[50 years of the Neonatal Screening Program in Catalonia.] / 50 años del Programa de Cribado Neonatal en Cataluña.

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation. That is how the Institute of Clinical Biochemistry was born, whose aims were diagnosis, research and teaching, along with the spirit of contributing to the prevention of mental retardation. The CNSP began with the detection of phenylketonuria (PKU), and, in 1982, the Program was expanded with the inclusion of congenital hypothyroidism detection. Towards 1990, the Program covered almost 100% of all newborns (NB) in Catalonia. In 1999, the CNSP was expanded with the incorporation of cystic fibrosis. It took fourteen years, until 2013, to make the largest expansion so far, with the incorporation of 19 metabolic diseases to the screening panel. The detection of sickle cell disease began in 2015 and in 2017 the detection of severe combined immunodeficiency was included. Currently, the CNSP includes 24 diseases in its main panel. Since 1969, 2,787,807 NBs have been screened, of whom 1,724 have been diagnosed with any of these diseases, and 252 of other disorders by differential diagnosis with those included in the main panel. The global prevalence is 1: 1,617 NBs affected by any of the diseases included in the CNSP and 1: 1,140 NBs if incidental findings diagnosed through the CNSP are included.

El Programa de Cribado Neonatal de Cataluña (PCNC) se inició en el año 1969, en Barcelona, impulsado por el Dr. Juan Sabater Tobella y apoyado por la Diputación de Barcelona y la Fundación Juan March. Así nació el Instituto de Bioquímica Clínica para acometer funciones asistenciales, de investigación y docencia, con el espíritu de contribuir a la prevención del retraso mental. El PCNC se inició con la detección de la fenilcetonuria (PKU) y en el año 1982 se amplió con la detección del hipotiroidismo congénito. Hacia el año 1990 la cobertura territorial llegó casi al 100% de todos los recién nacidos en Cataluña. En 1999 se amplió el PCNC con la incorporación de la fibrosis quística y tras catorce años, en 2013, se realizó la ampliación más numerosa hasta ahora, con la incorporación de la detección de 19 enfermedades metabólicas hereditarias. En el año 2015 comenzó la detección de la enfermedad de células falciformes y en el 2017 la detección de la inmunodeficiencia combinada grave. Actualmente, el PCNC incluye la detección de 24 enfermedades. Desde su inicio en el año 1969, se han cribado 2.787.807 recién nacidos, de los cuales 1.724 han sido diagnosticados de alguna de las 24 enfermedades que componen nuestro panel principal y 252 por diagnóstico diferencial de las primeras. En total la prevalencia global es de 1:1.617 RN afectos de alguna de las enfermedades incluidas en el PCNC y de 1:1.140 RN si se incluyen los hallazgos incidentales encontrados.

Value of urinary levels of interleukin-6, epidermal growth factor, monocyte chemoattractant protein type1 and transforming growth factor ß1 in predicting the extent of fibrosis lesions in kidney biopsies of patients with IgA nephropathy. / Valor de los niveles urinarios de interleucina 6, factor de crecimiento epidérmico, proteína quimioatractante de monocitos de tipo 1 y factor de crecimiento transformante ß1 para la predicción de la extensión de las lesiones de fibrosis en biopsias de enfermos con nefropatía IgA.

OBJECTIVE: To analyse the associations between urinary levels of IL-6 EGF, MCP-1 and TGFß1 and clinical, biochemical and histopathological characteristics in patients with primary IgA nephropathy and their ability to predict the extent of lesions of glomerular and/or interstitial sclerosis. PATIENTS AND METHODS: A total of 58 patients with IgA nephropathy were studied. We determined the urine levels of IL-6, EGF, MCP-1, and TGFß1 at the time of diagnosis. The extent of glomerular and interstitial fibrosis was analyzed by quantitative morphometry and kidney biopsies were classified according to the Oxford criteria. We analysed the ability of these molecules to predict the extent of glomerular and interstitial fibrosis lesions. RESULTS: IL-6, TGFß1 and MCP-1 were associated with focal glomerulosclerosis and interstitial fibrosis extension but not with the presence of mesangial, extracapillary or endocapillary proliferation. EGF showed a negative association with interstitial fibrosis. By categorising patients according to the Oxford classification, patients with T1 and T2 scores had significantly higher levels of IL-6, MCP-1, TGF-ß1 and significantly lower levels of EGF than patients with T0 scores. By multiple regression and logistic regression analyses, the levels of MCP-1, IL-6 and EGF were independent predictors of the fibrosis surface, after adjusting for age and eGFR. CONCLUSION: The urinary concentration of IL-6, EGF and MCP-1 provides additional information that significantly improves the estimation of the surface of interstitial fibrosis in patients with IgA nephropathy.

Clinical features, course and prognosis of idiopathic membranous nephropathy depending on the presence of antibodies against M-type phospholipase A2 receptor.

UNLABELLED: In membranous nephropathy, the presence of antibodies against M-type phospholipase A2 receptor is considered highly specific for idiopathic forms. However, no specific association to a particular clinical profile has been found for such antibodies. OBJECTIVE: To assess potential differences in initial clinical profile, course and prognosis of idiopathic membranous nephropathy depending on the presence of anti-PLA2R antibodies. METHODS: Eighty-five patients with idiopathic membranous nephropathy were included (55 anti-PLA2R-positive and 30 anti-PLA2R-negative). Clinical, biochemical and pathological variables were recorded at the time of diagnosis. Frequency of spontaneous remission, incidence of response to first-line therapy, frequency and number of recurrences, survival of renal function free from renal replacement therapy, survival of renal function free from chronic renal insufficiency and frequency of occurrence of malignant, infectious or autoimmune diseases during follow-up were recorded. RESULTS: At the time of diagnosis, anti-PLA2R-negative patients were significantly older and had a higher frequency of spontaneous remission. No differences were noted in the response to first-line treatment, frequency and number of recurrences, survival of renal function free from renal replacement therapy, or survival of renal function free from chronic renal insufficiency. CONCLUSIONS: Anti-PLA2R-negative patients with idiopathic membranous nephropathy were older and experienced spontaneous remission more often than anti-PLA2R-positive patients. No differences in terms of treatment response, recurrences, and final prognosis were observed between both groups of patients.

Prevalence, diagnostic value and clinical characteristics associated with the presence of circulating levels and renal deposits of antibodies against the M-type phospholipase A2 receptor in idiopathic membranous nephropathy.

UNLABELLED: The M-type phospholipase A2 receptor (PLA2R) has been identified as one of the target antigens of the autoimmune response in idiopathic membranous nephropathy (MN). The prevalence of anti-PLA2R antibodies in patients with idiopathic MN is around 70% but this varies in accordance with geographic region, and until present, anti-PLA2R has not been shown to be associated with any particular clinical profile of the disease. METHODS: We studied 64 adults with nephrotic syndrome who were diagnosed with MN, confirmed by renal biopsy. Forty-seven patients had idiopathic MN and 17 had secondary MN. We determined the presence of circulating anti-PLA2R antibodies by indirect immunofluorescence (IIF) and their titre by ELISA, and we analysed the presence of anti-PLA2R antibody renal deposits by immunohistochemical techniques. We calculated the sensitivity and specificity of the IIF and ELISA techniques for the identification of patients with renal deposits and for the identification of those with idiopathic MN and we tested whether there were differences in the clinical profile of the disease at the time of diagnosis according to the presence or absence of anti-PLA2R antibodies. RESULTS: We did not observe significant differences in the clinical-demographic variables between patients with idiopathic and secondary MN. The prevalence of anti-PLA2R glomerular deposits by IHC was 76.6%. The IIF and ELISA techniques had a similar sensitivity (IIF 94.4% and ELISA 97.2%) and specificity (100%) for the identification of patients with anti-PLA2R renal deposits and the detection of circulating anti-PLA2R antibodies. The determination of anti-PLA2R by IIF identified patients with idiopathic MN with a sensitivity of 72.3% and a specificity of 94.2%. A titre of antibodies >15RU/ml measured by ELISA had a sensitivity of 74.45% and a specificity of 94.2% for the identification of patients with idiopathic MN. Patients with idiopathic MN and anti-PLA2R had significantly higher proteinuria figures (13.25 [P25-P75: 9.05-15.87] compared to 9.43 [P25-P75: 6.30-15] g/day, P:.018). No statistical correlation was observed between the antibody titre measured by ELISA and age, glomerular filtration rate or 24-hour proteinuria or albuminaemia. CONCLUSIONS: The techniques employed to determine anti-PLA2R in patients with MN are highly specific for the diagnosis of idiopathic forms of the glomerular disease. The frequency with which patients with MN and anti-PLA2R were identified is similar to that reported in previous studies. Staining by immunohistochemistry is the most sensitive method for detecting cases of MN associated with the presence of anti-PLA2R antibodies. The IIF and ELISA techniques allow circulating anti-PLA2R antibodies to be detected in most patients with renal deposits, but they may very infrequently have false negative results. The concordance of these tests is high. Patients with idiopathic MN and anti-PLA2R antibody renal deposits have higher proteinuria than patients that are anti-PLA2R negative, but the differences have little clinical importance.

Treatment of idiopathic focal segmental glomerulosclerosis: options in the event of resistance to corticosteroids and calcineurin inhibitors.

Half of patients with nephrotic syndrome caused by primary focal segmental glomerulosclerosis (FSGS) have resistance to treatment with steroids. In the case of corticosteroid resistance,  the best evidence-based option has classically been treatment with calcineurin inhibitors,  although recent studies indicate that mycophenolate may have similar efficacy. In patients with resistance to calcineurin inhibitors,  there is no option that allows the clinical course of the disease to be modified, and this is supported by appropriately designed clinical trials, although observational studies have suggested the potential usefulness of mycophenolate, sirolimus, rituximab, apheresis or high galactose doses as treatment options. In FSGS of idiopathic origin, resistant to steroids and calcineurin inhibitors, before taking the decision whether or not to test other immunosuppressive drugs, it might be appropriate to conduct a systematic analysis that considers: 1) evaluating whether the dose and duration of treatment with steroids and calcineurin inhibitors were suitable, 2) analysing the level of P-glycoprotein expression in lymphocytes, 3) performing a new renal biopsy if there is no electron microscopic study available for the first, 4) in young patients,  considering a genetic study to rule out the presence of the podocin variant pR229Q in combination with heterozygous mutations in NPHS2,  and 5) evaluating the seriousness and difficulty of managing the nephrotic syndrome and the likelihood of progressive loss of renal function. Currently, there are multiple study avenues that attempt to identify the pathogenic mechanisms that cause podocyte injury and there are also several studies underway to analyse the efficacy of drugs such as adalimumab, fresolimumab, rosiglitazone, ACTH (corticotropin) or galactose at high doses, whose preliminary results have generated expectations that require confirmation in larger-scale clinical studies.  In the future, it is possible that a better understanding of the pathogenic pathway or pathways that cause FSGS may allow differentiation between immunomodulable and non-immunomodulable forms,  however, this continues to be a challenge currently.