RESUMEN
AIM: Complement activation is involved in the pathogenesis and progression of immunoglobulin A nephropathy (IgAN); however, the clinical implication of abnormal complement protein levels in serum and urine is not clear. To address this we analyzed the correlation between disease activity and complement proteins in serum and urine from IgAN patients, and compared to patients with other types of chronic kidney disease (CKD) as well as healthy controls. METHODS: We included 85 Chinese patients with IgAN, 23 patients with non-proliferative CKD, and 20 healthy individuals. Patients were divided according to the Oxford classification of M0E0S0T0 (group 1, n = 20), M1E1S0-1 T0-1 (group 2, n = 25), M1E1S0-1 T2 or M0E0S1T1-2 (group 3, n = 40). Complement factor H (CFH), mannose-binding lectin and membrane attack complex in serum and urine were measured by enzyme-linked immunosorbent assay. RESULTS: Urinary CFH, membrane attack complex and serum CFH were increased in both IgAN and CKD patients compared with healthy controls. The urinary excretion of CFH was the highest in IgAN patients with most tubulointerstitial damage (IgAN group 3). Urinary CFH and mannose-binding lectin levels were significantly higher in IgAN patients with crescents formation (C1-2) than in patients without (C0). Urinary complement protein excretion correlated negatively with estimated glomerular filtration rate, and positively with urinary retinol-binding protein and α1-microglobulin excretion indicating proximal tubule dysfunction. CONCLUSION: Increased urinary excretion of complement proteins in IgAN is related to chronic injury and tubular dysfunction. This warrants caution using urinary complement proteins as markers of disease activity.
Asunto(s)
Glomerulonefritis por IGA/complicaciones , Túbulos Renales Proximales/fisiopatología , Insuficiencia Renal Crónica/etiología , Adulto , Factor H de Complemento/análisis , Factor H de Complemento/orina , Complejo de Ataque a Membrana del Sistema Complemento/análisis , Complejo de Ataque a Membrana del Sistema Complemento/orina , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/fisiopatología , Humanos , Masculino , Lectina de Unión a Manosa/sangre , Lectina de Unión a Manosa/orina , Persona de Mediana EdadRESUMEN
BACKGROUND: After activation, the complement system is involved in the pathogenesis of Immunoglobulin A nephropathy (IgAN). Complement factor H (CFH) is a crucial inhibitory factor of the alternative pathway of the complement system. The study investigated the effects of urinary CFH levels on IgAN progression. METHODS: A total of 351 patients with IgAN participated in this study. They were followed up for an average of 51.8 ± 26.6 months. Renal outcome was defined as a composite endpoint, that included instances of end-stage renal disease (ESRD), ≥ 50% decline in estimated glomerular filtration rate (eGFR) or doubling of plasma creatinine levels. Urinary CFH levels were measured by enzyme-linked immunosorbent assay and calculated as the ratio of urinary CFH over creatinine (uCFH/uCr). RESULTS: In the whole cohort, uCFH/uCr values were associated with disease progression either as continuous [log(uCFH/uCr)] or categorical traits (dichotomous and quartile variables) after adjusting for eGFR, proteinuria, mean arterial blood pressure, histological grading and immunosuppressive therapy in the Cox proportional hazard model. Kaplan-Meier analysis showed that higher uCFH/uCr values at baseline predicted worse renal outcome during follow-up (log-rank, P < 0.001). Receiver operating characteristic curve (ROC) analysis showed that log(uCFH/uCr) had predictive value for renal outcome (area under curve [AUC] = 0.745), and the AUC increased to 0.805 after being incorporated into baseline eGFR and proteinuria. In subgroup analysis with eGFR ≥ 60 mL/min/1.73 m2, log(uCFH/uCr) had better predictive value (AUC = 0.724, P = 0.002) for renal outcome compared to eGFR (AUC = 0.582, P = 0.259) and proteinuria (AUC = 0.615, P = 0.114). CONCLUSIONS: Urinary CFH levels are associated with renal function decline and increased urinary CFH levels are a risk factor for progression of IgA nephropathy.
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Factor H de Complemento/orina , Glomerulonefritis por IGA/etiología , Glomerulonefritis por IGA/mortalidad , Adulto , Estudios de Cohortes , Femenino , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/complicaciones , Humanos , Estimación de Kaplan-Meier , Fallo Renal Crónico/etiología , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Curva ROCRESUMEN
The patient was a 48-year-old man hospitalized for jaundice and anemia after a 6-day history of diarrhea. Examination demonstrated hemolytic anemia, renal dysfunction, and thrombocytopenia. Typical hemolytic uremic syndrome (HUS) was suspected based on the preceding colitis; however, plasma exchange (PE) was performed because the possibility of atypical HUS (aHUS) could not be ignored, given that the patient was an adult male. After 4 days of PE, his laboratory results improved. Stool culture on admission yielded negative results for Escherichia coli serotype O157 and ADAMTS13 activity. Antinuclear antibodies were normal, and no other drugs or infections indicating HUS were detected. Four months after onset, he suffered recurrence of aHUS after colitis. As a result, aHUS was suspected and therefore, PE was performed on the day of hospitalization. We diagnosed aHUS due to a result indicating complement dysregulation on hemolytic assay testing, which detected a complement factor H abnormality. After undergoing PE and maintaining a stable condition, the interval between PEs was extended; however, on day 17 after the last PE, he suffered a recurrent aHUS attack again. He could not be weaned from PE and started showing an allergic reaction to PE treatment, thereby leading to a switch from PE to eculizumab. Since switching to eculizumab treatment, the patient has not experienced another aHUS attack and his condition remains stable.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Hemolítico-Urémico/tratamiento farmacológico , Intercambio Plasmático , Síndrome Hemolítico Urémico Atípico , Factor H de Complemento/orina , Síndrome Hemolítico-Urémico/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Prevención Secundaria , Resultado del TratamientoRESUMEN
BACKGROUND: Urinary (U)-complement components have been detected in patients with proteinuric renal diseases, and complement activation via the alternative pathway (AP) is believed to play a role in renal tubular damage. The present study aimed to examine the regulation of complement AP activation in patients with renal tubular damage by focusing on the balance between properdin (P) and factor H (fH). METHODS: In the in vivo studies, U concentrations of P, fH and membrane attack complex (MAC) were measured in patients with renal diseases using an enzyme-linked immunosorbent assay (ELISA), and their relationships with the clinical data were evaluated. In the in vitro studies, human proximal tubular epithelial cells (PTECs) were incubated with normal human serum (NHS), P-depleted serum (PDS), purified P and/or fH. Changes in cell morphology and phenotype were assessed by microscopy, real-time polymerase chain reaction (PCR), immunostaining and a cell viability assay. RESULTS: The U-P, fH and MAC concentrations were significantly higher in patients with renal disease than in normal controls and correlated with the U-protein and tubular damage markers. Furthermore, multivariate analysis revealed a relationship between P levels and tubular damage markers. There were no significant changes in morphology and mRNA expression in the AP components (P, fH, fB, C3, C5 and C9) after the addition of up to 25% NHS. Dose-dependent depositions of P or fH were observed after the addition of P or fH on PTECs. Depositions of P were not inhibited by fH in a mixture of a fixed concentration of P and a variable concentration of fH, and vice versa. Preincubation with the fixed concentration of P before the addition of NHS or PDS increased the depositions of P, C3 and MAC compared with incubation with intact NHS or intact PDS only; the depositions of C3 and MAC showed a serum-dependent trend. Preincubation with P before NHS addition significantly suppressed cell viability without causing morphological changes. CONCLUSIONS: In the pathogenesis of renal tubular damage, P can directly bind to PTECs and may accelerate AP activation by surpassing fH regulation.
Asunto(s)
Activación de Complemento , Factor H de Complemento/orina , Complejo de Ataque a Membrana del Sistema Complemento/orina , Enfermedades Renales/orina , Túbulos Renales Proximales/metabolismo , Properdina/orina , Adulto , Femenino , Regulación de la Expresión Génica , Humanos , Enfermedades Renales/patología , Túbulos Renales Proximales/patología , MasculinoRESUMEN
BACKGROUND: Glomerular damage in IgA nephropathy (IgAN) is mediated by complement activation via the alternative and lectin pathways. Therefore, we focused on molecules stabilizing and regulating the alternative pathway C3 convertase in urine which might be associated with IgAN pathogenesis. METHODS: Membrane attack complex (MAC), properdin (P), factor H (fH) and Complement receptor type 1 (CR1) were quantified in urine samples from 71 patients with IgAN and 72 healthy controls. Glomerular deposition of C5, fH and P was assessed using an immunofluorescence technique and correlated with histological severity of IgAN and clinical parameters. Fibrotic changes and glomerular sclerosis were evaluated in renal biopsy specimens. RESULTS: Immunofluorescence studies revealed glomerular depositions of C5, fH and P in patients with IgAN. Urinary MAC, fH and P levels in IgAN patients were significantly higher than those in healthy controls (p < 0.001), but CR1 was significantly lower than that in healthy controls (p < 0.001). Urinary MAC and fH levels were positively correlated with serum creatinine (sCr), urinary N-acetyl-ß-D-glucosaminidase (u-NAG), urinary ß2 microglobulin (u-Bm), urinary protein (p < 0.001), interstitial fibrosis (MAC: p < 0.01, fH: p < 0.05) and the percentage of global glomerular sclerosis (p < 0.01). Urinary P was positively correlated with u-NAG, u-Bm, and urinary protein (p < 0.01). CONCLUSIONS: Complement activation occurs in the urinary space in IgAN and the measurement of levels of MAC and fH in the urine could be a useful indicator of renal injury in patients with IgAN.
Asunto(s)
Activación de Complemento , Complejo de Ataque a Membrana del Sistema Complemento/orina , Glomerulonefritis por IGA/inmunología , Riñón/fisiopatología , Adolescente , Adulto , Anciano , Biomarcadores , Factor H de Complemento/orina , Vía Alternativa del Complemento , Proteínas del Sistema Complemento/análisis , Femenino , Fibrosis , Glomerulonefritis por IGA/fisiopatología , Glomerulonefritis por IGA/orina , Humanos , Glomérulos Renales/química , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Properdina/orina , Receptores de Complemento/análisis , Adulto JovenRESUMEN
Factor H plays a key inhibitory role in control of the activation of alternative pathway of complement system. The aim of the study was to investigate the predictive value of factor H as a biomarker of renal injury in IgA nephropathy (IgAN). Urine factor H concentration from 202 patients was measured and compared with that of 60 healthy volunteers. Forty-eight patients fulfilled Haas-I or II (group 1), 60 fulfilled Haas-III (group 2) and 94 fulfilled Haas-IV or V (group 3). Co-deposition of factor H and C3b in kidneys were investigated using confocal microscope. The levels of urinary factor H, when expressed as a ratio of urinary creatinine, were significantly higher in groups 3 than group 1 and 2, also significantly higher in group 2 than group 1. In addition, the levels of urinary factor H were significantly higher in those with factor H deposition in the kidney than those without deposition. The levels of urinary factor H may be a useful biomarker to evaluate kidney injury in IgAN.
Asunto(s)
Factor H de Complemento/orina , Glomerulonefritis por IGA/diagnóstico , Riñón/patología , Adulto , Biomarcadores/orina , Complemento C3b/metabolismo , Factor H de Complemento/metabolismo , Factor H de Complemento/normas , Creatinina/sangre , Creatinina/orina , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente Directa , Glomerulonefritis por IGA/clasificación , Glomerulonefritis por IGA/orina , Humanos , Riñón/metabolismo , Masculino , Microscopía Confocal , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estándares de Referencia , Adulto JovenRESUMEN
AIMS: Cis-diaminedichloroplatium II (CDDP) is an antineoplastic agent with serious renal toxicity, although the cause is not fully understood. The aim of this study was to clarify the functional roles of complement activation in cisplatin-nephropathy by examining the urinary complement components, C5b-9 and factor H. SUBJECTS: Five patients with advanced lung cancer were included in this study as they were due to receive CDDP or 1,1-cyclobutanedicarboxylatoplatinum II (CBDA). METHODS: Urine samples were collected before and after the chemotherapy for 13 days for measurements of C5b-9 (U-C5b-9), factor H (U-fH), albumin (U-Alb), beta2-microglobulin (U-beta2MG), and N-acetyl-beta-D-glucosamidase (NAG). RESULTS: The mean level of U-Alb during the 5 - 8 day period after CDDP treatment was significantly higher than before treatment (p < 0.01). There was no significant correlation between U-Alb and NAG (r = -0.031, p = 0.994), or U-Alb and U-beta2MG (r = 0.061, p = 0.978) during the 5 - 8 day after CDDP treatment. U-Alb, U-C5b-9 and U-fH clearly increased on Days 4 - 10 after CDDP treatment. In our three patients treated with CDDP, mean estimated glomerular filtration rate (eGFR) was slightly decreased at 7 and 13 days after the treatment, compared to that of pretreatment, whereas there was no difference of eGFR between 7 and 13 days. In patients treated with CBDA, these parameters were clearly at lower levels compared to those patients treated with CDDP. CONCLUSION: This study demonstrates that cisplatin may activate the complement pathway in the glomerulus, with factor H regulating the activation, resulting in decreased urinary albumin excretion and renoprotection.
Asunto(s)
Albuminuria/diagnóstico , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Activación de Complemento , Factor H de Complemento/orina , Complejo de Ataque a Membrana del Sistema Complemento/orina , Enfermedades Renales/inducido químicamente , Anciano , Anciano de 80 o más Años , Ensayo de Inmunoadsorción Enzimática , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Enfermedades Renales/orina , Pruebas de Función Renal , Modelos Lineales , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The complement system plays an important role in renal pathogenesis, and C5b-9, a terminal complement complex, is regarded as the principal mediator of proteinuria in idiopathic membranous nephropathy(MN). Since factor H regulates complement activation at the C3 step and is a crucial factor in complement-mediated tissue injury, the urinary excretion of factor H in patients with idiopathic MN was investigated. METHODS: Seven patients with biopsy-proven idiopathic MN were studied for twenty-four weeks. Urinary factor H levels were measured by ELISA from regularly collected urine samples, and then evaluated and compared with assays of urinary protein and C5b-9 excretion. RESULTS: During the study, five patients were treated with steroid therapy. All seven patients maintained stable renal function and showed a decline in urinary protein excretion. The mean level of urinary factor H was markedly elevated (156.1 +/- 47.1 U/mg U-Cr) before treatment (0 week), and gradually declined to 127.2 +/- 43.5 U/mg U-Cr at 12 weeks, and to 64.7 +/- 26.9 U/mg U-Cr) at 24 weeks. This followed decreases in urinary protein and urinary C5b-9 excretion. Percent change in urinary factor H level significantly decreased 24 weeks after treatment without affecting the plasma factor H level. CONCLUSION: These results suggest that factor H contributes to the regulatory mechanism of in situ complement activation, and thus the study of urinary factor H levels, as well as urinary C5b-9, may be significant in idiopathic MN.
Asunto(s)
Factor H de Complemento/orina , Glomerulonefritis Membranosa/diagnóstico , Adulto , Biomarcadores/orina , Complejo de Ataque a Membrana del Sistema Complemento/orina , Femenino , Glomerulonefritis Membranosa/etiología , Humanos , Masculino , Persona de Mediana Edad , Proteinuria/diagnóstico , Proteinuria/etiologíaRESUMEN
BACKGROUND: The BTA TRAK and BTA stat tests for bladder cancer use monoclonal antibodies (mAbs) X13.2 and X52.1 to detect factor H (FH)-related material in urine. The exact ligands remain unknown. METHODS: Western blot analyses of purified FH, recombinant factor H-related protein 1 (FHR-1), and serum and urine samples were used to identify the ligands of X13.2 and X52.1. Recombinant FH constructs were used to identify the target sites of X13.2 and X52.1. To analyze whether natural ligands of FH could compete with its recognition by the capture mAb X52.1, we used surface plasmon resonance analysis. The role of the ligands of X52.1 in the BTA TRAK assay was tested with use of purified proteins and FH-depleted samples. RESULTS: X13.2 bound to domain 3 of FH and FH-like protein 1, whereas X52.1 bound to domain 18 of FH and to FHR-1. Using specific FH depletion from a bladder cancer patient's urine and purified FH, we demonstrated that FH is the ligand recognized by the BTA TRAK test. By contrast, FHR-1 in urine reduced the FH-dependent test signal. CONCLUSIONS: FH is a tumor marker for bladder cancer. To reveal the presence of bladder cancer, the BTA TRAK assay detects FH, whereas FHR-1 is able to partly inhibit this detection. This indicates a special mechanism for a diagnostic immunoassay based on the combined effect of simultaneous positive and negative signals in a single sample.
Asunto(s)
Carcinoma de Células Transicionales/diagnóstico , Factor H de Complemento/orina , Neoplasias de la Vejiga Urinaria/diagnóstico , Anticuerpos Monoclonales/metabolismo , Antígenos de Neoplasias/orina , Sitios de Unión de Anticuerpos , Biomarcadores de Tumor/orina , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/orina , Proteínas Inactivadoras del Complemento C3b , Factor H de Complemento/inmunología , Factor H de Complemento/metabolismo , Humanos , Ligandos , Masculino , Unión Proteica , Estructura Terciaria de Proteína , Resonancia por Plasmón de SuperficieRESUMEN
BACKGROUND/AIMS: The complement system plays an important role in the pathogenesis of membranous nephropathy (MN). In order to elucidate the regulatory mechanism of complement activation, we demonstrated glomerular deposition and urinary excretion of complement factor H, which controls the alternative pathway and the amplification loop at the C3 step, in patients with idiopathic MN. METHODS: Renal biopsy specimens from 20 patients with idiopathic MN were studied immunohistochemically using monoclonal antibodies against complement components including factor H. SDS-PAGE and Western blotting analysis of urine samples were performed, and the urinary excretion of factor H and C5b-9 were measured by quantitative sandwich ELISA. RESULTS: Intense glomerular deposition of factor H was observed with C3b.C3c and C5b-9 at an early stage of the disease. Factor H was detected in Western blots of urine samples, but factor H-like protein 1 (FHL-1) was not. The mean level of urinary factor H was elevated (86.30 +/- 21.93 U/mg urinary creatinine) in comparison to that of normal controls (4.76 +/- 1.03 U/mg urinary creatinine). Urinary factor H level exhibited no correlation with clinical parameters; however, a negative correlation was found between urinary C5b-9/factor H and creatinine clearance (r = 0.662, p < 0.01). CONCLUSION: The source of glomerular and urinary factor H is supposedly a 150-kD protein. There was no evidence to suggest that FHL-1 is synthesized at the site of inflammation. The urinary C5b-9 to urinary factor H ratio is indicative of the degree of ongoing complement activation in the glomeruli and complement-mediated renal injury. These findings suggest that factor H contributes to the control mechanism of in situ complement activation and prevents renal damage in idiopathic MN.
Asunto(s)
Factor H de Complemento/orina , Glomerulonefritis Membranosa/orina , Glomérulos Renales/química , Empalme Alternativo , Biopsia , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/química , Proteínas Sanguíneas/genética , Western Blotting , Complemento C3b/análisis , Complemento C3c/análisis , Factor H de Complemento/análisis , Factor H de Complemento/química , Factor H de Complemento/fisiología , Complejo de Ataque a Membrana del Sistema Complemento/análisis , Complejo de Ataque a Membrana del Sistema Complemento/orina , Vía Alternativa del Complemento , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Femenino , Glomerulonefritis Membranosa/metabolismo , Humanos , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Peso MolecularRESUMEN
Between 1997 and 2000 we investigated in a prospective study the voided urine samples of all consecutive patients undergoing cystoscopy independent from their clinical background (n = 705) with the BTA-TRAK assay (Bard Diagnostics, Redmont, USA) detecting a complement factor H-related protein (CFHrP) and the NMP22 assay (Matritech, Newton, USA) measuring a nuclear matrix protein, which is supposed to be specific for bladder cancer. The individuals were divided into three groups concerning the clinical background: 233 patients had urological diseases, 268 patients had urinary bladder cancer and 150 patients had other urological malignancies. Based on the clinical findings we compared our results with well established diagnostic methods for urinary bladder cancer such as cytology and the detection of hematuria. In addition, we investigated urine samples from 30 healthy individuals and 24 patients with urinary tract infection without performing cystoscopy. Following the recommendations of the European Group on Tumor Markers we used 95% specificity for benign urological diseases and urinary tract infections, which resulted in a sensitivity of 17% for active bladder cancer for the BTA-TRAK assay and 31% for NMP22. We compared these results with the detection of hematuria (specificity: 72%) and cytology, which had a sensitivity of 64% and 89%, respectively. Subsequently, we calculated sensitivity and specificity for the detection of relapse of the disease. Again using 95% specificity, in this case for patients with no evidence of disease (NED), in patients with recurrent disease the BTA-TRAK assay showed 8% sensitivity as compared to 12% for the NMP22 assay. Due to an insufficient specificity and sensitivity, both tests can neither be clinically useful in screening of high risk patients, nor in primary diagnosis of bladder cancer. They cannot replace neither cystoscopy nor cytology. In the follow-up care more investigations may be necessary to prove the benefit of existing diagnostic strategies for the discrimination between active and inactive bladder cancer.
Asunto(s)
Factor H de Complemento/orina , Proteínas Nucleares/orina , Neoplasias de la Vejiga Urinaria/diagnóstico , Biomarcadores de Tumor/orina , Estudios de Casos y Controles , Cistoscopía , Diagnóstico Diferencial , Hematuria , Humanos , Técnicas para Inmunoenzimas , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/orina , Pronóstico , Estudios Prospectivos , Curva ROC , Juego de Reactivos para Diagnóstico , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/orina , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/patología , Infecciones Urinarias/orina , Orina/citología , Enfermedades Urológicas/diagnóstico , Enfermedades Urológicas/patología , Enfermedades Urológicas/orinaRESUMEN
BACKGROUND: Complement factor H (hCFH) plays a key inhibitory role in the control of the alternative complement pathway. We examined whether urinary hCFH (U-hCFH) levels is useful as an indirect indicator of renal damage. METHODS: Urine samples were obtained from 104 patients with renal disease. Urine was collected with 10 mM EDTA and U-hCFH levels were measured using the BTA TRAK Assay Kit. RESULTS: In the 62 patients with nephritis, the levels of U-hCFH were elevated (range 15-52,198 U/ml) over the normal range (0-14 U/ml). U-hCFH levels of patients with chronic renal failure, lupus nephritis, membranoproliferative glomerulonephritis, focal glomerulosclerosis were higher than that of IgA nephropathy patients (p < 0.05). In the patients with minimal change disease, showed high levels of U-hCFH during the nephrotic syndrome. U-hCFH was correlated significantly with urinary protein and urinary N-acetyl-beta-D-glucosaminidase. CONCLUSIONS: We demonstrated that U-hCFH was detected in the urine of nephritis patients.
Asunto(s)
Factor H de Complemento/orina , Glomerulonefritis Membranoproliferativa/orina , Biomarcadores , Activación de Complemento , Femenino , Humanos , Nefritis Lúpica/orina , Masculino , Persona de Mediana Edad , Nefritis Intersticial/orina , Nefrosis Lipoidea/orinaRESUMEN
BACKGROUND: One of the goals of a noninvasive test for bladder carcinoma screening would be to reduce surveillance cystoscopies among patients with a history of bladder carcinoma. In addition, an accurate bladder carcinoma marker could be used to screen a high-risk population. The authors examined the efficacy of the hyaluronic acid-hyaluronidase (HA-HAase) and BTA-Stat tests to detect and predict bladder carcinoma recurrence and tested their specificity for bladder carcinoma screening. METHODS: Over a four year period, the authors prospectively collected 225 urine specimens from 70 bladder carcinoma patients and analyzed them by the HA-HAase test. Tumors were identified during 178 visits, and in 47 specimens there was no evidence of disease (NED). Twenty six of these 70 patients were randomly selected to have the BTA-Stat test (111 surveillance visits). In a separate study, 401 former Department of Energy (DOE) workers, who are likely to be at a higher risk for bladder carcinoma, were screened by the HA-HAase and BTA-Stat urine tests. RESULTS: The HA-HAase test had an approximately 91.0% sensitivity, 70% specificity, 87% accuracy, 92% positive predictive value (PPV), and 67% negative predictive value (NPV) in the 70 bladder carcinoma patients. There were 14 false-positives; however, 6 of these had recurred in approximately 5 months. Only 4 out of 33 NED cases recurred in that time period (chi-square = 5.43; degrees of freedom [DF] = 1; P = 0.0198). Thus, a false-positive HA-HAase test carried a significant risk of recurrence within five months (relative risk [RR] = 3.5; odds ratio [OR] = 5.44). In a direct comparison, the HA-HAase and BTA-Stat had 94% and 61% sensitivity, 63% and 74% specificity, 87% and 64% accuracy, 89% and 88% PPV, and 77% and 38% NPV, respectively. While 6 of the 10 false-positive on the HA-HAase test recurred in 5 months (chi-square = 9.6; DF = 1; P = 0.004), only 1 of the 7 false-positives on the BTA-Stat test recurred in that time period (chi-square = 0.096; DF = 1; P = 0.756). The RR and OR for the HA-HAase test were 10.2 and 24, and for the BTA-Stat, 1.4 and 1.5, respectively. In the DOE worker screening study, the HA-HAase and BTA-Stat had 14% (56 out of 401) and 16.7% (67 out of 401) positive rates, respectively. Sixty three percent of the positives on the BTA-Stat test, but only 25% of the positives on the HA-HAase test, had benign urologic conditions. None of the biomarker positive cases with clinical follow-up (n = 29) had evidence of bladder carcinoma. CONCLUSIONS: The HA-HAase test is efficient and superior to the BTA-Stat for detecting and predicting bladder carcinoma recurrence. Noninvasive tests with low false positive rates could be used for bladder carcinoma screening in high-risk populations (e.g., those with occupational exposure to carcinogens or smokers).
Asunto(s)
Biomarcadores de Tumor/orina , Factor H de Complemento/orina , Ácido Hialurónico/orina , Hialuronoglucosaminidasa/orina , Neoplasias de la Vejiga Urinaria/diagnóstico , Humanos , Recurrencia Local de Neoplasia , Neoplasias de la Vejiga Urinaria/orinaRESUMEN
OBJECTIVE: To evaluate the role of BTA stat, BTA TRAK, UBC Rapid, UBC IRMA and voided urinary cytology in the detection of bladder transitional cell carcinoma (TCC). METHODS: The study included 78 patients with TCC of the bladder (group A), 62 patients with a history of bladder TCC without tumor recurrence at the time of examination (B, control group), 20 patients with other malignancy of the urinary tract (C), 38 patients with non-malignant urinary tract diseases (D), 10 patients with urinary tract infection (E) and 10 healthy volunteers (F). Except in group F, voided urine was collected before cystoscopy or cystectomy. RESULTS: The specificity and sensitivity in bladder cancer detection were 87.1 and 74.4%, respectively with BTA stat, 79.3 and 48.7%, respectively with UBC Rapid, 100 and 33.3%, respectively with cytology, 72.6 and 75.6%, respectively with BTA TRAK, 64.5 and 70.5%, respectively with UBC IRMA. CONCLUSIONS: The BTA stat and BTATRAK tests are superior to UBC Rapid, UBC IRMA and urinary cytology in detection of bladder TCC. In daily practice however cytology remains the best adjunct to cystoscopy because of its high sensitivity in Tis and 100% specificity. Cystoscopy cannot be replaced by any of evaluated methods.
Asunto(s)
Antígenos de Neoplasias/orina , Biomarcadores de Tumor/orina , Carcinoma de Células Transicionales/diagnóstico , Factor H de Complemento/orina , Queratinas/orina , Neoplasias de la Vejiga Urinaria/diagnóstico , Adulto , Anciano , Carcinoma de Células Transicionales/orina , Cistoscopía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Muestreo , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/orinaRESUMEN
OBJECTIVES: The BTA stat is a rapid, non-invasive, qualitative urine test that detects bladder tumor-associated antigen (human complement factor H related protein) in urine. The sensitivity of this test is superior to that of urine cytology in detecting primary and recurrent tumors of the urinary bladder. Intravesical instillations are widely used to avoid recurrences and even progression. The objective of this study was to evaluate the effect of intravesical treatments on the BTA stat Test. METHODS: 501 consecutive patients followed up for bladder cancer were studied, of which 490 were eligible for analysis. Three hundred and twenty-seven (66.7%) of the patients had no history of intravesical treatments, whereas the remaining 163 (33.3%) had received treatments: 66 (40.5%) at the time of evaluation. A voided urine sample was obtained prior to cystoscopy and split for culture and BTA stat testing. The overall sensitivity and specificity were calculated and compared to the patients with no, past and present instillations. RESULTS: The overall sensitivity for the BTA stat Test was 56.6%, and the specificity was 76.4%. The specificity of the BTA stat Test was 80.7, 70.7 and 65.3% in those with no, past or present intravesical instillation treatments, respectively. The difference in specificity between those with no and present instillations was significant (p = 0.023), whereas the notable difference between those with no and past instillations did not reach significance (p = 0.076), nor was the difference between patients with past and present instillations significant (p = 0.558). Present instillation of mitomycin C had the strongest adverse effect on the test as the specificity was only 25.0%, whereas past treatment did not interfere with testing. The adverse effect of BCG treatment on testing extended. CONCLUSION: The overall specificity of the test is decreased in patients receiving intravesical treatments, whereas past treatments did not interfere with testing in general. However, the adverse effect of BCG on testing seems to extend, and therefore it is suggested that the BTA stat Test should not be used in patients having received BCG, and in those with present instillation of any type.
Asunto(s)
Antígenos de Neoplasias/orina , Biomarcadores de Tumor/orina , Carcinoma de Células Transicionales/diagnóstico , Neoplasias de la Vejiga Urinaria/diagnóstico , Adyuvantes Inmunológicos/administración & dosificación , Administración Intravesical , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Vacuna BCG/administración & dosificación , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/orina , Factor H de Complemento/orina , Cistoscopía , Femenino , Estudios de Seguimiento , Humanos , Interferones/administración & dosificación , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Estudios Prospectivos , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/orina , Orina/citologíaRESUMEN
PURPOSE: The BTA stat test is a rapid, noninvasive, qualitative urine test that detects bladder tumor associated antigen (human complement factor H related protein) in urine. We compared BTA stat test to voided urine cytology in patients monitored for bladder cancer in a prospective trial, and determined whether this test is effective in detection of recurrence not seen by regular cystoscopy. MATERIALS AND METHODS: A total of 445 consecutive patients with bladder cancer were studied. A voided urine sample was obtained before cystoscopy and divided for culture, cytology and BTA stat testing. In cases of a positive BTA stat test but negative cystoscopy, excretory urography or renal ultrasound, random biopsies and collected ureteral urine samples for ureteral cytology were obtained. The overall sensitivity and specificity as well as positive and negative predictive values for BTA stat test, cytology and their combination were calculated. RESULTS: Of the 445 patients 118 (26.5%) had bladder cancer recurrence on cystoscopy, which was detected by BTA stat test and cytology in 63 (53.4%) and 21 (17.8%), respectively. Of the remaining 327 patients not having recurrent tumor on cystoscopy 81 (24.8%) had a positive BTA stat test. Excretory urography or renal ultrasound and random biopsies in 48 (59.3%) of these patients revealed 7 recurrences, making the total number of recurrent tumors 125 of 412 (30.3%). The overall sensitivities and specificities for the BTA stat test, cytology and their combination were 56.0%, 19.2%, 60.0% and 85.7%, 98.3% and 85.0%, respectively. CONCLUSIONS: The sensitivity for detection of recurrent tumor on BTA stat test is superior to that of voided urine cytology in all bladder cancer categories, whereas the specificity of voided urine cytology is higher than that for BTA stat test. However, a sixth of the patients with apparent false-positive BTA stat test results chosen for further investigation had recurrent tumors that were not found on routine cystoscopy. Although the sensitivity and specificity were highest when both tests were used, the differences were not significant overall. Therefore, the BTA stat test could potentially replace urine cytology for followup of superficial bladder cancer.
Asunto(s)
Antígenos de Neoplasias/orina , Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/orina , Factor H de Complemento/orina , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/orina , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/orina , Biomarcadores de Tumor , Cistoscopía , Humanos , Monitoreo Fisiológico , Estudios Prospectivos , Sensibilidad y Especificidad , Orina/citologíaRESUMEN
OBJECTIVES: To assess the diagnostic quality of human complement factor H-related protein (hcfHrp, BTA STAT(TM)) as a qualitative urinary marker for bladder cancer. METHODS: Urine samples of 354 individuals (76 healthy volunteers, 111 patients with benign urologic disorders, 167 patients with histologically proven bladder cancer) were examined prior to therapy for the presence of hcfHrp. RESULTS: Overall test sensitivity was 62.9%. Sensitivity of low-grade/low-stage tumors was <50% and was thus comparable to published sensitivities of urinary cytology. In high-stage, high-grade tumors sensitivity was 100 and 77.3%, respectively. Superficial tumors with high risk of progression (pT1G3) were detected significantly better (88.9% sensitivity) than low-risk superficial tumors (pTa G1-3/pT1G1-2; 48.2%; p < 0.001). The overall specificity (healthy individuals and patients with benign urologic disease) was 93.0%. CONCLUSION: Since test sensitivity is comparable to urinary cytology and specificity is excellent, hcfHrp should be further evaluated in prospective studies focussing on the follow-up of patients with bladder cancer.
Asunto(s)
Biomarcadores de Tumor/orina , Carcinoma de Células Transicionales/orina , Factor H de Complemento/orina , Neoplasias de la Vejiga Urinaria/orina , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Células Transicionales/diagnóstico , Factor H de Complemento/análisis , Intervalos de Confianza , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/diagnóstico , Enfermedades Urológicas/diagnóstico , Enfermedades Urológicas/orinaRESUMEN
OBJECTIVES: To compare the diagnostic value of two rapid tests, the bladder tumor antigen (BTA stat) test and the newly developed urinary bladder cancer (UBC) Rapid test, in patients having symptoms suggestive of urothelial cell carcinoma (UCC) and patients being followed up after transurethral resection. METHODS: One hundred eighty patients with a mean age of 65.8 years (range 22 to 92) were included in the present study. The tests were performed on voided urine samples. Fifty-seven patients had symptoms suggestive of UCC and 123 patients were being followed up after complete transurethral resection of UCC. The voided urine was evaluated by the BTA stat and UBC Rapid test, which detects cytokeratins 8 and 18. All patients underwent subsequent cystoscopic evaluation and biopsy of any suspicious lesion. RESULTS: In 53 patients with histologically proved UCC, the BTA stat had a sensitivity of 52.8% and the UBC Rapid test of 66%. According to the histologic stage, the sensitivity of the BTA stat was 42.8% in pTa tumors, 61.5% in pT1, and 70% in pT2 or higher tumors. The sensitivity of the UBC test was 60.7% in pTa, 69. 2% in pT1, and 80% in pT2 or higher tumors. For histologic grades 1 to 3, the sensitivity was 38.8%, 52.6%, and 68.7% for the BTA stat and 44.4%, 78.9%, and 75% for the UBC Rapid test, respectively. The specificity was 70% and 90% for the BTA stat and UBC Rapid test, respectively. CONCLUSIONS: The UBC Rapid test was superior to the BTA stat in both sensitivity and specificity. Both assays are simple office procedures and require no special knowledge. However, they cannot replace, but only lower, the number of cystoscopies during the follow-up of patients with previous UCC of the bladder.
Asunto(s)
Biomarcadores de Tumor , Carcinoma de Células Transicionales/diagnóstico , Factor H de Complemento/orina , Queratinas/orina , Neoplasias de la Vejiga Urinaria/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/orina , Biomarcadores de Tumor/normas , Carcinoma de Células Transicionales/cirugía , Carcinoma de Células Transicionales/orina , Cromatografía/normas , Factor H de Complemento/análisis , Cistoscopía/normas , Cistoscopía/estadística & datos numéricos , Estudios de Evaluación como Asunto , Estudios de Seguimiento , Humanos , Queratinas/análisis , Persona de Mediana Edad , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/cirugía , Neoplasias de la Vejiga Urinaria/orinaRESUMEN
BACKGROUND: Human complement factor H-related protein (hCFHrp) is produced by several bladder cancer cell lines and may be useful as a cancer marker. The aim of this study was to compare urinary hCFHrp and cytology for the detection of bladder cancer found by cystoscopy in patients with suggestive signs, symptoms, or preliminary test results. METHODS: The BTA TRAK assay, a quantitative enzyme immunoassay for the bladder tumor-associated antigen in urine, was compared with exfoliative cytology in 220 patients (155 men, 65 women; mean age, 64.2 years) presenting with signs, symptoms, or preliminary diagnostic results suggestive of this disease. Cystoscopy was the standard of detection. RESULTS: In the 100 patients found to have bladder cancer, the overall sensitivities of the BTA TRAK assay (at a previously determined decision threshold of 14 kilounits/L) and cytology were 66% (66 of 100) and 33% (33 of 100), respectively (P <0.001). The BTA TRAK assay proved to be statistically more sensitive than cytology for tumor grades I and II and for stage Ta and T1 tumors. In contrast, the overall specificity of the BTA TRAK assay in the 120 patients without cystoscopically confirmed bladder cancer was 69% (83 of 120) and that of cytology was 99% (119 of 120; P <0.001). The specificity of the BTA TRAK assay was higher in patients without benign or malignant genitourinary disease other than bladder cancer (76%; n = 89) than in patients with these conditions. When the BTA TRAK assay and cytology were used together such that a positive result in either test was scored as positive and the results compared with those of the BTA TRAK assay alone, increases in overall sensitivity and equivalent specificity were observed. CONCLUSION: Because of its relatively high sensitivity, the BTA TRAK assay could complement cytology as an adjunct to cystoscopy in the diagnosis and follow-up of most patients with bladder cancer.
Asunto(s)
Biomarcadores de Tumor/orina , Factor H de Complemento/orina , Neoplasias de la Vejiga Urinaria/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Juego de Reactivos para Diagnóstico , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/orina , Orina/citologíaRESUMEN
OBJECTIVE: The purpose of this study was to assess a new quantitative urinary tumor marker for transitional cell carcinoma of the urinary bladder (TCC), human complement factor H-related protein (hCFHrp, BTA TRAK). METHODS: Urine samples of 298 individuals (76 healthy volunteers, 118 patients with benign urologic disorders, 104 patients with histologically proven bladder cancer) were examined for the presence of hCFHrp. Samples of all patients were obtained prior to therapy. RESULTS: In comparison to healthy volunteers, patients with TCC had significantly higher urinary levels of hCFHrp (117.60 vs. 2.05 U/ml; p < 0.001). HCFHrp levels were positively correlated with tumor grade and stage. Patients with invasive TCC had significantly higher levels of hCFHrp than patients with superficial TCC (p = 0.001). Marker levels in superficial bladder cancer at high risk of tumor progression (pT1G3) were significantly higher as compared to low and intermediate grade superficial cancers. Elevated levels of hCFHrp were also found in patients with benign urologic disorders (median: 72.65 vs. 117.60 U/ml in cancer patients). Using a cutoff of 17.1 U/ml, hCFHrp had a sensitivity of 72.1% and, due to a high rate of false-positive determinations in patients with benign urologic disorders, a total specificity of 50.5%. CONCLUSIONS: HCFHrp (BTA TRAK) is a sensitive test for detection of bladder cancer and for identification of patients at high risk. Due to a high rate of false-positive results in patients with benign urologic diseases, the test should not be used in an unselected population.