Urinary CXCL10 specifically relates to HLA-DQ eplet mismatch load in kidney transplant recipients.

BACKGROUND: Urinary CXCL10 (uCXCL10) is associated with graft inflammation and graft survival, but the factors related to its excretion are not well known. HLA molecular matching at epitope level allow estimating the "dissimilarity" between donor and recipient HLA more precisely, being better related to further transplant outcomes. The relationship between uCXCL10 and HLA molecular mismatch has not been previously explored. METHODS: HLA class I and class II typing of some 65 recipients and their donors was retrospectively performed by high resolution sequence-specific-primer (Life Technologies, Brown Deer, WI). The HLA-Matchmaker 3.1 software was used to assess eplet matching. Urine samples collected on the day of the 1-year surveillance biopsy were available of these 65 patients. uCXCL10 was measured using a commercial enzyme-linked immunoassay kit. RESULTS: 1-year uCXCL10 was independently associated with HLA-DQB1 eplet mismatch load (ß 0.300, 95%CI 0.010-0.058, p = 0.006). Kidney transplant recipients with a HLA-DQB1 eplet mismatch load >3 showed higher values of uCXCL10 at 1-year (p = 0.018) than those with ≤3. Patients with a HLA-DQB1 eplet mismatch load >3 with subclinical AbMR had significantly higher levels of the logarithm of 1-year uCXCL10 (No AbMR 0.88, IQR 0.37; AbMR 1.38, IQR 0.34, p = 0.002) than those without AbMR. CONCLUSIONS: uCXCL10 specifically relates to HLA-DQ eplet mismatch load. This relationship can partly explain the previously reported association between uCXCL10 excretion and graft inflammation. An adequate evaluation of any potential non-invasive biomarker, such as uCXCL10, must take into account the HLA molecular mismatch.

Urinary C-X-C Motif Chemokine 10 Is Related to Acute Graft Lesions Secondary to T Cell- and Antibody-Mediated Damage.

BACKGROUND Non-invasive biomarkers of graft rejection are needed to optimize the management and outcomes of kidney transplant recipients. Urinary excretion of IFN-g-related chemokine CXCL10 is clearly associated with clinical and subclinical T cell-mediated graft inflammation, but its relationship with antibody-mediated damage has not been fully addressed. Further, the variables influencing levels of urinary CXCL10 excretion are unknown. MATERIAL AND METHODS A total of 151 kidney graft biopsies (92 surveillance and 59 indication biopsies) and 151 matched urine samples obtained before biopsy were prospectively analyzed. T cell-mediated rejection (TCMR) and antibody-mediated rejection (AbMR) were defined according to the 2017 Banff classification criteria. Urinary CXCL10 levels were measured by ELISA and corrected by urinary creatinine. RESULTS Banff scores 't', 'i', 'g', and 'ptc' were significantly related to urinary CXCL10 levels. Multivariate analysis showed that 't' (ß=0.107, P=0.001) and 'ptc' (ß=0.093, P=0.002) were significantly associated with urinary CXCL10. Donor-specific antibodies (DSAs) were related to the high excretion of urinary CXCL10 at 1 year after transplantation (odds ratio [OR] 17.817, P=0.003). Urinary CXCL10 showed good discrimination ability for AbMR (AUC-ROC 0.760, P=0.001). The third tertile of urinary CXCL10 remained significantly associated with AbMR (OR 4.577, 95% confidence interval 1.799-11.646, P=0.001) after multivariate regression analysis. CONCLUSIONS DSA was the only variable clearly related to high urinary CXCL10 levels. Urinary CXCL10 is a good non-invasive candidate biomarker of AbMR and TCMR, supplying information independent of renal function and other variables normally used to monitor kidney transplants.

CCL20 blockade increases the severity of nephrotoxic folic acid-induced acute kidney injury.

The chemokine CCL20 activates the CCR6 receptor and has been implicated in the pathogenesis of glomerular injury. However, it is unknown whether it contributes to acute kidney injury (AKI). We identified CCL20 as upregulated in a systems biology strategy combining transcriptomics of kidney tissue from experimental toxic folic acid-induced AKI and from stressed cultured tubular cells and have explored the expression and function of CCL20 in experimental and clinical AKI. CCL20 upregulation was confirmed in three models of kidney injury induced by a folic acid overdose, cisplatin or unilateral ureteral obstruction. In injured kidneys, CCL20 was expressed by tubular, endothelial, and interstitial cells, and was also upregulated in human kidneys with AKI. Urinary CCL20 was increased in human AKI and was associated with severity. The function of CCL20 in nephrotoxic folic acid-induced AKI was assessed by using neutralising anti-CCL20 antibodies or CCR6-deficient mice. CCL20/CCR6 targeting increased the severity of kidney failure and mortality. This was associated with more severe histological injury, nephrocalcinosis, capillary rarefaction, and fibrosis, as well as higher expression of tubular injury-associated genes. Surprisingly, mice with CCL20 blockade had a lower tubular proliferative response and a higher number of cells in the G2/M phase, suggesting impaired repair mechanisms. This may be related to a lower influx of Tregs, despite a milder inflammatory response in terms of chemokine expression and infiltration by IL-17+ cells and neutrophils. In conclusion, CCL20 has a nephroprotective role during AKI, both by decreasing tissue injury and by facilitating repair. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Long-Term Mortality among Hospitalized Non-ICU Patients with Acute Kidney Injury Referred to Nephrology.

BACKGROUND: Epidemiological studies of acute kidney injury (AKI) have focused on patients admitted to intensive care units (ICUs), and several have studied hospitalized non-ICU patients, but analysis of patients referred to Nephrology is sparse. We analyzed factors associated with short- and long-term morbimortality among hospitalized non-ICU patients with AKI who were referred to Nephrology. METHODS: A retrospective study with data prospectively collected from 170 non-ICU patients, with referral to the Nephrology Unit, recruited over a 4-year period, was performed. AKI was classified according to the criteria based on risk, injury, failure, loss of kidney function and end-stage kidney disease (RIFLE). Risk factors that could influence prognosis of AKI and long-term mortality were analyzed at admission. Early on, 1- and 10-year mortalities were correlated with AKI RIFLE class, clinical and demographic characteristics. RESULTS: Most patients were >65 years, with multiple comorbidities and frequent drug intake history. Median Charlson score was 6. Twenty-five percent of patients with previously unknown chronic kidney disease (CKD) were diagnosed with CKD during the study. Dialysis was required in 13.5% of patients. Hospital deaths were 22.4% and significantly associated with older age, RIFLE class L, higher peak serum creatinine, oliguria and decreased serum albumin levels. One-year (38.8%) and 10-year (68.8%) mortalities were significantly associated with age, prior cardiovascular disease, prior CKD and RIFLE class L. According to the Cox proportional hazard model, age, prior CKD and RIFLE class L were independent risk factors of death at 1 and 10 years. CONCLUSIONS: AKI in hospitalized non-ICU patients is associated with high early and late mortality. This study increases our understanding of AKI among this specific population and can improve their management.

Cobertura y costes del cribado oportunista de detección precoz del cáncer de cuello uterino en Cantabria / Coverage and costs of opportunistic screening for cervical cancer in Cantabria (Spain)

Objetivo Analizar el cribado del cáncer de cuello uterino en Cantabria, evaluando la cobertura y los costes del cribado, y calculando los costes directos conocidos de la enfermedad y los costes indirectos debidos a su mortalidad. Métodos En 189.111 mujeres entre 21 y 65 años de edad (población susceptible de cribado del cáncer de cuello uterino) del padrón del año 2011 de Cantabria se realizó un estudio descriptivo transversal cuantitativo y cualitativo de las citologías realizadas, y se analizaron los costes directos e indirectos debidos al tumor. Resultados Durante los años 2006 a 2011, el 51% de las mujeres del grupo de estudio se realizó una citología, y el 26% dos. En 2011 se hicieron 31.554 citologías en Cantabria y sus costes directos fueron de 2.904.760 Euros. Los costes directos asistenciales debidos al tumor fueron de 567.567 Euros, promedio anual para el periodo 2008-2010. Los costes indirectos anuales (promedio 2001-2008) del cáncer de cuello uterino ascienden a 386.122,02 Euros, en el escenario de referencia considerado. Conclusión Sólo un 26% de las mujeres de Cantabria se realizan citologías con la periodicidad aconsejada en el protocolo oportunista vigente. Los datos de costes presentados en este trabajo pueden ser útiles para futuras evaluaciones económicas(AU)

Objective To analyze cervical cancer screening performed in Cantabria by evaluating the coverage and costs of screening and by calculating the available direct costs of the disease and the indirect costs of cervical cancer mortality. Methods Screening for cervical cancer is performed in women aged between 21 and 65. According to the census for 2011 in Cantabria, there were 189.111 women in this age group. We performed a cross sectional, quantitative and qualitative study of the Pap smears performed and analyzed the direct and indirect costs of cervical cancer. Results Between 2006 and 2011, 51% of women studied had one Pap smear, and 26% had two. In 2011, 31.554 Pap smears were performed in opportunistic screening in Cantabria, and the direct cost was 2,904.760 Euros. The annual direct cost of cervical cancer (average 2008-2010) was 567.567 Euros. The annual indirect costs (average 2001-2008) of cervical cancer was 386.122.02 Euros, in the reference scenario considered. Conclusions Only 26% of women in Cantabria attended screening within the intervals recommended in the current opportunistic protocol. The cost data provided in this study may be useful for future economic evaluations (AU)

[Coverage and costs of opportunistic screening for cervical cancer in Cantabria (Spain)]. / Cobertura y costes del cribado oportunista de detección precoz del cáncer de cuello uterino en Cantabria.

OBJECTIVE: To analyze cervical cancer screening performed in Cantabria by evaluating the coverage and costs of screening and by calculating the available direct costs of the disease and the indirect costs of cervical cancer mortality. METHODS: Screening for cervical cancer is performed in women aged between 21 and 65. According to the census for 2011 in Cantabria, there were 189.111 women in this age group. We performed a cross sectional, quantitative and qualitative study of the Pap smears performed and analyzed the direct and indirect costs of cervical cancer. RESULTS: Between 2006 and 2011, 51% of women studied had one Pap smear, and 26% had two. In 2011, 31.554 Pap smears were performed in opportunistic screening in Cantabria, and the direct cost was 2,904.760 €. The annual direct cost of cervical cancer (average 2008-2010) was 567.567 €. The annual indirect costs (average 2001-2008) of cervical cancer was 386.122.02 €, in the reference scenario considered. CONCLUSIONS: Only 26% of women in Cantabria attended screening within the intervals recommended in the current opportunistic protocol. The cost data provided in this study may be useful for future economic evaluations.