Chronic kidney disease (CKD) and chronic kidney insufficiency (CKI) diagnosing equation in cirrhotic patients.

Cirrhotic patients can develop acute kidney injury (AKI), and chronic kidney disease (CKD). Therefore, renal functional evaluation is crucial in cirrhotic patients. However, serum creatinine and urea levels, as well as measured or estimated glomerular filtration rate is not reliable renal functional markers in these patients compared to other patient groups. In the present study, four original equations are designed and tested for screening chronic kidney disease (CKD) and chronic kidney insufficiency (CKI) in stable cirrhotic patients. MATERIAL & METHOD: estimated GFR (CKD-EPI creatinine and cystatin equations) were recorded in 175 adult stable patients suffering from cirrhosis, and these patients were classified as presenting or not CKD and CKI after evaluation by two independent nephrologists. Based on these data, the variables with the significant discriminating capability to identify CKD and CKI (based on creatinine and cystatin) were detected by applying the Student's t-test for two independent groups, later confirmed by the lambda test of Wilks, in order to obtain the renal function equations. RESULTS: CKD equation (creatinine) = 7.094238-0.043104 × CKD-EPI creatinine - 0.057537 × haematocrit. CKD equation (cystatin) = 8.375074-0.117218 × CKD-EPI cystatin. CKI equation (creatinine) = 0.428389-0.043214 × CKD-EPI creatinine +0.183051 × Child-Pugh score + 0.050162 × age (in years). CKI equation (cystatin) = 9.169579-0.139319 × CKD-EPI cystatin. CONCLUSION: Simple and reliable equations have been obtained for screening chronic kidney disease and chronic kidney insufficiency in cirrhotic patients.

Cranberry dosed extract: an effective therapy for recurrent Escherichia coli cystitis in elderly patients. The GerHogar Cysticlean® study / Extracto dosificado de arándano rojo: una terapia eficaz para la cistitis recurrente por Escherichia coli en pacientes de la tercera edad. El estudio GerHogar Cysticlean®

Abstract Introduction: Cystitis is the most prevalent urinary tract infection (UTI), and antibiotics are its conventional therapy. However, the prevalence rate of antibiotic resistance to uropathogens is significantly increased. Cranberry treatment has been associated with the inhibition of Escherichia coli (Ec) adherence to uroepithelial cells due to the anti-adhesive property related to its proanthocyanidins content, and cysticlean® (CYS) is a cranberry extract which contains 240 mg PACs per capsule. Since elderly people is one of the populations mostly exposed to cystitis and bacteria antibiotic resistance, it was decided to originally study the efficacy and safety of CYS, to treat cystitis instead of antibiotic, in elderly individuals. Material & Methods: Two groups were studied: Group 1 (G1): first cystitis episode was recorded within the last 3 months before the study initiation. Group 2 (G2): frequent cystitis recurrent episodes (1-2/month or more) within the last 3 months before the study initiation. G1 patients were treated with 1 capsule of CYS every 12 h for 1 month, while G2 patients were treated up to 12 months. Comparative evaluation was performed using Student test. Results: 160 elderly ambulatory and nursing home patients suffering from recurrent cystitis were treated with CYS. G1 and G2 had 38 and 122 subjects, respectively. Cranberry-based cystitis treatment was successful in 81.57 % and 81.96 % in G1 and G2 patients, respectively. Conclusion: CYS showed to be an effective alternative therapy to antibiotics to treat cystitis recurrences caused by Ec. Neither side effects nor adverse reactions have been reported.

Resumen Introducción: la cistitis es la infección del tracto urinario más común a nivel mundial y los antibióticos son su terapia convencional; sin embargo, la tasa de prevalencia de la resistencia de los uropatógenos a los antibióticos ha aumentado significativamente en los últimos tiempos. El tratamiento con arándano rojo se ha asociado con la inhibición de la adherencia de la Escherichia coli a las células uroepiteliales debido a la propiedad antiadherente relacionada con su contenido de proantocianidinas. La cysticlean® (CYS) es un extracto de arándano rojo que contiene 240 mg de PAC por cápsula. Objetivo: estudiar la eficacia y seguridad de la CYS en el tratamiento de la cistitis como reemplazo de los antibióticos en personas adultas mayores. Material y métodos: se estudiaron dos grupos, uno (G1) en el que el primer episodio de cistitis se registró dentro de los últimos 3 meses antes del inicio del estudio y otro (G2) en el que se registraron episodios recurrentes de cistitis frecuentes (≥1-2 al mes) en los últimos 3 meses antes del inicio del estudio. Los pacientes del G1 fueron tratados con 1 cápsula de CYS cada 12 horas durante 1 mes, mientras que los del G2 fueron tratados por 12 meses con el mismo esquema. La evaluación comparativa se realizó mediante la prueba de Student. Resultados: en el estudio participaron 160 pacientes ambulatorios de la tercera edad residentes de hogares de ancianos y con diagnóstico de cistitis recurrente. De estos, 38 se incluyeron en G1 y 122, en G2. El tratamiento de la cistitis a base de arándano rojo tuvo éxito en el 81,57 % y el 81,96 % de los pacientes de G1 y G2, respectivamente. Conclusión: la CYS demostró ser una terapia alternativa eficaz a los antibióticos para tratar las recurrencias de cistitis causadas por E. coli al no presentarse efectos secundarios ni reacciones adversas.

Is Kt/V useful in elderly dialysis patients? Pro and Con arguments.

Current guidelines for dialysis specify a minimum Kt/V. For haemodialysis (HD) patients, minimum treatment time and frequency is also specified. The guidelines allow for modification to take account of renal function. The guidelines are not specifically aimed at the elderly and may not be appropriate for all patients in this group. Increasing age is accompanied by physiological and pathological changes that may modify the patient's response to uraemia and dialysis. Frailty and multi-morbidity are likely, but to a variable extent. Elderly patients could be more susceptible to the effects of uraemia and require a higher dose of dialysis. Conversely, the generation rate of uraemic toxins is lower in elderly patients, potentially reducing the need for dialysis. In the elderly, quality of life may be more adversely affected by multimorbidity than uraemic symptoms, thus the dose of dialysis may be less relevant. Higher doses of dialysis may be more difficult to achieve in the elderly and may be less well tolerated. We conclude that the prescription of dialysis in the elderly should be individualized, taking multiple factors into account. An individualized Kt/V may be useful in controlling dialysis dose and detecting problems in delivery. However, achievement of a specified Kt/V may not result in any benefit to an elderly patient and could be counterproductive.

Glomerular filtration rate equations: a comprehensive review.

Since evaluation of glomerular filtration rate (GFR) is very important in daily medical care, and reliable methods for measuring GFR are too complicated, there has been along decades an enormous effort for developing accurate GFR equations. In the present review article, we performed a comprehensive analysis of the mainly described GFR equations, and we concluded that although MDRD, CKD-EPI, DRA and Gregori-Macías equations are valid to monitor renal function as well as to stage and follow up renal patients, the clinical nephrological evaluation still remains the best alternative for diagnosing renal health and disease.

Priority topics for European multidisciplinary guidelines on the management of chronic kidney disease in older adults.

PURPOSE: To identify and prioritize potential topics to be addressed in the development of European multidisciplinary guidelines on the management of chronic kidney disease stage 3b-5 in older patients. METHODS: We composed a list of 47 potential guideline topics by reviewing the literature, consulting online 461 nephrologists and 107 geriatricians, and obtaining expert input. A multidisciplinary panel of twelve experts then prioritized the topics during a face-to-face consensus meeting, following a nominal group technique structure with two voting rounds. Topics were rated on a 9-point scale ranging from 1 ('not at all important') to 9 ('critically important'). RESULTS: The highest rating (median; range) was assigned to 'Screening and referral' (8.5; 2.0). Eight topics shared the second highest rating with a median priority score of 8.0 (2.0) and included 'Starting dialysis or not' and 'Accurate assessment of renal function.' 'Targets for and treatment of diabetes' received the lowest rating with (3.0; 6.0). CONCLUSIONS: This joint initiative of the European Renal Association-European Dialysis Transplant Association (ERA-EDTA) and the European Union Geriatric Medicine Society (EUGMS) prioritized the development of guidance on interdisciplinary referral of older patients with chronic kidney disease stage 3b-5. Future guidance will therefore focus on identifying prognostic scores to predict death and progression to end-stage renal disease, as well as accurate tests for assessment of renal function in older kidney patients. This will contribute to more informed treatment decision making in this growing patient population.

A New Method for Individualized Digoxin Dosing in Elderly Patients.

BACKGROUND: Digoxin is a frequently prescribed drug in the elderly population. Estimated glomerular filtration rate is widely used to adjust dosages. The HUGE value is a tool for differentiating the presence or absence of chronic kidney disease in elderly patients. We aimed to investigate the usefulness of the HUGE value to predict the initial dose of digoxin in patients aged older than 70 years. METHODS: We reviewed retrospectively the medical records of patients aged older than 70 years with serum digoxin concentrations (SDCs) monitored over a 6-month period (63 patients). A linear regression relating the patient's SDC, maintenance dose of digoxin and the HUGE value was estimated to generate a dosage equation. This equation was validated retrospectively (33 patients) and prospectively (35 patients) in comparison with two existing methods based on creatinine clearance. RESULTS: An equation (HUGE_DIG) was generated to calculate the initial digoxin dose to reach a specific target SDC. Thus, to achieve a SDC of 0.8 ng/mL: Digoxin (mg/day) = 0.091 - 0.006 x HUGE. After retrospective validation, the calculated digoxin doses with this equation were administered in the prospective phase and we did not observe statistical differences between measured and desired SDCs. Moreover, the predictive performance of our equation was better than that obtained with the compared methods. CONCLUSIONS: We offer a new validated digoxin dosing equation for elderly patients. Our results support the need to perform digoxin dosing in elderly people, bearing in mind the changes in renal physiology secondary to ageing and not merely the estimated glomerular filtration rate.

Frailty phenotype and chronic kidney disease: a review of the literature.

Frailty is a construct originally coined by gerontologists to describe cumulative declines across multiple physiological systems that occur with aging and lead individuals to a state of diminished physiological reserve and increased vulnerability to stressors. Fried et al. provided a standardized definition for frailty, and they created the concept of frailty phenotype which incorporates disturbances across interrelated domains (shrinking, weakness, poor endurance and energy, slowness, and low physical activity level) to indentify old people who are at risk of disability, falls, institutionalization, hospitalization, and premature death. Some authors consider the presence of lean mass reduction (sarcopenia) as part of the frailty phenotype. The frailty status has been documented in 7 % of elderly population and 14 % of not requiring dialysis CKD adult patients. Sarcopenia increases progressively along with loss of renal function in CKD patients and is high in dialysis population. It has been documented that prevalence of frailty in hemodialysis adult patients is around 42 % (35 % in young and 50 % in elderly), having a 2.60-fold higher risk of mortality and 1.43-fold higher number of hospitalization, independent of age, comorbidity, and disability. The Clinical Frailty Scale is the simplest and clinically useful and validated tool for doing a frailty phenotype, while the diagnosis of sarcopenia is based on muscle mass assessment by body imaging techniques, bioimpedance analysis, and muscle strength evaluated with a handheld dynamometer. Frailty treatment can be based on different strategies, such as exercise, nutritional interventions, drugs, vitamins, and antioxidant agents. Finally, palliative care is a very important alternative for very frail and sick patients. In conclusion, since the diagnosis and treatment of frailty and sarcopenia is crucial in geriatrics and all CKD patients, it would be very important to incorporate these evaluations in pre-dialysis, peritoneal dialysis, hemodialysis, and kidney transplant patients in order to detect and consequently treat the frailty phenotype in these groups.

Impact of renal aging on drug therapy.

Elderly patients (age ≥ 65 years old) use up to 30% of all commonly prescribed medication, and they suffer more their adverse effects than the general population. In order to minimize this risk, physicians should avoid polypharmacy, dangerous pharmacological interactions and take into account pharmacodynamic and senile pharmacokinetic changes before prescribing any medication to the elderly. The present review article originally describes how renal physiology changes secondary to aging such as dysautonomia, glomerular filtration rate reduction, tubular back-filtration, sodium, calcium and magnesium loss, potassium retention, altered dilution-concentration capability, tubular frailty, genetics, internal milieu and body composition are senile changes that when combined predispose elderly people to suffer from pharmacological adverse effects. Knowledge of these physiological modifications associated with aging and their impact on the pharmacology of particular drugs may help to optimize drug use and to avoid complications in this age group.

Uso de agentes estimuladores de la eritropoyesis en pacientes con insuficiencia cardiaca congestiva / Erythropoiesis-stimulating agents in congestive heart failure patients

La insuficiencia cardiaca congestiva es un trastorno de elevada incidencia y prevalencia en el paciente anciano. La presencia de anemia se correlaciona también de forma negativa con el pronóstico para la vida del paciente. Este estudio revisa la evidencia disponible sobre el uso de agentes estimuladores de la eritropoyesis en pacientes con insuficiencia cardiaca. Aunque puede observarse alguna mejora en la calidad de vida del paciente, no se ha demostrado que reduzca la mortalidad, por lo cual, debido también a su elevado coste, se desaconseja este tipo de fármacos en pacientes con insuficiencia cardiaca congestiva (AU)

Congestive heart failure is a disease of high incidence and prevalence in the elderly. Anemia is associated with an increased mortality in these patients. This article reviews the cumulated evidence about the use of erythropoiesis-stimulating agents in congestive heart failure patients. Although some improvement in quality of life has been shown, it has not been found any decrement on mortality and, as a result, together with the high drug cost, it is not recommended the use of this kind of drugs in heart failure patients (AU)

[Erythropoiesis-stimulating agents in congestive heart failure patients]. / Uso de agentes estimuladores de la eritropoyesis en pacientes con insuficiencia cardiaca congestiva.

Congestive heart failure is a disease of high incidence and prevalence in the elderly. Anemia is associated with an increased mortality in these patients. This article reviews the cumulated evidence about the use of erythropoiesis-stimulating agents in congestive heart failure patients. Although some improvement in quality of life has been shown, it has not been found any decrement on mortality and, as a result, together with the high drug cost, it is not recommended the use of this kind of drugs in heart failure patients.

Creatinine, urea, uric acid, water and electrolytes renal handling in the healthy oldest old.

RENAL PHYSIOLOGY IN THE HEALTHY OLDEST OLD HAS THE FOLLOWING CHARACTERISTICS, IN COMPARISON WITH THE RENAL PHYSIOLOGY IN THE YOUNG: a reduced creatinine clearance, tubular pattern of creatinine back-filtration, preserved proximal tubule sodium reabsorption and uric acid secretion, reduced sodium reabsorption in the thick ascending loop of Henle, reduced free water clearance, increased urea excretion, presence of medulla hypotonicity, reduced urinary dilution and concentration capabilities, and finally a reduced collecting tubules response to furosemide which expresses a reduced potassium excretion in this segment due to a sort of aldosterone resistance. All physiological changes of the aged kidney are the same in both genders.

¿Migrar o no migrar? ¿Qué pasará con nuestra próxima generación de médicos? Estudio sobre causas y motivos en estudiantes avanzados de medicina en 11 universidades de España / Emigrate or not? How would the next Spanish generation of physicians decide? A study on emigration-related reasons and motivations of advanced medical students in 11 Universities in Spain

Objetivos: Explorar las intenciones y motivaciones de la migración profesional y los países depreferencia para la misma en un grupo de estudiantes avanzados de la carrera de Medicina.Diseño: Estudio de corte transversal y descriptivo.Emplazamiento: Once universidades de España.Participantes: Setecientos cuarenta estudiantes de los últimos dos cursos de la carrera deMedicina.Mediciones principales: Se utilizó un cuestionario autoadministrado sobre los planes de emigrar,los países de destino y las razones motivadoras de esta decisión.Resultados: De las 740 respuestas válidas, 711 (96%) correspondían a estudiantes españoles. Laopción de emigrar fue elegida por 375 (51%) de los estudiantes. Los países de destino por ordende elección fueron Reino Unido, Estados Unidos, Canadá y Portugal. Para 276 estudiantes, unarazón muy importante fue trabajar en un mejor sistema de salud, para 160 continuar con sueducación médica, para 269 trabajar en un mejor ambiente que le permita progresar y para243 la razón más importante fue ganar un mejor salario.Conclusiones: Nuestro estudio identifica factores emocionales que predisponen a la migraciónde los futuros médicos. El uso de intervenciones apropiadas podría modificar estas actitudes.Este estudio podría ser el punto de partida para explorar y analizar más en detalle las condicionesen que se forman y perciben al Sistema Nacional de Salud los futuros médicos de cara asu retención en España(AU)

Objectives: To explore intentions, motivations and country preferences related with professionalemigration in a sample of advanced medical students.Design: Cross sectional and descriptive study.Setting: 11 Universities in Spain.Participants: A total of 740 students in their two final courses.Primary measurements: The survey used a self administered questionnaire asking about plansto emigrate, preferred destination countries and reasons for wishing to work abroad.Results: A total of 740 valid questionnaires were collected, 711 (96%) from Spanish studentsand 26 (4%) from foreigner students. A preference to move abroad was indicated by 375 (51%)students, the most popular destinations being United Kingdom, USA, Canada and Portugal. Theanswers were classified using categories from ‘‘very important’’ to ‘‘not important’’. As a ‘‘veryimportant’’ reason, ‘‘To work in a better health care system’’ was chosen by 276 students, ‘‘Tocontinue with my medical education and training’’ by 160, ‘‘To work in an environment thatallows me to progress’’ by 269, and ‘‘To earn a better salary’’ by 243 students.Conclusions: The study illustrates various motivational factors which of why medical studentswish to move abroad in search of better professional conditions. The use of appropriate interventionscould modify these attitudes. This study could be a starting point for exploring andanalyzing the conditions of undergraduate medical students in Spain as a key to address theproblem of medical emigration(AU)

Effects of deferasirox on renal function and renal epithelial cell death.

Iron-chelating therapy results in a significant improvement in the life expectancy of patients with transfusional iron overload. However, alterations of renal function have been observed in some patients undergoing chelation therapy. In the present study we evaluated the effect of treatment with deferasirox iron chelator on the renal function in normal Wistar rats and in mouse and human cultured tubular cell lines. Results indicate that deferasirox given daily via intraperitoneal route for 7 days induced: (1) an increased urinary protein, albumin and glucose excretion, (2) tubular necrosis/apoptosis, (3) and increased tubular damage markers, in spite of normal glomerular function. Moreover, in vitro studies revealed that: (1) mouse MCT cultures resulted more susceptible to the antiproliferative/cytotoxic effect of deferasirox, mainly at 24h after treatment, than human HK-2 cultures, (2) MCT cell content of damage molecules increased after 24h of iron chelator treatment with slight changes in their excretion into the culture medium and (3) MCT cultures showed a significant evidence of apoptotic cell death through an increased expression and activation of caspase-3 and marked DNA fragmentation. In conclusion, this renal side effect of deferasirox-chelating therapy seems to be based on direct toxic effects of deferasirox on renal tubular cells.

Dysfunction of the thick loop of Henle and senescence: from molecular biology to clinical geriatrics.

UNLABELLED: The sodium-potassium-2 chloride bumetanide-sensitive transporter (NKCC2), a protein coded by gene SLC12A1, allows salt reabsorption in the thick ascending loop of Henle (TALH). The functional and clinical exploration of the TALH can be carried out using the Chaimowitz's test, which is based on the exploration of the tubular response to an acute overload of a hypotonic sodium chloride solution. Since this segment is normally responsible for the generation of free water clearance, its function can be assessed via the calculation of such clearance from the parameters obtained during this test. By applying the Chaimowitz's test, the presence of incompetence for sodium reabsorption in TALH in healthy old people was documented. Additionally, it was documented that in water-restricted old rats, a situation that normally induces an increase in the number of NKCC2 in young rats is absent in old ones. In the clinical setting, the increased urinary sodium loss usually found in healthy old people predisposes them to dehydration, hypotension and or hyponatremia when they are on low-sodium diet or under treatment with diuretics. These are commonly found in elderly people with geriatric syndromes such as delirium, gait disorders and incontinence. CONCLUSION: The NKCC2 transporter decrease in the thick ascending loop of Henle secondary to the ageing could explain the reduced sodium reabsorption of this segment in the healthy elderly and its potential clinical consequences of dehydration and serum sodium abnormalities.

Evaluation of oxidant-antioxidant balance in patients on maintenance haemodialysis: a comparative study of dialyzers membranes.

BACKGROUND: Haemodialysis (HD) exacerbates oxidative stress (OS). The polymethyl-methacrylate (PMMA)-BK-F membrane ameliorates OS and inflammation markers compared to polyacrylonitrile (PAN/AN69) and cellulose membranes. This may be due to the size of pore radius, high flux or other specific properties of PMMA membranes. AIM: To compare OS and inflammatory status in HD-treated end stage renal disease patients with membranes of different pore size radius and flux. METHODS: 47 patients of both sexes were studied. The HD membranes with which the patients were normally treated were changed to BK-P or B-3 membranes for 6 months. Intracellular and extracellular components of the oxidant-antioxidant balance (OAB), C-reactive protein (CRP), beta2-micro-globulin (beta2mu-globulin), albumin and transferrin were measured. RESULTS: A significant decrease in red cell membrane thiobarbituric acid reacting substances and an increase in cytosolic superoxide dismutase (SOD) and plasma total antioxidant substances were observed in all patients after 6 months of treatment with BK-P and B-3 membranes except SOD and CRP in patients previously dialysed with triacetate cellulose membranes. Albumin and transferrin remained unmodified. beta2mu-globulin significantly decreased after treatment with PMMA membranes. CONCLUSION: BK-P and B-3 HD membranes improved the OAB, beta2mu-globulin and CRP compared to PAN/AN69 and cellulose diacetate membranes.

Creatinine reabsorption by the aged kidney.

AIM: The handling of renal creatinine in human beings has classically been described as the result of two particular physiological processes: glomerular filtration and proximal tubular secretion. However, there are particular physiological situations in which tubular creatinine reabsorption has been documented, such as in the case of healthy newborns and premature babies. We performed a prospective study in order to evaluate if there is tubular creatinine reabsorption in healthy elderly people. PATIENTS AND METHOD: We studied prospectively nine healthy volunteers, four of them young (20-33 years old) and the remaining five, old (65-73 years old). Since creatinine is secreted in the proximal tubules, and its secretion can be completely blocked by cimetidine administration, a creatinine clearance with cimetidine reliably represents the glomerular filtration rate. Therefore, if the ratio creatinine clearance (Ccr)/creatinine clearance with cimetidine (CcrWC) is higher than one, this would indicate net creatinine secretion, whereas a ratio lower than one would indicate a net renal creatinine tubular reabsorption; a ratio equal to one indicates creatinine filtration. Finally, the Ccr, CcrWC, and Ccr/CcrWC ratios were compared between the young and old group. STATISTICAL TESTS: Mann-Whitney and Wilcoxon tests were used. RESULTS: As expected, creatinine clearance in the elderly was significantly lower than in the young [Ccr: 74.4 ml/min (47.9-100.9) (old) vs. 153.8 ml/min (108.3-199.2) (young), p = 0.014]. Similarly, the creatinine clearance with cimetidine (CcrWC) was significantly lower in the elderly compared to the young [CcrWC: 81.8 ml/min (69.2-94.5) (old) vs. 122.5 ml/min (82.6-162.4) (young), p = 0.028]. The ratio of Ccr/CcrWC was 0.9 in the elderly vs. 1.26 in the young (p = 0.014), indicating net creatinine reabsorption in the elderly and net creatinine secretion in the young. CONCLUSION: Our findings indicate that there seems to be a net reabsorption of creatinine in the renal tubules of healthy old persons.

Effect of different antihypertensive treatments on Ras, MAPK and Akt activation in hypertension and diabetes.

Ras GTPases function as transducers of extracellular signals regulating many cell functions, and they appear to be involved in the development of hypertension. In the present study, we have investigated whether antihypertensive treatment with ARBs (angiotensin II receptor blockers), ACEi (angiotensin-converting enzyme inhibitors) and diuretics induce changes in Ras activation and in some of its effectors [ERK (extracellular-signal-regulated kinase) and Akt] in lymphocytes from patients with hypertension without or with diabetes. ACEi treatment transiently reduced Ras activation in the first month of treatment, but diuretics induced a sustained increase in Ras activation throughout the 3 months of the study. In patients with hypertension and diabetes, ARB, ACEi and diuretic treatment increased Ras activation only during the first week. ACEi treatment increased phospho-ERK expression during the first week and also in the last 2 months of the study; however, diuretic treatment reduced phospho-ERK expression during the last 2 months of the study. In patients with hypertension and diabetes, antihypertensive treatments did not induce changes in phospho-ERK expression in lymphocytes. ACEi treatment reduced phospho-Akt expression in patients with hypertension and diabetes only in the first month of treatment. In conclusion, these findings show that antihypertensive treatments with ACEi, and diuretics to a lesser extent, modify Ras activation and some of its signalling pathways, although in different directions, whereas ARBs do not appear to have any influence on Ras signalling pathways.