RESUMO
Several experimental studies have shown that fibroblast growth factor 23 (FGF23) induces left ventricular hypertrophy (LVH). However, the opposite directional relationship, namely a potential effect of LVH on FGF23, remains uncertain. Here we evaluated the effects of LVH on FGF23 using cardiomyocyte-specific calcineurin A transgenic mice. At six weeks, these mice showed severe LVH, with elevated levels of serum intact FGF23. FGF23 levels were elevated in cardiomyocytes, but not osteocytes, of the transgenic animals. Moreover, transverse aortic constriction also upregulated myocardial FGF23 expression in wild type mice. The promoter region of the FGF23 gene contains two putative nuclear factors of activated T cells (NFAT)-binding sites, with NFAT1 activating the promoter in a proximal NFAT-binding site dependent manner. Neither serum, urinary, or fractional excretion values of calcium and phosphate nor serum levels of 1,25(OH)2 vitamin D were different between wild type and transgenic mice. Moreover, the renal expression of FGF receptors and α-Klotho was comparable. However, plasma levels of antidiuretic hormone were significantly increased in the transgenic mice, and aquaporin-2 immunohistochemical staining was mainly positive in the apical membrane of the collecting duct, compared to a primarily cytoplasmic staining in wild type mice. Real-time PCR analyses of kidney CYP27B1 and CYP24A1 expression in wild type mice showed that exogenous antidiuretic hormone blocked FGF23's actions on these vitamin D activating or inactivating enzymes. Finally, the renal resistance of transgenic mice to FGF23 was partly overcome by tolvaptan. Thus, LVH in transgenic mice is associated with an increase in myocardial and serum intact FGF23, with the kidneys being protected against FGF23 excess by elevated antidiuretic hormone levels.
Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Hipertrofia Ventricular Esquerda/sangue , Animais , Calcineurina/genética , Calcineurina/metabolismo , Modelos Animais de Doenças , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Osteócitos/metabolismo , Vasopressinas/sangueRESUMO
It is known that magnesium antagonizes phosphate-induced apoptosis of vascular smooth muscle cells and prevents vascular calcification. Here we tested whether magnesium can also counteract other pathological conditions where phosphate toxicity is involved, such as progression of chronic kidney disease (CKD). We explored how the link between the risk of CKD progression and hyperphosphatemia is modified by magnesium status. A post hoc analysis was run in 311 non-diabetic CKD patients who were divided into four groups according to the median values of serum magnesium and phosphate. During a median follow-up of 44 months, 135 patients developed end-stage kidney disease (ESKD). After adjustment for relevant clinical factors, patients in the lower magnesium-higher phosphate group were at a 2.07-fold (95% CI: 1.23-3.48) risk for incident ESKD and had a significantly faster decline in estimated glomerular filtration rate compared with those in the higher magnesium-higher phosphate group. There were no significant differences in the risk of these renal outcomes among the higher magnesium-higher phosphate group and both lower phosphate groups. Incubation of tubular epithelial cells in high phosphate and low magnesium medium in vitro increased apoptosis and the expression levels of profibrotic and proinflammatory cytokine; these changes were significantly suppressed by increasing magnesium concentration. Thus, magnesium may act protectively against phosphate-induced kidney injury.
Assuntos
Falência Renal Crônica/prevenção & controle , Magnésio/sangue , Fosfatos/sangue , Insuficiência Renal Crônica/complicações , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Linhagem Celular , Citocinas/metabolismo , Citoproteção , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Estimativa de Kaplan-Meier , Rim/fisiopatologia , Falência Renal Crônica/sangue , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/etiologia , Falência Renal Crônica/fisiopatologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Sulfato de Magnésio/farmacologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Fosfatos/toxicidade , Fatores de Proteção , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Fatores de TempoRESUMO
Vitamin D hydroxylated at carbon 25 (25(OH)D) is generally recognized as a precursor of active vitamin D. Despite its low affinity for the vitamin D receptor (VDR), both deficient and excessive 25(OH)D levels are associated with poor clinical outcomes. Here we studied direct effects of 25(OH)D3 on the kidney using 25(OH)D-1α-hydroxylase (CYP27B1) knockout mice. The effects of 25(OH)D3 on unilateral ureteral obstruction were analyzed as proximal tubular cells and macrophages are two major cell types that take up 25(OH)D and contribute to the pathogenesis of kidney injury. Excess 25(OH)D3 in obstructed mice worsened oxidative stress and tubulointerstitial fibrosis, whereas moderate levels of 25(OH)D3 had no effects. The exacerbating effects of excess 25(OH)D3 were abolished in CYP27B1/VDR double-knockout mice and in macrophage-depleted CYP27B1 knockout mice. Excess 25(OH)D3 upregulated both M1 marker (TNF-α) and M2 marker (TGF-ß1) levels of kidney-infiltrating macrophages. In vitro analyses verified that excess 25(OH)D3 directly upregulated TNF-α and TGF-ß1 in cultured macrophages but not in tubular cells. TNF-α and 25(OH)D3 cooperatively induced oxidative stress by upregulating iNOS in tubular cells. Aggravated tubulointerstitial fibrosis in mice with excess 25(OH)D3 indicated that macrophage-derived TGF-ß1 also had a key role in the pathogenesis of surplus 25(OH)D3. Thus, excess 25(OH)D3 worsens tubulointerstitial injury by modulating macrophage phenotype.
Assuntos
Calcifediol/farmacologia , Túbulos Renais/patologia , Macrófagos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Animais , Calcifediol/administração & dosagem , Calcifediol/metabolismo , Células Cultivadas , Feminino , Fibrose , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , Receptores de Calcitriol/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Obstrução Ureteral/complicaçõesRESUMO
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
This report describes the case of a 76-year-old man with ulcerative colitis who developed interstitial nephritis after starting 5-Aminosalicylic acid (5-ASA) therapy. The patient experienced an initial improvement in symptoms, but developed fatigue, anorexia, and severe renal dysfunction 2.5 months later. Renal biopsy confirmed drug-induced interstitial nephritis, and conservative treatment with fluid replacement and the discontinuation of 5-ASA improved the patient's condition. Clinicians should monitor patients receiving 5-ASA therapy for potential adverse effects, particularly renal injury, and promptly investigate symptoms of renal dysfunction. Early recognition and discontinuation of the offending agent may prevent further damage and improve patient outcomes.
Assuntos
Colite Ulcerativa , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Nefrite Intersticial , Insuficiência Renal , Masculino , Humanos , Idoso , Mesalamina/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/patologia , Rim/patologia , Insuficiência Renal/patologia , Anti-Inflamatórios não Esteroides/efeitos adversosRESUMO
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
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
Immune check point inhibitors (ICIs) are now increasingly used for cancer therapy. At the same time, by activating the immune system, ICIs induce unique side effects, termed immune-related adverse events (irAEs). Renal irAEs, although uncommon, result in acute tubulointerstitial nephritis. Recently, because of an increase in ICI administration, renal irAEs, including glomerulonephritis, are being increasingly reported. A 69-year-old man presented with nephrotic syndrome after use of the ICI nivolumab. He underwent renal biopsy and was diagnosed with membranous nephropathy (MN) without acute tubulointerstitial nephritis. Immunofluorescence staining was negative for IgG4 and phospholipase A2 receptor (PLA2R), suggesting a malignancy-associated pattern. Oral glucocorticoid therapy was started as the standard treatment for irAEs, which resulted in complete remission of the nephrotic syndrome in 20 months. We suggest his MN was induced or accelerated by immune activation due to nivolumab. It means that ICIs possibly induce not only acute tubulointerstitial nephritis but also nephrotic syndrome due to MN as renal irAEs which is treatable with glucocorticoid.
Assuntos
Adenocarcinoma de Pulmão , Glomerulonefrite Membranosa , Neoplasias Pulmonares , Síndrome Nefrótica , Adenocarcinoma de Pulmão/tratamento farmacológico , Idoso , Feminino , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/tratamento farmacológico , Glucocorticoides/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Nefrite Intersticial , Síndrome Nefrótica/induzido quimicamente , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/tratamento farmacológico , Nivolumabe/efeitos adversosRESUMO
A 74-year-old man presented with nephrotic syndrome and kidney insufficiency. Laboratory tests revealed monoclonal gammopathy of immunoglobulin A-lambda. Renal biopsy revealed diffuse mesangial proliferation and double-contoured basement membranes. Immunofluorescent analyses showed granular deposition of immunoglobulin A and C3 at the capillary walls and mesangial regions. Immunohistochemistry suggested monoclonal deposition of immunoglobulin A1-lambda. Electron microscopic analyses showed finely granular electron-dense deposits at mesangial and subendothelial areas. These findings suggested immunoglobulin A-type proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Based on the results of bone marrow aspiration, multiple myeloma was diagnosed. Because the renal manifestation was considered to be affected by monoclonal gammopathy, chemotherapy was initiated rather than immunomodulatory therapy. Although bortezomib and dexamethasone proved ineffective, second chemotherapy with elotuzumab, lenalidomide, and dexamethasone was successful, and kidney function recovered. Effective treatments for proliferative glomerulonephritis with monoclonal immunoglobulin deposits have not been established. This represents the first description of a patient successfully treated for proliferative glomerulonephritis with monoclonal immunoglobulin deposits by chemotherapy using elotuzumab.
Assuntos
Glomerulonefrite Membranoproliferativa/diagnóstico , Imunoglobulina A/imunologia , Cadeias lambda de Imunoglobulina/imunologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia por Agulha/métodos , Medula Óssea/patologia , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Glomerulonefrite Membranoproliferativa/etiologia , Glomerulonefrite Membranoproliferativa/imunologia , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Imunoglobulina A/efeitos dos fármacos , Imunoglobulina A/metabolismo , Imuno-Histoquímica/métodos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Masculino , Microscopia Eletrônica/métodos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/patologia , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologia , Paraproteinemias/etiologia , Paraproteinemias/imunologia , Insuficiência Renal/diagnóstico , Insuficiência Renal/etiologia , Resultado do TratamentoRESUMO
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.
RESUMO
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.