Genetic Variants Associated with Chronic Kidney Disease in a Spanish Population.

Chronic kidney disease (CKD) patients have many affected physiological pathways. Variations in the genes regulating these pathways might affect the incidence and predisposition to this disease. A total of 722 Spanish adults, including 548 patients and 174 controls, were genotyped to better understand the effects of genetic risk loci on the susceptibility to CKD. We analyzed 38 single nucleotide polymorphisms (SNPs) in candidate genes associated with the inflammatory response (interleukins IL-1A, IL-4, IL-6, IL-10, TNF-α, ICAM-1), fibrogenesis (TGFB1), homocysteine synthesis (MTHFR), DNA repair (OGG1, MUTYH, XRCC1, ERCC2, ERCC4), renin-angiotensin-aldosterone system (CYP11B2, AGT), phase-II metabolism (GSTP1, GSTO1, GSTO2), antioxidant capacity (SOD1, SOD2, CAT, GPX1, GPX3, GPX4), and some other genes previously reported to be associated with CKD (GLO1, SLC7A9, SHROOM3, UMOD, VEGFA, MGP, KL). The results showed associations of GPX1, GSTO1, GSTO2, UMOD, and MGP with CKD. Additionally, associations with CKD related pathologies, such as hypertension (GPX4, CYP11B2, ERCC4), cardiovascular disease, diabetes and cancer predisposition (ERCC2) were also observed. Different genes showed association with biochemical parameters characteristic for CKD, such as creatinine (GPX1, GSTO1, GSTO2, KL, MGP), glomerular filtration rate (GPX1, GSTO1, KL, ICAM-1, MGP), hemoglobin (ERCC2, SHROOM3), resistance index erythropoietin (SOD2, VEGFA, MTHFR, KL), albumin (SOD1, GSTO2, ERCC2, SOD2), phosphorus (IL-4, ERCC4 SOD1, GPX4, GPX1), parathyroid hormone (IL-1A, IL-6, SHROOM3, UMOD, ICAM-1), C-reactive protein (SOD2, TGFB1,GSTP1, XRCC1), and ferritin (SOD2, GSTP1, SLC7A9, GPX4). To our knowledge, this is the second comprehensive study carried out in Spanish patients linking genetic polymorphisms and CKD.

Clinical impact of the ERBP Working Group 2010 Recommendations for the anemia management in chronic kidney disease not on dialysis: ACERCA study.

BACKGROUND AND OBJECTIVE: The Anemia Working Group of ERBP in 2010 recommended a target hemoglobin (Hb) level in the range of 11-12 g/dL, without intentionally exceeding 13 g/dL during the treatment with erythropoiesis stimulating agents (ESAs). This study evaluated if there was a clinical impact of this statement in the anemia management of chronic kidney disease (CKD) patients treated with ESAs not on dialysis in routine clinical practice in Spain. METHODS: This was an observational and cross-sectional study carried out in CKD patients not on dialysis in Spain who initiated ESA treatment (naïve), or were shifted from a previous ESA to another ESAs (converted) since January 2011. RESULTS: Of 441 patients evaluated, 67.6% were naïve and 32.4% were converted. At the study visit, 42.5% of naïve patients achieved the Hb target of 11-12 g/dL, with a mean Hb of 11.3±1.3 g/dL (vs 10.1±0.9 g/dL at the start of ESA therapy). Only 35.3% of converted patients maintained Hb levels within the recommended target at the study visit. Yet, 8.2% of naïve patients and 7.9% of those converted had Hb levels >13 g/dL. Hb levels were similar across subgroups of patients, regardless of the presence of significant comorbidities. CONCLUSIONS: Anemia management in CKD patients treated with ESAs by Spanish nephrologists seems to be aimed at preventing Hb levels <11 g/dL, while <50% of patients were within the narrow recommended Hb target range. This, together with the lack of individualization in Hb targets according to patients' comorbidities show that there is still room for improvement in renal anemia management in the clinical setting.

Clinical impact of the ERBP Working Group 2010 Recommendations for the anemia management in chronic kidney disease not on dialysis: ACERCA study / Impacto clínico de las recomendaciones de 2010 del grupo de trabajo ERBP sobre el tratamiento de la anemia en la enfermedad renal crónica sin diálisis: estudio ACERCA

Background and objective: The Anemia Working Group of ERBP in 2010 recommended a targethemoglobin (Hb) level in the range of 11-12 g/dL, without intentionally exceeding 13g/dL during the treatment with erythropoiesis stimulating agents (ESAs). This study evaluated if there was a clinical impact of this statement in the anemia management of chronic kidney disease (CKD) patients treated with ESAs not on dialysis in routine clinical practice in Spain. Methods: This was an observational and cross-sectional study carried out in CKD patients not on dialysis in Spain who initiated ESA treatment (naive), or were shifted from a previous ESA to another ESAs (converted) since January 2011. Results: Of 441 patients evaluated, 67.6% were naive and 32.4% were converted. At the study visit, 42.5% of naive patients achieved the Hb target of 11-12 g/dL, with a mean Hb of11.3& #177; 1.3 g/dL (vs 10.1 ± 0.9 g/dL at the start of ESA therapy). Only 35.3% of converted patients maintained Hb levels within the recommended target at the study visit. Yet, 8.2% of naive patients and 7.9% of those converted had Hb levels >13 g/dL. Hb levels were similar across subgroups of patients, regardless of the presence of significant comorbidities. Conclusions: Anemia management in CKD patients treated with ESAs by Spanish nephrologists seems to be aimed at preventing Hb levels <11 g/dL, while <50% of patients were within the narrow recommended Hb target range. This, together with the lack of individualization in Hb targets according to patients’ comorbidities show that there is still room for improvement in renal anemia management in the clinical setting (AU)

Introducción y objetivo: El grupo de trabajo europeo en anemia-ERBP recomendó en 2010 mantener los niveles de Hb entre 11-12 g/dL sin exceder intencionadamente de 13 g/dL durante el tratamiento con agentes estimuladores de la eritropoyesis (AEE). Este estudió evaluó si se produjo un impacto clínico de esta declaración en el tratamiento de la anemia en la enfermedad renal crónica (ERC) con AEE en la práctica clínica. Metodología: Estudio transversal, observacional y multicéntrico en pacientes con anemia secundaria a ERC y no sometidos a diálisis, que iniciaron tratamiento de la anemia (nuevos)o pasaron de unos AEE a otros (transición de AEE) a partir de enero de 2011. Resultados: De los 441 pacientes evaluados, el 67,6% eran nuevos y el 32,4% estaban en situación de transición. En la visita de estudio, el 42,5% de los pacientes nuevos habían alcanzado el rango de Hb de 11-12 g/dL (niveles medios de 11,3 ± 1,3 g/dL frente a 10,1 ± 0,9 g/dL al inicio del tratamiento con AEE), y el 35,3% de pacientes en situación de transición mantuvieron los niveles de Hb dentro del rango recomendado. A pesar de ello, el 8,2% delos pacientes nuevos y el 7,9% de aquellos en situación de transición tenían niveles de Hb> 13 g/dL. Los niveles de Hb fueron similares, independientemente de la presencia o no de comorbilidades significativas. Conclusiones: En las Unidades de Nefrología de España, el manejo de la anemia en pacientes con ERC no en diálisis en tratamiento con AEE parece dirigido a evitar niveles de Hb < 11 g/dL, aunque menos del 50% de los pacientes se encuentran dentro del estrecho rango recomendado. Ello, junto a la falta de individualización del objetivo de Hb en función de la presencia de comorbilidades, muestra que aún queda margen de mejora en el tratamiento de la anemia en la ERC con AEE en la práctica clínica (AU)

Prevalence of anaemia and its clinical management in patients with stages 3-5 chronic kidney disease not on dialysis in Catalonia: MICENAS I study.

INTRODUCTION: Anaemia is a common complication of chronic kidney disease (CKD). The aim of this study was to determine the prevalence and clinical management of anaemia in patients with stages 3-5 CKD not on dialysis treated in outpatient Nephrology clinics (OC) in Catalonia. METHODS: Epidemiological, cross-sectional cohort, multicentre study under routine clinical practice conditions. Data collection by electronic data collection log-book (e-DCL) including personal information and data related to anaemia (haemoglobin, iron status, treatment with erythropoiesis-stimulating agents [ESA] and other anaemia treatments). Anaemia was defined as haemoglobin levels <13.5 g/dL in males or <12 g/dL in females or patients who receive treatment with ESA. RESULTS: We included 504 patients (56.4% male, mean age of 67.8 ± 15.5 years): 61.5% had stage 3 CKD, 30.2% stage 4 and 8.3% stage 5. The main causes of CKD were vascular and diabetic nephropathy. The prevalence of anaemia was 58.5% (n=295), however, only 14.9% of patients had haemoglobin levels <11 g/dL. Mean haemoglobin levels decreased and ESA treatment was more common as CKD progressed, but no significant differences were observed regarding the prescription of iron, according to CKD stages. ESA and intervals most frequently prescribed were darbepoetin alfa with a median dose of 40 µg/biweekly, followed by C.E.R.A. with a median dose of 75 µg/month and epoetin beta with a median dose of 5,000 IU/week. Among the patients with anaemia (n=295), 36.3% (n=107) had iron deficiency and only 53.3% of these patients were treated with iron supplements. CONCLUSIONS: This study demonstrates the high prevalence of anaemia, which increases as the disease progresses and its good control in a CKD patient population treated in Nephrology outpatient clinics in Catalonia. This control is achieved with moderate doses of ESA and iron supplements prescribed in more than 50% of anaemic CKD patients.

Factor de crecimiento fibroblástico 23 (FGF 23) y metabolismo fosfocálcico en la enfermedad renal crónica / Fibroblast growth factor 23 (FGF 23) and phosphocalcic metabolism in chronic kidney disease

Introducción y objetivos: A pesar de disponer de una información limitada, el conocimiento de los niveles relativos del factor de crecimiento fibrobástico 23 (FGF 23), fosfato (P), calcio (Ca), paratohormona intacta (PTHi) y 25/1,25 vitamina D3 en cada momento evolutivo de la insuficiencia renal crónica ha aportado datos para sustituir o al menos modificar antiguos paradigmas. Se definen estadios más precoces, se señalan amplias implicaciones pronósticas y se sugieren nuevas intervenciones terapéuticas. Planteamos un estudio transversal-descriptivo y analítico de estos parámetros en una amplia muestra de enfermos distribuidos en todo el espectro de la enfermedad renal crónica. Material y métodos: Evaluamos los niveles de FGF 23 con un ELISA de segunda generación que mide molécula intacta (Kainos Laboratories, Japón) en un diseño transversal de una población adulta con todos los estadios de la enfermedad renal crónica basados en CKD-EPI junto a niveles de Ca, P, paratohormona y metabolitos de la vitamina D. Resultados: Estudiamos a 251 enfermos (146 hombres y 77 mujeres) con una edad promedio de 62,5 (desviación estándar [DE]: 11,5) años, siendo el 43% de ellos diabéticos. Los niveles de FGF 23 aumentan progresivamente; este cambio es significativo en el estadio 4 en relación con el 1 (110,61 vs. 31,32 ng/l). La PTHi muestra un comportamiento similar. La 1,25 vitamina D baja (..) (AU)

Background and Objectives: The ample information available in relation to FGF 23, calcium, phosphorus, PTH, and 25/1,25 vitamin D has allowed us to define consistent values for each variable in each stage of chronic kidney disease (CKD). These values can define early stages, prognostic issues, and new treatment targets. We describe a cross-sectional study of these parameters in patients with different stages of CKD. Method: We measured FGF 23 by ELISA (intact molecule, Kainos Laboratory, Japan), calcium, phosphorus, PTH and vit D by standard methods. Results: We examined 251 patients, 146 of which were men, with a mean age of 62.5 (11.5) years and 43% prevalence of type II DM. Levels of FGF 23 rose progressively, in a very significant manner, in correlation with the evolution of CKD, especially in stage 4 as compared to stage 1 (110.61ng/L vs 31.32ng/L). The same happened with iPTH values. Additionally, levels of 1,25 vitamin D decreased in a similar manner. Calcium values did not change. 25 vit D3 levels were low at all times and showed no tendency for a steady decline. Phosphorus rose in stage 4 CKD. Levels of FGF 23 were negatively correlated with renal function indicators and positively correlated with PTH and P. Conclusions: During the evolution of CKD, changes of FGF 23 and PTH would be the earliest markers. Calcium and 25 vit D3 do not vary with changes in the progression of CKD. Values of FGF 23 show an important correlation with PTH, 1,25 vit D3, P and estimated glomerular filtration rate (AU)

Importancia de la hemodiafiltración precoz en el tratamiento de la acidosis láctica asociada a la administración de metformina / The importance of early haemodiafiltration in the treatment of lactic acidosis associated with the administration of metformin

La metformina es un fármaco muy utilizado en pacientes con diabetes tipo 2. La acidosis láctica asociada a metformina (ALAM) en pacientes diabéticos es poco frecuente, pero puede llegar a ser grave. De todas formas, la relación entre metformina y acidosis láctica ha sido muy controvertida. Presentamos siete casos de pacientes con ALAM que llegaron a nuestro centro en un período de un año y que fueron tratados de forma precoz con hemofiltración. Existen algunos factores de riesgo que parecen predisponer a esa patología, como fracaso renal agudo, situaciones de hipoxemia y sepsis, insuficiencia cardíaca o respiratoria, historia previa de acidosis láctica, hepatopatía y en cuadros de deshidratación. Es por ello por lo que se desaconseja su utilización en pacientes con filtrado glomerular inferior a 30 ml/min/1,73 m2. Todos los pacientes que presentamos fueron tratados de forma precoz con hemofiltración. La mortalidad de nuestra serie fue del 16,6%. Consideramos que la ALAM es una enfermedad grave que requiere un diagnóstico y un tratamiento precoces. El tratamiento renal sustitutivo no es la solución para todos los pacientes, pero puede mejorar el pronóstico en aquellos que están más graves si se inicia de forma precoz. Creemos importante limitar el uso de la metformina en los pacientes diabéticos con función renal alterada, a pesar de que todavía existe controversia en los distintos estudios publicados (AU)

Metformin is a drug widely used in type 2 diabetic patients. The metformin-associated lactic acidosis (MALA) in diabetic patients is rare but can be serious. However, the relationship between metformin and lactic acidosis has been controversial. We present seven cases of patients with ALAM who came to our centre over a period of one year and who were treated early with haemodiafiltration. There are some risk factors that appear to predispose to this pathology, such as: acute renal failure, hypoxemia and sepsis situations, cardiac or respiratory failure, previous history of lactic acidosis, liver disease and dehydration boxes. That is why their use is discouraged in patients with GFR below 30ml/min/1.73m2. All patients described were treated early with haemodiafiltration. The mortality in our series was 16.6%. We believe that ALAM is a serious condition that requires prompt diagnosis and early treatment. Renal replacement therapy is not the solution for all patients, but can improve prognosis in more severe if started early. We should limit the use of metformin in diabetic patients with impaired renal function, although there is still controversy in the various published studies (AU)

Fibroblast growth factor 23 (FGF 23) and phosphocalcic metabolism in chronic kidney disease.

BACKGROUND AND OBJECTIVES: The ample information available in relation to FGF 23, calcium, phosphorus, PTH, and 25/1,25 vitamin D has allowed us to define consistent values for each variable in each stage of chronic kidney disease (CKD). These values can define early stages, prognostic issues, and new treatment targets. We describe a cross-sectional study of these parameters in patients with different stages of CKD. METHOD: We measured FGF 23 by ELISA (intact molecule, Kainos Laboratory, Japan), calcium, phosphorus, PTH and vit D by standard methods. RESULTS: We examined 251 patients, 146 of which were men, with a mean age of 62.5 (11.5) years and 43% prevalence of type II DM. Levels of FGF 23 rose progressively, in a very significant manner, in correlation with the evolution of CKD, especially in stage 4 as compared to stage 1 (110.61 ng/L vs 31.32 ng/L). The same happened with iPTH values. Additionally, levels of 1,25 vitamin D decreased in a similar manner. Calcium values did not change. 25 vit D3 levels were low at all times and showed no tendency for a steady decline. Phosphorus rose in stage 4 CKD. Levels of FGF 23 were negatively correlated with renal function indicators and positively correlated with PTH and P. CONCLUSIONS: During the evolution of CKD, changes of FGF 23 and PTH would be the earliest markers. Calcium and 25 vit D3 do not vary with changes in the progression of CKD. Values of FGF 23 show an important correlation with PTH, 1,25 vit D3, P and estimated glomerular filtration rate.

The importance of early haemodiafiltration in the treatment of lactic acidosis associated with the administration of metformin.

Metformin is a drug widely used in type 2 diabetic patients. Metformin-associated lactic acidosis (MALA) in diabetic patients is rare but can be serious. However, the relationship between metformin and lactic acidosis is under debate. We present seven cases of patients with MALA who came to our centre over a period of one year and who were treated early with haemodiafiltration. There are some risk factors that appear to predispose patients to this pathology, such as: acute renal failure, situations of hypoxemia and sepsis, cardiac or respiratory failure, previous history of lactic acidosis, liver disease and dehydration. As such, the use of metformin is discouraged in patients with GFR below 30 ml/min/1.73 m(2). All patients in our study were treated early with haemodiafiltration. The mortality in our study was 16.6%. We believe that MALA is a serious condition that requires prompt diagnosis and early treatment. Renal replacement therapy is not the solution for all patients, but can improve prognosis in more severe cases if started early. We should limit the use of metformin in diabetic patients with impaired renal function, although there is still controversy in the medical literature.

Parálisis hipocaliémica como presentación de tirotoxicosis / Hypokaliemic paralysis as onset of thorytoxicosis

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