Epidemiology, Outcomes, and Complement Gene Variants in Secondary Thrombotic Microangiopathies.

BACKGROUND: The identification of complement defects as major drivers of primary atypical hemolytic uremic syndrome (HUS) has transformed the landscape of thrombotic microangiopathies (TMAs), leading to the development of targeted therapies and better patient outcomes. By contrast, little is known about the presentation, genetics, and outcomes of TMA associated with specific diseases or conditions, also referred to as secondary TMA. METHODS: In this study, we assessed the relative incidence, clinical and genetic spectra, and long-term outcomes of secondary TMA versus other TMAs in consecutive patients hospitalized with a first episode of TMA from 2009 to 2019 at two European reference centers. RESULTS: During the study period, 336 patients were hospitalized with a first episode of TMA. Etiologies included atypical HUS in 49 patients (15%), thrombotic thrombocytopenic purpura (TTP) in 29 (9%), shigatoxin-associated HUS in 70 (21%), and secondary TMA in 188 (56%). The main causes of secondary TMA were hematopoietic stem-cell transplantation ( n =56, 30%), solid-organ transplantation ( n =44, 23%), and malignant hypertension ( n =25, 13%). Rare variants in complement genes were identified in 32 of 49 patients (65%) with atypical HUS and eight of 64 patients (13%) with secondary TMA; pathogenic or likely pathogenic variants were found in 24 of 49 (49%) and two of 64 (3%) of them, respectively ( P < 0.001). After a median follow-up of 1157 days, death or kidney failure occurred in 14 (29%), eight (28%), five (7%), and 121 (64%) patients with atypical HUS, TTP, shigatoxin-associated HUS, and secondary TMA, respectively. Unadjusted and adjusted Cox regressions showed that patients with secondary TMA had the highest risk of death or kidney failure (unadjusted hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.85 to 6.07; P < 0.001; adjusted HR, 4.11; 95% CI, 2.00 to 8.46; P < 0.001; considering atypical HUS as reference). CONCLUSIONS: Secondary TMAs represent the main cause of TMA and are independently associated with a high risk of death and progression to kidney failure.

Lessons for the clinical nephrologist: an uncommon cause of pulmonary-renal syndrome.

Pulmonary-renal syndrome refers to the combination of elevated plasma creatinine concentration and/or abnormal urinalysis with diffuse alveolar hemorrhage, and involves both an urgent diagnostic approach and care. We report the case of a 24-year-old man presenting with diffuse alveolar hemorrhage as well as a nephritic syndrome associating kidney failure, moderate hypertension, hematuria and selective glomerular proteinuria. The initial high suspicion of anti-glomerular basement membrane (GBM) disease or ANCA-associated vasculitis justified intravenous pulse-corticotherapy in association with plasma exchange. Renal biopsy was remarkable for an IgA nephropathy, lesions of active thrombotic microangiopathy (TMA) and a positive staining for complement factor C4d. Because anti-GBM and ANCA antibodies returned negative, plasma exchange was discontinued, but oral corticosteroids were maintained to prevent alveolar hemorrhage recurrence. In the absence of renal function recovery, hemodialysis was initiated. TMA lesions are frequently seen in IgA nephropathy and are associated with a poorer prognosis. Complement activation seems to be involved in the development of those lesions and contributes to disease progression. Conversely, alveolar hemorrhage in the setting of IgA nephropathy is uncommon. It is thought to result from non-specific mucosal hemorrhage, an immune complex mediated basement membrane damage and an IgA-mediated capillaritis against basement membrane antigens.

Podocyte Antigen Staining to Identify Distinct Phenotypes and Outcomes in Membranous Nephropathy: A Retrospective Multicenter Cohort Study.

RATIONALE & OBJECTIVE: Membranous nephropathy (MN) is characterized by the deposition of immune complexes along glomerular basement membranes. M-Type phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), exostosin 1 and 2 (EXT1/2), and neural epidermal growth factor-like 1 protein (NELL-1) have been identified as established or potential podocyte antigens in MN. We investigated the association of podocyte antigen staining with MN clinical phenotype and outcomes. STUDY DESIGN: Multicenter retrospective cohort study. SETTING & PARTICIPANTS: 177 consecutive patients with MN unrelated to lupus erythematosus, identified after screening of 3,875 native kidney biopsies performed in the Belgian UCLouvain Kidney Disease Network from 2000 through 2018. PREDICTOR: Positive immunostaining for podocyte antigens on archived kidney biopsy samples. OUTCOMES: Association with different phenotypes (baseline characteristics of patients and pathologic findings on kidney biopsy), time to cancer and to kidney failure. ANALYTICAL APPROACH: Kaplan-Meier estimates and Cox regression analyses to assess time to cancer and kidney failure. RESULTS: 177 patients were followed up for a median of 4.0 (IQR, 1.3-8.0) years. Diagnosis of PLA2R-positive (PLA2R+), THSD7A+, and double-negative (PLA2R-/THSD7A-) MN was made in 117 (66.1%), 6 (3.4%), and 54 (30.5%) patients, respectively. Progression to kidney failure was similar in all groups. Although the number of patients with THSD7A+MN was small, they showed a higher incidence (50%) and increased risk for developing cancer during follow-up (adjusted HR, 5.0 [95% CI, 1.4-17.9]; P=0.01). 8% and 5% of patients with double-negative MN stained positively for EXT1/2 and NELL-1, respectively. Most patients with EXT1/2+MN were women, had features of systemic autoimmunity, and showed glomerular C1q deposits. LIMITATIONS: Retrospective design; small number of patients in the THSD7A group; lack of evaluation of immunoglobulin G subclasses deposition. CONCLUSIONS: Our real-world data describe the relative prevalence of subgroups of MN and support the hypothesis that a novel classification of MN based on podocyte antigen staining may be clinically relevant.

Eliminating Hepatitis C Virus From a Prevalent Kidney Transplant Recipient Population: A Single-Center Study in Belgium in the Direct-Acting Antivirals Era.

BACKGROUND: Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection. Although previous studies have reported positive results with DAAs after kidney transplantation (KT), their impact on the prevalence of HCV viremia (HCVv) in prevalent kidney transplant recipients (KTRs) remains ill defined. METHODS: We retrospectively reviewed the HCV status of all patients followed at Cliniques Universitaires Saint-Luc, Brussels, Belgium, outpatient KT clinic between January 2014 and December 2018. We collected the clinical features of KTRs treated with DAAs during this period and calculated the annual prevalence of HCVv over this period. RESULTS: Out of 1451 KTRs, 22 (1.52%) had HCVv in 2014 to 2018. From 2014 to 2018, the annual prevalence of HCVv dropped from 1.97% to 0.43%, (P < .001). Fourteen KTRs were treated with DAAs a median of 197 months (range: 5-374) after KT, mostly (79%) in 2017 after reimbursement restrictions of DAAs for KTRs in Belgium were removed. DAA treatment was safe with a sustained virological response rate at 12 weeks after treatment (SVR12) of 93%. Two patients died 14 months (lymphoma, despite SVR12) and 7 months (hepatocarcinoma, no SVR12) after DAAs initiation, respectively. Among HCVv KTRs not treated with DAAs (n = 8), 2 lost their graft, 5 died, and 1 is initiating therapy. The current prevalence of HCVv in the cohort is 0.08%, with a single patient currently on treatment. CONCLUSION: Treatment with DAAs led to a dramatic decrease of HCVv prevalence in this KTR cohort. DAA use was safe and effective. Elimination of HCV is possible at KT clinics.

Quantification of 18F-fluorodeoxyglucose uptake to detect residual nodal disease in locally advanced head and neck squamous cell carcinoma after chemoradiotherapy: results from the ECLYPS study.

BACKGROUND: The Hopkins criteria were introduced for nodal response evaluation after therapy in head and neck cancer, but its superiority over quantification is not yet confirmed. METHODS: SUVbody weight thresholds and lesion-to-background ratios were explored in a prospective multicenter study of standardized FDG-PET/CT 12 weeks after CRT in newly diagnosed locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients (ECLYPS). Reference standard was histology, negative FDG-PET/CT at 12 months after treatment or ≥ 2 years of negative follow-up. Area under the receiver operator characteristics curves (AUROC) were estimated and obtained thresholds were validated in an independent cohort of HNSCC patients (n = 127). RESULTS: In ECLYPS, 124 patients were available for quantification. With a median follow-up of 20.4 months, 23 (18.5%) nodal neck recurrences were observed. A SUV70 threshold of 2.2 (AUROC = 0.89; sensitivity = 79.7%; specificity = 80.8%) was identified as optimal metric to identify nodal recurrence within 1 year after therapy. For lesion-to-background ratios, an SUV50/SUVliver threshold of 0.96 (AUROC = 0.89; sensitivity = 79.7%; specificity = 82.8%) had the best performance. Compared with Hopkins criteria (AUROC = 0.81), SUV70 and SUV50/SUVliver provided a borderline significant (p = 0.040 and p = 0.094, respectively) improvement. Validation of thresholds yielded similar AUROC values (SUV70 = 0.93, SUV50/SUVliver = 0.95), and were comparable to the Hopkins score (AUROC = 0.91; not statistically significant). CONCLUSION: FDG quantification detects nodal relapse in LAHNSCC patients. When using EARL standardized PET acquisitions and reconstruction, absolute SUV metrics (SUV70 threshold 2.2) prove robust, yet ratios (SUV50/SUVliver, threshold 0.96) may be more useful in routine clinical care. In this setting, the diagnostic value of quantification is comparable to the Hopkins criteria. TRIAL REGISTRATION: US National Library for Medicine, NCT01179360. Registered 11 August 2010, https://clinicaltrials.gov/ct2/show/NCT01179360.

Clinical and mutational spectrum of hypoparathyroidism, deafness and renal dysplasia syndrome.

BACKGROUND: Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder, secondary to mutations in the GATA-3 gene. Due to its wide range of penetrance and expressivity, the disease may not always be recognized. We herein describe clinical and genetic features of patients with HDR syndrome, highlighting diagnostic clues. METHODS: Medical records of eight patients from five unrelated families exhibiting GATA-3 mutations were reviewed retrospectively, in conjunction with all previously reported cases. RESULTS: HDR syndrome was diagnosed in eight patients between the ages of 18 and 60 years. Sensorineural deafness was consistently diagnosed, ranging from clinical hearing loss since infancy in seven patients to deafness detected only by audiometry in adulthood in one single patient. Hypoparathyroidism was present in six patients (with hypocalcaemia and inaugural seizures in two out of six). Renal abnormalities observed in six patients were diverse and of dysplastic nature. Three patients displayed nephrotic-range proteinuria and reached end-stage renal disease (ESRD) between the ages of 19 and 61 years, whilst lesions of focal and segmental glomerulosclerosis were histologically demonstrated in one of them. Interestingly, phenotype severity differed significantly between a mother and son within one family. Five new mutations of GATA-3 were identified, including three missense mutations affecting zinc finger motifs [NM_001002295.1: c.856A>G (p.N286D) and c.1017C>G (p.C339W)] or the conserved linker region [c.896G>A (p.R299G)], and two splicing mutations (c.924+4_924+19del and c.1051-2A>G). Review of 115 previously reported cases of GATA-3 mutations showed hypoparathyroidism and deafness in 95% of patients, and renal abnormalities in only 60%. Overall, 10% of patients had reached ESRD. CONCLUSIONS: We herein expand the clinical and mutational spectrum of HDR syndrome, illustrating considerable inter- and intrafamilial phenotypic variability. Diagnosis of HDR should be considered in any patient with hypoparathyroidism and deafness, whether associated with renal abnormalities or not. HDR diagnosis is established through identification of a mutation in the GATA-3 gene.

[Towards a neuropsychological approach to autism] / Vers un abord neuro-psychologique de l'autisme.

Neuropsychology attributes mental activity to brain functioning. An inventory of the every-day life of the autist confirms a breakdown in behavior adapted to the world around him. Deficiency in the contribution of the right hemisphere, compromising social life, is accompanied by a mental life that is detached from reality, favorizing preconceived ideas that are inscribed in the logic governing the left hemispheric function. Inside each hemisphere homologous areas of the cerebral cortex, receiving and sharing the same information, react to messages according to their own mode. The left hemisphere applies itself to elementary information, treated sequentially, while the right hemisphere continuously brings up to date temporal and spatial synthesis coming from the sensorale contribution. Attachment to an object or attentiveness to the world: this alternative mode is the key to understanding. The disorder responsible for autism occurs in the perinatal period. It compromizes the maturation of right hemisphere functions where interaction with the surrounding environment should take precedence over attention to objects. Besides its interest in the orientation of research, the neuropsychological approach of Pervasive Development Disorder has the merit of demystifying the drama associated with autism. A better understanding of the nature of this disorder would be of great assistance in circumventing it.

[Human interaction, social cognition, and the superior temporal sulcus]. / Interrelations humaines, cognition sociale et sillon temporal supérieur.

Human beings are social animals. This ability to live together is ensured by cognitive functions, the neuroanatomical bases of which are starting to be unraveled by MRI-based studies. The regions and network engaged in this process are known as the "social brain ". The core of this network is the superior temporal sulcus (STS), which integrates sensory and emotional inputs. Modeling studies of healthy volunteers have shown the role of the STS.in recognizing others as biological beings, as well as facial and eye-gaze recognition, intentionality and emotions. This cognitive capacity has been described as the "theory of mind ". Pathological models such as autism, in which the main clinical abnormality is altered social abilities and communication, have confirmed the role of the STS in the social brain. Conceptualisation of this empathic capacity has been described as "meta cognition ", which forms the basis of human social organizationand culture.

Onco-nephrology: glomerular diseases with cancer.

Glomerular diseases occurring in the course of malignancies remain rare. Diverse glomerular lesions can be observed in a variety of neoplasms and involve different pathophysiologic links between the glomerulopathy and the cancer. The pathophysiology of solid tumor-associated glomerulopathies remains obscure, whereas in hematologic malignancy-induced paraneoplastic glomerulopathies, a molecular link can usually be demonstrated. The aim of this review is to provide an update on glomerular diseases associated with carcinoma and hematologic malignancies, covering epidemiology, pathophysiology, clinical presentation, and therapy. Special emphasis will be placed on the potential usefulness of novel biomarkers, such as antiphospholipase A2 receptor antibodies, for the diagnosis of membranous nephropathy, and on new associations and recent entities, including (proliferative) GN with nonorganized monoclonal immunoglobulin deposits and myeloproliferative neoplasm-related glomerulopathy.

[The Luys' body]. / Le corps de Luys.

In 1865, Jules Luys (1828-1897) described the 'accessory band of the superior olive' (red nucleus). In 1877, A. Forel completed the description and gave the name of Corpus Luysii (CL) to this grey sub-thalamic formation. In 1927, P. Martin's attribute the Hemiballismus to the destruction of the C.L. and specifies the function of the nucleus foreseen by Luys, which play a crucial role in the synthesis of automatic motor action. The new stimulation techniques of this nucleus in the treatment of Parkinson's disease would have opened a third life for the C.L. if its name hade not be changed into 'nucleus subthalamicus'. Jules Luys, a good anatomist, one of the pioneers in France of microscope and photography, ruined his reputation by his ramblings on hysteria and hypnosis which allowed the 'action of medications at distance', the 'storage of cerebral activities within magnetic crowns' and gave prominence to 'brain emanations'.