RESUMO
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by numerous fluid-filled cysts that frequently result in end-stage renal disease. While promising treatment options are in advanced clinical development, early diagnosis and follow-up remain a major challenge. We therefore evaluated the diagnostic value of Fetuin-A as a new biomarker of ADPKD in human urine. RESULTS: We found that renal Fetuin-A levels are upregulated in both Pkd1 and Bicc1 mouse models of ADPKD. Measurement by ELISA revealed that urinary Fetuin-A levels were significantly higher in 66 ADPKD patients (17.5 ± 12.5 µg/mmol creatinine) compared to 17 healthy volunteers (8.5 ± 3.8 µg/mmol creatinine) or 50 control patients with renal diseases of other causes (6.2 ± 2.9 µg/mmol creatinine). Receiver operating characteristics (ROC) analysis of urinary Fetuin-A levels for ADPKD rendered an optimum cut-off value of 12.2 µg/mmol creatinine, corresponding to 94% of sensitivity and 60% of specificity (area under the curve 0.74 ; p = 0.0019). Furthermore, urinary Fetuin-A levels in ADPKD patients correlated with the degree of renal insufficiency and showed a significant increase in patients with preserved renal function followed for two years. CONCLUSIONS: Our findings establish urinary Fetuin-A as a sensitive biomarker of the progression of ADPKD. Further studies are required to examine the pathogenic mechanisms of elevated renal and urinary Fetuin-A in ADPKD.
Assuntos
Progressão da Doença , Rim Policístico Autossômico Dominante/patologia , Rim Policístico Autossômico Dominante/urina , alfa-2-Glicoproteína-HS/urina , Adulto , Idoso , Animais , Biomarcadores/urina , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Falência Renal Crônica/urina , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/metabolismo , Curva ROC , Regulação para CimaRESUMO
Fetuin-A acts as an inhibitor of systemic and local ectopic calcification and inflammatory response, but the role of fetuin-A in the etiology of urolithiasis is still unclear. We aim to investigate the expression of fetuin-A in the serum, urine and renal tissue of patients with or without nephrolithiasis. 48 patients with nephrolithiasis (group A) and 32 individuals without urolithiasis (group B, control group) were enrolled into our study. Level of fetuin-A in serum and urine was measured by ELISA, and expression of fetuin-A in renal tissue was localized and assessed by immunohistochemistry, real-time polymerase chain reaction, and Western blotting, respectively. Indexes of oxidative stress in kidney were evaluated. Other routine serum and urine chemistries for inpatients were measured biochemically. The results showed that fetuin-A expressed widely in the proximal and distal renal tubule, the thin segment of Henle's loop and the collecting duct epithelium. There were no differences in serum fetuin-A level between the two groups. Compared with control group, cellular expression of P47phox and fetuin-A mRNAs in the renal tissue of patients with nephrolithiasis increased, the level of MDA in renal tissue and the level of urinary calcium also increased, but urinary and renal fetuin-A protein and the activities of SOD in renal tissue decreased. Correlation analysis showed that there was a negative correlation between the level of renal fetuin-A protein and the expression of P47phox mRNA and MDA. These results revealed that nephrolithiasis patients had lower fetuin-A protein level in urine and renal tissue.
Assuntos
Rim/metabolismo , Nefrolitíase/metabolismo , Nefrolitíase/urina , alfa-2-Glicoproteína-HS/metabolismo , alfa-2-Glicoproteína-HS/urina , Adulto , Biomarcadores/sangue , Biomarcadores/metabolismo , Biomarcadores/urina , Western Blotting , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Rim/patologia , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , NADPH Oxidases/genética , Nefrolitíase/genética , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Superóxido Dismutase/metabolismo , alfa-2-Glicoproteína-HS/genéticaRESUMO
We analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n = 17) and measured urinary excretion of fetuin-A (n = 85). The increased signals of urine samples were observed in Siaα2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography-tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40 ± 0.43; A2, 0.60 ± 0.53; A3 1.57 ± 1.13 ng/gCr; p = 7.29 × 10(-8)) and of GFR stages (G1, 0.39 ± 0.39; G2, 0.49 ± 0.45; G3, 1.25 ± 1.18; G4, 1.34 ± 0.80 ng/gCr; p = 3.89 × 10(-4)). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR<60 mL/min. Fetuin-A is demonstrated as a risk factor for both microalbuminuria and reduction of GFR in diabetic nephropathy with the odds ratio of 4.721 (1.881-11.844) and 3.739 (1.785-7.841), respectively. Collectively, the glycan profiling analysis is useful method to identify the urine biomarkers and fetuin-A is a candidate to predict the progression of diabetic nephropathy.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/urina , Análise em Microsséries/métodos , Lectinas de Plantas/metabolismo , alfa-2-Glicoproteína-HS/urina , alfa-Globulinas/metabolismo , alfa-Globulinas/urina , Biomarcadores/urina , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido N-Acetilneuramínico/metabolismo , Risco , alfa-2-Glicoproteína-HS/metabolismoRESUMO
The kidney has a remarkable capacity to withstand insults for an extended period of time. The sensitivities of individual renal cells to injury vary depending on their type, position in the nephron, local vascularization, and the nature of injury. The resulting kidney injury is a product of the interplay between cell dysfunction, cell death, proliferation, inflammation, and recovery. The Acute Kidney Injury Network (AKIN) defined Acute Kidney Injury (AKI) as "functional and structural disorder or signs of renal damage including any defect from blood and urine test, or tissue imaging that is less than 3 months". RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease) criteria is the most frequently used system. Ideal biomarker for AKI should be affordable, quick and measurable, precise and accurate, with prognostic ability to define severity of renal dysfunction, specific for renal, increase in the early stage dysfunction, with high sensitivity and specificity. Efforts to detect AKI in the earlier stage has resulted in some promising biomarkers such as KIM-1, NGAL, IL-18, Clusterin, etc. Cystatin C is a biomarker for glomerular filtration function, while 2-microglobulin, 1-microglobulin, NAG, RBP, IL-18, NGAL, Netrin-1, KIM-1, Clusterin, Sodium Hydrogen Exchanger Isoform and Fetuin A are biomarkers for tubular reabsorption function.
Assuntos
Injúria Renal Aguda/sangue , Injúria Renal Aguda/urina , Acetilglucosaminidase/urina , Injúria Renal Aguda/diagnóstico , Proteínas de Fase Aguda/urina , alfa-Globulinas/urina , Biomarcadores/sangue , Biomarcadores/urina , Clusterina/urina , Cistatina C/sangue , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Interleucina-18/urina , Lipocalina-2 , Lipocalinas/sangue , Lipocalinas/urina , Glicoproteínas de Membrana/urina , Fatores de Crescimento Neural/urina , Netrina-1 , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/urina , Receptores Virais , Proteínas de Ligação ao Retinol/urina , Índice de Gravidade de Doença , Trocador 3 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/urina , Proteínas Supressoras de Tumor/urina , alfa-2-Glicoproteína-HS/urina , Microglobulina beta-2/urinaRESUMO
BACKGROUND: The extracellular protein fetuin-A is a potent soluble inhibitor of calcification, and its deficiency has been associated with vascular calcification in dialysis patients. In proteinuric patients, significant urinary losses of fetuin-A may cause low serum fetuin-A levels. METHODS: In a cross-sectional study, urinary/serum concentrations of fetuin-A were investigated in proteinuric children with glomerular diseases and preserved renal function (n = 58) in comparison to healthy controls (n = 246). RESULTS: Mean fetuin-A serum concentrations were clearly reduced in children with nephrotic syndrome (0.25 ± 0.14 g/l, p < 0.001), slightly reduced in children with large proteinuria (0.39 ± 0.15 g/l, p < 0.05), and comparable to controls in those with mild proteinuria (0.45 ± 0.14 vs. 0.46 ± 0.12 g/l). Fetuin-A was positively correlated with serum protein (r = 0.58), albumin (r = 0.57), and calcium (r = 0.64), but negatively correlated with proteinuria (r = -0.41), albuminuria (r = -0.46), and urinary fetuin-A excretion (r = -0.48; each p < 0.001). The fractional excretion of fetuin-A was significantly associated with the degree of proteinuria and serum fetuin-A levels. However, the urinary loss of fetuin-A and albumin in nephrotic children differed by three orders of magnitude and the mean fractional excretion of fetuin-A was only 1/10 of that of albumin (0.016 ± 0.029 vs. 0.162 ± 0.403%; p < 0.001). CONCLUSIONS: Fetuin-A is clearly reduced in children with nephrotic syndrome and associated with the degree of hypoalbuminemia. This is due to urinary fetuin-A loss and/or reduced hepatic synthesis. Persistent fetuin-A deficiency may have an impact on cardiovascular morbidity in nephrotic children.