RESUMO
We investigated the impact of basal dietary sodium intake on the dapagliflozin-induced changes in albuminuria and blood pressure (BP) measured at home in patients with diabetic kidney disease (DKD).This was a secondary analysis of the Y-AIDA Study, in which DKD patients with estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine were administered dapagliflozin for 24 weeks, and dapagliflozin significantly improved albuminuria levels and home BP profiles. The effects on UACR, home-measured BP, and eGFR were compared between high- and low-sodium intake groups (HS and LS groups), which were created using baseline urinary sodium-to-creatinine ratio of 84 participants with available basal sodium-to-creatinine ratios. At baseline, clinic-/home-measured BPs, UACR, and eGFR, were comparable in the two groups. After 24 weeks, the reductions from baseline in ln-UACR were comparable in the two groups. In contrast, the reductions in evening home systolic BP and eGFR from baseline were larger in HS than in LS (BP: - 13 ± 2.08 vs. - 6 ± 1.88, P = 0.020; eGFR: - 3.33 ± 1.32 vs. 0.37 ± 1.29, P = 0.049). The home BP-lowering effects of dapagliflozin are larger in HS than LS, concomitant with a larger reduction in eGFR, suggesting a dapagliflozin-induced improvement in glomerular relative hyperfiltration in HS.
Assuntos
Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Glucosídeos/farmacologia , Sódio na Dieta/administração & dosagem , Idoso , Albuminúria/metabolismo , Albuminúria/urina , Pressão Sanguínea/efeitos dos fármacos , Creatinina/urina , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria. METHODS: We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24. RESULTS: Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR. CONCLUSIONS: In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.
Assuntos
Albuminúria/tratamento farmacológico , Compostos Benzidrílicos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Glucosídeos/uso terapêutico , Rim/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adulto , Idoso , Albuminúria/diagnóstico , Albuminúria/epidemiologia , Albuminúria/fisiopatologia , Compostos Benzidrílicos/efeitos adversos , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Monitorização Ambulatorial da Pressão Arterial , Ritmo Circadiano , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucosídeos/efeitos adversos , Hemoglobinas Glicadas/metabolismo , Humanos , Japão/epidemiologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Cyclosporine and prednisolone combination therapy has been used in the treatment of minimal change nephrotic syndrome (MCNS). However, few studies have evaluated the efficacy of cyclosporine combined with intravenous methylprednisolone pulse therapy (MPT) as a first-line treatment for new-onset MCNS. We conducted a retrospective clinical study to evaluate the efficacy and safety of cyclosporine combined with MPT and oral prednisolone for new-onset MCNS in adults. METHODS: Forty-six adult patients with biopsy-proven MCNS were analyzed retrospectively. This study included three groups. Group 1 (n = 17) was treated with intravenous MPT (0.5 or 1.0 g/day for 3 days) followed by oral cyclosporine (2-3 mg/kg/day) and prednisolone (30 mg/day). Group 2 (n = 15) was treated with intravenous MPT followed by oral prednisolone (0.4-0.8 mg/kg/day). Group 3 (n = 14) was treated with oral prednisolone (0.6-1.0 mg/kg/day) alone. RESULTS: The length of hospital stay was the shortest in Group 1 (P < 0.001). The mean duration to achieve <20 mg/day of prednisolone was also the shortest in Group 1 (P < 0.05). Complete remission rates were 100 % in Group 1, 85.7 % in Group 2, and 69.2 % in Group 3 during the 9-month follow-up (P = 0.073). The rate of adverse effects caused by prednisolone was less in Group 1 (P < 0.05). Multivariate analysis revealed that the independent determinants of durations of remission were the selectivity index (P = 0.004), eGFR (P = 0.001) and the use of cyclosporine (P = 0.045). CONCLUSIONS: Combination therapy with cyclosporine may be a beneficial treatment option for new-onset MCNS in adults because of its clinical efficacy and safety.
Assuntos
Anti-Inflamatórios/administração & dosagem , Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Metilprednisolona/administração & dosagem , Nefrose Lipoide/tratamento farmacológico , Adulto , Anti-Inflamatórios/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Feminino , Taxa de Filtração Glomerular , Humanos , Tempo de Internação , Masculino , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Nefrose Lipoide/fisiopatologia , Recidiva , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: In the 'Millennium Genome Project', we identified ATP2B1 as a gene responsible for hypertension through single-nucleotide polymorphism analysis. The ATP2B1 gene encodes the plasma membrane calcium ATPase isoform 1, which contributes to the maintenance of intracellular calcium homeostasis by removing calcium ions. METHOD: Since ATP2B1 knockout mice are reported to be embryo-lethal, we generated systemic heterozygous ATP2B1 null (ATP2B1(+/-)) mice, and evaluated the implication of ATP2B1 in blood pressure. RESULTS: ATP2B1(+/-) mice revealed significantly higher SBP as measured by a radiotelemetric method. Phenylephrine-induced vasoconstriction was significantly increased in vascular rings from ATP2B1(+/-) mice, and the difference in this contraction disappeared in the presence of a nitric oxide synthase (NOS) inhibitor. Vasorelaxation to acetylcholine was significantly attenuated in vascular rings from ATP2B1(+/-) mice. In addition, cultured endothelial cells of ATP2B1(+/-) mice showed that the phosphorylation (Ser-1177) level of endothelial NOS protein was significantly lower, and nitric oxide production in endothelial cells and aorta was lower compared with those in control mice. In contrast, neural NOS expression in vascular smooth muscle cells from ATP2B1(+/-) mice and control mice were not significantly different. CONCLUSION: These results suggest that decreased ATP2B1 gene expression is associated with impaired endothelial NOS activity and nitric oxide production, and the ATP2B1 gene plays a crucial role in the regulation of blood pressure.
Assuntos
Pressão Sanguínea/genética , Pressão Sanguínea/fisiologia , Hipertensão/genética , Hipertensão/fisiopatologia , Óxido Nítrico/biossíntese , ATPases Transportadoras de Cálcio da Membrana Plasmática/deficiência , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Animais , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/genética , Feminino , Expressão Gênica , Heterozigoto , Masculino , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/metabolismo , ATPases Transportadoras de Cálcio da Membrana Plasmática/fisiologia , Trocador de Sódio e Cálcio/genética , Vasoconstrição , VasodilataçãoRESUMO
Diuretics or calcium channel blockers (CCBs) are used concomitantly with an angiotensin II receptor blocker (ARB). However, it is not established which ARB-based combination therapy is the most effective and safe. This prospective randomized open-label study compared the efficacy and safety of a fixed-dose tablet of losartan (LST)-hydrochlorothiazide (HCTZ) (n = 99) and LST-amlodipine (AML) (n = 77) in Japanese patients whose hypertension was uncontrolled by ARB monotherapy. Blood pressure changed similarly over the 12-month study period. Only LST-HCTZ significantly increased serum uric acid (SUA) in patients with low baseline SUA (<5.6 mg/dL) but not in patients with high baseline SUA.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Diuréticos/administração & dosagem , Hipertensão/tratamento farmacológico , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hidroclorotiazida/administração & dosagem , Hipertensão/sangue , Hipertensão/fisiopatologia , Losartan/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Ácido Úrico/sangue , Adulto JovemRESUMO
During hemodialysis, amino acid loss through the dialysate remained a significant problem and was not clear in some dialyzers; therefore, we investigated amino acid loss with hydrophilic and nonhydrophilic polyester-polymer alloy membranes and polyacrylonitrile membranes. Nine maintenance hemodialysis patients were studied to assess amino acid loss during hemodialysis with the three membranes. Total amino acid losses were 85.7 ± 27.2 mg/L, 83.3 ± 16.1 mg/L, and 72.1 ± 22.5 mg/L with the hydrophilic, nonhydrophilic polyester-polymer alloy, and polyacrylonitrile membranes, respectively. Amino acid losses were greater with the hydrophilic membrane compared with the polyacrylonitrile membrane for ornithine (2.0 ± 0.6 vs. 1.4 ± 0.4 mg/L, P = 0.025), phenylalanine (2.4 ± 0.9 vs. 1.8 ± 0.8 mg/L, P = 0.012), and tryptophan (0.6 ± 0.2 vs. 0.4 ± 0.2 mg/L, P = 0.023). Amino acid losses were greater with the nonhydrophilic membrane than with the polyacrylonitrile membrane for ornithine (2.0 ± 0.4 vs. 1.4 ± 0.4 mg/L, P = 0.017), phenylalanine (2.3 ± 0.5 vs. 1.8 ± 0.8 mg/L, P = 0.018), tryptophan (0.7 ± 0.2 vs. 0.4 ± 0.2 mg/L, P = 0.003), and cystine (3.2 ± 0.7 vs. 2.0 ± 0.7 mg/L, P = 0.005). In conclusion, greater losses of ornithine, phenylalanine, tryptophan, and cystine were observed with polyester-polymer alloy than with polyacrylonitrile membranes during hemodialysis. Constant attention should be paid to the amino acid loss profile to improve nutritional control in hemodialysis patients.
Assuntos
Aminoácidos/metabolismo , Membranas Artificiais , Polímeros/química , Diálise Renal , Resinas Acrílicas/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Ligas , Soluções para Diálise/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Poliésteres/químicaRESUMO
We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na(+)-Ca(2+) exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/genética , Hipertensão/fisiopatologia , Músculo Liso Vascular/fisiopatologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Animais , Cálcio/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/fisiologia , Deleção de Genes , Homeostase/fisiologia , Camundongos , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Fenilefrina/farmacologia , ATPases Transportadoras de Cálcio da Membrana Plasmática/deficiência , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
Dialysis-related amyloidosis (DRA) is one of the major complications often seen in long-term dialysis patients, and is one of the factors that decreases quality of life. ß2-microglobulin (ß2-m) is considered to be a major pathogenic factor in dialysis-related amyloidosis. The Lixelle adsorbent column, with various capacities, has been developed to adsorb ß2-m from the circulating blood of patients with dialysis-related amyloidosis. Using a minimum type of ß2-m-adsorbing column (Lixelle S-15), we evaluated its therapeutic efficacy and safety in dialysis patients. Seventeen hemodialysis patients with DRA were treated with the S-15 column for one year. Treatment was performed three times a week in this study. During the study period, pinch strength, visual analog scale for joint pain, and activities of daily living were evaluated every three months, and blood sampling was performed every six months. After one year's treatment with the S-15 column, the ß2-m level decreased from 29.3±9.6mg/L to 24.7±5.1mg/L (P<0.05), and the high sensitive C-reactive protein level decreased from 2996±4380ng/mL to 1292±1774ng/mL. After one year of S-15 column use, pinch strength increased from 5.9±3.0pounds to 7.2±3.2pounds (P<0.05), and the visual analog scale for joint pain and activities of daily living score also improved. Long-term use of the Lixelle S-15 column is safe and effective for improvement of quality of life in chronic dialysis patients. Improvement of chronic inflammation may be one of the mechanisms through which the beneficial effects of the column is effected.
Assuntos
Amiloidose/terapia , Remoção de Componentes Sanguíneos/métodos , Diálise Renal/efeitos adversos , Microglobulina beta-2/sangue , Atividades Cotidianas , Adsorção , Amiloidose/etiologia , Artralgia/etiologia , Proteína C-Reativa/metabolismo , Desenho de Equipamento , Feminino , Humanos , Inflamação/etiologia , Inflamação/terapia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Qualidade de Vida , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Although obesity is recognized to be a risk factor for chronic kidney disease (CKD), few studies have reported the association between obesity and CKD in the young population. We investigated the relationship between obesity and renal function including proteinuria in young Japanese. METHODS: This cross-sectional study consisted of 16,031 men and 5,746 women aged from 20 to 39 years who received health examinations. The subjects were stratified into four age groups (20-24, 25-29, 30-34, and 35-39 years) or into four groups based on the number of risk factors (hypertension, hyperglycemia, dyslipidemia, and hyperuricemia). The relationship between obesity and risk factors and the relationship between obesity and estimated glomerular filtration rate (eGFR) were analyzed. RESULTS: There were no significant differences in eGFR between obese and nonobese groups, except in the male 35-39 years age group. Body mass index (BMI) in both men and women increased with increase in number of risk factors (P < 0.001). Multivariate analysis revealed that hypertension, hyperglycemia, dyslipidemia, and hyperuricemia were independently associated with obesity. Obesity and the risk factors were independently associated with proteinuria. CONCLUSION: The present study indicated that obesity was an independent risk factor for proteinuria in healthy subjects younger than 40 years of age. The other risk factors were independently associated with obesity. These findings suggest that obesity causes proteinuria concomitantly with other risk factors such as hypertension, diabetes, and dyslipidemia in young adults.
Assuntos
Povo Asiático , Índice de Massa Corporal , Taxa de Filtração Glomerular , Nefropatias/etiologia , Rim/fisiopatologia , Programas de Rastreamento , Obesidade/complicações , Proteinúria/etiologia , Adulto , Distribuição por Idade , Fatores Etários , Povo Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Doença Crônica , Estudos Transversais , Dislipidemias/complicações , Dislipidemias/etnologia , Feminino , Humanos , Hiperglicemia/complicações , Hiperglicemia/etnologia , Hipertensão/complicações , Hipertensão/etnologia , Hiperuricemia/complicações , Hiperuricemia/etnologia , Japão/epidemiologia , Nefropatias/etnologia , Nefropatias/fisiopatologia , Modelos Logísticos , Masculino , Programas de Rastreamento/métodos , Obesidade/etnologia , Obesidade/fisiopatologia , Razão de Chances , Proteinúria/etnologia , Proteinúria/fisiopatologia , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
Peritoneal calcification in three patients on continuous ambulatory peritoneal dialysis (CAPD) was reviewed, and the relation between the localization and extent of calcium deposits detected by abdominal computed tomography (CT) and clinical signs was evaluated. Case 1 was a 48-year-old man with abdominal pain, hemoperitoneum and secondary hyperparathyroidism after receiving CAPD for seven years. An abdominal CT revealed linear peritoneal calcification in the pelvic cavity and liver surface, and his symptoms resolved after switching to hemodialysis. His clinical course and pathological findings were compatible with those in progressive calcifying peritonitis. Case 2 was a 26-year-old man presenting with abdominal pain, vomiting and fullness two years after switching to hemodialysis, because of uncontrolled overhydration following 13 years of CAPD. Plaque-like calcification outlining the small intestine and parietal peritoneum was noted on CT. Case 3 was a 59-year-old man who had abdominal distention, vomiting and diarrhea three months after switching to hemodialysis due to loss of peritoneal function following 10 years of CAPD. CT revealed diffuse sheet-like calcification surrounding the bowel and mesentery, adherent dilated bowel loops and ascites. These CT findings suggested the existence of encapsulating peritoneal sclerosis (EPS) in cases 2 and 3. Findings from our three patients indicate that peritoneal calcification is not always accompanied by EPS; however, monitoring peritoneal calcification and other findings by abdominal CT, even after cessation of CAPD, is crucial to maintain vigilance on whether the subclinical signs, which are temporally diagnosed as progressive calcifying peritonitis, advance to EPS.