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.

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.

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.

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.

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.

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.

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. 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. Primary membranous nephropathy (PMN) is one of the most common causes of nephrotic syndrome in adults.1Couser W. Primary membranous nephropathy.Clin J Am Soc Nephrol. 2017; 12: 983-997Crossref PubMed Scopus (245) Google Scholar In 70%–80% of cases, the disease is mediated by autoantibodies targeting the phospholipase A2 receptor (PLA2R) expressed in podocytes and in 3%–5% by autoantibodies to thrombospondin type 1 domain–containing 7A (THSD7A).2Beck Jr., L.H. Bonegio R.G. Lambeau G. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1419) Google Scholar, 3Ronco P. Debiec H. Molecular pathogenesis of membranous nephropathy.Annu Rev Pathol. 2020; 15: 287-313Crossref PubMed Scopus (42) Google Scholar, 4Tomas N.M. Beck Jr., L.H. Meyer-Schwesinger C. et al.Thrombospondin type-1 domain–containing 7A in idiopathic membranous nephropathy.N Engl J Med. 2014; 371: 2277-2287Crossref PubMed Scopus (496) Google Scholar Spontaneous remission occurs in one-third of patients,5Polanco N. Gutiérrez E. Covarsí A. et al.Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy.J Am Soc Nephrol. 2010; 21: 697-704Crossref PubMed Scopus (248) Google Scholar and therefore an observational period of at least 6 months is recommended.6Waldman M. Austin H.A. Treatment of idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1617-1630Crossref PubMed Scopus (62) Google Scholar, 7Hofstra J.M. Fervenza F.C. Wetzels J.F.M. Treatment of idiopathic membranous nephropathy.Nat Rev Nephrol. 2013; 9: 443-458Crossref PubMed Scopus (88) Google Scholar, 8Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guidelines for glomerulonephritis.Kidney Int Suppl. 2012; 2 (139–27)Google Scholar Conversely, about 50% of cases with persistent nephrotic syndrome eventually progress to end-stage kidney disease, and immunosuppressive therapy is recommended for these patients. Controversy persists about the most effective type of immunosuppressive regimen. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for glomerulonephritis recommended a 6-month cyclic regimen of alternating alkylating agents (usually cyclophosphamide) plus corticosteroids for patients at high risk of progression, since it was the only regimen that was shown to be effective in preventing end-stage kidney disease.8Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guidelines for glomerulonephritis.Kidney Int Suppl. 2012; 2 (139–27)Google Scholar, 9Ponticelli C. Zucchelli P. Passerini P. et al.A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy.N Engl J Med. 1989; 320: 8-13Crossref PubMed Scopus (240) Google Scholar, 10Ponticelli C. Zucchelli P. Passerini P. et al.A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int. 1995; 48: 1600-1604Abstract Full Text PDF PubMed Scopus (336) Google Scholar, 11Ponticelli C. Altieri P. Scolari F. et al.A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.J Am Soc Nephrol. 1998; 9: 444-450Crossref PubMed Google Scholar, 12Jha V. Ganguli A. Saha T.K. et al.A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy.J Am Soc Nephrol. 2007; 18: 1899-1904Crossref PubMed Scopus (215) Google Scholar However, given the important number of serious adverse events associated with cumulative doses of alkylating agents, treatment alternatives were introduced. Calcineurin inhibitors (both cyclosporine and tacrolimus) have shown efficacy in inducing remission of nephrotic syndrome in about 70% of patients.13Cattran D.C. Appel G.B. Hebert L.A. et al.Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.Kidney Int. 2001; 59: 1484-1490Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar,14Praga M. Barrio V. Juárez G.F. Luño J. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial.Kidney Int. 2007; 71: 924-930Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar However, the main limitation of these drugs is the high rate of relapse after discontinuation. An observational study found a reduction in relapse rates when rituximab was administered at the time of tapering off cyclosporine or tacrolimus,15Segarra A. Praga M. Ramos N. et al.Successful treatment of membranous glomerulonephritis with rituximab in calcineurin inhibitor-dependent patients.Clin J Am Soc Nephrol. 2009; 4: 1083-1088Crossref PubMed Scopus (82) Google Scholar and a pilot study reported encouraging results of a combined therapy with cyclosporine plus rituximab in high-risk PMN patients.16Waldman M. Beck Jr., L.H. Braun M. et al.Membranous nephropathy: pilot study of a novel regimen cyclosporine and Int Full Text Full Text PDF PubMed Scopus Google Scholar the efficacy of rituximab monotherapy P. P. A. et in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: PubMed Scopus Google Scholar A of rituximab was to be effective for of remission in an observational P. P. G. rituximab to to therapy in idiopathic membranous nephropathy.Clin J Am Soc Nephrol. 2007; PubMed Scopus Google Scholar in clinical higher doses were for Debiec H. E. et for membranous nephropathy: a 6-month trial with Am Soc Nephrol. 2017; PubMed Scopus Google Scholar, F.C. Appel G.B. et or cyclosporine in the treatment of membranous nephropathy.N Engl J Med. PubMed Scopus Google Scholar, Debiec H. et rituximab and remission in membranous nephropathy.Clin J Am Soc Nephrol. PubMed Scopus Google Scholar the superior efficacy of rituximab versus cyclosporine in the of study was achieved a of F.C. Appel G.B. et or cyclosporine in the treatment of membranous nephropathy.N Engl J Med. PubMed Scopus Google Scholar The for comparing the 6-month cyclic alternating treatment with corticosteroids and cyclophosphamide with the alternatives was in a J. D.C. et and treatment of a Kidney Disease: Improving Global Outcomes (KDIGO) Int. Full Text Full Text PDF PubMed Scopus Google Scholar We the Treatment with Tacrolimus and and in study to cyclic alternating treatment of corticosteroids and cyclophosphamide with a sequential treatment of tacrolimus and rituximab in the and of nephrotic syndrome remission for 24 months. In the of after remission and the of anti-PLA2R autoantibodies the of the patients were for of were the for were the to in the study and of a of membranous nephropathy The 86 patients who the were assigned to the corticosteroid-cyclophosphamide group or to the tacrolimus-rituximab group in significant groups were at were in and anti-PLA2R was in showed at and patients patients with or anti-PLA2R at and patient was Kidney were months patients PMN and PMN to treatment patients was to the Kidney as of of 6 of 43 patients anti-PLA2R was at of 11 of 43 patients anti-PLA2R was at treatment of of 43 of 43 of of 43 of 43 A2 receptor receptor as or was to the Kidney Anti-PLA2R as In 6 of 43 patients anti-PLA2R was at In 11 of 43 patients anti-PLA2R was at in a A2 receptor receptor as or patients at least 1 month of the assigned patients in the corticosteroid-cyclophosphamide group and 6 in the tacrolimus-rituximab group the The in the corticosteroid-cyclophosphamide group and in the tacrolimus-rituximab the complete assigned to the corticosteroid-cyclophosphamide group a of methylprednisolone of in months and with a cumulative of The cumulative of methylprednisolone was The cumulative of cyclophosphamide was and of tacrolimus in the tacrolimus-rituximab group in patients in group a of rituximab in 2 1 in 1 at months and and 2 doses of tacrolimus month the follow-up period after the of the assigned patients in each group were to a to a of efficacy of the assigned In the corticosteroid-cyclophosphamide group, 2 patients were with rituximab at month 2 patients tacrolimus month and 1 patient cyclosporine month In the tacrolimus-rituximab group, the patients a 6-month cyclic treatment with corticosteroid and cyclophosphamide at month month or month the patients who were to a were to be was complete in of the 86 patients. patients (83.7%) in the corticosteroid-cyclophosphamide group and 25 patients (58.1%) in the tacrolimus-rituximab group a primary outcome of remission at 24 months (relative risk 95% confidence interval 1.08 to The significant in the primary outcome of in the corticosteroid-cyclophosphamide group and of in the tacrolimus-rituximab group 95% to The in the number of patients with complete or partial remission in both groups was significant at month and was the study outcome of complete or partial remission at to 24 cyclophosphamide risk of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 cyclophosphamide risk of of of of of of of of of of confidence the patients who the the patients who the of trial In both the primary outcome was the composite of complete or partial remission at 24 or 95% in a confidence The the patients who the the patients who the of trial In both the primary outcome was the composite of complete or partial remission at 24 months. or 95% shown in and 26 patients (60%) in the corticosteroid-cyclophosphamide group achieved complete remission at 24 months. In the tacrolimus-rituximab group, 11 patients (26%) achieved complete remission at 24 months 95% 1.34 to remission at to 24 cyclophosphamide risk of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 cyclophosphamide risk of of of of of of of of of of confidence the patients who the the patients who the of trial In both the primary outcome was the composite of complete or partial remission at 24 or 95% in a confidence The the patients who the the patients who the of trial In both the primary outcome was the composite of complete or partial remission at 24 months. or 95% A for a greater efficacy of the corticosteroid-cyclophosphamide treatment was found by of anti-PLA2R and were found in patients of patients were compared who achieved remission and with a significantly higher proportion of and a significantly higher were a at to at 24 months in the corticosteroid-cyclophosphamide group and at to 1 at 24 months in the tacrolimus-rituximab group a at to at 24 months in the corticosteroid-cyclophosphamide group and at to at 24 months in the tacrolimus-rituximab group was a for higher of rate in the corticosteroid-cyclophosphamide group than in the tacrolimus-rituximab group the follow-up 24 the of patients with a of were 1 in the corticosteroid-cyclophosphamide group and in the tacrolimus-rituximab group The of patients with at 24 months were in the corticosteroid-cyclophosphamide group and in the tacrolimus-rituximab group The only patient who end-stage kidney disease was a who assigned to the corticosteroid-cyclophosphamide group. months after treatment was the study of persistent and and to rituximab doses of 1 response was and was months after Anti-PLA2R showed a significant decrease in both groups The of patients who achieved response at and 6 months were significantly higher in the corticosteroid-cyclophosphamide group (77% and 92%, than in the tacrolimus-rituximab group (45% and 70%, patients who achieved response the study remission of nephrotic syndrome at 24 months. response at months and 6 months was associated with remission at 24 months. patients showed a in anti-PLA2R and a significantly proportion of compared with patients who achieved a complete or partial remission of nephrotic syndrome of anti-PLA2R and of response to treatment phospholipase A2 of were compared with the in a phospholipase A2 of were compared with the of the 36 patients in the corticosteroid-cyclophosphamide group, and of the 25 patients in the tacrolimus-rituximab group who achieved partial remission a relapse The in the tacrolimus-rituximab group occurred at month months after tacrolimus discontinuation. of occurred in patients who an response at month 6 and were by a of anti-PLA2R The relapse occurred in a patient in anti-PLA2R at Tacrolimus was in 2 patients and the one was with The relapse in the corticosteroid-cyclophosphamide group occurred at month in an patient who response at month In the relapse was by a of anti-PLA2R and the patient was with patients 6 the corticosteroid-cyclophosphamide group and the tacrolimus-rituximab at least 1 adverse adverse events were of or but were were adverse events and adverse events patient in the corticosteroid-cyclophosphamide group than in the tacrolimus-rituximab group patients in the corticosteroid-cyclophosphamide group and kidney and were common in the tacrolimus-rituximab group. was a significant the of and the of both in the trial and in each treatment group for the group and for the cyclophosphamide group, for the adverse events occurred the months of the trial of but only of the serious adverse events occurred events to treatment for the in number of events adverse adverse adverse events in at least of patients or serious adverse and kidney for patients as for events as for the in number of events groups. in a for patients as for events as were significant in the of serious adverse events groups. The only of serious kidney occurred in the tacrolimus-rituximab group, of the serious occurred in the corticosteroid-cyclophosphamide group. cases of were of was to be to the treatment occurred in the corticosteroid-cyclophosphamide group and at and 11 and 1 in the tacrolimus-rituximab group at 1 Anti-PLA2R was at in the patients with the time of the 2 patients in the corticosteroid-cyclophosphamide group were in clinical The study to the that sequential therapy with tacrolimus and rituximab was superior to cyclic alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in patients with In found that treatment with corticosteroid and cyclophosphamide was effective than sequential treatment with tacrolimus and rituximab in inducing The of was in the corticosteroid-cyclophosphamide group, with a significant in the number of at months. most were complete in the corticosteroid-cyclophosphamide group, most were partial in the tacrolimus-rituximab group. with calcineurin inhibitors and rituximab have that these drugs effective at inducing remission in that the of calcineurin inhibitors in PMN be to in a C. M. et of kidney podocytes is a target of the of cyclosporine Med. PubMed Scopus Google Scholar However, found that tacrolimus induced a decrease in anti-PLA2R in with A. V. et follow-up study of membranous nephropathy with tacrolimus and corticosteroids versus cyclical corticosteroids and Int 2017; Full Text Full Text PDF PubMed Scopus Google Scholar The main limitation of calcineurin inhibitors is the high relapse rate after in of patients. In the F.C. Appel G.B. et or cyclosporine in the treatment of membranous nephropathy.N Engl J Med. PubMed Scopus Google Scholar rituximab at 1 and after and 2 at month 6 the patient complete was compared with cyclosporine given for months. were significant in the number of at months. However, a higher proportion of patients in the cyclosporine group after treatment and the number of patients in remission at 24 months was significantly higher in the rituximab group In the number of at 6 months was in the tacrolimus-rituximab group than in the corticosteroid-cyclophosphamide group. at month 6 the in remission the number of complete after rituximab An important was the number of after tacrolimus discontinuation. This with a observational study that reported a of at the of calcineurin to in PMN patients who to cyclosporine or A. Praga M. Ramos N. et al.Successful treatment of membranous glomerulonephritis with rituximab in calcineurin inhibitor-dependent patients.Clin J Am Soc Nephrol. 2009; 4: 1083-1088Crossref PubMed Scopus (82) Google Scholar The pathogenesis of after tacrolimus in PMN and the rituximab rituximab is effective in the number of nephrotic syndrome in kidney as disease and and M. et for nephrotic syndrome or nephrotic a 2014; Full Text Full Text PDF PubMed Scopus Google P. P. et in or idiopathic nephrotic Am Soc Nephrol. 2014; PubMed Scopus Google Scholar In the the number of for the than number of at 24 months. the response rate of in the tacrolimus-rituximab group was similar to that with in Debiec H. E. et for membranous nephropathy: a 6-month trial with Am Soc Nephrol. 2017; PubMed Scopus Google F.C. Appel G.B. et or cyclosporine in the treatment of membranous nephropathy.N Engl J Med. PubMed Scopus Google Scholar and than that after cyclosporine or tacrolimus the of rituximab D.C. Appel G.B. Hebert L.A. et al.Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.Kidney Int. 2001; 59: 1484-1490Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar,14Praga M. Barrio V. Juárez G.F. Luño J. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial.Kidney Int. 2007; 71: 924-930Abstract Full Text Full Text PDF PubMed Scopus (216) Google A. V. et follow-up study of membranous nephropathy with tacrolimus and corticosteroids versus cyclical corticosteroids and Int 2017; Full Text Full Text PDF PubMed Scopus Google Scholar the it be that the tacrolimus-rituximab group in the corticosteroid-cyclophosphamide and were higher anti-PLA2R a higher of and a of in group. these at have the an outcome in the tacrolimus-rituximab group. the of anti-PLA2R autoantibodies as a of the disease in 70%–80% of patients with a cumulative number of have the of of anti-PLA2R to clinical to the and to the of immunosuppressive Jr., L.H. Bonegio R.G. Lambeau G. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1419) Google M. Wetzels P. The anti-PLA2R in membranous nephropathy: and a after Int. Full Text Full Text PDF PubMed Scopus Google Scholar, Fervenza F.C. A for a to membranous nephropathy.J Am Soc Nephrol. 2017; PubMed Scopus Google Scholar, E. G. A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy.J Am Soc Nephrol. 2014; PubMed Scopus Google Scholar, P. Debiec H. et receptor outcome of membranous nephropathy.J Am Soc Nephrol. PubMed Scopus Google Scholar, A2 receptor and treatment of membranous nephropathy: a J Am Soc Nephrol. 2014; 9: PubMed Scopus Google Scholar We found that both corticosteroid-cyclophosphamide and tacrolimus-rituximab induced a significant reduction in anti-PLA2R response occurred in the corticosteroid-cyclophosphamide group. and in a reduction in than drugs as rituximab or calcineurin and have the of alkylating agents in the most cases of A. et remission in membranous nephropathy: cyclophosphamide versus Int. Full Text Full Text PDF PubMed Scopus Google Scholar, et for membranous nephropathy: a controlled 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, C. and in mediated kidney Rev Nephrol. 15: PubMed Scopus Google Scholar response was by clinical remission in the of the of anti-PLA2R for a treatment of the The rate of adverse was significantly higher patients with were in the number of serious adverse have shown that in PMN by serious J.M. Wetzels risk after cyclophosphamide treatment in idiopathic membranous nephropathy.Clin J Am Soc Nephrol. 2014; 9: PubMed Scopus Google P. A. et of rituximab compared with steroids and cyclophosphamide for idiopathic membranous nephropathy.J Am Soc Nephrol. 2017; PubMed Scopus Google Scholar However, cumulative doses of cyclophosphamide were higher than in have that of doses of the results in M. H. et of idiopathic membranous nephropathy in patients with cyclophosphamide and 2009; PubMed Scopus Google Scholar Anti-PLA2R to treatment in patients in a response is have reported encouraging results with the of of cyclophosphamide as a for cyclophosphamide in patients with the alternating cyclic regimen of corticosteroids and V. A. G. cyclophosphamide and is a and effective treatment for idiopathic membranous nephropathy.Clin Kidney J. 2017; PubMed Scopus Google P. cyclophosphamide and steroids immunological and clinical remission in and primary membranous 23: PubMed Scopus Google Scholar the it be important to the of doses of corticosteroids the of the of treatment with corticosteroids and cyclophosphamide be compared with calcineurin inhibitors and treatment with tacrolimus 6 months or higher and doses of rituximab the remission rates in patients with tacrolimus-rituximab be in The study important was of and outcome The by or of anti-PLA2R and anti-PLA2R were in a number of patients. were about the of rituximab was However, study was a controlled trial that compared the cyclic alternating treatment with corticosteroids and cyclophosphamide versus the alternatives treatment with tacrolimus and with a and follow-up period that to important about the treatment of PMN in clinical In treatment with corticosteroid-cyclophosphamide induced remission of nephrotic syndrome in a significantly greater number of patients than treatment with were in the group. This randomized, controlled trial with a was by the and at in 1 in the A complete of study and is in the of the and study for the trial in the The study was J. G. A. et al.A and open-label controlled randomized trial to the efficacy of sequential treatment with tacrolimus-rituximab versus steroids plus cyclophosphamide in patients with primary membranous nephropathy: the Kidney J. PubMed Scopus Google Scholar A and the of the and the of the the trial at The trial is at patients with PMN were patients were for an observational period of at least 6 months. were a decrease of the observational and the observational patients the of with receptor for at least 2 months and controlled for at least with in of or the In the of a was were causes of membranous nephropathy or disease, treatment with another or or to drugs treatment with corticosteroids months immunosuppressive months or to or with a risk for the patient and or Full as as and in We a in for with an to with corticosteroid-cyclophosphamide or tacrolimus-rituximab. 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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).

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.

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.

BACKGROUND: Control of oral anticoagulant treatment has been reported to be suboptimal, but previous studies suggest that patient self-management improves control. OBJECTIVE: To compare the quality of control and the clinical outcomes of oral anticoagulant treatment in self-managed patients versus patients following conventional management. DESIGN: Randomized, controlled trial. SETTING: University-affiliated hospital in Spain. PATIENTS: 737 patients with indications for anticoagulant treatment. INTERVENTION: The self-management group (n = 368) received simple instructions for using a portable coagulometer weekly and self-adjusting treatment dose. The conventional management group (n = 369) received usual care in an anticoagulation clinic (monthly measurement and control of international normalized ratio [INR], managed by hematologists). MEASUREMENTS: Percentage of INR values within the target range and major related complications. RESULTS: The median follow-up period was 11.8 months (range, 0.3 to 16.9 months). The unadjusted percentages of in-range INRs were 58.6% in the self-management group and 55.6% in the conventional management group (difference, 3.0 percentage points [95% CI, 0.4 to 5.4 percentage points]). Twenty-seven patients (7.3%) in the conventional management group and 8 (2.2%) in the self-management group had major complications related to anticoagulant treatment. The unadjusted risk difference for major complications between groups was 5.1 percentage points (exact 95% CI, 1.7 to 8.5 percentage points). Fewer patients had minor hemorrhages in the self-management group (14.9%) than in the conventional management group (36.4%). Fifteen patients (4.1%) in the conventional management group and 6 (1.6%) in the self-management group died (unadjusted risk difference, 2.5 percentage points [exact 95% CI, 0.0 to 5.1 percentage points]). LIMITATIONS: The trial was performed at only 1 center and was not blinded. The dropout rate in the intervention group was 21%. CONCLUSIONS: Compared with conventional management by an anticoagulation clinic, self-management of oral anticoagulant treatment achieved a similar level of control. Of note, major complications and minor hemorrhages were less common in the self-management group.