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BACKGROUND: The Agatston score, commonly used to quantify coronary artery calcification (CAC), is determined by the plaque area and density. Despite an excellent predictability of the Agatston score for cardiovascular events, the density of CAC has never been studied in patients with pre-dialysis chronic kidney disease (CKD). This study aimed to analyze the CAC density and its association with serum mineral levels in CKD. METHODS: We enrolled patients with pre-dialysis CKD who had diabetes mellitus, prior cardiovascular disease history, elevated low-density lipoprotein cholesterol levels, or smoking history. The average CAC density was calculated by dividing the Agatston score by the total area of CAC. RESULTS: The mean estimated glomerular filtration rate (eGFR) of 109 enrolled patients was 35.7 mL/min/1.73 m2. The correlation of the Agatston score with density was much weaker than that with the total area (R2 = 0.19, P < 0.001; and R2 = 0.99, P < 0.001, respectively). Multivariate analyses showed that serum magnesium level was inversely associated with the density, but not with the total area, after adjustment for demographics and clinical factors related to malnutrition-inflammation-atherosclerosis syndrome and mineral and bone disorders including fibroblast growth factor 23 (P = 0.006). This inverse association was pronounced among patients with higher serum phosphate levels (P for interaction = 0.02). CONCLUSION: CAC density was inversely associated with serum magnesium levels, particularly in patients with higher serum phosphate levels.
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The authors of Freedom study enrolling primary osteoporosis patients argued that the anti-fracture effect of denosmab is not dependent on baseline estimated glomerular filtration rate(eGFR)by showing the non-significant interaction term between treatment and CKD stage. However, given disproportionate numbers of patients in each subgroup(4069, 2817, and only 73 patients, in CKD stage 2, 3, and, 4, respectively), this study seems to lack the statistical power to reach a definite conclusion on the effect modification by CKD stage. Truly, the serum concentration of infused denosmab in patients with CKD stage 4 is equivalent to that in patients without CKD, the risk of developing life-threatening or prolonged hypocalcemia is huge even under active vitamin D therapy in this population. In hemodialysis patients, this drug is relatively safer because each dialysis session delivers calcium into the circulation 3 times a week. However, even with concomitant administration of massive active vitamin D, the increase of intact PTH levels greater than 1000 pg/mL by this agent is not rare. In other words, this drug worsens secondary hyperparathyroidism. Moreover, reportedly, calcium and active vitamin D administered to avoid hypocalcemia can lead to ectopic calcification especially under the low bone turnover induced by this agent. In fact, transient hypercalcemia often follows hypocalcemia by the inevitable calcium supplementation.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Denosumab/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Cálcio/sangue , Denosumab/efeitos adversos , Fraturas Ósseas , Humanos , Hipocalcemia/sangue , Diálise Renal , Fatores de RiscoRESUMO
A 33-year-old Japanese man was admitted with severe edema, and a renal biopsy confirmed minimal change nephrotic syndrome (MCNS). CT revealed his severe chronic sinusitis, and he first received antimicrobial therapy, which resulted in decreased proteinuria. The surgical operation for sinusitis resulted in the complete disappearance of proteinuria without corticosteroid or immunosuppressant therapy within one week. MCNS may be triggered by infection, but there are no previously reported cases of MCNS that is completely remitted by infection control alone. Therefore, we herein report the first case of MCNS that attained complete remission following therapy for chronic sinusitis alone, which suggests a strong etiology of chronic sinusitis for MCNS.
Assuntos
Nefrose Lipoide/etiologia , Sinusite/complicações , Sinusite/cirurgia , Adulto , Doença Crônica , Humanos , Masculino , Proteinúria/etiologia , Indução de RemissãoRESUMO
Vascular calcification (VC) is a life-threatening complication of CKD. Severe protein restriction causes a shortage of essential amino acids, and exacerbates VC in rats. Therefore, we investigated the effects of dietary l-lysine, the first-limiting amino acid of cereal grains, on VC. Male Sprague-Dawley rats at age 13 weeks were divided randomly into four groups: low-protein (LP) diet (group LP), LP diet+adenine (group Ade), LP diet+adenine+glycine (group Gly) as a control amino acid group, and LP diet+adenine+l-lysine·HCl (group Lys). At age 18 weeks, group LP had no VC, whereas groups Ade and Gly had comparable levels of severe VC. l-Lysine supplementation almost completely ameliorated VC. Physical parameters and serum creatinine, urea nitrogen, and phosphate did not differ among groups Ade, Gly, and Lys. Notably, serum calcium in group Lys was slightly but significantly higher than in groups Ade and Gly. Dietary l-lysine strongly suppressed plasma intact parathyroid hormone in adenine rats and supported a proper bone-vascular axis. The conserved orientation of the femoral apatite in group Lys also evidenced the bone-protective effects of l-lysine. Dietary l-lysine elevated plasma alanine, proline, arginine, and homoarginine but not lysine. Analyses in vitro demonstrated that alanine and proline inhibit apoptosis of cultured vascular smooth muscle cells, and that arginine and homoarginine attenuate mineral precipitations in a supersaturated calcium/phosphate solution. In conclusion, dietary supplementation of l-lysine ameliorated VC by modifying key pathways that exacerbate VC.
Assuntos
Lisina/administração & dosagem , Uremia/dietoterapia , Calcificação Vascular/prevenção & controle , Adenina/administração & dosagem , Alanina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Arginina/farmacologia , Cálcio/sangue , Cálcio/urina , Fosfatos de Cálcio/metabolismo , Células Cultivadas , Precipitação Química/efeitos dos fármacos , Creatinina/urina , Suplementos Nutricionais , Homoarginina/farmacologia , Humanos , Lisina/sangue , Lisina/farmacologia , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Osteoporose/prevenção & controle , Prolina/farmacologia , Ratos , Ratos Sprague-Dawley , Soluções , Uremia/induzido quimicamente , Uremia/complicações , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismoRESUMO
Osteoporosis is one of the major complications of glucocorticoid therapy. Osteoporosis is usually defined by the levels of bone mineral density (BMD) assessed by dual energy X-ray absorptiometry (DEXA); however, glucocorticoids often induce fractures in patients with normal BMD. Thus, novel diagnostic approaches are required. In this study, we examined whether multidetector-row computed tomography (MDCT) is useful to assess the bone status in glucocorticoid-induced osteoporosis (GIO). Because bisphosphonates have been proven to prevent bone fracture in GIO, we tried to detect the therapeutic effects of bisphosphonates in GIO by MDCT. Fifteen Japanese patients with immunoglobulin A nephropathy who had normal renal function were enrolled in this open-label randomized trial. Patients were randomly divided into three groups-calcitriol (VD), menatetrenone (VK), or bisphosphonate (Bis). Bone conditions were analyzed twice by three different methods-bone turnover markers, DEXA, and MDCT-at the start and 6 months after the start of therapy. Both bone markers and DEXA could not detect significant differences among the therapeutic groups; however, MDCT-based analyses detected the preventive effects of bisphosphonates in GIO. Compared to VD, Bis improved structural indices, such as bone volume fraction, trabecular separation, marrow star volume, and structure model index whereas the difference between VD and VK was not significant. Finite element analysis revealed that simulated fracture load in the Bis group was significantly improved. These findings suggested that MDCT-based assessment is superior to bone markers and/or DEXA in assessing the therapeutic effect of bisphosphonates on GIO.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Glucocorticoides/efeitos adversos , Osteoporose/induzido quimicamente , Osteoporose/tratamento farmacológico , Adolescente , Adulto , Biomarcadores/metabolismo , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Calcitriol/uso terapêutico , Feminino , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores/métodos , Estudos Prospectivos , Vitamina K 2/análogos & derivados , Vitamina K 2/uso terapêutico , Adulto JovemRESUMO
The serum glycoprotein fetuin-A is an important inhibitor of extraosseous calcification. The importance of fetuin-A has been confirmed in fetuin-A null mice, which develop widespread extraosseous calcification including the kidney. However, the mechanism how fetuin-A protects kidneys from nephrocalcinosis remains uncertain. Here, we demonstrate that intratubular fetuin-A plays a role in the prevention of nephrocalcinosis in the proximal tubules. Although normal rat kidney did not express mRNA for fetuin-A, we found punctate immunohistochemical staining of fetuin-A mainly in the S1 segment of the proximal tubules. The staining pattern suggested that fetuin-A passed through the slit diaphragm, traveled in the proximal tubular lumen, and was introduced into proximal tubular cells by megalin-mediated endocytosis. To test this hypothesis, we inhibited the function of megalin by intravenous injection of histidine-tagged soluble receptor-associated protein (His-sRAP), a megalin inhibitor. His-sRAP injection diminished fetuin-A staining in the proximal tubules and led to urinary excretion of fetuin-A. We further analyzed the role of fetuin-A in nephrocalcinosis. Continuous injection of parathyroid hormone (PTH) 1-34 induced nephrocalcinosis mainly in the proximal tubules in rats. His-sRAP retained fetuin-A in renal tubular lumen and thereby protected the kidneys of PTH-treated rats from calcification. Our findings suggest that tubular luminal fetuin-A works as a natural inhibitor against calcification in the proximal tubules under PTH-loaded condition.
Assuntos
Túbulos Renais Proximais/metabolismo , Nefrocalcinose/metabolismo , Nefrocalcinose/prevenção & controle , alfa-2-Glicoproteína-HS/metabolismo , Animais , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Lisossomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos WistarRESUMO
The combination of serum 25-hydroxyvitamin D (25D) and fibroblast growth factor 23 (FGF23) levels predict hard renal outcomes in patients with chronic kidney disease (CKD), independent of classical markers of mineral and bone disorders, including serum phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D levels, and active vitamin D therapy. In a prospective cohort study of 738 Japanese pre-dialysis outpatients with CKD, we examined potentially non-linear associations between 25D and FGF23 levels and estimated glomerular filtration rate (eGFR) changes in 727 patients with at least a 6-month observation period and no history of admission by acute kidney injury. We used multiple regression analyses with restricted cubic spline functions using annualized eGFR decline as a dependent variable. A significantly non-linear positive relationship between 25D and eGFR changes was observed. The annualized eGFR decline was greater in patients with 25D concentrations <25 and 23 ng/ml in univariate and multivariate analyses, respectively. Above this threshold, the eGFR decline plateaued. FGF23 showed a linear negative association with eGFR changes. After dividing the patients into four groups according to median 25D and FGF23 levels, the annualized eGFR changes in the Low FGF23-Low 25D, High FGF23-High 25D, and High FGF23-Low 25D groups were 0.49 (95% confidence intervals: -2.83 to 3.81), -1.24 (-5.00 to 2.52), -4.77 (-8.85 to -0.69), respectively, relative to the Low FGF23-High 25D group (P for trend, 0.02). Thus, combined use of FGF23 and 25D is useful to predict eGFR change in patients with CKD as well as hard renal outcomes.
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Tubulointerstitial fibrosis (TIF) is one of the major problems in nephrology because satisfactory therapeutic strategies have not been established. Here, we demonstrate that maxacalcitol (22-oxacalcitriol (OCT)), an analog of active vitamin D, protects the kidney from TIF by suppressing the autoinduction of transforming growth factor-ß1 (TGF-ß1). OCT suppressed the tubular injury index, interstitial volume index, collagen I positive area, and mRNA levels of extracellular matrix genes in unilateral ureteral-obstructed kidneys in rats. Although the renoprotective mechanism of active vitamin D in previous studies has been mainly attributed to the suppression of renin, OCT did not affect renal levels of renin or angiotensin II. We found that TGF-ß1 itself induces its expression in a phospho-Smad3 (pSmad3)-dependent manner, and that OCT ameliorated TIF by abrogating this 'autoinduction'. Under the stimulation of TGF-ß1, pSmad3 bound to the proximal promoter region of the TGF-ß1 gene. Both OCT and SIS3, a Smad3 inhibitor, abrogated the binding of pSmad3 to the promoter and consequently attenuated the autoinduction. TGF-ß1 increased both the nuclear levels of protein phosphatase Mg(2+)/Mn(2+)-dependent 1A (PPM1A), a pSmad3 phosphatase, and the interaction levels between the vitamin D receptor (VDR) and PPM1A. In the absence of OCT, however, the interaction between pSmad3 and PPM1A was weak; therefore, it was insufficient to dephosphorylate pSmad3. The PPM1A/VDR complex was recruited to pSmad3 in the presence of both TGF-ß1 and OCT. This recruitment promoted the dephosphorylation of pSmad3 and attenuated the pSmad3-dependent production of TGF-ß1. Our findings provide a novel approach to inhibit the TGF-ß pathway in fibrotic diseases.
Assuntos
Calcitriol/análogos & derivados , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Fosfoproteínas Fosfatases/metabolismo , Receptores de Calcitriol/metabolismo , Proteína Smad3/metabolismo , Angiotensina II/metabolismo , Animais , Sequência de Bases , Calcitriol/farmacologia , Linhagem Celular , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fibrose , Imuno-Histoquímica , Nefropatias/metabolismo , Túbulos Renais/química , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Masculino , Dados de Sequência Molecular , Fosforilação , Substâncias Protetoras/farmacologia , Proteína Fosfatase 2C , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Renina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologiaRESUMO
PURPOSE: Low 25-hydroxyvitamin D (25D), increased levels of fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), and alkaline phosphatase (ALP) were reported to be risk factors for mortality in chronic kidney disease (CKD). However, the independent associations of these factors with cardiovascular disease (CVD), the leading cause of death among CKD patients, remain unclear. Our purpose was to identify which of these factors predict incident CVD in CKD. METHODS: In this prospective cohort study, we enrolled 738 predialysis outpatients in the two nephrology departments. We employed Cox proportional hazards analyses to elucidate predictors of the endpoint, defined as fatal or non-fatal cardiovascular event requiring hospitalization. Multiple imputation was performed for missing values. RESULTS: Mean estimated glomerular filtration rate (eGFR) was 35 mL/min/1.73 m(2). During a median duration of 4.4 years, 86 patients developed the endpoint, of whom 62 patients achieved it before the initiation of dialysis. Multivariable analyses revealed that high serum intact FGF23 levels predicted the outcome preceding dialysis initiation (hazard ratio (HR) per lnFGF23 (SD), 1.64 (1.27-2.30)), while 25D, PTH, and bone-specific ALP did not. Adding FGF23 to the conventional model of age, sex, diabetes, prior CVD, pulse pressure, and eGFR, led to a net reclassification improvement of 6.87% (P=0.04). Not censoring the patients at the start of dialysis and continuing follow-up even after dialysis, FGF23 levels did not predict the outcome (HR, 1.16 (0.91-1.48)). Complete case analyses yielded similar results. CONCLUSIONS: Intact FGF23 levels in predialysis CKD predicted incident cardiovascular events requiring hospitalization before starting dialysis, but did not predict events during the entire follow-up period, including post dialysis initiation.
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Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Fatores de Crescimento de Fibroblastos/sangue , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Idoso , Fosfatase Alcalina/sangue , Biomarcadores/sangue , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/complicações , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Feminino , Fator de Crescimento de Fibroblastos 23 , Taxa de Filtração Glomerular , Humanos , Japão/epidemiologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Modelos de Riscos Proporcionais , Estudos Prospectivos , Diálise Renal , Fatores de Tempo , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
BACKGROUND AND OBJECTIVES: Hyperphosphatemia, vitamin D deficiency, hyperparathyroidism, and high serum fibroblast growth factor 23 (FGF23) levels, when studied separately, were found to predict the progression of CKD. However, studies with simultaneous measurement of mineral bone disorder (MBD)-related factors were scarce. This study aimed to identify factors predicting renal outcome independent of other factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a prospective cohort study of 738 Japanese predialysis outpatients in the nephrology departments of two hospitals. The outcome was defined as a doubling of serum creatinine or initiation of dialysis. RESULTS: Mean estimated GFR (eGFR) was 35 ml/min per 1.73 m(2). At enrollment, the increase in intact FGF23 with decreasing eGFR was the earliest among changes in MBD-related factors, followed by 1,25-dihydroxyvitamin D decrease, parathyroid hormone increase, and phosphate increase. During a median duration of 4.4 years, 213 patients reached the endpoint. In a multivariable Cox model, high FGF23 and low 25-hydroxyvitamin D (25D) levels were the only MBD-related factors associated with a higher risk of renal endpoint (adjusted hazard ratio [95% confidence interval] per unit change of log FGF23 and 10 ng/ml of 25D: 1.83 [1.28-2.61] and 0.61 [0.41-0.90], respectively). There was no significant interaction between 25D and FGF23 (P=0.11). Active vitamin D therapy, serum phosphate, 1,25-dihydroxyvitamin D, and parathyroid hormone levels were not related to the renal endpoint. Treating death as a competing risk or multiple imputation for missing values yielded similar results. CONCLUSIONS: Combined use of two markers is useful for the risk stratification of renal outcome.
Assuntos
Doenças Ósseas/sangue , Fatores de Crescimento de Fibroblastos/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Vitamina D/análogos & derivados , Idoso , Biomarcadores/sangue , Doenças Ósseas/complicações , Intervalos de Confiança , Creatinina/sangue , Progressão da Doença , Feminino , Fator de Crescimento de Fibroblastos 23 , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , Insuficiência Renal Crônica/complicações , Medição de Risco , Vitamina D/sangueRESUMO
No study has reported the current status of the management of chronic kidney disease mineral bone disorder (CKD-MBD) in Japan. Using the Osaka Vitamin D Study in CKD (OVIDS-CKD), we examined the prevalence of patients with serum calcium, phosphate, parathyroid hormone (PTH), or 25-hydroxyvitamin D levels outside the target of KDOQI guidelines. Eighty-four percent of the patients had 25-hydroxyvitamin D <30 ng/mL. Significant determinants of poor vitamin D status were female gender, diabetes, high PTH, and high urinary protein (2+ or greater). The percentage of patients with intact PTH higher than the target was 8% in CKD stage 3a, while between 20-22% in stages 3b to 5. The patients indicated for ergocalciferol were 7, 18, and 19% in stages 3a, 3b, and 4, respectively, and those indicated for active vitamin D were 21% in stage 5. Since neither ergocalciferol nor cholecalciferol is available in 2011 in Japan, we have no choice but to prescribe alfacalcidol or calcitriol; however, the percent of patients receiving these drugs was only 1, 4, 8, and 14% in stages 3a, 3b, 4, and 5, respectively, indicating that PTH and vitamin D status are not well controlled in Japan. In contrast, more than 80% of the patients met the target of serum calcium and phosphate. Contrary to expectations, nearly 20% of the patients had hypophosphatemia in stage 3 and 5, possibly because of strict protein restriction. Given these results, nephrologists should consider prescribing active vitamin D, especially for females and patients with diabetes, massive proteinuria, or secondary hyperparathyroidism.