Puigvert Foundation

BACKGROUND: Current knowledge of the risk for postoperative pulmonary complications (PPCs) rests on studies that narrowly selected patients and procedures. Hypothesizing that PPC occurrence could be predicted from a reduced set of perioperative variables, we aimed to develop a predictive index for a broad surgical population. METHODS: Patients undergoing surgical procedures given general, neuraxial, or regional anesthesia in 59 hospitals were randomly selected for this prospective, multicenter study. The main outcome was the development of at least one of the following: respiratory infection, respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax, or aspiration pneumonitis. The cohort was randomly divided into a development subsample to construct a logistic regression model and a validation subsample. A PPC predictive index was constructed. RESULTS: Of 2,464 patients studied, 252 events were observed in 123 (5%). Thirty-day mortality was higher in patients with a PPC (19.5%; 95% [CI], 12.5-26.5%) than in those without a PPC (0.5%; 95% CI, 0.2-0.8%). Regression modeling identified seven independent risk factors: low preoperative arterial oxygen saturation, acute respiratory infection during the previous month, age, preoperative anemia, upper abdominal or intrathoracic surgery, surgical duration of at least 2 h, and emergency surgery. The area under the receiver operating characteristic curve was 90% (95% CI, 85-94%) for the development subsample and 88% (95% CI, 84-93%) for the validation subsample. CONCLUSION: The risk index based on seven objective, easily assessed factors has excellent discriminative ability. The index can be used to assess individual risk of PPC and focus further research on measures to improve patient care.

The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

Individuals who are at risk for autosomal dominant polycystic kidney disease are often screened by ultrasound using diagnostic criteria derived from individuals with mutations in PKD1. Families with mutations in PKD2 typically have less severe disease, suggesting a potential need for different diagnostic criteria. In this study, 577 and 371 at-risk individuals from 58 PKD1 and 39 PKD2 families, respectively, were assessed by renal ultrasound and molecular genotyping. Using sensitivity data derived from genetically affected individuals and specificity data derived from genetically unaffected individuals, various diagnostic criteria were compared. In addition, data sets were created to simulate the PKD1 and PKD2 case mix expected in practice to evaluate the performance of diagnostic criteria for families of unknown genotype. The diagnostic criteria currently in use performed suboptimally for individuals with mutations in PKD2 as a result of reduced test sensitivity. In families of unknown genotype, the presence of three or more (unilateral or bilateral) renal cysts is sufficient for establishing the diagnosis in individuals aged 15 to 39 y, two or more cysts in each kidney is sufficient for individuals aged 40 to 59 y, and four or more cysts in each kidney is required for individuals > or = 60 yr. Conversely, fewer than two renal cysts in at-risk individuals aged > or = 40 yr is sufficient to exclude the disease. These unified diagnostic criteria will be useful for testing individuals who are at risk for autosomal dominant polycystic kidney disease in the usual clinical setting in which molecular genotyping is seldom performed.

BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

BACKGROUND: No externally validated risk score for postoperative pulmonary complications (PPCs) is currently available. The authors tested the generalizability of the Assess Respiratory Risk in Surgical Patients in Catalonia risk score for PPCs in a large European cohort (Prospective Evaluation of a RIsk Score for postoperative pulmonary COmPlications in Europe). METHODS: Sixty-three centers recruited 5,859 surgical patients receiving general, neuraxial, or plexus block anesthesia. The Assess Respiratory Risk in Surgical Patients in Catalonia factors (age, preoperative arterial oxygen saturation in air, acute respiratory infection during the previous month, preoperative anemia, upper abdominal or intrathoracic surgery, surgical duration, and emergency surgery) were recorded, along with PPC occurrence (respiratory infection or failure, bronchospasm, atelectasis, pleural effusion, pneumothorax, or aspiration pneumonitis). Discrimination, calibration, and diagnostic accuracy measures of the Assess Respiratory Risk in Surgical Patients in Catalonia score's performance were calculated for the Prospective Evaluation of a RIsk Score for postoperative pulmonary COmPlications in Europe cohort and three subsamples: Spain, Western Europe, and Eastern Europe. RESULTS: The full Prospective Evaluation of a RIsk Score for postoperative pulmonary COmPlications in Europe data set included 5,099 patients; 725 PPCs were recorded for 404 patients (7.9%). The score's discrimination was good: c-statistic (95% CI), 0.80 (0.78 to 0.82). Predicted versus observed PPC rates for low, intermediate, and high risk were 0.87 and 3.39% (score <26), 7.82 and 12.98% (≥ 26 and <45), and 38.13 and 38.01% (≥ 45), respectively; the positive likelihood ratio for a score of 45 or greater was 7.12 (5.93 to 8.56). The score performed best in the Western Europe subsample-c-statistic, 0.87 (0.83 to 0.90) and positive likelihood ratio, 11.56 (8.63 to 15.47)-and worst in the Eastern Europe subsample. The predicted (5.5%) and observed (5.7%) PPC rates were most similar in the Spain subsample. CONCLUSIONS: The Assess Respiratory Risk in Surgical Patients in Catalonia score predicts three levels of PPC risk in hospitals outside the development setting. Performance differs between geographic areas.

PURPOSE: We evaluate the prognostic factors of recurrence, progression and disease specific mortality in patients with primary superficial Ta and T1 transitional cell carcinoma of the bladder. MATERIALS AND METHODS: We studied a cohort of 1,529 patients with primary superficial transitional cell carcinoma of the bladder treated with transurethral resection and random bladder biopsies. Mean followup was 4.2 years. Statistical analysis was performed using the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model with stepwise forward selection. All p values were 2-sided, with odds ratios and 95% confidence intervals. RESULTS: Multiple tumors (odds ratio 2), tumor greater than 3 cm. (1.65) and carcinoma in situ (1.6) increased, whereas intravesical bacillus Calmette-Guerin (BCG) instillations (0.39) decreased the risk of recurrence. Grade 3 disease (odds ratio 19.9), multiple tumors (1.9), tumor greater than 3 cm. (1.7) and carcinoma in situ (2.1) increased, whereas BCG (0.3) decreased the risk of progression. Grade 3 disease (odds ratio 14) and carcinoma in situ (odds ratio 3) increased the risk of disease specific mortality. CONCLUSIONS: Neither tumor stage nor dysplasia influenced tumor evolution. Multiple tumors, tumor greater than 3 cm. and intravesical BCG instillations were risk factors of recurrence and progression. Carcinoma in situ influenced recurrence, progression and disease specific mortality. Finally, the main predictor of progression and mortality was grade 3 disease.

In an attempt to document the efficacy of potassium citrate in stone formation, 57 patients with active lithiasis (2 or more stones during the preceding 2 years) and hypocitraturia were randomly allocated into 2 groups, with 1 group taking 30 to 60 mEq. potassium citrate daily in wax matrix tablet formation and the other group receiving placebo. In 18 patients receiving potassium citrate for 3 years stone formation significantly declined after treatment from 1.2 +/- 0.6 to 0.1 +/- 0.2 per patient year (p < 0.0001), in 13 patients (72%) the disease was in remission and all patients showed a reduced stone formation rate individually. In contrast, 20 patients taking placebo medication for 3 years showed no significant change in stone formation rate (1.1 +/- 0.4 to 1.1 +/- 0.3 per patient year) and in only 4 patients (20%) was the disease in remission. The stone formation rate during potassium citrate treatment was significantly lower than during the placebo treatment (0.1 +/- 0.2 versus 1.1 +/- 0.3 per patient year, p < 0.001). Potassium citrate therapy caused a significant increase in urinary citrate, pH and potassium, whereas placebo did not. Adverse reactions to potassium citrate were mild causing only 2 patients in the potassium citrate group and 1 in the placebo group to withdraw from the study. In summary, our randomized trial showed the efficacy of potassium citrate in preventing new stone formation in idiopathic hypocitraturic calcium nephrolithiasis.

PURPOSE: We identified risk groups in primary superficial bladder cancer according to progression, mortality and recurrence rates. MATERIALS AND METHODS: The prognostic factors of progression, mortality and recurrence were identified by multivariate analysis in a cohort of 1,529 patients with primary superficial bladder cancer. Risk groups were designed by combining the relative risk of these prognostic factors. We performed survival analysis of progression, tumor mortality and recurrence by risk group using the Kaplan-Meier method. Relative risk in each group was calculated by Cox regression. We present timetables of progression, mortality and recurrence by risk group. RESULTS: Risk groups were classified as low-grade 1 stage Ta disease and a single grade 1 stage T1 tumor, intermediate-multiple grade 1 stage T1 tumors, grade 2 stage Ta disease and a single grade 2 stage T1 tumor, and high-multiple grade 2 stage T1 tumors, grade 3 stages Ta and T1 disease, and any stage disease associated with carcinoma in situ. Survival analysis of progression, mortality and recurrence revealed a statistically significant difference among the 3 risk groups. The rates of recurrence, progression and mortality were 37%, 0% and 0% in the low, 45%, 1.8% and 0.73% in the intermediate, and 54%, 15% and 9.5% in the high risk group, respectively. The relative risks of recurrence, progression and mortality in the low versus the intermediate and high risk groups were 1.37, 2.84 and 1, and 1.87, 24.76 and 14.69, respectively. CONCLUSIONS: Risk group classification based on prognostic factors defines progression, mortality and recurrence rates in primary superficial bladder cancer. It may be useful for designing treatment and followup strategies.

PURPOSE: Although the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines all provide an excellent evidence-based framework for the management of nonmuscle invasive bladder cancer, these guidelines vary with respect to important issues such as risk level definitions and management strategies for these risk categories. Therefore, we built on the existing framework provided by current guidelines, and provide consensus on the definitions of low, intermediate and high risk nonmuscle invasive bladder cancer, as well as practical recommendations for the treatment of patients in each of these risk categories. MATERIALS AND METHODS: An international committee of experts on bladder cancer management identified and analyzed the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines as well as the published English language literature related to the treatment and management of nonmuscle invasive bladder cancer available as of April 2010. RESULTS: Based on review of the current guidelines and literature, the International Bladder Cancer Group developed practical recommendations for the management of nonmuscle invasive bladder cancer. CONCLUSIONS: Complete transurethral bladder tumor resection is recommended for all patients with nonmuscle invasive bladder cancer. For low risk disease a single, immediate chemotherapeutic instillation after transurethral bladder tumor resection is recommended. For intermediate or high risk disease there is no significant benefit from an immediate, postoperative chemotherapeutic instillation. For intermediate risk disease intravesical bacillus Calmette-Guérin with maintenance or intravesical chemotherapy is recommended. For high risk disease bacillus Calmette-Guérin induction plus maintenance is recommended. The appropriate management of recurrence depends on the patient level of risk as well as previous treatment, while the management of treatment failure depends on the type of failure as well as the level of risk for recurrence and disease progression.

CONTEXT.—: Controversies and uncertainty persist in prostate cancer grading. OBJECTIVE.—: To update grading recommendations. DATA SOURCES.—: Critical review of the literature along with pathology and clinician surveys. CONCLUSIONS.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

Recent developments in the genetics and physiology of cystinuria do not support the traditional classification, which is based on the excretion of cystine and dibasic amino acids in obligate heterozygotes. Mutations of only two genes (SLC3A1 and SLC7A9), identified by the International Cystinuria Consortium (ICC), have been found to be responsible for all three types of the disease. The ICC set up a multinational database and collected genetic and clinical data from 224 patients affected by cystinuria, 125 with full genotype definition. Amino acid urinary excretion patterns of 189 heterozygotes with genetic definition and of 83 healthy controls were also included. All SLC3A1 carriers and 14% of SLC7A9 carriers showed a normal amino acid urinary pattern (i.e., type I phenotype). The rest of the SLC7A9 carriers showed phenotype non-I (type III, 80.5%; type II, 5.5%). This makes the traditional classification imprecise. A new classification is needed: type A, due to two mutations of SLC3A1 (rBAT) on chromosome 2 (45.2% in our database); type B, due to two mutations of SLC7A9 on chromosome 19 (53.2% in this series); and a possible third type, AB (1.6%), with one mutation on each of the above-mentioned genes. Clinical data show that cystinuria is more severe in males than in females. The two types of cystinuria (A and B) had a similar outcome in this retrospective study, but the effect of the treatment could not be analyzed. Stone events do not correlate with amino acid urinary excretion. Renal function was clearly impaired in 17% of the patients.

BACKGROUND: Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs. OBJECTIVE AND RATIONALE: In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. SEARCH METHODS: We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'male infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org. OUTCOMES: The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes. WIDER IMPLICATIONS: Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human male infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.

El síndrome hemolítico urémico (SHU) es una entidad clínica definida por la tríada anemia hemolítica no inmune, trombocitopenia e insuficiencia renal aguda, en la que las lesiones subyacentes están mediadas por un proceso de microangiopatía trombótica (MAT) sistémico. Distintas causas pueden desencadenar el proceso de MAT que caracteriza el SHU. En este documento consideramos SHU atípico (SHUa) como el subtipo de SHU en el que los fenómenos de MAT son fundamentalmente consecuencia del daño producido en el endotelio de la microvasculatura renal y de otros órganos por desregulación de la actividad del sistema del complemento. En los últimos años se han identificado diversas mutaciones en genes del sistema del complemento asociados a SHUa, que explicarían aproximadamente el 60% de los casos de SHUa, y se han caracterizado funcionalmente numerosas mutaciones y polimorfismos asociados a SHUa que han permitido determinar que la patología se produce como consecuencia de la deficiente regulación de la activación del complemento sobre las superficies celulares y que lleva al daño endotelial mediado por la activación del C5 y de la vía terminal del complemento. Eculizumab es un anticuerpo monoclonal humanizado que inhibe la activación del C5, bloqueando la generación de la molécula proinflamatoria C5a y la formación del complejo de ataque de membrana. En estudios prospectivos en pacientes con SHUa su administración ha demostrado la interrupción rápida y sostenida del proceso de MAT, con una mejora significativa de la función renal a largo plazo y una reducción importante de la necesidad de diálisis y el cese de la terapia plasmática. En función de las evidencias científicas publicadas y la experiencia clínica acumulada, el Grupo Español de SHUa publicamos un documento de consenso con recomendaciones para el tratamiento de la enfermedad (Nefrología 2013;33(1):27-45). En la presente versión online del documento se actualizan los contenidos sobre la clasificación etiológica de las MAT, la fisiopatología del SHUa, su diagnóstico diferencial y su manejo terapéutico. Haemolytic uraemic syndrome (HUS) is a clinical entity defined as the triad of nonimmune haemolytic anaemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). Different causes can induce the TMA process that characterizes HUS. In this document we consider atypical HUS (aHUS) a sub-type of HUS in which the TMA phenomena are the consequence of the endotelial damage in the microvasculature of the kidneys and other organs due to a disregulation of the activity of the complement system. In recent years, a variety of aHUs-related mutations have been identified in genes of the the complement system, which can explain approximately 60% of the aHUS cases, and a number of mutations and polymorphisms have been functionally characterized. These findings have stablished that aHUS is a consequence of the insufficient regulation of the activiation of the complement on cell surfaces, leading to endotelial damage mediated by C5 and the complement terminal pathway. Eculizumab is a monoclonal antibody that inhibits the activation of C5 and blocks the generation of the pro-inflammatory molecule C5a and the formation of the cell membrane attack complex. In prospective studies in patients with aHUS, the use of Eculizumab has shown a fast and sustained interruption of the TMA process and it has been associated with significative long-term improvements in renal function, the interruption of plasma therapy and important reductions in the need of dialysis. According to the existing literature and the accumulated clinical experience, the Spanish aHUS Group published a consensus document with recommendations for the treatment of aHUs (Nefrologia 2013;33[1]:27-45). In the current online version of this document, we update the aetiological classification of TMAs, the pathophysiology of aHUS, its differential diagnosis and its therapeutic management.

BACKGROUND: Ingestion of cranberry (Vaccinium macrocarpon Ait.) has traditionally been utilized for prevention of urinary tract infections. The proanthocyanidins (PACs) in cranberry, in particular the A-type linkages have been implicated as important inhibitors of primarily P-fimbriated E. coli adhesion to uroepithelial cells. Additional experiments were required to investigate the persistence in urine samples over a broader time period, to determine the most effective dose per day and to determine if the urinary anti-adhesion effect following cranberry is detected within volunteers of different origins. METHODS: Two separate bioassays (a mannose-resistant hemagglutination assay and an original new human T24 epithelial cell-line assay) have assessed the ex-vivo urinary bacterial anti-adhesion activity on urines samples collected from 32 volunteers from Japan, Hungary, Spain and France in a randomized, double-blind versus placebo study. An in vivo Caenorhabditis elegans model was used to evaluate the influence of cranberry regimen on the virulence of E. coli strain. RESULTS: The results indicated a significant bacterial anti-adhesion activity in urine samples collected from volunteers that consumed cranberry powder compared to placebo (p < 0.001). This inhibition was clearly dose-dependent, prolonged (until 24 h with 72 mg of PAC) and increasing with the amount of PAC equivalents consumed in each cranberry powder regimen. An in vivo Caenorhabditis elegans model showed that cranberry acted against bacterial virulence: E. coli strain presented a reduced ability to kill worms after a growth in urines samples of patients who took cranberry capsules. This effect is particularly important with the regimen of 72 mg of PAC. CONCLUSIONS: Administration of PAC-standardized cranberry powder at dosages containing 72 mg of PAC per day may offer some protection against bacterial adhesion and virulence in the urinary tract. This effect may offer a nyctohemeral protection.

Recently, the European Medicines Agency approved the use of the vasopressin V2 receptor antagonist tolvaptan to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adult patients with chronic kidney disease stages 1-3 at initiation of treatment with evidence of rapidly progressing disease. In this paper, on behalf of the ERA-EDTA Working Groups of Inherited Kidney Disorders and European Renal Best Practice, we aim to provide guidance for making the decision as to which ADPKD patients to treat with tolvaptan. The present position statement includes a series of recommendations resulting in a hierarchical decision algorithm that encompasses a sequence of risk-factor assessments in a descending order of reliability. By examining the best-validated markers first, we aim to identify ADPKD patients who have documented rapid disease progression or are likely to have rapid disease progression. We believe that this procedure offers the best opportunity to select patients who are most likely to benefit from tolvaptan, thus improving the benefit-to-risk ratio and cost-effectiveness of this treatment. It is important to emphasize that the decision to initiate treatment requires the consideration of many factors besides eligibility, such as contraindications, potential adverse events, as well as patient motivation and lifestyle factors, and requires shared decision-making with the patient.

BACKGROUND AND OBJECTIVES: The increasing number of podocyte-expressed genes implicated in steroid-resistant nephrotic syndrome (SRNS), the phenotypic variability, and the uncharacterized relative frequency of mutations in these genes in pediatric and adult patients with SRNS complicate their routine genetic analysis. Our aim was to compile the clinical and genetic data of eight podocyte genes analyzed in 110 cases (125 patients) with SRNS (ranging from congenital to adult onset) to provide a genetic testing approach. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Mutation analysis was performed by sequencing the NPHS1, NPHS2, TRPC6, CD2AP, PLCE1, INF2, WT1 (exons 8 and 9), and ACTN4 (exons 1 to 10) genes. RESULTS: We identified causing mutations in 34% (37/110) of SRNS patients, representing 67% (16/24) familial and 25% (21/86) sporadic cases. Mutations were detected in 100% of congenital-onset, 57% of infantile-onset, 24 and 36% of early and late childhood-onset, 25% of adolescent-onset, and 14% of adult-onset patients. The most frequently mutated gene was NPHS1 in congenital onset and NPHS2 in the other groups. A partial remission was observed in 7 of 26 mutation carriers treated with immunosuppressive agents and/or angiotensin-converting enzyme inhibitors. Patients with NPHS1 mutations showed a faster progression to ESRD than patients with NPHS2 mutations. None of these mutation carriers relapsed after kidney transplantation. CONCLUSIONS: We propose a genetic testing algorithm for SRNS based on the age at onset and the familial/sporadic status. Mutation analysis of specific podocyte-genes has a clinical value in all age groups, especially in children.

A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab.

BACKGROUND: Postoperative respiratory failure (PRF) is the most frequent respiratory complication following surgery. OBJECTIVE: The objective of this study was to build a clinically useful predictive model for the development of PRF. DESIGN: A prospective observational study of a multicentre cohort. SETTING: Sixty-three hospitals across Europe. PATIENTS: Patients undergoing any surgical procedure under general or regional anaesthesia during 7-day recruitment periods. MAIN OUTCOME MEASURES: Development of PRF within 5 days of surgery. PRF was defined by a partial pressure of oxygen in arterial blood (PaO2) less than 8 kPa or new onset oxyhaemoglobin saturation measured by pulse oximetry (SpO2) less than 90% whilst breathing room air that required conventional oxygen therapy, noninvasive or invasive mechanical ventilation. RESULTS: PRF developed in 224 patients (4.2% of the 5384 patients studied). In-hospital mortality [95% confidence interval (95% CI)] was higher in patients who developed PRF [10.3% (6.3 to 14.3) vs. 0.4% (0.2 to 0.6)]. Regression modelling identified a predictive PRF score that includes seven independent risk factors: low preoperative SpO2; at least one preoperative respiratory symptom; preoperative chronic liver disease; history of congestive heart failure; open intrathoracic or upper abdominal surgery; surgical procedure lasting at least 2 h; and emergency surgery. The area under the receiver operating characteristic curve (c-statistic) was 0.82 (95% CI 0.79 to 0.85) and the Hosmer-Lemeshow goodness-of-fit statistic was 7.08 (P = 0.253). CONCLUSION: A risk score based on seven objective, easily assessed factors was able to predict which patients would develop PRF. The score could potentially facilitate preoperative risk assessment and management and provide a basis for testing interventions to improve outcomes.The study was registered at ClinicalTrials.gov (identifier NCT01346709).

Abstract Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10 −12 ) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10 −14 ), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10 −103 ) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10 −49 ), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10 −93 ), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10 −23 and OR = 3.39, P = 5.2 × 10 −82 , respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

Male infertility is a multifactorial complex disease with highly heterogeneous phenotypic representation and in at least 15% of cases, this condition is related to known genetic disorders, including both chromosomal and single-gene alterations. In about 40% of primary testicular failure, the etiology remains unknown and a portion of them is likely to be caused by not yet identified genetic anomalies. During the last 10 years, the search for 'hidden' genetic factors was largely unsuccessful in identifying recurrent genetic factors with potential clinical application. The armamentarium of diagnostic tests has been implemented only by the screening for Y chromosome-linked gr/gr deletion in those populations for which consistent data with risk estimate are available. On the other hand, it is clearly demonstrated by both single nucleotide polymorphisms and comparative genomic hybridization arrays, that there is a rare variant burden (especially relevant concerning deletions) in men with impaired spermatogenesis. In the era of next generation sequencing (NGS), we expect to expand our diagnostic skills, since mutations in several hundred genes can potentially lead to infertility and each of them is likely responsible for only a small fraction of cases. In this regard, system biology, which allows revealing possible gene interactions and common biological pathways, will provide an informative tool for NGS data interpretation. Although these novel approaches will certainly help in discovering 'hidden' genetic factors, a more comprehensive picture of the etiopathogenesis of idiopathic male infertility will only be achieved by a parallel investigation of the complex world of gene environmental interaction and epigenetics.