Influencia de los genotipos del sistema renina-angiotensina en la respuesta antiproteinúrica a dosis altas de olmesartán en nefropatías proteinúricas no diabéticas / The influence of renin-angiotensin system genotypes on the antiproteinuric response to high doses of olmesartan in non-diabetic proteinuric nephropathies

Objetivo: Evaluar la respuesta antiproteinúrica a un tratamiento multifactorial basado en dosis elevadas de antagonistas de los receptores de la angiotensina II (ARAII) (olmesartán) en pacientes con nefropatías proteinúricas no diabéticas, según tres de los polimorfismos del sistema renina-angiotensina (SRA): inserción/deleción del gen de la enzima convertidora de angiontensina (ECA), M235T del gen del angiotensinógeno y A1166C del receptor AT1 (rAT1) para la angiotensina II. Material y métodos: Se estudiaron 53 pacientes con nefropatía proteinúrica no diabética, con un tiempo medio de evolución de 84,4 ± 15 meses. Género varón en 41 (77,4 %); edad media 49,7 ± 3 años; índice de masa corporal 30 ± 6 kg/m2. Todos recibieron olmesartán (40 mg/12 h) asociado a un promedio de 2,4 ± 1,6 fármacos antihipertensivos durante una mediana de tiempo de 13 meses (rango intercuartil 7-25 meses). Resultados: La presión arterial (PA) sistólica descendió de 145 ± 14 hasta 128 ± 14 mmHg (p < 0,001) y la PA diastólica desde 85 ± 11 a 79 ± 7 mmHg (p < 0,01). La presión de pulso pasó de 53,5 ± 14 a 48 ± 12 mmHg (p < 0,05). La proteinuria se redujo de 2,74 ± 1,6 a 0,9 ± 1 g/24 h (p < 0,001), representando un descenso promedio del 67,1 %. Según los polimorfismos del SRA, la respuesta antiproteinúrica fue: polimorfismo del gen del angiotensiógeno: genotipo TT: 76,8 %; genotipo MM: 67,3 %; genotipo MT: 65,8 %, significativamente mayor (p < 0,05) para genotipo TT respecto de MM y MT. Polimorfismo del gen de la ECA: genotipo DD: 71,4 %; genotipo ID: 60,6 %, genotipo II: 34,8 %, significativamente mayor (p < 0,05) para genotipo DD respecto a ID e II, y asimismo (p < 0,05) para el genotipo ID respecto a II. Polimorfismo del gen del rAT1: genotipo AC: 85,2 %; genotipo CC: 73,7 %; genotipo AA: 62,7 %; significativamente mayor para el genotipo AC (p < 0,05) respecto a AA y CC. Las diferencias entre la proteinuria inicial y final del período de seguimiento fueron significativas (p < 0,01) para las asociaciones genotípicas: DD/AA, DD/MT, DD/MM, DD/TT y DD/AC, si bien la asociación con mayor efecto antiproteinúrico fue DD/AC (89,9 %, p < 0,05 %). Conclusiones: La administración de dosis altas de olmesartán en pacientes con nefropatía proteinúrica no diabética comporta reducciones significativas en la proteinuria. Este descenso fue independiente del control tensional y de otros factores de confusión. Los polimorfismos del SRA pueden modular la respuesta antiproteinúrica al tratamiento con ARAII

Objective: To assess the antiproteinuric response to multifactorial treatment based on high doses of angiotensin II receptor antagonists (ARBs) (olmesartan) in patients with non-diabetic proteinuric nephropathies, according to three renin-angiotensin system (RAS) polymorphisms: insertion/deletion of the angiotensin converting enzyme (ACE) gene, the angiotensinogen gene M235T and the angiotensin II type 1 receptor (AT1R) A1166C. Material and method: We studied 53 patients with non-diabetic proteinuric nephropathy with a mean progression time of 84.4±15 months. 41 were males (77.4%); mean age 49.7±3 years, body mass index 30±6kg/m2. All received olmesartan (40mg/12h) associated with a mean of 2.4±1.6 antihypertensive drugs for a median period of 13 months (interquartile range 7-25 months). Results: Systolic blood pressure (BP) decreased from 145±14mmHg to 128±14mmHg (P<.001) and diastolic BP from 85±11mmHg to 79±7mmHg (P<.01). Pulse pressure decreased from 53.5±14mmHg to 48±12mmHg (P<.05). Proteinuria decreased from 2.74±1.6g/24h to 0.9±1g/24h (P<.001), representing a mean decrease of 67.1%. According to RAS polymorphisms, antiproteinuric response was: angiotensinogen gene polymorphism: genotype TT: 76.8%; genotype MM: 67.3%; genotype MT: 65.8%, significantly higher (P<.05) for genotype TT compared to genotypes MM and MT. Polymorphism of the ACE gene: genotype DD: 71.4%; genotype ID: 60.6%, genotype II: 34.8%, significantly higher (P<.05) for genotype DD compared to genotypes ID and II, and also (P<.05) for genotype ID compared to II. AT1R gene polymorphism: genotype AC: 85.2%; genotype CC: 73.7%; genotype AA: 62.7%; significantly higher for genotype AC (P<.05) compared to genotypes AA and CC. The differences between initial and final proteinuria for the follow-up period were significant (P<.01) for genotypic associations DD/AA, DD/MT, DD/MM, DD/TT and DD/AC, although the association with the highest antiproteinuric effect was DD/AC (89.9%, P<.05%). Conclusions: Administering high doses of olmesartan in patients with non-diabetic proteinuric nephropathy results in significant reductions in proteinuria. This decrease was independent of blood pressure control and other confounding factors. RAS polymorphisms may modulate the antiproteinuric response to treatment with ARBs

The influence of renin-angiotensin system genotypes on the antiproteinuric response to high doses of olmesartan in non-diabetic proteinuric nephropathies.

OBJECTIVE: To assess the antiproteinuric response to multifactorial treatment based on high doses of angiotensin II receptor antagonists (ARBs) (olmesartan) in patients with non-diabetic proteinuric nephropathies, according to three renin-angiotensin system (RAS) polymorphisms: insertion/deletion of the angiotensin converting enzyme (ACE) gene, the angiotensinogen gene M235T and the angiotensin II type 1 receptor (AT1R) A1166C. MATERIAL AND METHOD: We studied 53 patients with non-diabetic proteinuric nephropathy with a mean progression time of 84.4±15 months. 41 were males (77.4%); mean age 49.7±3 years, body mass index 30±6kg/m2. All received olmesartan (40mg/12h) associated with a mean of 2.4±1.6 antihypertensive drugs for a median period of 13 months (interquartile range 7-25 months). RESULTS: Systolic blood pressure (BP) decreased from 145±14mmHg to 128±14mmHg (P<.001) and diastolic BP from 85±11mmHg to 79±7mmHg (P<.01). Pulse pressure decreased from 53.5±14mmHg to 48±12mmHg (P<.05). Proteinuria decreased from 2.74±1.6g/24h to 0.9±1g/24h (P<.001), representing a mean decrease of 67.1%. According to RAS polymorphisms, antiproteinuric response was: angiotensinogen gene polymorphism: genotype TT: 76.8%; genotype MM: 67.3%; genotype MT: 65.8%, significantly higher (P<.05) for genotype TT compared to genotypes MM and MT. Polymorphism of the ACE gene: genotype DD: 71.4%; genotype ID: 60.6%, genotype II: 34.8%, significantly higher (P<.05) for genotype DD compared to genotypes ID and II, and also (P<.05) for genotype ID compared to II. AT1R gene polymorphism: genotype AC: 85.2%; genotype CC: 73.7%; genotype AA: 62.7%; significantly higher for genotype AC (P<.05) compared to genotypes AA and CC. The differences between initial and final proteinuria for the follow-up period were significant (P<.01) for genotypic associations DD/AA, DD/MT, DD/MM, DD/TT and DD/AC, although the association with the highest antiproteinuric effect was DD/AC (89.9%, P<.05%). CONCLUSIONS: Administering high doses of olmesartan in patients with non-diabetic proteinuric nephropathy results in significant reductions in proteinuria. This decrease was independent of blood pressure control and other confounding factors. RAS polymorphisms may modulate the antiproteinuric response to treatment with ARBs.

Trasplante renal con injertos procedentes de donantes en parada cardíaca Maastricht tipo III / Kidney transplantation with grafts from type III Maastricht non-beating-heart donors

El trasplante renal (TR) con riñones de donantes fallecidos en parada cardíaca (PC) está creciendo en nuestro país. La mayoría procede de donantes con los criterios de Maastricht tipo II, si bien en los últimos años el donante fallecido tras limitación de tratamientos de soporte vital (LTSV) es una realidad en algunos países europeos y norteamericanos y constituye el Maastricht tipo III. Se presenta una serie de 6 TR con riñones de donantes fallecidos tras PC como consecuencia de LTSV en tres hospitales del Sector Málaga. Tras consensuar protocolo de actuación en el que la valoración como donante fue siempre posterior a la decisión de LTSV, se planteó a las familias la opción de donación. La preservación de los riñones se realizó mediante sonda de doble balón tipo Porges que se colocó antes de la PC. En dos casos la LTSV se realizó en la Unidad de Cuidados Intensivos y en el tercero en quirófano. Los tiempos desde inicio LTSV hasta la PC oscilaron entre 15 y 40 minutos, con un tiempo de parada circulatoria antes del inicio de la (..) (AU)

Kidney transplantation (KT) with kidneys from non-beating-heart donors (NBHD) is a growing trend in Spain. The majority of these kidneys come from type II Maastricht patients, although in recent years, organ donations from patients deceased due to cardiac arrest following limitation of life-sustaining therapy has already been in practice in certain European and North American countries, and it involves type III Maastricht patients. We present a series of 6 KT using kidneys from NHBD as a consequence of limitation of life-sustaining therapy in three different hospitals in the sector of Malaga. After agreeing upon a protocol for evaluating the potential of a patient for organ donation, which was always after deciding to limit life-sustaining therapy, the patients' families were given the option of organ donation. Kidneys were preserved using a Porges double balloon catheter, which was placed prior to cardiac arrest. In two cases, the limitation of life-sustaining therapy took place in the intensive care unit, and in the third case, in the operating room. The interval between limitation of life-sustaining therapy and cardiac (..) (AU)

Kidney transplantation with grafts from type III Maastricht non-beating-heart donors.

Kidney transplantation (KT) with kidneys from non-beating-heart donors (NBHD) is a growing trend in Spain. The majority of these kidneys come from type II Maastricht patients, although in recent years, organ donations from patients awaiting cardiac arrest following limitation of life-sustaining therapy has already been in practice in certain European and North American countries, involving type III Maastricht patients. We present a series of 6 KT using kidneys from NHBD as a consequence of limitation of life-sustaining therapy in three different hospitals in the sector of Malaga. After agreeing upon a protocol for evaluating the potential of a patient for organ donation after the decision for limiting life-sustaining therapy, the patients' families were given the option of organ donation. Kidneys were preserved using a Porges double balloon catheter, which was placed prior to cardiac arrest. In two cases, the limitation of life-sustaining therapy took place in the intensive care unit, and in the third case, in the operating room. The interval between limitation of life-sustaining therapy and cardiac arrest ranged between 15 minutes and 40 minutes, with an interval of circulatory arrest prior to perfusion of 5-11 minutes. Perfusion-cooling of the kidneys was initially carried out using saline solution, followed by organ preservation solution (Celsior or Belzer) and extraction of the kidney using a rapid surgical technique. True or functional hot ischaemia times were 60 minutes, 59 minutes, and 50 minutes, respectively, for each of the three donors. Kidneys were evaluated for viability using time intervals for the procedure (including hypotension prior to cardiac arrest), macroscopic appearance, and histopathology of a sample taken from each kidney. The recipients of these 6 kidneys had given their consent to receive organs from expanded-criteria donors. Cold ischaemia lasted between 9 hours and 20 hours (mean: 14.6 hours). One recipient developed haemorrhagic complications during the immediate postoperative period and required a transplantectomy. The other five currently retain functioning grafts. All had delayed graft function, necessitating haemodialysis. The range of estimated glomerular filtration rates at the most recent follow-up evaluation was 23.0-106 ml/min/1.73 m(2). In conclusion, type III Maastricht donors provide valid kidneys for transplantation, although this series showed that supported functional hot ischaemia was very important, the consequence of accumulated ischaemic damage starting in the agonal phase, circulatory arrest, and organ preservation using cold solutions. As such, to improve the quality of results obtained using kidneys from these types of donors would involve a very careful selection of optimal donors and minimisation of total functional ischaemia times.