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1.
Curr Opin Nephrol Hypertens ; 33(1): 102-109, 2024 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-37800660

RESUMEN

PURPOSE OF REVIEW: The consequences of climate change, including heat and extreme weather events impact kidney function in adults and children. The impacts of climate change on kidney development during gestation and thereby on kidney function later in life have been poorly described. Clinical evidence is summarized to highlight possible associations between climate change and nephron mass. RECENT FINDINGS: Pregnant women are vulnerable to the effects of climate change, being less able to thermoregulate, more sensitive to the effects of dehydration, and more susceptible to infections. Exposure to heat, wildfire smoke, drought, floods and climate-related infections are associated with low birth weight, preterm birth and preeclampsia. These factors are associated with reduced nephron numbers, kidney dysfunction and higher blood pressures in offspring in later life. Exposure to air pollution is associated with higher blood pressures in children and has variable effects on estimated glomerular filtration rate. SUMMARY: Climate change has important impacts on pregnant women and their unborn children. Being born too small or too soon is associated with life-time risk of kidney disease. Climate change may therefore have a dual effect of impacting fetal kidney development and contributing to cumulative postnatal kidney injury. The impact on population kidney health of future generations may be significant.


Asunto(s)
Hipertensión , Preeclampsia , Nacimiento Prematuro , Adulto , Humanos , Recién Nacido , Embarazo , Femenino , Cambio Climático , Hipertensión/epidemiología , Nefronas
2.
Anat Rec (Hoboken) ; 303(10): 2613-2631, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-31587509

RESUMEN

Nephron number in humans varies up to 13-fold, likely reflecting the impact of multiple factors on kidney development, including inherited body size and ethnicity, as well as maternal health and nutrition, fetal exposure to gestational diabetes or preeclampsia and other environmental factors, which may potentially be modifiable. Such conditions predispose to low or high offspring birth weight, growth restriction or preterm birth, which have all been associated with increased risks of higher blood pressures and/or kidney dysfunction in later life. Low birth weight, preterm birth, and intrauterine growth restriction are associated with reduced nephron numbers. Humans with hypertension and chronic kidney disease tend to have fewer nephrons than their counterparts with normal blood pressures or kidney function. A developmentally programmed reduction in nephron number therefore enhances an individual's susceptibility to hypertension and kidney disease in later life. A low nephron number at birth may not lead to kidney dysfunction alone except when severe, but in the face of superimposed acute or chronic kidney injury, a kidney endowed with fewer nephrons may be less able to adapt, and overt kidney disease may develop. Given that millions of babies are born either too small, too big or too soon each year, the population impact of altered renal programming is likely to be significant. Many gestational exposures are modifiable, therefore urgent attention is required to implement public health measures to optimize maternal, fetal, and child health, to prevent or mitigate the consequences of developmental programming, to improve the health future generations.


Asunto(s)
Desarrollo Fetal/fisiología , Nefronas/fisiopatología , Nacimiento Prematuro/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Peso al Nacer/fisiología , Humanos , Nefronas/patología , Insuficiencia Renal Crónica/patología
3.
Circulation ; 140(9): 739-750, 2019 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-31291786

RESUMEN

BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). METHODS: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. RESULTS: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). CONCLUSIONS: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.


Asunto(s)
Canagliflozina/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/patología , Insuficiencia Renal Crónica/patología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Fallo Renal Crónico/prevención & control , Masculino , Persona de Mediana Edad , Efecto Placebo , Modelos de Riesgos Proporcionales , Riesgo , Prevención Secundaria , Resultado del Tratamiento
4.
N Engl J Med ; 380(24): 2295-2306, 2019 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-30990260

RESUMEN

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).


Asunto(s)
Canagliflozina/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Fallo Renal Crónico/prevención & control , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Anciano , Canagliflozina/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Creatinina/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/complicaciones , Método Doble Ciego , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Fallo Renal Crónico/epidemiología , Masculino , Persona de Mediana Edad , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos
5.
Diabetes Obes Metab ; 20(12): 2899-2904, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29987919

RESUMEN

Sodium retention and volume overload are the main determinants of poor response to renin-angiotensin-aldosterone system (RAAS) inhibition in patients with diabetes. As volume excess can exist without symptoms, biomarkers are needed to identify a priori which patients are volume overloaded and may experience less benefit from RAAS inhibition. N-terminal pro-brain natriuretic peptide (NT-proBNP) is released in the setting of increased cardiac wall stress and volume overload. We conducted a post hoc analysis among 5081 patients with type 2 diabetes mellitus participating in the ALTITUDE trial to investigate whether NTproBNP can predict the effects of additional therapy with aliskiren on cardio-renal endpoints. Aliskiren compared to placebo reduced the risk of the primary cardio-renal endpoint events by 20% (95% confidence interval [CI] 16 to 61) and 2% (95% CI -42 to 30) in the two lowest NT-proBNP tertiles, and it increased the risk by 25% (95% CI -4 to 96) in the highest NT-proBNP tertile (P value for trend = 0.009). Similar trends were observed for the cardiovascular and end-stage renal disease endpoints. Effects of aliskiren compared to placebo on safety outcomes (hyperkalaemia and hospitalization for acute kidney injury) were independent of NT-proBNP. In conclusion, baseline NT-proBNP may be used as a marker to predict the response to aliskiren with regard to cardio-renal outcomes when added to standard therapy with RAAS inhibition.


Asunto(s)
Amidas/uso terapéutico , Antihipertensivos/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/prevención & control , Fumaratos/uso terapéutico , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Anciano , Biomarcadores/sangre , Enfermedades Cardiovasculares/etiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/etiología , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Sistema Renina-Angiotensina/efectos de los fármacos , Factores de Riesgo , Resultado del Tratamiento
6.
Am J Nephrol ; 46(6): 462-472, 2017 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-29253846

RESUMEN

BACKGROUND: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. METHODS: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin -versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. CONCLUSION: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. TRIAL REGISTRATION: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.

8.
Lancet Diabetes Endocrinol ; 4(4): 309-17, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26774608

RESUMEN

BACKGROUND: The primary results of the ALTITUDE trial showed no benefit of aliskiren on renal outcomes (doubling of serum creatinine and end-stage renal disease) when used as an adjunct to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease. We did a prespecified analysis of the ALTITUDE trial to analyse the effects of aliskiren on surrogate renal outcomes in all patients and on primary renal outcomes in subgroups of patients. METHODS: In the double-blind, randomised, controlled ALTITUDE trial, 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease were randomly assigned (1:1) to receive aliskiren 300 mg per day or placebo as an adjunct to ACE inhibitors or ARBs. Randomisation was stratified on the basis of baseline urinary albumin-to-creatinine ratio and presence of cardiovascular disease history, and treatment assignments were masked to all patients and study staff. Patients were followed up for a median of 2·6 years (IQR 2·0-3·2). In our secondary analysis, we investigated prespecified intermediate renal outcomes of transitions in albuminuria stages (ie, transitions between normoalbuminuria, microalbuminuria, and macroalbuminuria) and rate of change of estimated glomerular filtration rate (eGFR). We investigated all outcomes in the intention-to-treat population. The primary composite renal outcome of ALTITUDE was defined as a sustained doubling of serum creatinine, end-stage renal disease, or renal death. The ALTITUDE trial is registered with ClinicalTrials.gov, number NCT00549757. FINDINGS: Aliskiren significantly decreased progression (hazard ratio [HR] 0·83, 95% CI 0·75-0·93) and increased regression (HR 1·29, 95% CI 1·19-1·39) of transitions in albuminuria classes. The annual rate of change of eGFR was -3·1 mL/min/1·73 m(2) per year (95% CI -2·9 to -3·3) in the aliskiren group and -3·0 mL/min/1·73 m(2) per year (-2·8 to -3·2) in the placebo group (p=0·52). eGFR change during the first 6 months was significantly larger with aliskiren than with placebo (-2·5 mL/min/1·73 m(2), 95% CI -2·9 to -2·2 vs -1·4 mL/min/1·73 m(2), 95% CI -1·7 to -1·0; p<0·0001). Subsequent eGFR change did not differ significantly between groups (-2·8 mL/min/1·73 m(2) per year, 95% CI -3·0 to -2·6 with aliskiren vs -3·1 mL/min/1·73 m(2) per year, 95% CI -3·3 to -2·8 with placebo; p=0·068). The absence of a benefit of aliskiren on the primary composite renal endpoint in the overall population was also seen in various subgroups. INTERPRETATION: Aliskiren showed no beneficial effect on hard renal outcomes in the overall population or in various subgroups, but delayed progression to microalbuminuria and macroalbuminuria, and improved regression to microalbuminuria and normoalbuminuria. Whether the chosen intermediates are poor surrogates for clinical outcomes or whether off-target effects disrupt the association between the surrogate and clinical outcomes requires further study. FUNDING: Novartis.


Asunto(s)
Albuminuria/epidemiología , Amidas/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fumaratos/efectos adversos , Fallo Renal Crónico/epidemiología , Anciano , Albuminuria/inducido químicamente , Antagonistas de Receptores de Angiotensina , Antihipertensivos , Creatinina/orina , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Fallo Renal Crónico/inducido químicamente , Masculino , Países Bajos/epidemiología , Prevalencia , Pronóstico , Tasa de Supervivencia
9.
Nat Rev Nephrol ; 11(3): 135-49, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25599618

RESUMEN

An adverse intrauterine environment is associated with an increased risk of elevated blood pressure and kidney disease in later life. Many studies have focused on low birth weight, prematurity and growth restriction as surrogate markers of an adverse intrauterine environment; however, high birth weight, exposure to maternal diabetes and rapid growth during early childhood are also emerging as developmental risk factors for chronic diseases. Altered programming of nephron number is an important link between exposure to developmental stressors and subsequent risk of hypertension and kidney disease. Maternal, fetal, and childhood nutrition are crucial contributors to these programming effects. Resource-poor countries experience the sequential burdens of fetal and childhood undernutrition and subsequent overnutrition, which synergistically act to augment the effects of developmental programming; this observation might explain in part the disproportionate burden of chronic disease in these regions. Numerous nutritional interventions have been effective in reducing the short-term risk of low birth weight and prematurity. Understanding the potential long-term benefits of such interventions is crucial to inform policy decisions to interrupt the developmental programming cycle and stem the growing epidemics of hypertension and kidney disease worldwide.


Asunto(s)
Peso al Nacer , Enfermedades Renales/epidemiología , Enfermedades Renales/etiología , Desnutrición/complicaciones , Salud Global , Humanos , Hipertensión/epidemiología , Hipertensión/etiología , Recién Nacido de Bajo Peso , Recién Nacido , Factores de Riesgo
10.
Lancet ; 382(9888): 273-83, 2013 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-23727166

RESUMEN

Developmental programming of non-communicable diseases is now an established paradigm. With respect to hypertension and chronic kidney disease, adverse events experienced in utero can affect development of the fetal kidney and reduce final nephron number. Low birthweight and prematurity are the most consistent clinical surrogates for a low nephron number and are associated with increased risk of hypertension, proteinuria, and kidney disease in later life. Rapid weight gain in childhood or adolescence further compounds these risks. Low birthweight, prematurity, and rapid childhood weight gain should alert clinicians to an individual's lifelong risk of hypertension and kidney disease, prompting education to minimise additional risk factors and ensuring follow-up. Birthweight and prematurity are affected substantially by maternal nutrition and health during pregnancy. Optimisation of maternal health and early childhood nutrition could, therefore, attenuate this programming cycle and reduce the global burden of hypertension and kidney disease in the future.


Asunto(s)
Protección a la Infancia , Hipertensión/embriología , Riñón/embriología , Insuficiencia Renal Crónica/embriología , Adulto , Peso al Nacer/fisiología , Presión Sanguínea/fisiología , Índice de Masa Corporal , Niño , Desarrollo Infantil/fisiología , Femenino , Desarrollo Fetal/fisiología , Tasa de Filtración Glomerular/fisiología , Humanos , Hipertensión/genética , Recién Nacido de Bajo Peso , Recién Nacido , Recien Nacido Prematuro , Riñón/crecimiento & desarrollo , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Bienestar Materno , Nefronas/patología , Embarazo , Complicaciones del Embarazo , Proteinuria/etiología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Factores de Riesgo , Aumento de Peso/fisiología
12.
N Engl J Med ; 367(23): 2204-13, 2012 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-23121378

RESUMEN

BACKGROUND: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). CONCLUSIONS: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).


Asunto(s)
Amidas/uso terapéutico , Antihipertensivos/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fumaratos/uso terapéutico , Enfermedades Renales/prevención & control , Renina/antagonistas & inhibidores , Anciano , Amidas/efectos adversos , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Diabetes Mellitus Tipo 2/complicaciones , Método Doble Ciego , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Fumaratos/efectos adversos , Humanos , Hiperpotasemia/inducido químicamente , Hipopotasemia , Enfermedades Renales/epidemiología , Enfermedades Renales/etiología , Masculino , Persona de Mediana Edad , Pacientes Desistentes del Tratamiento , Insuficiencia del Tratamiento
13.
J Renin Angiotensin Aldosterone Syst ; 13(3): 387-93, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22333485

RESUMEN

INTRODUCTION: Patients with type 2 diabetes are at enhanced risk for macro- and microvascular complications. Albuminuria and/or reduced kidney function further enhances the vascular risk. We initiated the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). Aliskiren, a novel direct renin inhibitor, which lowers plasma renin activity, may thereby provide greater cardio-renal protection compared with angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) alone. MATERIALS AND METHODS: ALTITUDE is a randomized, double-blind, placebo-controlled study in high risk type 2 diabetic patients receiving aliskiren 300 mg once daily or placebo added to recommended cardio-renal protective treatment including ACEi or ARB, but not both. The number of patients randomized was 8606. RESULTS: Baseline characteristics (median, IQR) are: age 65 (58, 72) years, male 68%, BMI 29.1 (25.7, 32.2) kg/m(2), cardiovascular disease 47.9%, blood pressure 134.7 (126, 150)/74.3 (67, 81) mmHg, HbA(1c) 7.5 (6.6, 8.6)%, LDL-cholesterol 2.4 (1.9, 3.0) mmol/L, haemoglobin 130 (119, 143) g/L, serum creatinine 115 (91, 137) µmol/L, eGFR 51.7 (42, 65) ml/min per 1.73 m(2), geometric mean UACR 198.9 (52, 2886) mg/g and frequency of micro/macroalbuminuria 25.7% and 58.2%. ALTITUDE is an event-driven trial to continue until 1628 patients experience a primary cardiovascular-renal event. CONCLUSIONS: ALTITUDE will determine the potential cardio-renal benefit and safety of aliskiren in combination with ACEi or ARB in high risk patients with type 2 diabetes.


Asunto(s)
Amidas/uso terapéutico , Antihipertensivos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Determinación de Punto Final , Fumaratos/uso terapéutico , Riñón/patología , Miocardio/patología , Anciano , Albuminuria/complicaciones , Albuminuria/tratamiento farmacológico , Amidas/farmacología , Antihipertensivos/farmacología , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/tratamiento farmacológico , Estudios de Cohortes , Femenino , Fumaratos/farmacología , Humanos , Riñón/efectos de los fármacos , Masculino , Persona de Mediana Edad
14.
Hypertension ; 58(1): 2-7, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21632472

RESUMEN

Emerging data show that increased serum uric acid (SUA) concentration is an independent risk factor for end-stage renal disease. Treatment with the antihypertensive drug losartan lowers SUA. Whether reductions in SUA during losartan therapy are associated with renoprotection is unclear. We therefore tested this hypothesis. In a post hoc analysis of 1342 patients with type 2 diabetes mellitus and nephropathy participating in the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan Trial, we determined the relationship between month 6 change in SUA and renal endpoints, defined as a doubling of serum creatinine or end-stage renal disease. Baseline SUA was 6.7 mg/dL in placebo and losartan-treated subjects. During the first 6 months, losartan lowered SUA by -0.16 mg/dL (95% CI: -0.30 to -0.01; P=0.031) as compared with placebo. The risk of renal events was decreased by 6% (95% CI: 10% to 3%) per 0.5-mg/dL decrement in SUA during the first 6 months. This effect was independent of other risk markers, including estimate glomerular filtration rate and albuminuria. Adjustment of the overall treatment effects for SUA attenuated losartan's renoprotective effect from 22% (95% CI: 6% to 35%) to 17% (95% CI: 1% to 31%), suggesting that approximately one fifth of losartan's renoprotective effect could be attributed to its effect on SUA. Losartan lowers SUA levels compared with placebo treatment in patients with type 2 diabetes mellitus and nephropathy. The degree of reduction in SUA is subsequently associated with the degree in long-term renal risk reduction and explains part of losartan's renoprotective effect. These findings support the view that SUA may be a modifiable risk factor for renal disease.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/prevención & control , Tasa de Filtración Glomerular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Losartán/administración & dosificación , Ácido Úrico/sangre , Creatinina/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/sangre , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
15.
Kidney Int ; 80(3): 282-7, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21451458

RESUMEN

Intervention in the renin-angiotensin-aldosterone-system (RAAS) is associated with slowing the progressive loss of renal function. During initiation of therapy, however, there may be an acute fall in glomerular filtration rate (GFR). We tested whether this initial fall in GFR reflects a renal hemodynamic effect and whether this might result in a slower decline in long-term renal function. We performed a post hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial. Patients assigned to losartan had a significantly greater acute fall in estimated (eGFR) during the first 3 months compared to patients assigned to placebo, but a significantly slower long-term mean decline of eGFR thereafter. A large interindividual difference, however, was noticed in the acute eGFR change. When patients were divided into tertiles of initial fall in eGFR, the long-term eGFR slope calculated from baseline was significantly higher in patients with an initial fall compared to those with an initial rise. When eGFR decline was calculated from 3 months to the final visit, excluding the initial effect, patients with a large initial fall in eGFR had a significant lower long-term eGFR slope compared to those with a moderate fall or rise. This relationship was independent of other risk markers or change in risk markers for progression of renal disease such as blood pressure and albuminuria. Thus, the greater the acute fall in eGFR, during losartan treatment, the slower the rate of long-term eGFR decline. Hence, interpretation of trial results relying on slope-based GFR outcomes should separate the initial drug-induced GFR change from the subsequent long-term effect on GFR.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/prevención & control , Tasa de Filtración Glomerular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Riñón/efectos de los fármacos , Losartán/uso terapéutico , Anciano , Biomarcadores/sangre , Creatinina/sangre , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/fisiopatología , Método Doble Ciego , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Análisis de Regresión , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
16.
Rambam Maimonides Med J ; 2(4): e0061, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23908819

RESUMEN

Epidemiologic studies now strongly support the hypothesis, proposed over two decades ago, that developmental programming of the kidney impacts an individual's risk for hypertension and renal disease in later life. Low birth weight is the strongest current clinical surrogate marker for an adverse intrauterine environment and, based on animal and human studies, is associated with a low nephron number. Other clinical correlates of low nephron number include female gender, short adult stature, small kidney size, and prematurity. Low nephron number in Caucasian and Australian Aboriginal subjects has been shown to be associated with higher blood pressures, and, conversely, hypertension is less prevalent in individuals with higher nephron numbers. In addition to nephron number, other programmed factors associated with the increased risk of hypertension include salt sensitivity, altered expression of renal sodium transporters, altered vascular reactivity, and sympathetic nervous system overactivity. Glomerular volume is universally found to vary inversely with nephron number, suggesting a degree of compensatory hypertrophy and hyperfunction in the setting of a low nephron number. This adaptation may become overwhelmed in the setting of superimposed renal insults, e.g. diabetes mellitus or rapid catch-up growth, leading to the vicious cycle of on-going hyperfiltration, proteinuria, nephron loss and progressive renal functional decline. Many millions of babies are born with low birth weight every year, and hypertension and renal disease prevalences are increasing around the globe. At present, little can be done clinically to augment nephron number; therefore adequate prenatal care and careful postnatal nutrition are crucial to optimize an individual's nephron number during development and potentially to stem the tide of the growing cardiovascular and renal disease epidemics worldwide.

17.
J Am Soc Nephrol ; 21(8): 1355-60, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20634296

RESUMEN

There are many methods to screen for abnormal amounts of proteinuria to identify patients at risk for progression of renal disease, but which method best predicts renal risk is unknown. Here, we analyzed a subset of 701 patients with type 2 diabetes and nephropathy participating in the Reduction of Endpoints in Non Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial to compare the ability of urinary protein excretion (UPE) and urinary albumin excretion (UAE) from a 24-hour urine collection and urinary albumin concentration (UAC) and the albumin:creatinine ratio (ACR) from a first-morning void in predicting renal events. The primary outcome measure was the time to a doubling of serum creatinine or end-stage renal disease. During follow-up, 202 events occurred. The hazard ratios for the risk of a renal outcome (95% CIs) associated with 1-SD increment in the log-transformed measures were 3.16 (2.60 to 3.86) for UAE, 3.02 (2.53 to 3.62) for UPE, 3.23 (2.67 to 3.91) for UAC, and 4.36 (3.50 to 5.45) for ACR. The area under the ROC curve was significantly higher for ACR compared with the other measures. In conclusion, measurement of the albumin:creatinine ratio in a first-morning void is the superior method to predict renal events in patients with type 2 diabetes and nephropathy.


Asunto(s)
Albuminuria/orina , Creatinina/orina , Diabetes Mellitus Tipo 2/orina , Nefropatías Diabéticas/orina , Albuminuria/etiología , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/complicaciones , Progresión de la Enfermedad , Femenino , Humanos , Fallo Renal Crónico/etiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas
18.
J Am Soc Nephrol ; 21(6): 898-910, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20150537

RESUMEN

Abundant evidence supports the association between low birth weight (LBW) and renal dysfunction in humans. Anatomic measurements of infants, children, and adults show significant inverse correlation between LBW and nephron number. Nephron numbers are also lower in individuals with hypertension compared with normotension among white and Australian Aboriginal populations. The relationship between nephron number and hypertension among black individuals is still unclear, although the high incidence of LBW predicts low nephron number in this population as well. LBW, a surrogate for low nephron number, also associates with increasing BP from childhood to adulthood and increasing risk for chronic kidney disease in later life. Because nephron numbers can be counted only postmortem, surrogate markers such as birth weight, prematurity, adult height, reduced renal size, and glomerulomegaly are potentially useful for risk stratification, for example, during living-donor assessment. Because early postnatal growth also affects subsequent risk for higher BP or reduced renal function, postnatal nutrition, a potentially modifiable factor, in addition to intrauterine effects, has significant influence on long-term cardiovascular and renal health.


Asunto(s)
Recién Nacido de Bajo Peso , Enfermedades Renales/epidemiología , Nefronas/anatomía & histología , Enfermedad Crónica , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Recién Nacido , Enfermedades Renales/fisiopatología , Nefronas/embriología , Nefronas/crecimiento & desarrollo , Tamaño de los Órganos , Factores de Riesgo
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