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La litiasi renal, també coneguda comunament com a càlculs renals o pedres al ronyó, es tracta d'una malaltia amb una incidència a l'alça i amb una taxa de recurrència molt elevada, ja que més del 50% dels pacients que han patit un episodi tornaran a formar un càlcul renal en un termini de 5 anys. Sabent això, l'estudi presentat té com a objectiu desenvolupar un projecte per a l'empresa Devicare sobre un nou test per a l'anàlisi de les pedres de ronyó, basat en un kit que permetrà recollir la pedra expulsada pel pacient, ser enviada al laboratori i que sigui analitzada. Gràcies a la combinació de microscòpia estereoscòpica, microscòpia electrònica d'escombrada amb microanàlisi per energia dispersiva de raigs-X i espectroscòpia d’infrarojos, s’aconsegueix un diagnòstic i tractament més específic, reduint les possibilitats de recurrència de la malaltia. Aquesta prova compta amb servei a domicili de recollida de la mostra i informes personalitzats tant per al pacient com per a l'uròleg, així com una futura implementació en una App per a telèfons mòbils. Després d'una anàlisi econòmica i considerant els paràmetres del VAN, TIR, WACC i el període de retorn, s'ha arribat a la conclusió que el projecte presentat és viable per a l' empresa ja que els resultats són coherents amb el que es considera viable en l'àmbit financer La litiasis renal, también conocida comúnmente como cálculos renales o piedras en el riñón, se trata de una enfermedad con una incidencia al alza y con una tasa de recurrencia muy elevada, ya que más del 50% de los pacientes que han sufrido un episodio volverán a formar un cálculo renal en un plazo de 5 años. Sabiendo esto, el estudio presentado tiene como objetivo desarrollar un proyecto para la empresa Devicare sobre un nuevo test para el análisis de las piedras de riñón, basado en un kit que permitirá recoger la piedra expulsada por el paciente y ser enviada al laboratorio y que sea analizada. Gracias a la combinación de microscopía estereoscópica, microscopía electrónica de barrido con microanálisis por energía dispersiva de rayos-X y espectroscopia de infrarrojos, se consigue un diagnóstico y tratamiento más específico, reduciendo las posibilidades de recurrencia de la enfermedad. Dicha prueba cuenta con servicio a domicilio de recogida de la muestra e informes personalizados tanto para el paciente como para el urólogo, así como una futura implementación en una App para teléfonos móviles. Tras un análisis económico y considerando los parámetros del VAN, TIR, WACC y el periodo de retorno, se ha llegado a la conclusión que el proyecto presentado es viable para la empresa ya que los resultados son coherentes con lo que se considera viable en el ámbito financiero. Renal lithiasis, also commonly known as kidney stones, is a disease with a rising incidence and a very high recurrence rate, as more than 50% of patients who have suffered an episode will re-form a kidney stone within 5 years. Knowing this, the study presented aims to develop a project for the company Devicare on a new test for the analysis of kidney stones, based on a kit that will allow the stone expelled by the patient to be collected and sent to the laboratory for analysis. Thanks to the combination of stereo microscopy, scanning electron microscopy with energy dispersive X-ray microanalysis and infrared spectroscopy, a more specific diagnosis and treatment is achieved, reducing the chances of recurrence of the disease. This test includes a home service for sample collection and personalised reports for both the patient and the urologist, as well as a future implementation in a smartphone App. After an economic analysis and considering the parameters of NPV, IRR, WACC and payback period, it has been concluded that the project presented is viable for the company as the results are consistent with what is considered financially viable.

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence. The strengths of recommendations are provided in the full report. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.

The quality of life, morbidity and mortality of people receiving renal replacement therapy is affected both by the renal disease itself and its treatment. The therapy that best improves renal function and quality of life is transplantation. Objectives: To study the quality of life, morbidity and mortality of people receiving renal replacement therapy over a five-year period. Design: A longitudinal multicentre study of a cohort of people with chronic kidney disease. Methods: Patients from the Girona health area receiving peritoneal dialysis were studied, gathering data on sociodemographic and clinical variables through an ad hoc questionnaire, quality of life using the SF-36 questionnaire, and social support with the MOS scale. Results: Mortality was 47.2%. Physical functioning was the variable that worsened most in comparison with the first measurement (p = 0.035). Those receiving peritoneal dialysis (p = 0.068) and transplant recipients (p = 0.083) had a better general health perception. The social functioning of transplant recipients improved (p = 0.008). Conclusions: People with chronic kidney disease had a high level of mortality. The dimension of physical functioning worsens over the years. Haemodialysis is the therapy that most negatively effects general health perception. Kidney transplantation has a positive effect on the dimensions of energy/vitality, social functioning and general health perception.

Objective: Noninvasive screening of hypo- and hyperkalemia can prevent fatal arrhythmia in end-stage renal disease (ESRD) patients, but current methods for monitoring of serum potassium ([K+]) have important limita-tions. We investigated changes in nonlinear dynamics and morphology of the T wave in the electrocardiogram (ECG) of ESRD patients during hemodialysis (HD), assessing their relationship with [K+]and designing a [K+]estimator. Methods: ECG recordings from twenty-nine ESRD patients undergoing HD were processed. T waves in 2-min windows were extracted at each hour during an HD session as well as at 48 h after HD start. T wave nonlinear dynamics were characterized by two indices related to the maximum Lyapunov exponent (¿t, ¿wt) and a divergence-related index (¿). Morphological variability in the T wave was evaluated by three time warping- based indices (dw, reflecting morphological variability in the time domain, and da and dNLa, in the amplitude domain). [K+]was measured from blood samples extracted during and after HD. Stage-specific and patient- specific [K+]estimators were built based on the quantified indices and leave-one-out cross-validation was per-formed separately for each of the estimators. Results: The analyzed indices showed high inter-individual variability in their relationship with [K+]. Never-theless, all of them had higher values at the HD start and 48 h after it, corresponding to the highest [K+]. The indices ¿ and dw were the most strongly correlated with [K+](median Pearson correlation coefficient of 0.78 and 0.83, respectively) and were used in univariable and multivariable linear [K+]estimators. Agreement between actual and estimated [K+]was confirmed, with averaged errors over patients and time points being 0.000 ±0.875 mM and 0.046 ±0.690 mM for stage-specific and patient-specific multivariable [K+]estimators, respectively. Conclusion: ECG descriptors of T wave nonlinear dynamics and morphological variability allow noninvasive monitoring of [K+]in ESRD patients. Significance: ECG markers have the potential to be used for hypo- and hyperkalemia screening in ESRD patients.

Chronic kidney disease (CKD), a collective term for many causes of progressive renal failure, is increasing worldwide due to ageing, obesity and diabetes. However, these factors cannot explain the many environmental clusters of renal disease that are known to occur globally. This study uses data from the UK Renal Registry (UKRR) including CKD of uncertain aetiology (CKDu) to investigate environmental factors in Belfast, UK. Urbanisation has been reported to have an increasing impact on soils. Using an urban soil geochemistry database of elemental concentrations of potentially toxic elements (PTEs), we investigated the association of the standardised incidence rates (SIRs) of both CKD and CKD of uncertain aetiology (CKDu) with environmental factors (PTEs), controlling for social deprivation. A compositional data analysis approach was used through balances (a special class of log contrasts) to identify elemental balances associated with CKDu. A statistically significant relationship was observed between CKD with the social deprivation measures of employment, income and education (significance levels of 0.001, 0.01 and 0.001, respectively), which have been used as a proxy for socio-economic factors such as smoking. Using three alternative regression methods (linear, generalised linear and Tweedie models), the elemental balances of Cr/Ni and As/Mo were found to produce the largest correlation with CKDu. Geogenic and atmospheric pollution deposition, traffic and brake wear emissions have been cited as sources for these PTEs which have been linked to kidney damage. This research, thus, sheds light on the increasing global burden of CKD and, in particular, the environmental and anthropogenic factors that may be linked to CKDu, particularly environmental PTEs linked to urbanisation. The Tellus Project was funded by the Department of Enterprise, Trade and Investment (NI) and by the ‘Building Sustainable Prosperity’ fund of the EU Regional Development Programme. Chemical analysis of the urban soil samples was co-financed by the Northern Ireland Environment Agency. The Northern Ireland Statistics and Research Agency (NISRA) is thanked for providing the multiple deprivation measures (MDMs). The study received ethics approval in March 2018, NHS National Research Ethics Committee REC reference: 15/EM/0366. We thank all the UK Renal Centres for providing data to the UK Renal Registry. The views and opinions expressed in this article are those of the authors and do not reflect the views of the UK Renal Registry or UK Renal Association. JJE and VPG received financial support through the project METhods for COmpositional analysis of DAta (CODAMET), Ministerio de Ciencia, Innovación y Universidades, Spain (Ref: RTI2018-095518-B-C21/C22, 2019-2021).

Associations between glomerular filtration rate (GFR) and cardiometabolic risk factors have been reported in adult and pediatric patients with renal disease. We aimed to assess the relationship between the estimated GFR (eGFR) and cardiometabolic risk factors in apparently healthy children. A longitudinal study in 401 asymptomatic Caucasian children (mean age 8 years) followed up after 4 years (mean age 12 years). GFR was estimated using the pediatric form of the FAS-equation. Children were classified at baseline according to their obesity status (normal weight and overweight) and according to eGFR levels (lower, average, and higher). The association of eGFR with anthropometric data [body mass index (BMI) and waist], blood pressure [systolic (SBP) and diastolic (DBP)], metabolic parameters [glucose, insulin resistance (HOMA-IR) and serum lipids], and renal ultrasonography measurements were assessed at baseline and follow-up. Baseline eGFR associated with several cardiometabolic risk factors at follow-up including higher waist, SBP, HOMA-IR, and kidney size (all p

Rationale & objective: Alport syndrome (AS) is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in COL4A3, COL4A4 or COL4A5 genes. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS). Study design: Retrospective cohort study. Setting & participants: 82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected. Observations: A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families) while 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 years (95% CI, 58-73), without significant differences across sex (P=0.79), causative genes (P=0.55) or types of variant (P=0.99). Microhematuria was the most common kidney manifestation (92.1%) and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of eGFR decline was -1.46 mL/min/1.73 m2 per year (-1.66 to -1.26) for the overall group, with no significant differences between ADAS genes (P=0.24). Limitations: The relatively small size of this series from a single country, potentially limiting generalizability. Conclusions: ADAS patients have a wide spectrum clinical presentations ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice. This study was funded by the Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional (FEDER) funds, RETIC REDINREN RD16/0009 FIS FEDER FUNDS (PI15/01824, PI16/01998, PI18/00362, PI19/01633), and the Catalan Government (AGAUR 2017/SGR-00676)

Màster en Economia de la Salut i del Medicament (UPF Barcelona School of Management) Mentora: Anna García Altés Objetivo: Estimar el impacto presupuestario de ampliar la atención de personas con enfermedad renal crónica terminal bajo la modalidad de hemodiálisis, según la perspectiva de la Caja Costarricense de Seguro Social, con un horizonte temporal de cinco años. Métodos: Se utilizó un modelo de análisis de impacto presupuestario considerando la estructura de costes actual por sesión de hemodiálisis en la Caja Costarricense de Seguro Social (CCSS), ajustando los costes por infraestructura física, equipamiento y mantenimientos con información de proyecto reciente del Hospital de Liberia; los demás costes directos e indirectos se mantienen fijos. La población objetivo se estimó con base en el porcentaje de prevalencia global (1), a partir de la población proyectada para Costa Rica (2), se resta los pacientes actualmente en diálisis continua y trasplantados con funcionamiento renal (vivos). Se asume un 20% del total pacientes requieren la modalidad hemodiálisis. Una tasa de difusión de un 20% en el año 1 a un 100% en el año 5. Un promedio institucional de 4,5 pacientes por máquina y 3 sesiones semanales. Los costes se presentan en dólares estadounidenses. Se aplica una tasa de descuento del 8,31%. Se utiliza como alternativa de análisis el coste por sesión de hemodiálisis de un proveedor externo para evaluar el coste de oportunidad de los recursos. Resultados: Al final de 5 años, bajo el escenario de costes de la CCSS, el coste total descontado es de US$15 973 978,3 mientras que la alternativa privada de US$21 285 015,4. Discusión: Para una mayor atención de personas en ERC-5 bajo la modalidad de hemodiálisis, representa un coste menor ampliando la propia capacidad instalada que si lo realiza mediante una contratación a nivel privado. Las autoridades deberían analizar con mayor profundidad las variables sensibilizadas que afectaron el modelo para incorporar estrategias de reducción de costes futuros y eficiencia de los recursos. Objective: To estimate the budgetary impact of expanding the healthcare of people with terminal chronic kidney disease (CKD) by hemodialysis treatment, from the Caja Costarricense de Seguro Social perspective, within five years. Methods: A budget impact analysis model was performed from the current cost structure per hemodialysis treatment session in the Caja Costarricense de Seguro Social (CCSS). Data are from the infrastructure facilities, equipment, and maintenance costs from Hospital de la Anexión, Liberia; other direct and indirect costs remain fixed. The target population was estimated based on the percentage of global prevalence (1), assuming census projection on the total population for Costa Rica (2). Patients currently on continuous dialysis and those with kidney transplant on functional status (alive) were subtracted. It was assumed that 20% of all patients require hemodialysis treatment. An increasing diffusion rate of 20% per year is considered. An institutional ratio of 4.5 patients per hemodialysis machine and three weekly sessions is assumed. Costs were converted to 2021 U.S. dollars using exchange rates for currency conversion. A discount rate of 8.31% applies. An external provider's cost per hemodialysis treatment session is used as an alternative analysis to assess the opportunity cost of resources. Results: After five years, when considering the CCSS cost scenario, the total discounted cost estimated is US$ 15,973,978.3, while the private alternative represents US$ 21,285,015.4. Discussion: The treatment cost for people with CKD-5 is lower when expanding the healthcare facilities than with a third party contract for private healthcare. The authorities should analyze in-depth the sensitized variables affecting the model to incorporate strategies for reducing future to achieve resource efficiency.

Although some study has been made into quality of life in patients with peritoneal dialysis, little is known about how this relates to social support. The aim of this paper was to study health-related quality of life, perceived social support and the experiences of people receiving peritoneal dialysis. A cross-sectional study was conducted using quantitative and qualitative methodologies, between June 2015 and March 2017. Fifty-five patients receiving peritoneal dialysis were studied. The most affected quality of life dimensions were the effects of the disease, the burden of the disease, occupational status, sleep and satisfaction. The physical component of the quality of life questionnaire was negatively associated with the number of hospital admissions over the previous year (p = 0.027) and positively associated with social support (p = 0.002). With regard to the mental component, age (p = 0.010) and social support (p = 0.041) were associated with a better quality of life. Peritoneal dialysis, while not a panacea, is experienced as being less aggressive than hemodialysis, allowing greater autonomy and improved perceived health. Greater symptomology corresponded to worse quality of life and to perceiving the disease as a burden. Patients had to adapt to the new situation despite their expectations. Social support was observed to be a key factor in perceived quality of life.

BACKGROUND AND OBJECTIVES: Diabetic kidney disease is the leading cause of end-stage chronic kidney disease. The renin-angiotensin-aldosterone system (RAAS) blockade has been shown to slow the progression of diabetic kidney disease. Our objectives were: to study the percentage of patients with diabetic kidney disease treated with RAAS blockade, to determine its renal function, safety profile and assess whether its administration is associated with increased progression of CKD after 3 years of follow-up. MATERIALS AND METHODS: Retrospective study. 197 diabetic kidney disease patients were included and divided into three groups according to the treatment: patients who had never received RAAS blockade (non-RAAS blockade), patients who at some point had received RAAS blockade (inconstant-RAAS blockade) and patients who received RAAS blockade (constant-RAAS blockade). Clinical characteristics and analytical variables such as renal function, electrolytes, glycosylated haemoglobin and glomerular filtration rate according to chronic kidney disease -EPI and MDRD formulas were assessed. We also studied their clinical course (baseline, 1 and 3 years follow-up) in terms of treatment group, survival, risk factors and renal prognosis. RESULTS: Non-RAAS blockade patients had worse renal function and older age (p

Background/Aims: Recurrent acute kidney injury (AKI) is common among patients after a first hospitalized AKI. However, little is known about the prognosis of recurrent AKI episodes in chronic kidney disease (CKD) development, cardiovascular events and mortality. Methods: A retrospective study included patients admitted to our Hospital from 2000 to 2010. AKI was defined according to the Acute Dialysis Quality Initiative criteria. In the follow-up period after the first AKI episode, clinical, laboratory data and the number of repeated AKI episodes, etiology and severity were recorded. Results: Among the 359 AKI survivor patients included, 250 new AKI episodes were observed in 122 patients (34%). Variables independently associated to new episodes were: type 2 DM [OR 1.2, 95%CI 1.2-3.8, p=0.001], ischemic heart disease [OR 1.9; 95%CI 1.1-3.6, p=0.012], and SCr at the first AKI event>2,6 mg/dl [OR 1.2; 95%CI 1.03-1.42, p=0.02]. Development of CKD during four years follow-up was more frequent in patients with recurrent AKI, HR [2.2 (95% CI: 1.09-4.3, p=0.003)] and 44% of recurrent AKI patients who developed CKD occurred during the first 6 months after the initial event. Cardiovascular events were more frequent among patients with recurrent AKI patients than in those with one AKI episode (47.2% vs 24%, p=0.001). Mortality at 4 years was higher in the patient subgroup with several episodes of AKI as compared with those with a single episode [HR: 4.5 (95% CI 2.7-7.5) pConclusion: Episodes of recurrent AKI have a high potential to be associated with relevant complications such as cardiovascular events, mortality and CKD development.

We have previously shown that rat allogeneic DC, made immature by adenoviral gene transfer of the dominant negative form of IKK2, gave rise in-vitro to a unique population of CD4+CD25− regulatory T cells (dnIKK2-Treg). These cells inhibited Tcell response in-vitro, without needing cell-to-cell contact, and induced kidney allograft survival prolongation in-vivo. Deep insight into the mechanisms behind dnIKK2-Treg-induced suppression of Tcell proliferation remained elusive. Here we document that dnIKK2-Treg release extracellular vesicles (EV) riched in exosomes, fully accounting for the cell-contact independent immunosuppressive activity of parent cells. DnIKK2-Treg-EV contain a unique molecular cargo of specific miRNAs and iNOS, which, once delivered into target cells, blocked cell cycle progression and induced apoptosis. DnIKK2-Treg-EV-exposed T cells were in turn converted into regulatory cells. Notably, when administered in-vivo, dnIKK2-Treg-EV prolonged kidney allograft survival. DnIKK2-Treg-derived EV could be a tool for manipulating the immune system and for discovering novel potential immunosuppressive molecules in the context of allotransplantation.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome after transplantation and is associated with an increased risk of allograft loss. MN may occur either as a recurrent or as a de novo disease. As in native kidneys, the pathophysiology of the MN recurrence is in most cases associated with antiphospholipid A2 receptor antibodies. However, the posttransplant course has some distinct features when compared with primary MN, including a lower chance of spontaneous remission and a greater requirement for adjuvant immunosuppressive therapy to induce complete remission. Although the efficacy of rituximab in primary MN is now well established, no randomized studies have assessed its effectiveness in MN after transplant, and there are no specific recommendations for the management of these patients. This review aims to synthesize and update the pathophysiology of posttransplant MN, as well as to address unsolved issues specific to transplantation, including the prognostic value of antiphospholipid A2 receptor, the risk of living-related donation, the link between de novo MN and rejection, and different therapeutic strategies so far deployed in posttransplant MN. Lastly, we propose a management algorithm for patients with MN who are planning to receive a kidney transplant, including pretransplant considerations, posttransplant monitoring, and the clinical approach after the diagnosis of recurrence.

This study aimed to investigate whether different levels of fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) in prediabetes are associated with hyperfiltration. Methods A prospective cohort of 2,022 individuals aged 30–74 years took part in the PREDAPS Study. One cohort of 1,184 participants with prediabetes and another cohort of 838 participants with normal FPG and normal HbA1c were followed for 5 years. Hyperfiltration was defined as an estimated glomerular filtration rate (eGFR) above the age- and gender-specific 95th percentile for healthy control participants, while hypofiltration was defined as an eGFR below the 5th percentile. The prevalence of hyperfiltration was compared for different levels of prediabetes: level 1 of prediabetes: FPG

Renal size is an important parameter for the evaluation and diagnosis of kidney disease and has been associated with several cardiovascular risk factors in patients with kidney failure. These results are however discordant and studies in healthy children are lacking. We aimed to study the association between renal size (length and volume) and cardiovascular risk parameters in healthy children. Clinical, analytical and ultrasound parameters [renal length, renal volume, perirenal fat and carotid intima-media thickness (cIMT)] were determined in 515 healthy prepubertal children (176 lean, 208 overweight and 131 obese). Renal length and volume associated significantly and positively with several anthropometric and cardiovascular risk parameters including cIMT and systolic blood pressure (SBP) (all p

End-stage renal disease (ESRD) patients undergoing hemodialysis (HD) are at high risk of arrhythmias and sudden cardiac death as a result of blood potassium con-centration ([K+]) changes.The aim of this study is to investigate if dw, a time-warping-based electrocardiogram (ECG) biomarker of T-wave morphology changes,reflects [K+] evolution in HD patients, facilitating non-invasive [K+] monitoring and avoiding in-hospital blood tests analysis. 48-hour ECGs and a set of hourly collected blood samples from 12 ESRD patients were acquired and analyzed. dw was calculated between a reference T-wave,measured at the end of the HD session, and the T-waves corresponding to each hour along the whole HD session,when [K+] was measured from blood samples. The values of dw correlated with the relative variations in [K+] with respect to the reference value (end of HD,¿[K+]), with a median (interquartile) correlation coefficient of 0.90(0.30), evidencing a strong relation between them. Our findings support the use of dw as a surrogate of¿[K+],suggesting a potential use of dw for non-invasive hyperkalemia monitoring both in hospital and ambulatory settings.

Background The use of metformin in patients with type 2 diabetes mellitus has been associated with lactic acidosis. However, the information available in patients with moderate-severe chronic kidney disease is scarce. Methods The ALIMAR-C2 study is a case-control study to assess the association between metformin and lactic acidosis in patients with type 2 diabetes mellitus and moderate-severe chronic kidney disease. The study will be performed with computerized registered electronic health records from eight Spanish hospitals linked to their corresponding primary care health areas from 2010 to 2016, comprising approximately 22.1 million person-years of follow-up. Logistic regression will be used to assess the crude and adjusted risk of lactic acidosis associated with metformin use overall and stratifying by use and dose categories, and chronic kidney disease stage. The overall case fatality rate of lactic acidosis, as well as the case fatality rate stratified by chronic kidney disease stage, will be calculated. Discussion The ALIMAR-C2 study will provide useful information about the risk of lactic acidosis in type 2 diabetes mellitus patients with renal impairment using metformin. Electronic supplementary material The online version of this article (10.1186/s12882-019-1389-8) contains supplementary material, which is available to authorized users.

Resumen Antecedentes y objetivos: Este estudio post hoc analizó la percepción de la importancia de la enfermedad renal crónica (ERC) en el cribado de la dislipidemia y en la elección del tratamiento con estatinas entre médicos de Atención Primaria (MAP) y otras especialidades mediante cuestionario Delphi. Métodos: El cuestionario incluyó 4 bloques de preguntas alrededor del paciente dislipémico con alteración del metabolismo hidrocarbonado. Aquí se presentan los resultados relacionados con la consideración de la ERC en el cribado y la elección de la estatina. Resultados: De los 497 expertos incluidos, el 58% eran MAP y el 42%, especialistas (35, el 7%, nefrólogos). Hubo consenso en realizar un cribado de la dislipidemia en los pacientes con ERC, sin diferencias entre MAP y especialistas; y también en realizar el cribado en la práctica clínica habitual. Sin embargo, no se alcanzó el consenso en considerar el filtrado glomerular estimado (aunque sí entre MAP y nefrólogos) o la albuminuria en la elección de la estatina, ni en su determinación durante el seguimiento después de instaurar un tratamiento con estatinas (aunque hubo consenso entre nefrólogos). Conclusiones: El consenso en analizar el perfil lipídico en los pacientes con ERC indica el reconocimiento del alto riesgo cardiovascular de esta enfermedad. La ausencia de acuerdo en considerar la función renal o la albuminuria, tanto en la elección de la estatina como durante el seguimiento, indica un conocimiento limitado de las diferencias entre estatinas en relación con la ERC, por lo que sería deseable disponer de una guía/documento de consenso sobre uso de estatinas en la ERC. Abstract Background and objectives: This post hoc study analysed the perception of the relevance of chronic kidney disease (CKD) in dyslipidaemia screening and the choice of statin among primary care physicians (PCPs) and other specialists through a Delphi questionnaire. Methods: The questionnaire included 4 blocks of questions concerning dyslipidaemic patients with impaired carbohydrate metabolism. This study presents the results of the impact of CKD on screening and the choice of statin. Results: Of the 497 experts included, 58% were PCPs and 42% were specialists (35, 7% were nephrologists). There was consensus by both PCPs and specialists, with no difference between PCPs and specialists, that CKD patients should undergo a dyslipidaemia screening and that the screening should be part of routine clinical practice. However, there was no consensus in considering the estimated glomerular filtration rate (eGFR) (although there was consensus among PCPs and nephrologists), or considering albuminuria when selecting a statin, or in determining albuminuria during follow-up after having initiated treatment with statins (although there was consensus among the nephrologists). Conclusions: The consensus to analyse the lipid profile in CKD patients suggests acknowledgment of the high cardiovascular risk of this condition. However, the lack of consensus in considering renal function or albuminuria, both when selecting a statin and during follow-up, suggests a limited knowledge of the differences between statins in relation to CKD. Thus, it would be advisable to develop a guideline/consensus document on the use of statins in CKD.

Cada vegada és més elevat el percentatge de població que contreu una malaltia d’insuficiència renal, moment a partir del qual els ronyons deixen de realitzar correctament les seves funcions i és necessari accedir a un trasplantament de ronyó o bé iniciar una teràpia renal substitutiva (TSR) per remeiar la pèrdua de funció renal. L’elecció de la TSR a la qual es sotmetrà el pacient, després d’una adequada i completa informació sobre els avantatges i inconvenients de les diferents modalitats existents, és completament lliure, a no ser que existeixi una contraindicació per alguna d’elles. Actualment, segons les dades d’IDESCAT de l’any 2016, dels 10.523 casos d’insuficiència renal a Catalunya, un 40,7% dels pacients escull la TSR de l’hemodiàlisi (HD) mentre que un 4% es decanta per la modalitat de la diàlisi peritoneal (DP). El document es centra en la teràpia renal de la DP, realitzada des del domicili del pacient, amb l’objectiu de promoure aquesta modalitat de tractament posant solució al punt feble que presenta: la falta de control i seguiment del malalt renal. Es proposa la incorporació de tecnologia IoT (Internet of Things) per establir un pont d’informació entre el domicili del pacient i l’hospital, permetent una monitorització a temps real. Les xifres de nous casos de malalts renals a Catalunya que inicien un TSR han augmentat un 29,2% en els últims 10 anys i el tractament de DP poc a poc augmenta la seva popularitat, passant de 197 usuaris l’any 2001 a 426 usuaris l’any 2016. La tendència a iniciar un TSR a edat avançada augmenta, de manera que la població contreu insuficiència renal a una major edat (actualment, un 69,4% dels malalts són majors de 60 anys), sent aquest sector de la població el que contempla amb més inseguretat la proposta de la DP. La solució que es planteja consisteix en monitoritzar els paràmetres necessaris per dur a terme un control adequat de l’estat del pacient -la temperatura corporal, la pressió sanguínia, el pes abans i després de la sessió de tractament i el color de la solució de diàlisi- a partir de diferents sensors. L’ecosistema Fiware permetrà la comunicació entre els dispositius físics i la resta de components de Fiware, gestionarà i emmagatzemarà les dades registrades, brindarà mecanismes de seguretat i permetrà un anàlisi de les dades a temps real. Finalment, amb el suport d’una aplicació mòbil i d’una aplicació web –que poden ser fàcilment creades a partir de les interfícies de programació disponibles a la plataforma Fiware-, es permet la consulta dels paràmetres monitoritzats als pacients i metges. El cost de les TSR suposa un percentatge molt elevat del cost total del Servei de la Salut, el qual estaria interessat en la transició cap a la DP. S’ha estimat una reducció de costos de 31M per l’any 2016 si es produís una transició de la situació actual (4.279 casos d’HD i 426 de DP) a l’escenari on tots els potencials usuaris de DP duguessin a terme aquesta variant de tractament (4.418 casos de DP i 287 d’HD). Així doncs, el marge de benefici de la proposta d’incorporar IoT és ampli, arribant a una rendibilitat màxima de 13,5M.

Vancomycin has usually been associated with nephrotoxicity. Generally, this toxicity is presented as proximal tubular cells injury with or without necrosis and as acute interstitial nephritis. However, development of both lesions is uncommonly described in literature. We present a case of vancomycin-induced nephrotoxicity resulting in both acute interstitial nephritis and tubular cells damage confirmed by renal biopsy. Peak and trough levels of 77.11 and 63.60 μg/mL, respectively, were obtained at the first plasma determination. After 8 more plasma determinations and several hemodialysis sessions, vancomycin levels were undetectable 1 month after therapy was stopped. To our knowledge, this is the case report with the highest vancomycin trough levels developing both lesions and describing total vancomycin washout after a biopsy-proven vancomycin toxicity. In conclusion, early vancomycin therapeutic drug monitoring should be performed in order to avoid toxicities where, as seen in our patient, antibiotic exposure could last around 1 month after last dose administration.

An increased risk of cardiovascular disease, independent of conventional risk factors, is present even at minor levels of renal impairment and is highest in patients with end-stage renal disease (ESRD) requiring dialysis. Renal dysfunction changes the level, composition and quality of blood lipids in favour of a more atherogenic profile. Patients with advanced chronic kidney disease (CKD) or ESRD have a characteristic lipid pattern of hypertriglyceridaemia and low HDL cholesterol levels but normal LDL cholesterol levels. In the general population, a clear relationship exists between LDL cholesterol and major atherosclerotic events. However, in patients with ESRD, LDL cholesterol shows a negative association with these outcomes at below average LDL cholesterol levels and a flat or weakly positive association with mortality at higher LDL cholesterol levels. Overall, the available data suggest that lowering of LDL cholesterol is beneficial for prevention of major atherosclerotic events in patients with CKD and in kidney transplant recipients but is not beneficial in patients requiring dialysis. The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD provides simple recommendations for the management of dyslipidaemia in patients with CKD and ESRD. However, emerging data and novel lipid-lowering therapies warrant some reappraisal of these recommendations. AO was supported by Spanish Government ISCIII FEDER funds (PI16/02057, ISCIII-RETIC REDinREN RD16/0009) and Community of Madrid (B2017/BMD-3686 CIFRA2-CM).

Proton Pump Inhibitors (PPIs) have been associated with chronic kidney disease (CKD). Our objective was to quantify the association between PPI use and incident CKD in a population-based cohort. Methods and findings We used a population-based retrospective cohort, including people aged 15 years or over, between January 1, 2005 and December 31, 2012. PPI use was measured in a follow-up session by recording prescriptions. Incident CKD was defined as an estimated glomerular filtration rate < 60 ml/ min/1.73 m2 and/or urinary albumin level to creatinine level ≥ 30 mg/g, in two or more determinations over a period of at least 3 months of the follow-up. Proton Pump Inhibitor use was associated with incident CKD in analysis adjusted for different clinical variables (Hazard Ratio (HR) 1.18; 95% CI 1.04–1.51) in individuals who used PPI in the basal visit (HR 1.37; 95% CI 1.25–1.50) and in those who started to use PPI during the follow-up. High doses of PPI increased the risk of incident CKD (HR 1.92; 95%CI 1.00–6.19) for any type of exposure to PPIs (HR 2.40; 95%CI 1.65–3.46) and for individuals who used high doses throughout the follow-up. This risk of incident CKD increased after three months’ exposure to PPIs, (HR1.78; 95% CI 1.39–2.25) between the third and sixth months and (HR 1.30; 95%CI 1.07–1.72) after the sixth month. Conclusions PPI use is associated with a higher risk of incident CKD. This association is greater for high doses and becomes apparent after three months’ exposure This work was partly funded by the research project PI15/00140 from FIS, ‘Instituto de Salud Carlos III’, ISCIII, Spanish Ministry of Economy and Competitiveness and by the project ‘Grant to improve the scientific productivity of the research groups of the University of Girona 2016-2018’ (MPCUdG2016

Background: Chronic kidney disease (CKD) patients experience a high risk of cardiovascular disease (CV); however, the factors involved in CV-related morbidity and mortality in these patients have not been fully defined. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine, which exhibits pleiotropic activities on endothelial, vascular smooth muscle and inflammatory cells, with relevant effects on atheromatous plaque formation. On this basis, the present study aims to investigate the role of TRAIL in atheromatosis progression in CKD patients. Methods: Circulating TRAIL levels were measured in 378 CKD patients belonging to the Spanish National Observatory of Atherosclerosis in Nephrology (NEFRONA) study. All patients were free of previous CV events. Carotid and femoral B-mode ultrasound was performed to detect the presence of plaque at baseline and after 24 months of follow-up. Results: The lowest levels of TRAIL at baseline were significantly (p

Background— It is unknown whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cutoff levels in this vulnerable patient population have not previously been defined. Methods and Results— In this multicenter study, we examined the clinical utility of 7 more sensitive cTn assays (3 sensitive and 4 high-sensitivity cTn assays) in patients presenting with symptoms suggestive of acute myocardial infarction. Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as Modification of Diet in Renal Disease–estimated glomerular filtration rate −1 ·1.73 m −2 ). The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography and serial levels of high-sensitivity cTnT. Acute myocardial infarction was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn levels (≥99th percentile), acute myocardial infarction was the most common diagnosis for all assays (range, 45%–80%). In patients with renal dysfunction, diagnostic accuracy at presentation, quantified by the area under the receiver-operator characteristic curve, was 0.87 to 0.89 with no significant differences between the 7 more sensitive cTn assays and further increased to 0.91 to 0.95 at 3 hours. Overall, the area under the receiver-operator characteristic curve in patients with renal dysfunction was only slightly lower than in patients with normal renal function. The optimal receiver-operator characteristic curve–derived cTn cutoff levels in patients with renal dysfunction were significantly higher compared with those in patients with normal renal function (factor, 1.9–3.4). Conclusions— More sensitive cTn assays maintain high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay-specific optimal cutoff levels, which are higher in patients with renal dysfunction, should be considered. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00470587.

Diabetic kidney disease (DKD) remains the most common cause of chronic kidney disease and multiple therapeutic agents, primarily targeted at the renin-angiotensin system, have been assessed. Their only partial effectiveness in slowing down progression to end-stage renal disease, points out an evident need for additional effective therapies. In the context of diabetes, endothelin-1 (ET-1) has been implicated in vasoconstriction, renal injury, mesangial proliferation, glomerulosclerosis, fibrosis and inflammation, largely through activation of its endothelin A (ETA) receptor. Therefore, endothelin receptor antagonists have been proposed as potential drug targets. In experimental models of DKD, endothelin receptor antagonists have been described to improve renal injury and fibrosis, whereas clinical trials in DKD patients have shown an antiproteinuric effect. Currently, its renoprotective effect in a long-time clinical trial is being tested. This review focuses on the localization of endothelin receptors (ETA and ETB) within the kidney, as well as the ET-1 functions through them. In addition, we summarize the therapeutic benefit of endothelin receptor antagonists in experimental and human studies and the adverse effects that have been described. This work was partially supported by a research grant ISCIII-FEDER PI14/00557.

Accurately determining renal function is essential for clinical management of HIV patients. Classically, it has been evaluated by estimating glomerular filtration rate (eGFR) with the MDRD-equation, but today there is evidence that the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has greater diagnostic accuracy. To date, however, little information exists on patients with HIV-infection. This study aimed to evaluate eGFR by CKD-EPI vs. MDRD equations and to stratify renal function according to KDIGO guidelines. Methods: Cross-sectional, single center study including adult patients with HIV-infection. Results: Four thousand five hundred three patients with HIV-infection (864 women; 19%) were examined. Median age was 45 years (IQR 37–52), and median baseline creatinine was 0.93 mg/dL (IQR 0.82–1.05). A similar distribution of absolute measures of eGFR was found using both formulas (p = 0.548). Baseline median eGFR was 95.2 and 90.4 mL/min/1.73 m2 for CKD-EPI and MDRD equations (p 90 mL/min/1.73 m2) in 73% patients and “mild reduced GFR” (60–89 mL/min/1.73 m2) in 24.3% of the patients, formerly classified as >60 mL/min/1.73 m2 with MDRD. Conclusions: There was good correlation between CKD-EPI and MDRD. Estimating renal function using CKD-EPI equation allowed better staging of renal function and should be considered the method of choice. CKD-EPI identified a significant proportion of patients (24%) with mild reduced GFR (60–89 mL/min/1.73 m2)

Background Percutaneous coronary intervention (PCI) reduces mortality in most myocardial infarction (MI) patients but the effect on elderly patients with comorbidities is unclear. Our aim was to analyse the effect of PCI on in-hospital mortality of MI patients, by age, sex, ST elevation on presentation, diabetes mellitus (DM) and chronic kidney disease (CKD). Methods Cohort study of 79,791 MI patients admitted at European hospitals during 2000–2014. The effect of PCI on in-hospital mortality was analysed by age group (18–74, ≥ 75 years), sex, presence of ST elevation, DM and CKD, using propensity score matching. The number needed to treat (NNT) to prevent a fatal event was calculated. Sensitivity analyses were conducted. Results PCI was associated with lower in-hospital mortality in ST and non-ST elevation MI (STEMI and NSTEMI) patients. The effect was stronger in men [Odds ratio (95% confidence interval) 0.30 (0.25–0.35)] than in women [0.46 (0.39–0.54)] aged ≥ 75 years, and in NSTEMI [0.22 (0.17–0.28)] than in STEMI patients [0.40 (0.31–0.5)] aged < 75 years. PCI reduced in-hospital mortality risk in patients with and without DM or CKD (54–72% and 52–73% reduction in DM and CKD patients, respectively). NNT was lower in patients with than without CKD [≥ 75 years: STEMI = 6(5–8) vs 9(8–10); NSTEMI = 10(8–13) vs 16(14–20)]. Sensitivity analyses such as exclusion of hospital stays < 2 days yielded similar results. Conclusions PCI decreased in-hospital mortality in MI patients regardless of age, sex, and presence of ST elevation, DM and CKD. This supports the recommendation for PCI in elderly patients with DM or CKD.

Background/Aims Height-adjusted total kidney volume (htTKV) is the best marker of disease progression in early autosomal dominant polycystic kidney disease (ADPKD) when renal function still remains normal. The usefulness of cystatin-C as a biomarker to assess renal function according to renal volume has not been studied in ADPKD patients. Methods Observational and cross-sectional study of 62 ADPKD patients. htTKV, creatinine and cystatin-C estimated glomerular filtration rate (eGFR) were determined. Correlations between htTKV and eGFR were studied. A control group was used to determine the association between renal function differences and htTKV. Results htTKV significantly correlated with cystatin-C-eGFR (r = -0.384, p = 0.002) but not with creatinine- eGFR (r = -0.225, p = 0.078). With htTKV stratified into tertiles, a significant difference of cystatin-C-eGFR but not in creatinine-eGFR was detected in the third tertile when compared with the first tertile group (110.0 +/- 22.2 vs 121.3 +/- 7.2; p = 0.023 and 101.8 +/- 17.2 vs 106.9 +/- 15.1; p = 0.327 respectively). When cystatin-C-eGFR of the controls was used as the reference, htTKV above 605 ml/m identified with a 75% sensitivity and 84.9% specificity those patients with a significant worse kidney function. However, this cut-off value could not be identified using creatinine-eGFR. Conclusions Cystatin-C-eGFR but not creatinine-eGFR correlated with htTKV in ADPKD patients in early stages of the disease. Differences in cystatin-C-eGFR but not in creatinine-eGFR have been identified through htTKV tertiles. A htTKV above 605 ml/m is associated with a worse renal function only if cystatin-C-eGFR is used. Cystatin-C-eGFR should be studied in prospective studies of early stages of ADPKD to determine its usefulness as an early marker of disease progression.

INTRODUCTION: Secondary hyperparathyroidism (SHPT) and vitamin D deficiency are common at kidney transplantation and are associated with some early and late complications. This study was designed to evaluate whether paricalcitol was more effective than nutritional vitamin D for controlling SHPT in de novo kidney allograft recipients. METHODS: This was a 6-month, investigator-initiated, multicenter, open-label, randomized clinical trial. Patients with pretransplantation iPTH between 250 and 600 pg/ml and calcium 110 pg/ml at 6 months. Secondary endpoints were bone mineral metabolism, renal function, and allograft protocol biopsies. RESULTS: The primary outcome occurred in 19.6% of patients in the PAR group and 36.2% of patients in the CAL group (P = 0.07). However, there was a higher percentage of patients with iPTH

Curs 2015-2016, Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates renal phosphate reabsorption by decreasing the expression of NaPi-IIa cotransporter in the brush border membrane (BBM) of renal proximal tubules, taking part in a hormonal axis which include vitamin D and parathyroid hormone (PTH) to maintain phosphate and calcium homeostasis. Several studies demonstrated a significant increase in plasma FGF23 levels in diseases which involve kidney failure or in renal nephrectomy, indicating a key role of the kidney in direct or indirect FGF23 clearance. Here we try to demonstrate: 1) if the kidney can directly clear FGF23 and 2) the time-course of the FGF23 effect in phosphate handling. For the first goal, we injected recombinant human FGF23 (rhFGF23) in normal rats and analyzed by immunofluorescence techniques whether we could detect it in kidney: no FGF23 was detected in renal cells, neither at 2 nor at 12 hours post administration probably at least in part of technical issues. For the second objective, blood, urine and kidneys were collected at several intervals after rhFGF23 administration. rhFGF23 showed a peak in plasma 2 h after injection, decreasing to less than a half after 6 h and to almost background levels after18 h. rhFGF23 was not detected in urine at any time point. After 6 h of FGF23 injection a decrease in NaPi-IIa (mRNA and protein) was observed in the kidney, in parallel with an enhanced urinary phosphate excretion. Although NaPi-IIa protein remained reduced 18 h post administration, its mRNA levels as well as urinary excretion of phosphate tended to return to their basal levels. No alterations in plasma phosphate levels were found in any of the groups. Furthermore, vitamin D receptor (VDR) protein expression was transiently decreased in the kidney, whereas no alterations in 24-hydroxylase (CYP24a1) were found. Measurements of FGF23 protein abundance in kidney were not valid, due to technical reasons. Thus, our findings are not conclusive regarding the possibility that FGF23 is filtered in the kidney and excreted in the urine. On the other hand, they indicate that the major action of FGF23 on phosphate excretion and NaPi-IIa expression takes place 6 h after injection, with urinary phosphate but not NaPi-IIa recovering to basal levels after 18 h.

Biobanks are useful platforms to build bridges between basic, translational, and clinical research and clinical care. They are repositories of high-quality human biological samples ideal for evaluating their histological characteristics and also their genome, transcriptome, and proteome. The Spanish Renal Research Network Biobank contains more than 76,500 well-preserved frozen samples of a wide variety of kidney diseases, collected from 5450 patients seen by over 70 nephrology services throughout the Spanish territory.To determine and to report the results of the quality control of samples and processes conducted in our biobank, implemented in accordance with the requirements of the ISO 9001:2008 international standard.Two types of quality controls were performed: (1) systematic, that is, measurement of viable peripheral blood mononuclear cells (PBMCs) obtained and purity of nucleic acids and (2) ad-hoc, that is, viability of thawed PBMC, DNA extraction process reproducibility, and the integrity and functionality of nucleic acids, implemented on a routine basis.PBMC isolation by Ficoll yielded reproducible results and its cryopreserved viability was90%. Acceptable A260/A280 ratios were obtained for the vast majority of the DNA (n = 2328) and RNA (n = 78) samples analyzed. DNA integrity was demonstrated by agarose gels and by β-globulin gene polymerase chain reaction (PCR) amplification of 1327 and 989 bp fragments. DNA of acceptable quality had at least three bands of β-globulin amplified obtained (n = 26/30). RNA integrity number (RIN) determinations obtained RIN numbers ≥7 (n = 87/96). The amplifiability of nucleic acids was confirmed by qPCR and RT-qPCR of β-actin and GAPDH genes. Long storage or delayed processing time did not affect the quality of the samples analyzed. The processes of DNA extraction also yielded reproducible results.These results clearly indicate that our PBMC, DNA, and RNA stored samples meet the required quality standards to be used for biomedical research, ensuring their long-term preservation.

Los pacientes con Enfermedad Renal Crónica Avanzada sufren restricciones en su dieta habitual que propician que estos padezcan elevados porcentajes de malnutrición y ocasionan perjuicios a nivel global de la persona, los cuales desemboca en un deterioro de su estado de salud. La causa de MN en los estadios avanzados de la enfermedad es la inadecuada ingesta de nutrientes vinculada fundamentalmente a la anorexia propia de la toxicidad urémica, y a las frecuentes restricciones dietéticas asociadas, así como a la incomprensión del modo óptimo de alimentación que debería seguir este tipo de pacientes. Así en la ERCA, con la adecuación y adaptación de la dieta a este tipo de pacientes, se mejora su condición física y se retrasa la progresión de la enfermedad renal. Precisamente enfermería tiene un aspecto relevante del control de la ERC, en este trabajo, mediante un programa de intervención nutricional (PIN) se tratará de corregir el nivel nutricional de estos pacientes. El seguimiento del PIN se realizará mediante la medición de parámetros antropométricos y bioquímicos como: pliegues cutáneos, transferrina, Colesterol total así como el cribado nutricional realizado médiate la escala Valoración Global Subjetiva. Los datos sociodemográficos serán recogidos según la Escala de Valoración Sociofamiliar de Gijón. Analizando finalmente si el PIN ha sido efectivo.

Cardiovascular disease, closely related to an early appearance of hypertension, is the most common mortality cause among autosomal dominant polycystic kidney disease patients (ADPKD). The development of hypertension is related to an increase in renal volume. Whether the increasing in the renal volume before the onset of hypertension leads to a major cardiovascular risk in ADPKD patients remains unknown. Observational and cross-sectional study of 62 normotensive ADPKD patients with normal renal function and a group of 28 healthy controls. Renal volume, blood pressure, and renal (urinary albumin excretion), blood vessels (carotid intima media thickness and carotid-femoral pulse wave velocity), and cardiac (left ventricular mass index and diastolic dysfunction parameters) asymptomatic organ damage were determined and were considered as continuous variables. Correlations between renal volume and the other parameters were studied in the ADPKD population, and results were compared with the control group. Blood pressure values and asymptomatic organ damage were used to assess the cardiovascular risk according to renal volume tertiles. Even though in the normotensive range, ADPKD patients show higher blood pressure and major asymptomatic organ damage than healthy controls. Asymptomatic organ damage is not only related to blood pressure level but also to renal volume. Multivariate regression analysis shows that microalbuminuria is only associated with height adjusted renal volume (htTKV). An htTKV above 480 mL/m represents a 10 times higher prevalence of microalbuminuria (4.8% vs 50%, P 336 mL/m) show higher urinary albumin excretion, but the 3rd tertile htTKV (htTKV > 469 mL/m) group shows the worst cardiovascular risk profile. Normotensive ADPKD patients show in the early stages of the disease with slight increase in renal volume, higher cardiovascular risk than healthy controls. An htTKV above 468 mL/m is associated with the greatest increase in cardiovascular risk of normotensive ADPKD patients with normal renal function. Early strategies to slow the progression of the cardiovascular risk of these patients might be beneficial in their long-term cardiovascular survival.

Diabetic kidney disease is the leading cause of end-stage renal disease. Albuminuria is recognized as the most important prognostic factor for chronic kidney disease progression. For this reason, blockade of renin-angiotensin system remains the main recommended strategy, with either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, other antiproteinuric treatments have begun to be studied, such as direct renin inhibitors or aldosterone blockers. Beyond antiproteinuric treatments, other drugs such as pentoxifylline or bardoxolone have yielded conflicting results. Finally, alternative pathogenic pathways are being explored, and emerging therapies including antifibrotic agents, endothelin receptor antagonists, or transcription factors show promising results. The aim of this review is to explain the advances in newer agents to treat diabetic kidney disease, along with the background of the renin-angiotensin system blockade.

[Abstract] Background. Patients with cardiovascular (CV) disease have an increased circulating angiotensin-converting enzyme 2 (ACE2) activity, but there is little information about changes in ACE2 in chronic kidney disease (CKD) patients without history of CV disease. We examined circulating ACE2 activity in CKD patients at stages 3–5 (CKD3-5) and in dialysis (CKD5D) without any history of CV disease. Methods. Circulating ACE2 activity was measured in human ethylenediamine-tetraacetic acid (EDTA)-plasma samples from the NEFRONA study (n = 2572): control group (CONT) (n = 568), CKD3-5 (n = 1458) and CKD5D (n = 546). Different clinical and analytical variables such as gender; age; history of diabetes mellitus (DM), dyslipidemia and hypertension; glycaemic, renal, lipid and anaemia profiles; vitamin D analogues treatment and antihypertensive treatments (angiotensin-converting enzyme inhibitor and angiotensin receptor blockade) were analysed. Circulating ACE2 and ACE activities were measured using modified fluorimetric assay for EDTA-plasma samples, where zinc chloride was added to recover enzymatic activity. Results. In CKD3-5 and CKD5D, significant decrease in circulating ACE2 activity was observed when compared with CONT, but no differences were found between CKD3-5 and CKD5 when performing paired case-control studies. By multivariate linear regression analysis, male gender and advanced age were identified as independent predictors of ACE2 activity in all groups. Diabetes was identified as independent predictor of ACE2 activity in CKD3-5. Significant increase in the activity of circulating ACE was found in CKD3-5 and CKD5D when compared with CONT and in CKD5D when compared with CKD3-5. By multiple regression analysis, female gender and younger age were identified as independent predictors of ACE activity in CONT and CKD3-5. Diabetes was also identified as an independent predictor of ACE activity in CKD3-5 patients. Conclusions. Circulating ACE2 and ACE activities can be measured in human EDTA-plasma samples with zinc added to recover enzymatic activity. In a CKD population without previous history of CV disease, ACE2 activity from human EDTA-plasma samples directly correlated with the classical CV risk factors namely older age, diabetes and male gender. Our data suggest that circulating ACE2 is altered in CKD patients at risk for CV event.

Chronic kidney disease is characterized by Vitamin D deficiency and activation of the renin-angiotensin-aldosterone system. Increasing data show that vitamin D receptor agonists (VDRAs) exert beneficial effects in renal disease and possess anti inflammatory properties, but the underlying mechanism remains unknown. Emerging evidence suggests that “a disintegrin and metalloproteinase” (ADAM)/epidermal growth factor receptor (EGFR) signalling axis contributes to renal damage. Aldosterone induces EGFR transactivation regulating several processes including cell proliferation and fibrosis. However, data on tubular epithelial cells is scarce.We have found that, in cultured tubular epithelial cells, aldosterone induced EGFR transactivation via TGF- 𝛼/ADAM17. Blockade of the TGF-𝛼/ADAM17/EGFR pathway inhibited aldosterone-induced proinflammatory gene upregulation. Moreover, among the potential downstream mechanisms, we found that TGF-𝛼/ADAM17/EGFR inhibition blocked ERK and STAT-1 activation in response to aldosterone. Next, we investigated the involvement of TGF-𝛼/ADAM17/EGFR axis in VDRA anti-inflammatory effects. Preincubation with the VDRA paricalcitol inhibited aldosterone-induced EGFR transactivation, TGF- 𝛼/ADAM-17 gene upregulation, and downstream mechanisms, including proinflammatory factors overexpression. In conclusion, our data suggest that the anti-inflammatory actions of paricalcitol in tubular cells could depend on the inhibition of TGF- 𝛼/ADAM17/EGFR pathway in response to aldosterone, showing an important mechanism of VDRAs action Chronic kidney disease is characterized by Vitamin D deficiency and activation of the renin-angiotensin-aldosterone system. Increasing data show that vitamin D receptor agonists (VDRAs) exert beneficial effects in renal disease and possess anti inflammatory properties, but the underlying mechanism remains unknown. Emerging evidence suggests that “a disintegrin and metalloproteinase” (ADAM)/epidermal growth factor receptor (EGFR) signalling axis contributes to renal damage. Aldosterone induces EGFR transactivation regulating several processes including cell proliferation and fibrosis. However, data on tubular epithelial cells is scarce.We have found that, in cultured tubular epithelial cells, aldosterone induced EGFR transactivation via TGF- 𝛼/ADAM17. Blockade of the TGF-𝛼/ADAM17/EGFR pathway inhibited aldosterone-induced proinflammatory gene upregulation. Moreover, among the potential downstream mechanisms, we found that TGF-𝛼/ADAM17/EGFR inhibition blocked ERK and STAT-1 activation in response to aldosterone. Next, we investigated the involvement of TGF-𝛼/ADAM17/EGFR axis in VDRA anti-inflammatory effects. Preincubation with the VDRA paricalcitol inhibited aldosterone-induced EGFR transactivation, TGF- 𝛼/ADAM-17 gene upregulation, and downstream mechanisms, including proinflammatory factors overexpression. In conclusion, our data suggest that the anti-inflammatory actions of paricalcitol in tubular cells could depend on the inhibition of TGF- 𝛼/ADAM17/EGFR pathway in response to aldosterone, showing an important mechanism of VDRAs action, This work was supported by grants from the Instituto de Salud Carlos III (ISCIIIRETIC REDINREN RD12, PI11/ 01854, PI041/00041, PI13/00047, PIE13/00051, and PI0/ 00072), Comunidad den Madrid (Fibroteam S2010/BMD-232; CIFRA S2010/BMD-2378), Sociedad Española de Nefrología, European Network (FP7-HEALTH-2013-INNOVATION-1- 602422), and Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to Alberto Ortiz

Molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) relies on mutation screening of PKD1 and PKD2, which is complicated by extensive allelic heterogeneity and the presence of six highly homologous sequences of PKD1. To date, specific sequencing of PKD1 requires laborious long-range amplifications. The high cost and long turnaround time of PKD1 and PKD2 mutation analysis using conventional techniques limits its widespread application in clinical settings. We performed targeted next-generation sequencing (NGS) of PKD1 and PKD2. Pooled barcoded DNA patient libraries were enriched by in-solution hybridization with PKD1 and PKD2 capture probes. Bioinformatics analysis was performed using an in-house developed pipeline. We validated the assay in a cohort of 36 patients with previously known PKD1 and PKD2 mutations and five control individuals. Then, we used the same assay and bioinformatics analysis in a discovery cohort of 12 uncharacterized patients. We detected 35 out of 36 known definitely, highly likely, and likely pathogenic mutations in the validation cohort, including two large deletions. In the discovery cohort, we detected 11 different pathogenic mutations in 10 out of 12 patients. This study demonstrates that laborious long-range PCRs of the repeated PKD1 region can be avoided by in-solution enrichment of PKD1 and PKD2 and NGS. This strategy significantly reduces the cost and time for simultaneous PKD1 and PKD2 sequence analysis, facilitating routine genetic diagnostics of ADPKD. This project was funded by the Spanish Plan Nacional SAF2008-00357 (NOVADIS); the Instituto de Salud Carlos III (FIS/FEDER PI11/00733; PI12/01523 and PI13/01731); the European Commission/n7th Framework Program, Project N. 261123 (GEUVADIS), and Project N. 262055 (ESGI); Spanish Renal Network for Research 16/06, RETICS, Instituto de Investigación Carlos III: REDinREN/RD06/0016 and RD012/0021 FEDER funds; the Catalan Government (AGAUR/n2009/SGR-1116); and the Fundación Renal Iñigo Álvarez de Toledo in Spain. D. T. is a PhD student supported by the Spanish Ministry of Economy and Competiveness. R. T. is supported by Intensification Programm of Research Activity ISCIII/Generalitat de Catalunya (programm I3SN). We acknowledge support of the Spanish Ministry of Economy and Competitiveness, ‘Centro de/nExcelencia Severo Ochoa 2013-2017’, SEV-2012-0208.

We studied the non-obese diabetic (NOD) mice model because it develops autoimmune diabetes that resembles human type 1 diabetes. In diabetic mice, urinary albumin excretion (UAE) was ten-fold increased at an “early stage” of diabetes, and twenty-fold increased at a “later stage” (21 and 40 days, respectively after diabetes diagnosis) as compared to non-obese resistant controls. In NOD Diabetic mice, glomerular enlargement, increased glomerular filtration rate (GFR) and increased blood pressure were observed in the early stage. In the late stage, NOD Diabetic mice developed mesangial expansion and reduced podocyte number. Circulating and urine ACE2 activity were markedly increased both, early and late in Diabetic mice. Insulin administration prevented albuminuria, markedly reduced GFR, blood pressure, and glomerular enlargement in the early stage; and prevented mesangial expansion and the reduced podocyte number in the late stage of diabetes. The increase in serum and urine ACE2 activity was normalized by insulin administration at the early and late stages of diabetes in Diabetic mice. We conclude that the Diabetic mice develops features of early kidney disease, including albuminuria and a marked increase in GFR. ACE2 activity is increased starting at an early stage in both serum and urine. Moreover, these alterations can be completely prevented by the chronic administration of insulin. This work was supported by grants from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (ISCIII-FEDER. PI081688), and Fundación Senefro. J.P. is funded in part through the project ISCIII-FEDER PI10/01370

Background Kidney disease is associated with an increased total mortality and cardiovascular morbimortality in the general population and in patients with Type 2 diabetes. The aim of this study is to determine the prevalence of kidney disease and different types of renal disease in patients with type 2 diabetes (T2DM). Methods Cross-sectional study in a random sample of 2,642 T2DM patients cared for in primary care during 2007. Studied variables: demographic and clinical characteristics, pharmacological treatments and T2DM complications (diabetic foot, retinopathy, coronary heart disease and stroke). Variables of renal function were defined as follows: 1) Microalbuminuria: albumin excretion rate & 30 mg/g or 3.5 mg/mmol, 2) Macroalbuminuria: albumin excretion rate & 300 mg/g or 35 mg/mmol, 3) Kidney disease (KD): glomerular filtration rate according to Modification of Diet in Renal Disease < 60 ml/min/1.73 m2 and/or the presence of albuminuria, 4) Renal impairment (RI): glomerular filtration rate < 60 ml/min/1.73 m2, 5) Nonalbuminuric RI: glomerular filtration rate < 60 ml/min/1.73 m2 without albuminuria and, 5) Diabetic nephropathy (DN): macroalbuminuria or microalbuminuria plus diabetic retinopathy. Results The prevalence of different types of renal disease in patients was: 34.1% KD, 22.9% RI, 19.5% albuminuria and 16.4% diabetic nephropathy (DN). The prevalence of albuminuria without RI (13.5%) and nonalbuminuric RI (14.7%) was similar. After adjusting per age, BMI, cholesterol, blood pressure and macrovascular disease, RI was significantly associated with the female gender (OR 2.20; CI 95% 1.86–2.59), microvascular disease (OR 2.14; CI 95% 1.8–2.54) and insulin treatment (OR 1.82; CI 95% 1.39–2.38), and inversely associated with HbA1c (OR 0.85 for every 1% increase; CI 95% 0.80–0.91). Albuminuria without RI was inversely associated with the female gender (OR 0.27; CI 95% 0.21–0.35), duration of diabetes (OR 0.94 per year; CI 95% 0.91–0.97) and directly associated with HbA1c (OR 1.19 for every 1% increase; CI 95% 1.09–1.3). Conclusions One-third of the sample population in this study has KD. The presence or absence of albuminuria identifies two subgroups with different characteristics related to gender, the duration of diabetes and metabolic status of the patient. It is important to determine both albuminuria and GFR estimation to diagnose KD.

Resumen Antecedentes y objetivos: La enfermedad renal crónica (ERC) y la ateromatosis son 2 enfermedades interrelacionadas que aumentan el riesgo de morbimortalidad cardiovascular. Los objetivos del proyecto ILERVAS son: 1) conocer la prevalencia de enfermedad ateromatosa subclínica y de enfermedad renal oculta; 2) valorar el impacto de su diagnóstico precoz sobre la morbimortalidad cardiovascular y la progresión de la ERC; 3) disponer de una plataforma de datos y muestras biológicas. Métodos: Estudio de intervención aleatorizado. Entre 2015 y 2017 se incluirá a 19.800 personas (9.900 en el grupo de intervención y 9.900 en el grupo control) entre 45 y 70 años, sin antecedentes de enfermedad cardiovascular y que presenten al menos un factor de riesgo cardiovascular, seleccionadas aleatoriamente de los centros de atención primaria (AP) de la provincia de Lérida. Un equipo técnico experto se desplazará con una unidad móvil para realizar las exploraciones basales al grupo de intervención: ecografía arterial (carótida, femoral, transcraneal y aorta abdominal), medición del índice tobillo-brazo, espirometría, detección de los productos de glicación avanzada y analítica seca de sangre y orina. Adicionalmente, se recogerán muestras de sangre y orina que serán almacenadas en el biobanco para identificar nuevos biomarcadores con biología de sistemas. Los participantes serán seguidos hasta 2025 para la identificación de eventos cardiovasculares, cambios de tratamiento y modificación de estilos de vida. Conclusiones: El proyecto ILERVAS permitirá conocer la prevalencia de enfermedad vascular y de enfermedad renal subclínicas, evaluar si su diagnóstico precoz tiene un beneficio en la salud e investigar factores de riesgo emergentes. Abstract Background and objectives: Chronic kidney disease (CKD) and atherosclerosis are 2 interrelated diseases that increase the risk of cardiovascular morbidity and mortality. The objectives of the ILERVAS project are: 1) to determine the prevalence of subclinical arterial disease and hidden kidney disease; 2) to assess the impact of early diagnosis of both diseases on cardiovascular morbidity and mortality and also on the progression of CKD; 3) to have a platform of data and biological samples. Methods: Randomized intervention study. From 2015 to 2017, 19,800 people (9,900 in the intervention group and 9,900 in the control group) aged between 45 and 70 years without previous history of cardiovascular disease and with at least one cardiovascular risk factor will be randomly selected from the primary health care centres across the province of Lérida. A team of experts will travel around in a mobile unit to carry out the following baseline tests on the intervention group: Artery ultrasound; (carotid, femoral, transcranial and abdominal aorta); ankle-brachial index; spirometry; determination of advanced glycation end products; dried blood spot and urine spot tests. Additionally, blood and urine samples will be collected and stored in the biobank to identify new biomarkers using omics studies. Participants will be followed up until 2025 for identification of cardiovascular events, treatment changes and changes in lifestyle. Conclusions: The ILERVAS project will reveal the prevalence of subclinical vascular disease and hidden kidney disease, determine whether or not their early diagnosis brings health benefits and will also allow investigation of new risk factors.

Pregunta clínica d’investigació: És més eficaç un programa d’entrenament de la força progressiu en la intensitat de la càrrega (de moderada a vigorosa) respecte a l’entrenament d’intensitat moderada fixa, en la reducció de les complicacions respiratòries i del risc de mortalitat en pacients amb Fibrosi Sistèmica Nefrogènica? Objectiu: Comparar l’efecte d’un programa d’entrenament de la força d’intensitat progressiva respecte d’un programa d’intensitat fixa, sobre la força de la musculatura respiratòria en pacients amb Fibrosi Sistèmica Nefrogènica d’entre 18 i 80 anys. A més, de quantificar i comparar els canvis en la funció pulmonar, en la capacitat funcional, en la qualitat de vida i en la freqüència respiratòria. Metodologia: Estudi Clínic Aleatoritzat de tipus triple cec (estan cegats l’I-P i l’I-S, l’estadístic i els F-Av). La població elegible són les persones diagnosticades amb la NSF que habiten Catalunya i que compleixen els criteris de selecció per a participar en l’estudi. La mida mostral necessària és de 65 persones (n) i s’utilitza la tècnica de mostreig per conglomerat, en la qual es divideix la població en funció de les diferents regions sanitàries. Per a cadascun d’aquests conglomerats, es realitza un procés de mostreig aleatori simple per a prendre les 5 sub-mostres, i posteriorment un procés d’aleatorització simple per a cadascuna d’aquestes, de manera que s’assignen els participants en un dels dos grups d’estudi: el grup control, que realitza l’entrenament de força de la musculatura respiratòria d’intensitat progressiva, del 50 al 70% de la MIP, o el grup control, que realitza l’entrenament de força respiratòria d’intensitat fixa al 50% de la MIP. L’estudi és de tipus multicèntric i es porta a terme en 5 hospitals públics de Catalunya. La duració del tractament és de 8 setmanes, amb una freqüència de 6 sessions setmanals, de les quals 3 són supervisades i 3 no-supervisades. Clinical research question: A progressive strength training program in load intensity (moderate to vigorous) is more effective than fixed moderate intensity training, in reducing respiratory complications and risk of mortality in patients with Nephrogenic Systemic Fibrosis? Objective: To compare the effect of a progressive intensity strength training program with a fixed intensity program, on the strength of the respiratory muscles in patients with Nephrogenic Systemic Fibrosis between 18 and 80 years old. In addition, to quantify and compare changes in lung function, functional capacity, quality of life, and respiratory rate. Methodology: Randomized clinical trial triple-blind (researchers, statistics and evaluators are blinded). The eligible population are people diagnosed with NSF who live in Catalunya and who meet the selection criteria to participate in the study. The required sample size is 65 people (n) and the cluster sampling technique is used, in which the population is divided according to the different health regions. For each of these clusters, a simple random sampling process is performed to take the 5 sub-samples, and then a simple randomization process for each of these, so the participants are assigned to one of the two study groups: the control group, which performs the strength training of the respiratory muscles on progressive intensity, from 50 to 70% of the MIP, or the control group, which performs the respiratory strength training at fixed intensity of 50% of the MIP. The study is multicentre and is carried out in 5 public hospitals in Catalunya. The duration of treatment is 8 weeks, with a frequency of 6 weekly sessions, of which 3 are supervised and the other 3 unsupervised.