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BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are major genetic polycystic kidney diseases that can progress to end-stage kidney disease (ESKD). Longitudinal data on the clinical characteristics associated with clinical outcomes in polycystic kidney disease (PKD), including the development of ESKD and cardiovascular disease (CVD) are lacking in Japan. To address this unmet need the authors are establishing a novel, web-based, Nationwide Cohort Registry Study-the Japanese Registry of PKD (JRP). METHODS: The JRP is a prospective cohort study for ADPKD (aim to recruit n = 1000 patients), and both a retrospective and prospective study for ARPKD (aim to recruit n = 100). In the prospective registry, patients will be followed-up for 10 years every 6 months and 12 months for patients with ADPKD and ARPKD, respectively. Data collection will be recorded on Research Electronic Data Capture (REDCap) starting on April 1, 2024, with recruitment ending on March 31, 2029. (jRCT 1030230618). RESULTS: Data to be collected include: baseline data, demographics, diagnostic and genetic information, radiological and laboratory findings, and therapeutic interventions. During follow-up, clinical events such as development of ESKD, hospitalization, occurrence of extra kidney complications including CVD events, and death will be recorded, as well as patient-reported health-related quality of life for patients with ADPKD. CONCLUSIONS: The JRP is the first nationwide registry study for patients with ADPKD and ARPKD in Japan, providing researchers with opportunities to advance knowledge and treatments for ADPKD and ARPKD, and to inform disease management and future clinical practice.
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INTRODUCTION: Recent advances in dialysis therapy have made it possible to remove middle molecules. Removal of small-middle molecules, such as ß2-microglobulin, can now be achieved with conventional hemodialysis (HD), and removal of large-middle molecules has become a target, particularly for α1-microglobulin (AMG, 33 kD). The AMG reduction rate has emerged as a target for improvement of various clinical symptoms, but the effects on prognosis have yet to be determined. The "Japanese study of the effects of AMG (α1-microglobulin) reduction rates on survival" (JAMREDS) was started in April 2020, with the goal of determining if the AMG reduction rate associates with the risk of mortality and cardiovascular disease (CVD) events. METHODS: JAMREDS is a prospective observational study in patients on HD to examine the effects of: (1) AMG reduction rate on survival outcome and CVD events; (2) dialysis treatment modalities (HD, intermittent infusion hemodiafiltration(iHDF), pre/post-dilution online HDF) on survival and CVD events (based on AMG reduction rates with treatment mode); and (3) AMG reduction rates on survival and CVD events in patients undergoing each therapy (iHDF, pre/post-dilution online HDF). The number of planned subjects was 4,000 in preplanning. Data are collected using RED-Cap, which is an EDC system. A total of 9,930 patients were enrolled at the beginning of the study at 59 registered facilities. The JAMREDS observation period will continue until the end of 2023, after which the data will be cleaned and confirmed before analysis. CONCLUSION: This study may provide new evidence for the relationship between the amount of removed large-middle molecules (such as AMG) and the mortality and CVD risk. Comparisons with convection volumes will also be of interest.
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alfa-Globulinas , Doenças Cardiovasculares , Diálise Renal , Humanos , Estudos Prospectivos , Diálise Renal/mortalidade , Doenças Cardiovasculares/mortalidade , Masculino , Feminino , Japão , Falência Renal Crônica/terapia , Falência Renal Crônica/mortalidade , Pessoa de Meia-Idade , Idoso , População do Leste AsiáticoRESUMO
In vivo iron levels can be adjusted through intestinal iron absorption to be maintained at a suitable level; however, optimal iron levels in hemodialysis (HD) patients are unclear. In this study, we investigated total body iron (TBI), calculated as the sum of red blood cell (RBC) iron and iron stores, during courses of low-dose oral iron replacement therapy, and evaluated in vivo iron sufficiency and its indicators in HD patients. We analyzed data on 105 courses of low-dose iron replacement therapy administered to 83 patients on maintenance HD over 7 months. We evaluated changes in TBI, RBC iron, and iron stores from the initiation of treatment to month 7 in two groups of patients, namely, iron-therapy responders and non-responders. TBI showed significant increases until month 4 and plateaued thereafter in iron-therapy responders, and tended to increase and then reached a similar plateau in non-responders (month 7: 1900 ± 447 vs. 1900 ± 408 mg). Steady-state TBI was strongly correlated with body surface area (y = 1628.6x - 791.91, R2 = 0.88, p < 0.001). We observed constant TBI during oral iron replacement therapy suggesting the activation of a "mucosal block". The results suggest that body surface area has utility for estimating the required TBI with regression equations.
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Anemia Ferropriva , Eritropoetina , Falência Renal Crônica , Humanos , Ferro/metabolismo , Estudos Retrospectivos , Ferritinas , Diálise Renal/efeitos adversos , Anemia Ferropriva/tratamento farmacológico , Eritropoetina/metabolismo , Falência Renal Crônica/etiologia , Hemoglobinas/metabolismoRESUMO
Fibulin7 (Fbln7) is a matricellular protein that is structurally similar to short fibulins but does not possess elastogenic abilities. Fbln7 is localized on the cell surface of the renal tubular epithelium in the adult kidney. We previously reported that Fbln7 binds artificial calcium phosphate particles in vitro, and that heparin counteracts this binding by releasing Fbln7 from the cell surface. Fbln7 gene (Fbln7) deletion in vivo decreased interstitial fibrosis and improved renal function in a high phosphate diet-induced chronic kidney disease mouse model. However, the contribution of Fbln7 during acute injury response remains largely unknown. We hypothesized that Fbln7 serves as an exacerbating factor in acute kidney injury (AKI). We employed three AKI models in vivo and in vitro, including unilateral ureteral obstruction (UUO), cisplatin-induced AKI, and calcium oxalate (CaOx)-induced AKI. Here, we report that Fbln7KO mice were protected from kidney damage in a CaOx-induced AKI model. Using HEK293T cells, we found that Fbln7 overexpression enhanced the CaOx-induced upregulation of EGR1 and LAMB3, and that heparin treatment canceled this effect. Interestingly, the protective function observed in Fbln7KO kidneys was limited to the CaOx-induced AKI model, while Fbln7KO mice were not protected against UUO-induced renal fibrosis or cisplatin-induced renal tubular damage. Taken together, our study indicates that Fbln7 mediates the local deposition of CaOx and damages the renal tubular epithelium. Releasing Fbln7 from the cell surface via heparin/heparin derivatives or Fbln7 inhibitory antibodies may provide a general strategy to mitigate calcium crystal-induced kidney injuries.
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Injúria Renal Aguda , Oxalato de Cálcio , Proteínas de Ligação ao Cálcio , Animais , Humanos , Camundongos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Oxalato de Cálcio/metabolismo , Cisplatino , Células HEK293 , Heparina/farmacologia , Rim/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Camundongos KnockoutRESUMO
BACKGROUND AND HYPOTHESIS: Tolvaptan, a vasopressin V2 receptor antagonist, is used for treating autosomal dominant polycystic kidney disease (ADPKD). We focused on changes in urinary osmolality (U-Osm) after tolvaptan initiation to determine whether they were associated with the therapeutic response to tolvaptan. METHODS: This was a single-centre, prospective, observational cohort study. Seventy-two patients with ADPKD who received tolvaptan were recruited. We analysed the relationship between changes in U-Osm and annual estimated glomerular filtration rate (eGFR) in terms of renal prognostic value using univariable and multivariable linear regression analyses. RESULTS: The mean value of U-Osm immediately before tolvaptan initiation was 351.8 ± 142.2 mosm/kg H2O, which decreased to 97.6 ± 23.8 mosm/kg H2O in the evening. The decrease in U-Osm was maintained in the outpatient clinic 1 month later. However, the values of U-Osm showed higher variability (160.2 ± 83.8 mosm/kg H2O) than did those in the first evening of tolvaptan administration. Multivariate analysis revealed that the baseline eGFR, baseline urinary protein, and U-Osm change in the evening of the day of admission (initial U-Osm drop) were significantly correlated with the subsequent annual change in eGFR. CONCLUSIONS: U-Osm can be measured easily and rapidly, and U-Osm change within a short time after tolvaptan initiation may be a useful index for the renal prognosis in actual clinical practice.
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BACKGROUND: Clinical practice guidelines recommend antihypertensive and tolvaptan therapies for patients with autosomal dominant polycystic kidney disease (ADPKD) in Japan. However, tolvaptan therapy may pose an economic burden. The Japanese Ministry of Health, Labour and Welfare supports patients with intractable diseases. This study aimed to confirm the impact of the intractable disease system in Japan on the clinical treatment of ADPKD. METHODS: We analyzed the data of 3768 patients with ADPKD having a medical subsidy certificate from the Japanese Ministry of Health, Labour and Welfare in 2015-2016. The following quality indicators were use: the adherence rate to the 2014 clinical practice guideline for polycystic kidney disease (prescription rates of antihypertensive agents and tolvaptan in this cohort) and the number of Japanese patients with ADPKD nationwide started on renal replacement therapy in 2014 and 2020. RESULTS: Compared with new applications from 2015 to 2016, the prescription rates of antihypertensives and tolvaptan for the indicated patients at the 2017 renewal application increased by 2.0% (odds ratio = 1.41, p = 0.008) and 47.4% (odds ratio = 10.1, p > 0.001), respectively. These quality indicators improved with antihypertensive treatment, especially in patients with chronic kidney disease stages 1-2 (odds ratio = 1.79, p = 0.013) and in those aged < 50 years (odds ratio = 1.70, p = 0.003). The number of patients with ADPKD who were started on renal replacement therapy in Japan decreased from 999 in 2014 to 884 in 2020 in the nationwide database (odds ratio = 0.83, p < 0.001). CONCLUSIONS: The Japanese public intractable disease support system contributes to improvement of ADPKD treatment.
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Rim Policístico Autossômico Dominante , Humanos , Tolvaptan/uso terapêutico , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/tratamento farmacológico , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Japão/epidemiologia , Anti-Hipertensivos/uso terapêutico , Sistema de RegistrosRESUMO
BACKGROUND: With the constant need for technique improvement for ensuring correct diagnoses and precise treatment, imaging examinations that use contrast media have become unavoidable and indispensable. However, the long-term effects of contrast media on renal function remain unclear in populations with advanced renal failure. This study aimed to examine the relationship between contrast media exposure and long-term trends in renal function in patients with renal failure. METHODS: This retrospective cohort study included patients with a definitive diagnosis of chronic kidney disease who visited medical institutions in Japan between April 2012 and December 2020. The cohort was divided into contrast agent therapy and non-contrast agent therapy groups. The assessment indices were the number of contrast exposures and renal function decline. Renal function decline was calculated based on observed chronic kidney disease stage trends and glomerular filtration rate correspondence tables sourced from various guidelines. A stratified analysis focusing on changes in renal function while accounting for the acceleration of chronic kidney disease progression was also performed. RESULTS: After adjusting for patient background with propensity score matching, 333 patients each were included in both groups. The observation period was 5.3 ± 2.1 and 4.9 ± 2.2 years per case in the contrast-enhanced and non-contrast-enhanced groups, respectively. The baseline estimated glomerular filtration rate at the beginning of the observation period was 55.2 ± 17.8 mL/min/1.73 m2 in the contrast-enhanced groups (P = 0.65). Although only slightly different in both groups, the glomerular filtration rate change was 1.1 ± 3.3 mL/min/1.73 m2/year in the contrast agent therapy group and tended to be higher with contrast media exposure. Stratified analysis showed that the annual glomerular filtration rate changes in patients with more contrast media exposures and altered renal function were 7.9 ± 7.1 mL/min/1.73 m2/year and 4.7 ± 3.6 mL/min/1.73 m2/year in the contrast agent therapy and non-contrast agent therapy groups, respectively (1.69 times, P < 0.05). CONCLUSION: We were able to identify a clinical trend of successful measures for preventing adverse renal outcomes associated with contrast media exposure. However, increased frequency of contrast media exposure has a long-term effect on renal function in patients with altered it. Appropriate treatment choices related to contrast media may control chronic kidney disease.
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Meios de Contraste , Insuficiência Renal Crônica , Humanos , Meios de Contraste/efeitos adversos , Estudos Retrospectivos , Rim , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/epidemiologia , Taxa de Filtração GlomerularRESUMO
The distribution volume of uric acid is affected by the amount of extracellular water (ECW), while urea distribution volume can be considered as total body water (TBW). Thus, the ratio of distribution volumes of uric acid and urea can be paralleled to and be considered as the proxy of ECW/TBW. A total of 108 patients at our facility was included. The uric acid and urea distribution volume ratio (UUVdR) calculated from the single-pool model, which was measured within 1 month of the time when the bioimpedance index was measured. ECW/TBW at the end of the HD session was measured by InBody S10. We investigated the association between the UUVdR and the ECW/TBW values and the factors affecting the residuals of the regression equation. We also evaluated the predictive ability of overhydration or dehydration in randomly selected two groups, i.e., the training group and the validation group. ECW/TBW correlated highly with UUVdR. Multivariate analysis demonstrated that only creatinine and ECW/TBW were significantly associated with regression residuals. The cutoff values of UUVdR for overhydration and dehydration were 0.666 and 0.579, respectively, in the training group. Their AUC were 0.872 and 0.898, respectively. The sensitivity and specificity values in the validation group were 0.571 and 0.868 for overhydration, and 0.444 and 0.953 for dehydration, respectively. UUVdR might be a proxy of hydration status in hemodialysis patients. It may be possible to predict hydration status without dedicated devices in the epidemiological study.
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Ácido Úrico , Intoxicação por Água , Humanos , Desidratação/diagnóstico , Água Corporal , Impedância Elétrica , Diálise Renal , ÁguaRESUMO
OBJECTIVE: The study aimed to investigate the neonatal outcomes of infants born to mothers on hemodialysis. STUDY DESIGN: This retrospective, case-control, and observational study included 17 infants born to 16 mothers on dialysis in 2003 to 2016. We compared their clinical characteristics to those of 51 gestational age- and sex-matched control infants. Statistical comparisons were made between the two groups by using the Wilcoxon-Mann-Whitney test for continuous variables and the Chi-square test or Fisher's exact test for categorical variables. RESULTS: Of the 16 pregnancies of mothers on dialysis, 15 (94%) deliveries were premature (<37 weeks), and 16/17 (94%) infants survived to discharge. The incidences of neonatal complications, such as intraventricular hemorrhage, bronchopulmonary dysplasia, patent ductus arteriosus, and periventricular leukomalacia, were not significantly different between the groups. However, 5/17 (29%) of the infants had congenital anomalies. CONCLUSION: Although infants born to mothers on dialysis have a high risk of prematurity, they do not have any additional risk of neonatal complications, except for congenital anomalies. The potential risk of congenital anomalies should be investigated further. KEY POINTS: · Preterm birth rate among mothers on hemodialysis was 94%.. · Complications in these infants were similar to controls.. · Twenty-nine percent of infants had congenital anomalies..
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Mortalidade Infantil , Nascimento Prematuro , Gravidez , Recém-Nascido , Lactente , Humanos , Feminino , Estudos de Casos e Controles , Estudos Retrospectivos , Diálise Renal , Idade GestacionalRESUMO
The production of erythropoietin (EPO), the main regulator of erythroid differentiation, is regulated by hypoxia-inducible factor (HIF). HIF2α seems to be the principal regulator of EPO transcription, but HIF1α and 3α also may have additional influences on erythroid maturation. HIF is also involved in the regulation of iron, an essential component in erythropoiesis. Iron is essential for the organism but is also highly toxic, so its absorption and retention are strictly controlled. HIF also induces the synthesis of proteins involved in iron regulation, thereby ensuring the availability of iron necessary for hematopoiesis. Iron is a major component of hemoglobin and is also involved in erythrocyte differentiation and proliferation and in the regulation of HIF. Renal anemia is a condition in which there is a lack of stimulation of EPO synthesis due to decreased HIF expression. HIF prolyl hydroxylase inhibitors (HIF-PHIs) stabilize HIF and thereby allow it to be potent under normoxic conditions. Therefore, unlike erythropoiesis-stimulating agents, HIF-PHI may enhance iron absorption from the intestinal tract and iron supply from reticuloendothelial macrophages and hepatocytes into the plasma, thus facilitating the availability of iron for hematopoiesis. The only HIF-PHI currently on the market worldwide is roxadustat, but in Japan, five products are available. Clinical studies to date in Japan have also shown that HIF-PHIs not only promote hematopoiesis, but also decrease hepcidin, the main regulator of iron metabolism, and increase the total iron-binding capacity (TIBC), which indicates the iron transport capacity. However, concerns about the systemic effects of HIF-PHIs have not been completely dispelled, warranting further careful monitoring.
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Anemia , Eritropoetina , Inibidores de Prolil-Hidrolase , Insuficiência Renal Crônica , Humanos , Inibidores de Prolil-Hidrolase/farmacologia , Prolil Hidroxilases , Anemia/metabolismo , Ferro/metabolismo , Eritropoetina/metabolismo , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia , Hipóxia , Insuficiência Renal Crônica/metabolismoRESUMO
INTRODUCTION: Hypoxia-inducible factor prolyl hydroxylase domain inhibitors (HIF-PHI) are a new treatment for renal anemia. HIF-PHI is believed to increase iron usage to improve availability of iron for erythropoiesis. Therefore, there is concern that HIF-PHI might be prone to iron deficiency and that thrombosis might be induced by increased platelet and transferrin levels due to this iron deficiency. METHODS: Relationship of iron-related factors with platelet count (PLT) and total iron-binding capacity (TIBC; which reflects the transferrin level) were examined in 29 patients who were treated with darbepoetin alfa (DA) and then switched to roxadustat (Rox). To determine how changes in PLT and TIBC related to changes in iron-related factors, univariable and multivariable linear regression models were applied. To examine what iron-related factors on Day 0 influenced change in PLT, we used receiver operating characteristic (ROC) curves and logistic regression analysis for a rate of change in PLT ≤0% as the endpoint. Logistic regression analysis was performed with the reference group having serum ferritin (s-ft) or Transferrin saturation below the corresponding cutoff value (low vs. high). RESULTS: Multivariable analysis showed significant positive correlations between the rate of change in PLT and the change in s-ft and red blood cells (RBC) count {ß-coefficients; 0.40 [95% confidence interval (CI): 0.17-0.62], p = 0.001} (ß-coefficients; 30.45 [95% CI: 10.90-50.00], p = 0.004). The rate of change in TIBC was significantly positively correlated with only the change in RBC count. The ROC showed a significant cutoff value for s-ft of 77.2 ng/mL (sensitivity 63.6%, specificity 83.3%, area under the curve 0.76, 95% CI 0.55-0.96). Multivariable logistic regression also showed that only high s-ft was significantly elevated (9.46, 95% CI 1.42-63.30, p = 0.020). CONCLUSIONS: This study showed that changes in PLT were correlated with s-ft and amount of hematopoiesis. This suggests that an increase in PLT due to iron levels is less likely when s-ft is 77.2 ng/mL or higher at the time of switching from DA to Rox. In contrast, TIBC was only related to hematopoiesis in these patients. Control of s-ft before initiation of HIF-PHI treatment and gradual hematopoiesis might reduce the risk of thrombosis when switching from erythropoiesis-stimulating agents to HIF-PHI.
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Inibidores de Prolil-Hidrolase , Insuficiência Renal Crônica , Darbepoetina alfa , Ferritinas , Humanos , Hipóxia , Ferro , Prolil Hidroxilases , Inibidores de Prolil-Hidrolase/uso terapêutico , Insuficiência Renal Crônica/terapia , TransferrinasRESUMO
BACKGROUND: Tolvaptan, a vasopressin V2 receptor antagonist, is used to treat autosomal-dominant polycystic kidney disease (ADPKD). Although tolvaptan curbs disease progression, a few reports have examined factors related to treatment response. The estimated glomerular filtration rate (eGFR) decreases soon after tolvaptan is initiated. We investigated whether initial eGFR decline affects renal prognosis of patients. METHODS: This was a single-center, retrospective observational cohort study. Eighty-three patients with ADPKD who initiated tolvaptan were selected. We analyzed the relationship of the initial eGFR change with clinical parameters and analyzed the annual eGFR change in terms of renal prognostic value using univariable and multivariable linear regression analyses. RESULTS: The initial eGFR change was - 4.6 ± 8.0%/month. The initial eGFR change correlated significantly with the annual eGFR change in multivariable analysis, suggesting that the larger decline in the initial eGFR change, the better the renal prognosis. Furthermore, the change in fractional excretion (FE) of free water (FEH2O) correlated positively with initial eGFR change. FEH2O and urea nitrogen FE (FEUN) increased significantly; however, sodium FE (FENa) level remained unchanged. In approximately half of the patients, FENa unexpectedly decreased. CONCLUSIONS: The initial eGFR decline might be caused by suppressing glomerular hyperfiltration, due to the pharmacological effect of tolvaptan, and/or by reducing renal plasma flow, due to potential volume depletion. The initial eGFR change reflects the tolvaptan effect, can be easily evaluated in clinical practice, and may be useful as one of the clinical indicator for predicting renal prognosis in patients under tolvaptan.
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Rim Policístico Autossômico Dominante , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Taxa de Filtração Glomerular , Humanos , Rim , Rim Policístico Autossômico Dominante/tratamento farmacológico , Estudos Retrospectivos , Tolvaptan/farmacologia , Tolvaptan/uso terapêuticoRESUMO
BACKGROUND: Factors affecting decline in renal function and cyst growth in patients with autosomal polycystic kidney disease (ADPKD) are not fully described, particularly in Japan. METHODS: This was the first multi-facility, prospective, observational cohort study conducted in ADPKD patients at 14 centers in Japan. Patients in the J-PKD registry were assessed from December 2009 to June 2012 (follow-up until June 2017). Patients' data including estimated glomerular filtration rate (eGFR) and total kidney volume (TKV) were assessed initially and a maximum of five times annually. Contributing factors to eGFR decline and TKV growth were identified using multiple linear regression analysis. RESULTS: Of the 340 patients in the J-PKD registry, data analysis was performed for 192 patients in whom serial changes for both eGFR and TKV were obtained. eGFR slope, eGFR change, and TKV change values were as follows: - 2.7 (- 4.2 to - 1.5) (ml/min/1.73 m2/year), - 5.0 (- 9.6 to - 2.3) (%/year), and 4.78 (0.86-8.22) (%/year), respectively. Lower high-density lipoprotein (HDL) cholesterol was an independent predictor of eGFR decline, using both eGFR slope and change (P = 0.04, P = 0.02, respectively), whereas lower hemoglobin and higher uric acid were significantly associated with greater eGFR change only (P = 0.02, P = 0.002, respectively). Younger age and higher fasting blood sugar were independent predictors of greater TKV change (P = 0.01, P = 0.02, respectively). CONCLUSIONS: This real-world study in Japan identified risk factors for renal function decline in ADPKD patients. These included lower HDL cholesterol, lower hemoglobin and higher uric acid for eGFR decline, and youth and higher blood sugar levels for TKV growth.
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Rim/patologia , Rim/fisiopatologia , Rim Policístico Autossômico Dominante/patologia , Rim Policístico Autossômico Dominante/fisiopatologia , Adulto , Fatores Etários , Glicemia/metabolismo , HDL-Colesterol/sangue , Progressão da Doença , Jejum , Feminino , Seguimentos , Taxa de Filtração Glomerular , Hemoglobinas/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Ácido Úrico/sangueRESUMO
Longitudinal studies evaluating the association between visceral fat area (VFA) and kidney function decline in patients with chronic kidney disease (CKD) are limited, and little is known about VFA interactions contributing to the kidney prognosis (e.g. interactions between VFA ≥ 100 cm2 and age, sex, and CKD category). In this study, we stratified patients with CKD according to VFA category, as well as age, sex, CKD category, hyperglycemia, and diabetes mellitus, and determined the ability of obesity-related indicators (body mass index, waist circumference, subcutaneous fat area, visceral-to-subcutaneous fat ratio) to predict the renal prognosis. Kidney outcomes (≥ 50% estimated glomerular filtration rate decline or end-stage kidney disease) were examined in 200 patients with CKD (median follow-up, 12.3 years). On multivariable Cox analysis, an increase in VFA (10-cm2 increase) was significantly associated with kidney outcomes in the entire cohort, and VFA was significantly associated with kidney disease progression even in the VFA < 100 cm2 sub-cohort. Interestingly, the hazard ratio (HR) was higher for VFA (10-cm2 increase) than for the VFA ≥ 100 cm2 sub-cohort (HR 1.33 vs. 1.07). Overall, VFA was found to be the most versatile obesity-related indicator associated with kidney disease progression. VFA was associated with the primary outcome in the sub-cohorts of CKD stages 1-2, hyperglycemia, and diabetes mellitus. A high VFA was a significant kidney prognostic factor in the entire CKD cohort, with greater significance in patients with VFA < 100 cm2 than in patients with VFA ≥ 100 cm2. Our results may provide new insights into strategies for treating CKD.
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Adiposidade , Taxa de Filtração Glomerular , Gordura Intra-Abdominal/fisiopatologia , Rim/fisiopatologia , Obesidade Abdominal/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/diagnóstico por imagem , Valor Preditivo dos Testes , Prognóstico , Insuficiência Renal Crônica/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Fibroblast growth factor-23 (FGF23) is a hormone indispensable for maintaining phosphate homeostasis. In response to phosphate intake, FGF23 is secreted from osteocytes/osteoblasts and acts on the kidney to increase urinary phosphate excretion. However, the mechanism by which these cells sense phosphate intake remains elusive. Calciprotein particles are nanoparticles of calcium-phosphate precipitates bound to serum protein fetuin-A and are generated spontaneously in solution containing calcium, phosphate, and fetuin-A to be dispersed as colloids. In cultured osteoblastic cells, increase in either calcium or phosphate concentration in the medium induced FGF23 expression, which was dependent on calciprotein particle formation. When transition of calcium-phosphate precipitates from the amorphous phase to the crystalline phase was blocked by bisphosphonate, the calciprotein particle size was reduced and FGF23 expression was augmented, suggesting that small calciprotein particles containing amorphous calcium-phosphate precipitates function as a more potent FGF23 inducer than larger calciprotein particles containing crystalline calcium-phosphate precipitates. In mice, bolus phosphate administration by oral gavage transiently increased circulating calciprotein particle levels followed by a modest increase in FGF23 expression and serum FGF23 levels. However, continuous dietary phosphate load induced robust and persistent increase in circulating calciprotein particles and FGF23 levels. We confirmed by in vivo imaging that calciprotein particles injected intravenously extravasated into the bone marrow and were deposited on the inner surface of the bone, indicating that these particles have direct access to osteoblasts. Thus, we propose that osteoblasts induce FGF23 expression and secretion when they sense an increase in extracellular calciprotein particles following phosphate ingestion.
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Fatores de Crescimento de Fibroblastos , Osteoblastos , Animais , Osso e Ossos , Fator de Crescimento de Fibroblastos 23 , Camundongos , Osteócitos , FosfatosRESUMO
BACKGROUND: Hemodialysis patients are prone to constipation, which can adversely affect their quality of life (QOL). Elobixibat, a highly selective inhibitor of the ileal bile acid transporter, can increase the bile acid level in the colon and, subsequently, enhance colonic motility and secretion. In hemodialysis patients with chronic constipation, it may have a novel action mechanism. However, the effect of elobixibat on such patients' QOL had not been reported. This study aimed to evaluate the effect of elobixibat on the QOL of hemodialysis patients with chronic constipation. METHODS: This was a multicenter, observational study that used the Japanese version of the Patient Assessment of Constipation-Quality of Life (PAC-QOL) questionnaire on 27 patients (18 men and nine women, age range 47-90 years), who satisfied the Rome 3 diagnostic criteria for functional constipation and were already taking other drugs for constipation. These patients were administered elobixibat 10 mg/day and were asked to respond to the PAC-QOL questionnaire at baseline and after 4 weeks. Bayesian statistics were used to confirm our results. RESULTS: The number of spontaneous bowel movements per week increased significantly from 2.6 ± 1.2 to 4.1 ± 2.1 (p < 0.001), and the Bristol Stool Form Scale score significantly improved from 1.9 ± 0.8 to 3.6 ± 0.7 (p < 0.001). The Cronbach's alpha was 0.95, and the Guttman split-half reliability coefficient was 0.90. There were significant decreases in the physical discomfort scores from 1.94 ± 0.79 to 0.97 ± 0.72 (p < 0.001); psychosocial discomfort from 1.16 ± 0.93 to 0.63 ± 0.58 (p < 0.001); worries/ concerns from 1.84 ± 0.73 to 1.27 ± 0.59 (p < 0.001), and satisfaction from 2.79 ± 0.61 to 1.98 ± 0.77 (p < 0.001). The total PAC-QOL score significantly decreased from 1.83 ± 0.79 to 1.17 ± 0.56 (p < 0.001). Bayesian statistics confirmed the results' significance. CONCLUSIONS: Elobixibat reduced the PAC-QOL scores for hemodialysis patients with chronic constipation and improved the patients' QOL. It may serve as a new option for treating constipation in hemodialysis patients.
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Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/etiologia , Dipeptídeos/uso terapêutico , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Diálise Renal/efeitos adversos , Simportadores/antagonistas & inibidores , Tiazepinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Colo/efeitos dos fármacos , Defecação/efeitos dos fármacos , Dipeptídeos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários , Tiazepinas/farmacologiaRESUMO
BACKGROUND: Though anemia is a sign of poor renal prognosis in chronic kidney disease (CKD), hemoglobin (Hb) levels are typically higher in autosomal dominant polycystic kidney disease (ADPKD) than in other kidney diseases, and anemia has not been examined as a potential prognosticator. Thus, we investigated anemia as a factor for renal prognosis in ADPKD. METHODS: In total, 115 non-dialysis patients, 48 men and 67 women, with ADPKD were evaluated. The renal outcome of a 50% reduction in the estimated glomerular filtration rate or renal replacement therapy was examined using the Cox regression analysis and Kaplan-Meier analysis. RESULTS: Patients were followed for a median of 5.5 years and 50 patients had reached the end point. The mean age of the patients at the first visit was 45.9 ± 13.3 years. The overall mean Hb was 12.90 ± 1.85 g/dL, and the mean Hb in men and women was 13.82 ± 1.72 g/dL and 12.25 ± 1.65 g/dL, respectively. Hb levels and uric protein content were statistically significant factors for poor renal prognosis, while hypertension and genetic mutations failed to reach significance. Furthermore, statistical significance was found in men with Hb < 12 g/dL and in women with Hb < 11 g/dL. Anemia had significant association with kidney disease progression in patients with ADPKD. CONCLUSIONS: We found that anemia might be a factor for poor renal prognosis in ADPKD. Furthermore, a sex difference was found, wherein men with Hb < 12 g/dL and women with Hb < 11 g/dL were at risk of renal disease progression.
Assuntos
Anemia/sangue , Anemia/etiologia , Hemoglobinas/metabolismo , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/fisiopatologia , Adulto , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Rim Policístico Autossômico Dominante/genética , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores Sexuais , Canais de Cátion TRPP/genéticaRESUMO
BACKGROUND: Although it is widely accepted that the autosomal dominant polycystic kidney disease (ADPKD) patients with large liver cysts have a significant decrement in quality of life (QOL), there is insufficient evidence that clearly demonstrates the relationship between the size of the liver cysts and QOL. Therefore, we started this prospective longitudinal study to investigate the impact of liver cysts on QOL. METHODS: We grouped the 111 included ADPKD patients into 4 groups (control group A; < 25%, group B; 25-49%, group C; 50-75%, group D; > 75%) according to liver cysts-parenchyma ratio (CPR). QOL was measured by FANLTC + FACT-Hep scores. We compared QOL scores and several clinical parameters amongst these groups for 3 years. RESULTS: The number of patients in group A, B, C, and D was 31, 14, 14, and 23, respectively. Although there were no significant differences in AST (p = 0.107), ALT (p = 0.925), and serum albumin (p = 0.212) between the four groups, platelet count was significantly decreased along with the extension of cyst volume (p = 0.030). Overall, the mean FANLTC and FACT-Hep scores were 71.8 ± 12.5, and 32.4 ± 5.8, respectively. FANLTC (p = 0.017) and FACT-Hep scores (p = 0.003) were significantly decreased with increasing cyst volume. From the data collected at the time of registration, multivariate linear regression analysis demonstrated that the CPR had a significant influence on FANLTC and FACT-Hep scores. CONCLUSION: In this cross-sectional and prospective longitudinal study, we demonstrate the relationship between liver cyst volume and QOL in ADPKD patients. We hope to establish the long-term influence on QOL in this ongoing prospective longitudinal study.
Assuntos
Cistos/patologia , Fígado/patologia , Rim Policístico Autossômico Dominante/complicações , Qualidade de Vida , Adulto , Estudos Epidemiológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/patologia , Rim Policístico Autossômico Dominante/psicologiaRESUMO
Roxadustat (Rox), a hypoxia-inducible factor (HIF) stabilizer, is now available for the treatment of anemia in hemodialysis (HD) patients. To investigate hematopoietic effect and iron metabolism, this study involved 30 HD patients who were initially treated with darbepoetin (DA), a conventional erythropoietin-stimulating agent, and then switched to Rox. We measured erythrocyte, reticulocyte indices, and iron-related factors at every HD during the first two weeks after the treatment switch (Days 0-14) and again on Days 21 and 28. We measured erythropoietin (EPO) concentration every week and examined their changes from Day-0 values. The same variables were measured in 15 HD patients who continued DA at every HD for one week. Iron-related factors were also measured on Days 14 and 28. In the Rox group, hepcidin significantly decreased from Day 2. The reticulocyte hemoglobin content (CHr) significantly increased on Day 4, but decreased with a significant increase in reticulocyte count from Day 7. Log10(serum ferritin) significantly decreased after Day 11. Log10(EPO concentration) was lower at all time points. Compared with the DA group, the Rox group showed significant differences in all variables except CHr. These results suggest that Rox improves hematopoiesis and iron metabolism early after administration independent of EPO concentration.
Assuntos
Anemia/tratamento farmacológico , Darbepoetina alfa/uso terapêutico , Glicina/análogos & derivados , Hematínicos/uso terapêutico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Ferro/metabolismo , Isoquinolinas/uso terapêutico , Insuficiência Renal Crônica/terapia , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Anemia/genética , Anemia/patologia , Contagem de Células , Substituição de Medicamentos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Eritropoetina/genética , Eritropoetina/metabolismo , Feminino , Ferritinas/genética , Ferritinas/metabolismo , Regulação da Expressão Gênica , Glicina/uso terapêutico , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Hemoglobinas/genética , Hemoglobinas/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/agonistas , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Reticulócitos/efeitos dos fármacos , Reticulócitos/metabolismo , Transferrina/genética , Transferrina/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), one of the most common hereditary kidney diseases, causes gradual growth of cysts in the kidneys, leading to renal failure. Owing to the advanced technology of next-generation sequencing (NGS), genetic analyses of the causative genes PKD1 and PKD2 have been improved. METHODS: We performed genetic analyses of 111 Japanese ADPKD patients using hybridization-based NGS and long-range (LR)-PCR-based NGS. Additionally, genetic analyses in exon 1 of PKD1 using Sanger sequencing because of an extremely low coverage of NGS and those using multiplex ligation-dependent probe amplification (MLPA) were performed. RESULTS: The detection rate using NGS for 111 patients was 86.5%. One mutation in exon 1 of PKD1 and five deletions detected by MLPA were identified. When combined, the total detection rate was 91.9%. CONCLUSION: Although NGS is useful, we propose the addition of Sanger sequencing for exon 1 of PKD1 and MLPA as indispensable for identifying mutations not detected by NGS.