM and CVE, the HR in older individuals became significant at eGFR < 60. Fully adjusted HR for ACM in the eGFR 45 to 59 category were 1.61; 95%CI, 1.37-1.89 and 1.19; 95%CI, 1.10-1.28 in 60- to 74-year-olds and ≥ 75-year-olds, respectively; for CVE HR were 1.28; 95%CI, 1.08-1.51 and 1.12; 95%CI, 0.99-1.26. Conclusions: In a region with low coronary disease incidence, the risk of death and CVE increased with decreasing eGFR. In ≥ 75-year-olds, the eGFR 45 to 59 category, which had borderline risk for CVE, included many individuals without significant additional risk

Estimated Glomerular Filtration Rate, Cardiovascular Events and Mortality Across Age Groups Among Individuals Older Than 60 Years in Southern Europe.

INTRODUCTION AND OBJECTIVES: Individuals with a decreased estimated glomerular filtration rate (eGFR) are at increased risk of all-cause (ACM) and cardiovascular mortality; there is ongoing debate about whether older individuals with eGFR 45 to 59mL/min/1.73 m2 are also at increased risk. We evaluated the association between eGFR and ACM and cardiovascular events (CVE) in people aged 60 to 74 and ≥ 75 years in a population with a low coronary disease incidence. METHODS: We conducted a retrospective cohort study by using primary care and hospital electronic records. We included 130 233 individuals aged ≥ 60 years with creatinine measurement between January 1, 2010 and December 31, 2011; eGFR was estimated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. The independent association between eGFR and the risk of ACM and hospital admission due to CVE were determined with Cox and Fine-Gray regressions, respectively. RESULTS: The median was age 70 years, and 56.1% were women; 13.5% had eGFR < 60 (69.7% eGFR 45-59). During a median follow-up of 38.2 months, 6474 participants died and 3746 had a CVE. For ACM and CVE, the HR in older individuals became significant at eGFR < 60. Fully adjusted HR for ACM in the eGFR 45 to 59 category were 1.61; 95%CI, 1.37-1.89 and 1.19; 95%CI, 1.10-1.28 in 60- to 74-year-olds and ≥ 75-year-olds, respectively; for CVE HR were 1.28; 95%CI, 1.08-1.51 and 1.12; 95%CI, 0.99-1.26. CONCLUSIONS: In a region with low coronary disease incidence, the risk of death and CVE increased with decreasing eGFR. In ≥ 75-year-olds, the eGFR 45 to 59 category, which had borderline risk for CVE, included many individuals without significant additional risk.

Guía ERBP sobre la diabetes en la enfermedad renal crónica estadio 3B o mayor: ¿metformina para todos? / ERBP guideline on management of patients with diabetes and chronic kidney disease stage 3B or higher. Metformin for all?

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Desarrollo de la «Guía de consenso para el uso de medicamentos en insuficiencia renal» / Development of the "Consensus guidelines for the use of drugs in renal failure"

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The European Renal Association - European Dialysis and Transplant Association Registry Annual Report 2014: a summary.

Background: This article summarizes the European Renal Association - European Dialysis and Transplant Association Registry's 2014 annual report. It describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2014 within 35 countries. Methods: In 2016, the ERA-EDTA Registry received data on patients who in 2014 where undergoing RRT for ESRD, from 51 national or regional renal registries. Thirty-two registries provided individual patient level data and 19 provided aggregated patient level data. The incidence, prevalence and survival probabilities of these patients were determined. Results: In 2014, 70 953 individuals commenced RRT for ESRD, equating to an overall unadjusted incidence rate of 133 per million population (pmp). The incidence ranged by 10-fold; from 23 pmp in the Ukraine to 237 pmp in Portugal. Of the patients commencing RRT, almost two-thirds were men, over half were aged ≥65 years and a quarter had diabetes mellitus as their primary renal diagnosis. By day 91 of commencing RRT, 81% of patients were receiving haemodialysis. On 31 December 2014, 490 743 individuals were receiving RRT for ESRD, equating to an unadjusted prevalence of 924 pmp. This ranged throughout Europe by more than 10-fold, from 157 pmp in the Ukraine to 1794 pmp in Portugal. In 2014, 19 406 kidney transplantations were performed, equating to an overall unadjusted transplant rate of 36 pmp. Again this varied considerably throughout Europe. For patients commencing RRT during 2005-09, the 5-year-adjusted patient survival probabilities on all RRT modalities was 63.3% (95% confidence interval 63.0-63.6). The expected remaining lifetime of a 20- to 24-year-old patient with ESRD receiving dialysis or living with a kidney transplant was 21.9 and 44.0 years, respectively. This was substantially lower than the 61.8 years of expected remaining lifetime of a 20-year-old patient without ESRD.