Cerebrospinal fluid levels of sortilin-1, lipocalin-2, autotaxin, decorin and interleukin-33 in patients with idiopathic intracranial hypertension / Níveis de sortilina-1, lipocalina-2, autotaxina, decorina e interleucina-33 no líquido cefalorraquidiano em pacientes com hipertensão intracraniana idiopática

Abstract Background Idiopathic intracranial hypertension (IIH) is characterized by increased cerebrospinal fluid (CSF) pressure of unknown cause. It has been suggested that the inflammatory process plays a role in the pathophysiology of the disease. Sortilin-1, lipocalin-2, autotaxin, decorin, and interleukin-33 (IL-33) are among the factors involved in inflammatory processes. Objective To investigate the CSF levels of sortilin-1, lipocalin-2, autotaxin, decorin, and IL-33 in patients with IIH. Methods A total of 24 IIH patients and 21 healthy controls were included in the study. Demographic characteristics of the patients and of the control group as well as CSF pressures were evaluated. Sortilin-1, lipocalin-2, autotaxin, decorin and IL-33 levels in the CSF were measured. Results The CSF levels lipocalin-2, sortilin-1, autotaxin, IL-33 and CSF pressure were significantly higher in the patients group compared with the control group (p < 0.001). Decorin levels were reduced in patients (p < 0.05). There was no correlation between the autotaxin and IL-33 levels and age, gender, CSF pressure, and body mass index. The results of our study showed that inflammatory activation plays an important role in the development of the pathophysiology of IIH. In addition, the fact that the markers used in our study have never been studied in the etiopathogenesis of IIH is important in explaining the molecular mechanism of this disease. Conclusion Studies are needed to evaluate the role of these cytokines in the pathophysiology of the disease. It is necessary to evaluate the effects of these molecules on this process.

Resumo Antecedentes A hipertensão intracraniana idiopática (HII) é caracterizada pelo aumento da pressão do líquido cefalorraquidiano (LCR) de causa desconhecida. Tem sido sugerido que o processo inflamatório desempenha um papel na fisiopatologia da doença. Sortilina-1, lipocalina-2, autotaxina, decorina e interleucina-33 (IL-33) estão entre os fatores envolvidos nos processos inflamatórios. Objetivo Investigar os níveis de sortilina-1, lipocalina-2, autotaxina, decorina e IL-33 no LCR de pacientes com HII. Métodos Um total de 24 pacientes com HII e 21 controles saudáveis foram incluídos no estudo. Foram avaliadas as características demográficas dos pacientes e do grupo controle, bem como as pressões liquóricas. Os níveis de sortilina-1, lipocalina-2, autotaxina, decorina e IL-33 no LCR foram medidos. Resultados Os níveis no líquido cefalorraquidiano lipocalina-2, sortilina-1, autotaxina, IL-33 e pressão liquórica foram significativamente maiores no grupo de pacientes em comparação com o grupo controle (p < 0,001). Os níveis de decorina foram reduzidos nos pacientes (p < 0,05). Não houve correlação entre os níveis de autotaxina e IL-33 e idade, sexo, pressão liquórica e índice de massa corporal. Os resultados do nosso estudo mostraram que a ativação inflamatória desempenha um papel importante no desenvolvimento da fisiopatologia da HII. Além disso, o fato de os marcadores utilizados em nosso estudo nunca terem sido estudados na etiopatogenia da HII é importante para explicar o mecanismo molecular dessa doença. Conclusão Estudos são necessários para avaliar o papel dessas citocinas na fisiopatologia da doença. É necessário avaliar os efeitos dessas moléculas nesse processo

Could CA 19-9 be a useful biomarker in the diagnosis, prognosis, and prediction of adequate relief in lower urinary tract obstructions? / O antígeno carboidrato CA 19-9 poderia ser um biomarcador útil no diagnóstico, prognóstico e acompanhamento da obstrução baixa do trato urinário?

ABSTRACT Introduction: posterior urethral valves represent an important cause of childhood chronic kidney disease. The identification of biomarkers that indicate early kidney damage and even adequate clearance could reduce how many patients head towards kidney failure. Objective: this study evaluated how this easy-analysis biomarker (CA 19-9) could help identifying potential renal damage and adequate clearance in obstructive uropathies. Methods: 46 female Wistar rats were divided into 5 groups, with different patterns of partial urinary tract obstruction: group control; group OIV: infravesical obstruction; group OIVd: infravesical obstruction with reversion, obstruction relief 7 postoperative days later; group OUu: unilateral ureteral obstruction; group OUb: bilateral ureteral obstruction. The CA 19-9s performance was compared to another biomarker: Ngal. Determination of basal CA 19-9 and Ngal in urine and blood and serum creatinine levels was performed in the rats prior to surgery (T0) and after 14 days (T1). Group OIVd underwent intermediate (Ti) collection before clearance. Results: the urinary concentration of CA 19-9 increased in groups OIV, OIVd and OUb; elevation at T1 and Ti, reached statistical significance compared to the T0 value (p<0,05). Changes in urinary CA 19-9 were more expressive in infravesical obstruction groups (AUC 0.81). Obstruction relief in group OIVd promoted significant urinary CA 19-9 reduction (p<0,05) in the final evaluation. Conclusions: CA 19-9 urinary concentration increased in partial urinary tract obstruction. Its best performance was in the bladder neck obstruction group, in which the elevation was detected early (6 days after infravesical obstruction) and the CA19-9 urinary concentration declined after clearance.

RESUMO Introdução: a válvula de uretra posterior representa uma importante causa de doença renal crônica na infância. A identificação de biomarcadores que monitorem danos renais precoces e o sucesso da desobstrução do trato urinário podem reduzir o número de pacientes que evoluem para insuficiência renal. Objetivo: avaliar o desempenho do biomarcador antígeno carboidrato CA 19-9 nas obstruções parciais do trato urinário. Método: 46 ratas Wistar foram divididas em 5 grupos: grupo controle; grupo OIV: obstrução infravesical; grupo OIVd: obstrução infravesical com alívio da obstrução após 7 dias; grupo OUu: obstrução ureteral unilateral; grupo OUb: obstrução ureteral bilateral. O desempenho do CA 19-9 foi comparado a outro biomarcador, a Ngal. A dosagem de CA 19-9 e Ngal na urina e no sangue, e os níveis de creatinina sérica foram avaliados nas ratas antes da cirurgia (T0) e após 14 dias (T1). O grupo OIVd foi submetido a uma coleta intermediária (Ti). Resultados: a concentração urinária de CA19-9 aumentou nos grupos OIV, OIVd e OUb; a elevação em T1 e Ti alcançou significância estatística em relação ao valor de T0 (p<0,05). As alterações no CA 19-9 urinário foram mais expressivas nos grupos de obstrução infravesical (AUC 0,81). O alívio da obstrução no grupo OIVd promoveu redução do CA 19-9 urinário (p<0,05). Conclusões: a concentração urinária de CA19-9 aumentou na obstrução parcial do trato urinário. Seu melhor desempenho foi no grupo de obstrução infravesical, no qual a elevação foi detectada precocemente (6 dias de pós-operatório) com queda após a retirada do fator obstrutivo.

Biomarkers of acute kidney injury in patients with nephrotic syndrome / Biomarcadores de lesão renal aguda em pacientes com síndrome nefrótica

ABSTRACT Introduction: Emergence of acute kidney injury (AKI) in patients with nephrotic syndrome (NS) requires prompt diagnosis and differentiation between acute tubular necrosis (ATN) and proliferative glomerulonephritis. We studied the potential use of commercial urinary biomarkers' tests in the diagnosis of AKI in patients with NS. Methods: A cross sectional estimate of urinary concentrations of KIM-1 and NGAL was performed in 40 patients with NS: 9 with proliferative glomerulopathy, being 4 with AKI and 31 without proliferative glomerulopathy, being 15 with AKI. AKI was defined using the KDIGO criteria. Results: The mean age was 35 ± 16 years. The main diagnoses were focal and segmental glomerulosclerosis (10, 25%), membranous glomerulopathy (10, 25%), minimal change disease (7, 18%), lupus nephritis (6, 15%), and proliferative glomerulonephritis (3, 8%). Patients with ATN had higher levels of urinary KIM-1 (P = 0.0157) and NGAL (P = 0.023) than patients without ATN. The urinary concentrations of KIM-1 (P= 0.009) and NGAL (P= 0.002) were higher in patients with AKI than in patients without AKI. Urinary NGAL and KIM-1 levels were significantly higher in patients with ATN without proliferative glomerulonephritis than in patients with proliferative glomerulonephritis (P = 0.003 and P=0.024, respectively). Conclusions: Neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) estimates correlated with histological signs of ATN and were able to discriminate patients with AKI even in conditions of NS. Furthermore, urinary levels of NGAL and KIM-1 may be useful in the differential diagnosis of acute tubular necrosis and exudative glomerulonephritis in patients with nephrotic syndrome.

RESUMO Introdução: O surgimento de lesão renal aguda (LRA) em pacientes com síndrome nefrótica (SN) requer diagnóstico imediato e diferenciação entre necrose tubular aguda (NTA) e glomerulonefrite proliferativa. Avaliamos o uso potencial de testes de biomarcadores urinários comerciais no diagnóstico de LRA em pacientes com SN. Métodos: Uma estimativa transversal das concentrações urinárias de KIM-1 e NGAL foi realizada em 40 pacientes com SN: 9 com glomerulopatia proliferativa, sendo 4 com LRA e 31 sem glomerulopatia proliferativa, sendo 15 com LRA. A LRA foi definida usando os critérios da KDIGO. Resultados: A média de idade foi de 35 ± 16 anos. Os principais diagnósticos foram glomeruloesclerose segmentar e focal (10, 25%), glomerulopatia membranosa (10, 25%), doença por lesão mínima (7, 18%), nefrite lúpica (6, 15%) e glomerulonefrite proliferativa (3, 8 %). Os pacientes com NTA apresentaram níveis mais elevados de KIM-1 urinário (P = 0,0157) e NGAL (P = 0,023) do que pacientes sem NTA. As concentrações urinárias de KIM-1 (P = 0,009) e NGAL (P = 0,002) foram maiores em pacientes com LRA do que em pacientes sem LRA. Os níveis urinários de NGAL e KIM-1 foram significativamente maiores em pacientes com NTA sem glomerulonefrite proliferativa do que em pacientes com glomerulonefrite proliferativa (P = 0,003 e P = 0,024, respectivamente). Conclusões: As estimativas de lipocalina associada a gelatinase de neutrófilos (NGAL) e molécula de lesão renal 1 (KIM-1) se correlacionaram com sinais histológicos de NTA, e foram capazes de discriminar pacientes com LRA mesmo em condições de SN. Além disso, os níveis urinários de NGAL e KIM-1 podem ser úteis no diagnóstico diferencial de necrose tubular aguda e glomerulonefrite exsudativa em pacientes com síndrome nefrótica.

Medición del NGAL urinario en el donante para detectar función retardada del injerto renal en el receptor / NGAL as a marker to detect donor risk factors for delayed graft function

Resumen Introducciónen el trasplante renal de donante fallecido es importante tener marcadores tempranos que ayuden a predecir la funcionalidad adecuada del injerto renal. La medición de creatinina continóa siendo el marcador de elección para definir si los riñones de un posible donante son aptos para ser trasplantados. La lipocalina asociada a la gelatinasa del neutrófilo urinaria (NGALu) es un biomarcador que ha sido utilizado para el diagnóstico temprano de lesión renal aguda, pero su comportamiento es incierto en el donante fallecido. Este estudio tiene como objetivo determinar si los niveles de NGALu del donante pueden predecir la función retardada del injerto (FRI) en los receptores. Métodología: cohorte prospectiva en la que se evaluaron los niveles de NGALu del donante al momento de la extracción renal; se aplicó estadística descriptiva y pruebas no paramétricas. Se exploró el comportamiento de este biomarcador en el donante del injerto renal para determinar si es un factor predictivo de función retardada del injerto. Resultados: se evaluaron 27 donantes de criterios óptimos; el 74,1 % eran hombres, la edad tuvo una mediana de 27 años (rango: 18,8-43,3); la principal causa de muerte fue trauma encefalocraneano, seguido por el accidente cerebrovascular. La creatinina tuvo una mediana de 0,8 mg/dl y los valores de NGALu tuvieron una mediana de 11,1ng/ml (4,2-33,6). En total se realizaron 46 trasplantes, de los cuales el 15,2 % presentaron función retardada del injerto y dos pacientes necesitaron terapia de reemplazo renal en la primera semana luego del trasplante. Los valores de NGALu agrupados de acuerdo a presencia o no de función retardada del injerto fueron de 11,1 ng/ml (3-17,3) en los pacientes sin función retardada del injerto y 11,2 ng/ml en los pacientes con dicha función (7,7-39,4) (p=0,40). En el análisis multivariado no se encontró ningón factor asociado al desarrollo de función retardada del injerto. Conclusión: en este estudio la medición de uNGAL en donantes fallecidos de criterios óptimos no predijo función retardada del injerto.

Abstract Introduction: For deceased donor renal transplantation, it is important to have early markers that can predict the functional outcome of the transplant. Currently, creatinine is the marker of choice for determining whether a potential donor's kidneys are suitable for transplantation. Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a biomarker that has been utilized to diagnose early-stage acute kidney injury, but its behavior in deceased donors is uncertain. The objective of this study was to determine whether donor uNGAL levels can predict delayed graft function in recipients. Methodology: A prospective cohort utilizing descriptive statistics and non-parametric median tests was carried out to evaluate donor uNGAL levels at the time of kidney removal. The behavior of this biomarker was analyzed in kidney transplant donors to evaluate its use as a predictive factor for DGF. Results: A total of 27 standard criteria transplants were evaluated, including 7 (25.9%) women and 20 (74.1%) men with a median age of 27 years (18.75-43.25). The principal cause of death was traumatic head injury, followed by stroke. The median creatinine level was 0.8 mg/dl (0.57-1), and the median uNGAL level was 11.1 ng/ml (4.2-33.6). In total, 46 transplants were performed, of which 15.22% (7 patients) presented with delayed graft function and 2 patients needed renal replacement therapy within the first week after transplantation. The patients were grouped according to the presence of DGF, with median uNGAL values of 11.1 ng/ml (3-17.3) in patients without DGF and median values of 11.2 ng/ml (7.7-39.4) (p=0.4) in those with delayed graft function. No factors were found to be associated with the development of delayed graft function in the multivariate analysis. Discussion: in this study, uNGAL measurements in deceased standard criteria donors did not predict delayed graft function.

Utilidad de la lipocalina asociada a la gelatinasa de neutrófilo urinaria como marcador temprano de insuficiencia renal aguda posterior a una cirugía cardíaca / Utility of the associated lipocalin to neutrophil gelatinase urinary as a marker early of renal failure acute after surgery cardiac

El objetivo del trabajo es determinar los niveles urinarios de la lipocalina asociada a la gelatinasa del neutrófilo (neutrophil gelatinase-associated lipocalin, NGAL) en los pacientes que desarrollan insuficiencia renal aguda después de una cirugía cardíaca y su comparación con las concentraciones de creatinina sérica. El estudio incluyó una cohorte de 21 pacientes de entre 32 y 80 años, sometidos a una cirugía cardíaca en el Servicio de Salud Pública (Hospital San Roque) entre abril y agosto de 2011. Se determinaron los niveles urinarios de NGAL antes de la cirugía, a las 2 horas y a las 6 horas de la intervención. Los pacientes con insuficiencia renal aguda fueron diagnosticados según el criterio de clasificación AKIN. Seis pacientes (30%) desarrollaron insuficiencia renal aguda, cuyo diagnóstico basado en la creatinina sérica se retrasó por 2 o 3 días poscirugía. Por el contrario, los niveles urinarios de NGAL se elevaron significativamente a las 2 horas. En la medición de la NGAL urinaria a las 2 horas de la cirugía, el área bajo la curva ROC fue de 0,962; con una sensibilidad del 100% y una especificidad del 84,6% para predecir insuficiencia renal aguda con un valor de corte de 6,2 ng/ml. Se obtuvieron valores similares cuando se los corrigió por creatinina urinaria. La NGAL urinaria a las 2 horas poscirugía cardíaca fue un marcador precoz para predecir la insuficiencia renal aguda.(AU)

The objective of the study was to determine urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) in patients who develop acute renal failure after cardiac surgery and its comparison with serum creatinine concentrations. The study included a cohort of 21 patients between 32 and 80 years who underwent cardiac surgery in the Public Health Service (Hospital San Roque) during April and August 2011. Urinary NGAL levels were measured before surgery, 2 hours and 6 hours after the intervention. Patients with acute renal failure were diagnosed according to the AKIN classification criteria. Six patients (30%) developed acute renal failure and diagnosis based on serum creatinine was delayed by 2 to 3 days after surgery. By contrast, urinary NGAL levels were significantly elevated 2 hours after surgery. In the measurement of urinary NGAL at 2 hours post-surgery, the area under the ROC curve was 0.962, with a sensitivity 100% and specificity 84.6% to predict acute renal failure with a cut-off point of 6.2 ng/mL, similar values were obtained when they were corrected by urinary creatinine. Urinary NGAL levels 2 hours post-cardiac surgery proved to be an early marker for predicting acute renal failure.(AU)

Reproducción y fertilidad humana: aspectos biomédicos de la familia de las lipocalinas: biología, patobiología y bioclínica / Human reproduction and fertility: biomedical aspects of the lipocalin family: biology, pathobiology and bioclinic aspects

La familia de genes de las lipocalinas (LCN) está compuesta por varios miembros que comparten una estructura común y que se han duplicado en forma repetida durante la evolución expandiéndose a más de 150 genes conocidos, de ellos al menos veinte reportados en la especie humana. El grupo de proteínas de las LCN está constituido por varios elementos que comparten la propiedad común de unión de ligandos lipofílicos. Las LCN funcionan en un amplio rango de sistemas incluyendo quimiorrecepción y transporte en fisiología sensorial del gusto y olor, coloración, modulación hemato-inmune, síntesis de prostanglandina D2, neuro-fisiología, fisiología reproductiva y fertilidad, embriogénesis, proliferación y división celular, supervivencia y apoptosis celular. Es evidente su rol en patobiología y bioclínica reproductiva y de la fertilidad al observar que varias LCN tienen niveles alterados de expresión en diferentes eventos patofisiológicos. Esta revisión resume hallazgos e implicaciones

The family of the lipocalin (LCN) genes is composed by various members that share a common structure and haveduplicated repeatedly during evolution expanding to more than 150 known genes of which at least 20 have been reported in the human species. The group of lipocalin-related proteins is comprised by a number of elements which share various common properties such as binding to different lipophilic ligands. Lipocalins are involved in a broad range of systems including chemoreception and transport functions in sensory physiology of taste and smell, coloration, modulation of hemato-immune response, synthesis of prostaglandin D2, neurophysiology, physiology of reproduction and fertility, embryogenesis, cell proliferation and division, and cell survival and apoptosis. Its role is evident in the pathophysiology and bioclinical aspects of reproduction and fertility consistent with the observation of altered levels of expression of several lipocalins in different pathophysiological events. This review summarizes findings and implications on this topic.