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Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct disorders typically associated with pathogenic variants in TSC1 and TSC2 for the former and PKD1 and PKD2 for the latter. TSC2 and PKD1 lie adjacent to each other, and large deletions comprising both genes lead to TSC2/PKD1 contiguous gene deletion syndrome (CGS). In this study, we describe a young female patient exhibiting symptoms of TSC2/PKD1 CGS in which genetic analysis disclosed two noncontiguous partial gene deletions in TSC2 and PKD1 that putatively are responsible for the manifestations of the syndrome. Further analysis revealed that both deletions appear to be de novo on the maternal chromosome, presumably with a germline origin. Despite extensive analysis, no maternal chromosomal rearrangement triggering these pathogenic variants was detected. This case elucidates a unique pathogenesis for TSC2/PKD1 CGS, diverging from the common contiguous deletions typically observed, marking the first reported instance of TSC2/PKD1 CGS caused by independent, functionally significant partial gene deletions.
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Thrombotic microangiopathy (TMA), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and multisystem organ dysfunction, is a life-threatening disease. Patients with TMA who do not exhibit a severe ADAMTS-13 deficiency (defined as a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13 activity ≥10%: TMA-13n) continue to experience elevated mortality rates. This study explores the prognostic indicators for augmented mortality risk or necessitating chronic renal replacement therapy (composite outcome: CO) in TMA-13n patients. We included 42 TMA-13n patients from January 2008 to May 2018. Median age of 41 years and 60% were female. At presentation, 62% required dialysis, and 57% warranted intensive care unit admission. CO was observed in 45% of patients, including a 9-patient mortality subset. Multivariate logistic regression revealed three independent prognostic factors for CO: early administration of eculizumab (median time from hospitalization to eculizumab initiation: 5 days, range 0-19 days; odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02-0.94), presence of neuroradiological lesions (OR, 6.67; 95% CI, 1.12-39.80), and a PLASMIC score ≤4 (OR, 7.39; 95% CI, 1.18-46.11). In conclusion, TMA-13n patients exhibit a heightened risk of CO in the presence of low PLASMIC scores and neuroradiological lesions, while early eculizumab therapy was the only protective factor.
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RATIONALE & OBJECTIVE: A previous study that evaluated associations of kidney biopsy findings with disease progression in patients with C3 glomerulopathy (C3G) proposed a prognostic histologic index (C3G-HI) that has not yet been validated. Our objective was to validate the performance of the C3G-HI in a new patient population. STUDY DESIGN: Multicenter, retrospective cohort study. SETTING & PARTICIPANTS: 111 patients fulfilling diagnostic criteria of C3G between January 1995 and December 2019, from 33 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). PREDICTORS: Demographic, clinical parameters, C3G-HI total activity score, and the C3G-HI total chronicity score. OUTCOME: Time to kidney failure. ANALYTICAL APPROACH: Intraclass correlation coefficients and κ statistic were used to summarize inter-rater reproducibility for assessment of histopathology in kidney biopsies. The nonlinear relationships of risk of kidney failure with the total activity score and total chronicity score were modeled using Cox proportional hazards analysis that incorporated cubic splines. RESULTS: The study group included 93 patients with C3 glomerulonephritis and 18 with dense-deposit disease. Participants had an overall meanage of 35±22 (SD) years. Forty-eight patients (43%) developed kidney failure after a mean follow-up of 65±27 months. The overall inter-rater reproducibility was very good for the total activity score (intraclass correlation coefficient [ICC]=0.63) and excellent for total chronicity score (ICC=0.89). Baseline estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and treatment with immunosuppression were the main determinants of kidney failure in a model with only clinical variables. Only tubular atrophy and interstitial fibrosis were identified as predictors in a model with histological variables. When the total activity score and total chronicity score were added to the model, only the latter was identified as an independent predictor of kidney failure. LIMITATIONS: Only a subset of the kidney biopsies was centrally reviewed. Residual confounding. CONCLUSIONS: We validated the performance of C3G-HI as a predictor of kidney failure in patients with C3G. The total chronicity score was the principal histologic correlate of kidney failure.
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Complemento C3/inmunología , Glomerulonefritis Membranoproliferativa/patología , Túbulos Renales/patología , Insuficiencia Renal/patología , Adolescente , Adulto , Atrofia , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Fibrosis , Tasa de Filtración Glomerular , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Glomerulonefritis Membranoproliferativa/inmunología , Glomerulonefritis Membranoproliferativa/metabolismo , Humanos , Inmunosupresores/uso terapéutico , Riñón/patología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Proteinuria , Insuficiencia Renal/inmunología , Insuficiencia Renal/metabolismo , Reproducibilidad de los Resultados , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Improving knowledge about normal urine composition in children is important for early prevention of lithiasis. We describe urinary excretion values of calcium (Ca), magnesium (Mg), phosphate (P), citrate (Cit), uric acid (Ur), and oxalate (Ox) in healthy children with and without a family history of lithiasis, using a 12-h urine collection protocol. METHODS: Urine samples were obtained from 184 children (5-12 years): a spot sample collected in the afternoon, and a 12-h overnight sample. Solute/creatinine (Cr) and 12-h solute excretion was calculated. RESULTS: Urinary excretion values of the studied solutes are presented as percentile values, separately for each type of sample. Due to age-related differences in the solute/creatinine ratios, except for Ca and Cit, results are described according to the child's age. The presence of excretion values related to an increased risk of lithiasis was more common in children with a family history. CONCLUSIONS: We report data from urine samples collected by using a simplified collection protocol. The observed differences between children with and without a family history of lithiasis could justify that in population studies aimed at setting reference values, the former are excluded.
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Litiasis/orina , Calcio/orina , Niño , Preescolar , Ácido Cítrico/orina , Creatinina/orina , Femenino , Humanos , Litiasis/genética , Magnesio/orina , Masculino , Oxalatos/orina , Fosfatos/orina , Valores de Referencia , Ácido Úrico/orinaRESUMEN
UNLABELLED: Intra-articular corticosteroid injections (IACI) are one of the mainstays of treatment for children with juvenile idiopathic arthritis. The most important disadvantage of IACI is the pain associated with the procedure. Little is known about the children or parents' perception of this pain. This study was undertaken to determine whether patients and their parents prefer sedation to receive IACI or not and why. A survey form was presented to patients and/or their parents from January to March 2010 to evaluate their choice of anesthesiologist-controlled deep sedation (with sevoflurane) vs. no sedation-no local anesthesia and the reasons for it. All participants had experienced the two options. In addition, there were two visual analog scales (VAS) to evaluate pain associated with blood draws and IACI, respectively. A total of 45 patients and their parents filled out the survey form. There were 34 females; the median age was 10.6 years, and the median duration of the disease was 6.4 years. Median VAS score was 1.3 for pain associated with blood draws, and 6, for IACI. Most children preferred sedation for IACI (26 vs. 15), although four did not show preference for either method. Children who preferred sedation for IACI were younger (p = 0.03) and had a shorter course of disease (p = 0.04). CONCLUSIONS: While most children prefer to receive IACI under sedation, a majority of parents prefer to avoid its risks. Children who prefer IACI without sedation are significantly older and have a longer course of disease.
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Artritis Juvenil/tratamiento farmacológico , Sedación Consciente/métodos , Glucocorticoides/administración & dosificación , Dolor/tratamiento farmacológico , Prioridad del Paciente/estadística & datos numéricos , Adolescente , Anestésicos por Inhalación/administración & dosificación , Niño , Recolección de Datos , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inyecciones Intraarticulares , Masculino , Éteres Metílicos/administración & dosificación , Dimensión del Dolor , Padres , Pacientes , SevofluranoRESUMEN
Incidence and prevalence of urolithiasis is apparently increasing worldwide, also among children and adolescents. Nevertheless, robust data have only been obtained in a few countries. In Spain, a voluntary Registry for Pediatric Renal Lithiasis has been active since 2015. Irregular participation limits its applicability, as well as its limitation to patients with a stone available for morphocompositional study, to obtain data about incidence and prevalence. On the other hand, findings about typology of stones and clinical and analytical characteristics of these subjects have been communicated in several meetings. Other valuable efforts in this field are the elaboration of guidelines for the collection and processing of urine samples for the study of urolithiasis in pediatric patients with the consensus of the Spanish Society for Pediatric Nephrology (AENP) as well as the Spanish Society for Laboratory Medicine (SEQC), the collaborative network RenalTube for the diagnosis of primary tubulopathies and the registry of patients with Primary Hyperoxaluria (OxalSpain). In many hospitals from the public healthcare system, pediatric nephrologists are the specialists in charge of the management of children with kidney stones, but there is no formal regulation on this competence. Other specialists, such as urologists, pediatric surgeons or pediatric urologists, in many cases do not offer a complete insight into the etiopathogenic mechanisms and the consequent medical treatment. Access to medication according to standards of treatment is warranted, provided a correct diagnosis is achieved, but criteria for the reimbursement of certain therapies, such as RNAi drugs for primary hyperoxaluria, are arguable.
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Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is a genetic syndrome. Its main characteristics are bony dysplasia, prenatal and postnatal growth deficiencies, microcephaly, and cerebrovascular disease. Several other features have been added recently. We report an individual with MOPDII affected by congenital renal dysplasia and hyperosmolar coma diabetic onset. Renal dysplasia has not been previously described in individuals with MOPDII. By publishing cases of unusual genetic disorders, it will be possible to broaden the spectrum of these rare syndromes, and improve the diagnosis and management of comorbidities.
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Thrombotic microangiopathy (TMA) has different etiological causes, and not all of them are well understood. In atypical hemolytic uremic syndrome (aHUS), the TMA is caused by the complement dysregulation associated with pathogenic mutations in complement components and its regulators. Here, we describe a pediatric patient with aHUS in whom the relatively benign course of the disease confused the initial diagnosis. A previously healthy 8-year-old boy developed jaundice, hematuria, hemolytic anemia, thrombopenia, and mild acute kidney injury (AKI) in the context of a diarrhea without hypertension nor oliguria. Spontaneous and complete recovery was observed from the third day of admission. Persistent low C3 plasma levels after recovery raised the suspicion for aHUS, which prompted clinicians to discard the initial diagnosis of Shigatoxin-associated HUS (STEC-HUS). A thorough genetic and molecular study of the complement revealed the presence of an isolated novel pathogenic C3 mutation. The relatively benign clinical course of the disease as well as the finding of a de novo pathogenic C3 mutation are remarkable aspects of this case. The data are discussed to illustrate the benefits of identifying the TMA etiological factor and the relevant contribution of the MCP aHUS risk polymorphism to the disease severity.
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Síndrome Hemolítico Urémico Atípico/genética , Complemento C3/genética , Proteína Cofactora de Membrana/genética , Síndrome Hemolítico Urémico Atípico/diagnóstico , Niño , Humanos , Masculino , Mutación , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
INTRODUCTION: The analysis of 24-h urine is the gold standard to diagnose metabolic abnormalities in the stone-forming patient. However, urinary composition changes throughout the day and analyzing the whole 24-h urine may mask peaks of increased risk of crystallization. OBJECTIVE: To examine variations of stone-promoting and stone-inhibiting factors in urine using split 24-h samples from healthy and stone-forming children. STUDY DESIGN: Urine was collected from 87 healthy and 26 stone-forming children using a split collection procedure (12-h daytime urine and 12-h overnight urine). Urine volume, pH, calcium (Ca), magnesium (Mg), phosphate (P), citrate (Cit), uric acid (Ur), and oxalate (Ox) were determined, and the Ca/Cit ratio was calculated. RESULTS: The overnight urine samples in both groups had higher levels of P and Mg, lower volume, lower pH, and less citrate and uric acid. As can be seen in the table, higher percentages of healthy and stone-forming children had altered 12-h night urine than 24-h urine with regards to Ca/Cr, Cit/Cr and Ca/Cit ratios. All healthy subjects and all stone-forming children (except one) with altered Cit/Cr ratios or Ca/Cit ratios in the 24-h sample also had altered ratios in the 12-h overnight sample. DISCUSSION: This study indicates that urine composition changes throughout the day, and that there is daily variability in most of the parameters related to kidney stone formation. Furthermore, 12-h overnight samples seem to be more sensitive than 24-h samples in detecting the most common urinary abnormalities. The main limitation of this study is the relative low sample size of stone-forming children, owing to the low prevalence of nephrolithiasis in childhood. CONCLUSIONS: We observed a higher excretion of stone-promoting substances and a lower citrate in urine at night. However, the study results do not provide enough evidence to conclude that the use of a 12-h overnight sample collection can replace 24 h urine analysis in the metabolic evaluation of children with lithiasis.
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Calcio , Cálculos Renales , Oxalato de Calcio , Niño , Ácido Cítrico , Humanos , Cálculos Renales/diagnóstico , Cálculos Renales/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND AND OBJECTIVES: C3 glomerulopathy is a complement-mediated disease arising from abnormalities in complement genes and/or antibodies against complement components. Previous studies showed that treatment with corticosteroids plus mycophenolate mofetil (MMF) was associated with improved outcomes, although the genetic profile of these patients was not systematically analyzed. This study aims to analyze the main determinants of disease progression and response to this therapeutic regimen. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a retrospective, multicenter, observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy (n=81) or dense deposit disease (n=16) between January 1995 and March 2018 were enrolled. Multivariable and propensity score matching analyses were used to evaluate the association of clinical and genetic factors with response to treatment with corticosteroids and MMF as measured by proportion of patients with disease remission and kidney survival (status free of kidney failure). RESULTS: The study group comprised 97 patients (84% C3 glomerulopathy, 16% dense deposit disease). Forty-two patients were treated with corticosteroids plus MMF, and this treatment was associated with a higher rate of remission and lower probability of kidney failure (79% and 14%, respectively) compared with patients treated with other immunosuppressives (24% and 59%, respectively), or ecluzimab (33% and 67%, respectively), or conservative management (18% and 65%, respectively). The therapeutic superiority of corticosteroids plus MMF was observed both in patients with complement abnormalities and with autoantibodies. However, patients with pathogenic variants in complement genes only achieved partial remission, whereas complete remissions were common among patients with autoantibody-mediated forms. The main determinant of no remission was baseline proteinuria. Relapses occurred after treatment discontinuation in 33% of the patients who had achieved remission with corticosteroids plus MMF, and a longer treatment length of MMF was associated with a lower risk of relapse. CONCLUSIONS: The beneficial response to corticosteroids plus MMF treatment in C3 glomerulopathy appears independent of the pathogenic drivers analyzed in this study.
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Complemento C3/análisis , Glomerulonefritis/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Ácido Micofenólico/uso terapéutico , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Niño , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Glomerulonefritis/diagnóstico , Glomerulonefritis/inmunología , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Ácido Micofenólico/efectos adversos , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Factores de Riesgo , España , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Thrombotic microangiopathy (TMA) is an important complication associated with several diseases that are rare and life-threatening. TMA is common to thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). TTP is defined by a severe deficiency of ADAMTS13, and early treatment is associated with good prognosis. The diagnosis of HUS can be difficult due to the potential multiple etiologies, and the best treatment option in most cases is not well-established yet. The implementation of a multidisciplinary team (MDT) could decrease the time to diagnosis and treatment for HUS and may improve the outcomes of these patients. OBJECTIVE: To determine the impact of MDT on morbidity and mortality [death or chronic renal replacement therapy (CRRT) requirements], incidence and response time [(RT) defined as the period between hospital admission and the first day of direct therapy administration], length of stay at an intensive care unit (ICU-LOS) and total hospitalization (T-LOS) were also assessed. METHODS: We compared a pre-MDT implementation period (from January/2008 to May/2016) versus post-MDT period (from May/2016 to December/2016). The screening TMA diagnosis was made according the following criteria: hemolytic anemia, thrombocytopenia and acute renal damage and without ADAMTS13 deficiency. An online chat was implemented to provide instant medical information. RESULTS: Twenty-eight patients were included. The incidence changed from 2.3 cases/pre-MDT: (all cases: n = 18) to 10 cases/year post-MDT (all cases: n = 10). Two patients died in pre-MDT and post- MDT (11% versus 20%, P = 0.60). From pre-MDT, the number of patients who required CRRT by post-MDT decreased from 7 (39%) to 0, P = 0.03. Similarly, RT, ICU-LOS and T-LOS [median(p25-p75)] decreased from 10 (2-12) days to 0.5 (0-1.5) days, P = 0.04, from 16 (9-30) days to 10 (4-13) days, P = 0.01 and from 33 (22-53) days to 16 (12-32) days, P < 0.01, respectively. CONCLUSION: MDT implementation was associated with a greater number of patients who meet TMA criteria. A decrease in the RT and T-LOS periods were observed and associated with better outcomes in these patients.