Several genes have been implicated in genetic forms of nephrotic syndrome occurring in children. It is now known that the phenotypes associated with mutations in these genes display significant ...variability, rendering genetic testing and counselling a more complex task. This review will focus on the recent clinical findings associated with those genes known to be involved in isolated steroid-resistant nephrotic syndrome in children and, thereby, propose an approach for appropriate mutational screening. The recurrence of proteinuria after transplantation in patients with hereditary forms of nephrotic syndrome will also be discussed.
Mutations in NPHS1, which encodes nephrin, are the main causes of congenital nephrotic syndrome (CNS) in Finnish patients, whereas mutations in NPHS2, which encodes podocin, are typically responsible ...for childhood-onset steroid-resistant nephrotic syndrome in European populations. Genotype-phenotype correlations are not well understood in non-Finnish patients. We evaluated the clinical presentation, kidney histology, and disease progression in non-Finnish CNS cases by mutational screening in 107 families (117 cases) by sequencing the entire coding regions of NPHS1, NPHS2, PLCE1, WT1, LAMB2, PDSS2, COQ2, and NEPH1. We found that CNS describes a heterogeneous group of disorders in non-Finnish populations. We identified nephrin and podocin mutations in most families and only rarely found mutations in genes implicated in other hereditary forms of NS. In approximately 20% of cases, we could not identify the underlying genetic cause. Consistent with the major role of nephrin at the slit diaphragm, NPHS1 mutations associated with an earlier onset of disease and worse renal outcomes than NPHS2 mutations. Milder cases resulting from mutant NPHS1 had either two mutations in the cytoplasmic tail or two missense mutations in the extracellular domain, including at least one that preserved structure and function. In addition, we extend the spectrum of known NPHS1 mutations by describing long NPHS1 deletions. In summary, these data demonstrate that CNS is not a distinct clinical entity in non-Finnish populations but rather a clinically and genetically heterogeneous group of disorders.
Urinary losses of macromolecules in nephrotic syndrome (NS) reflect a dysfunction of the highly permselective glomerular filtration barrier. Genetic studies of hereditary forms of NS have led to the ...identification of proteins playing a crucial role in slit-diaphragm signalling, regulation of actin cytoskeleton dynamics, maintenance of podocyte integrity and cell–matrix interactions. This review will focus on recent molecular and clinical findings in the field of genetics of NS, thereby providing a better understanding of the complex glomerular filtration barrier physiology.
Background
IgA nephropathy (IgAN) and Henoch-Schönlein purpura are common glomerular disorders in children sharing the same histopathologic pattern of IgA deposits within the mesangium, even if their ...physiopathology may be different. Repeated exposure to pathogens induces the production of abnormal IgA1. The immune complex deposition in the renal mesangium in IgAN or potentially in small vessels in Henoch-Schönlein purpura induces complement activation via the alternative and lectin pathways. Recent studies suggest that levels of membrane attack complex (MAC) in the urine might be a useful indicator of renal injury. Because of the emerging availability of therapies that selectively block complement activation, the aim of the present study is to investigate whether MAC immunostaining might be a useful marker of IgA-mediated renal injury.
Methods
We conducted immunohistochemistry analysis of the MAC on renal biopsies from 67 pediatric patients with IgAN and Henoch-Schönlein purpura. We classified their renal biopsies according to the Oxford classification, retrieved symptoms, biological parameters, treatment, and follow-up.
Results
We found MAC expression was significantly related to impaired renal function and patients whose clinical course required therapy. MAC deposits tend to be more abundant in patients with decreased glomerular filtration rate (
p
= 0.02), patients with proteinuria > 0.750 g/day/1.73 m
2
, and with nephrotic syndrome. No correlation with histological alterations was observed.
Conclusions
We conclude that MAC deposition could be a useful additional indicator of renal injury in patients with IgAN and Henoch-Schönlein purpura, independent of other indicators.
Abstract Following the 2016 guidelines for blood pressure measurement, diagnosis and investigation of pediatric hypertension, we now present evidence-based guidelines for the prevention and treatment ...of hypertension in children. These guidelines were developed by Hypertension Canada’s Guideline Committee pediatric subgroup after thorough evaluation of the available literature. Included are 10 guidelines specifically addressing health behaviour management, indications for drug therapy in children with hypertension, choice of therapy for children with primary hypertension and goals of therapy for children with hypertension. While the pediatric literature is inherently limited by small numbers of participants, fewer trials, and a prolonged latency to the development of vascular outcomes, this manuscript reflects the current and highest level of evidence and provides guidance for primary care practitioners on the management of pediatric hypertension. Studies of therapeutic lifestyle modifications in children are available to guide current management and more antihypertensive drugs have been studied in children since the Food and Drug Administration Modernization Act. Consistent with Hypertension Canada’s guideline policy, diagnostic and therapeutic algorithm tools will be developed and the guidelines will be reviewed annually and updated according to new evidence.
A Mendelian inheritance underlies a nonnegligible proportion of hereditary kidney diseases, suggesting that the encoded proteins are essential for maintenance of the renal function. The ...identification of genes involved in congenital anomalies of the kidney and in familial forms of nephrotic syndrome significantly increased our understanding of the renal development and kidney filtration barrier physiology. This review will focus on the classical phenotype and clinical heterogeneity observed in the monogenic forms of these disorders. In addition, the role of susceptibility genes in kidney diseases with a complex inheritance will also be discussed.
The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin ...cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif-containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLCε1, the identification of mutations that may alter the putative INF2-IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS.
Before it becomes completely random Abda, Assil; Leduc, Jean-Michel; Benoit, Geneviève ...
Canadian medical education journal,
08/2022, Letnik:
13, Številka:
4
Journal Article
We present the inaugural evidence-based Canadian recommendations for the measurement of blood pressure in children and the diagnosis and evaluation of pediatric hypertension. Rates of pediatric ...hypertension are increasing concomitant with increased rates of childhood obesity. With this, there is growing awareness of the need to measure blood pressure in children. Consequently, the present recommendations have been developed to address an important gap and improve the clinical care of children. For 2016, a total of 15 recommendations are presented. These are categorized in a fashion similar to that of the existing adult recommendations. Specifically, we present recommendations on (1) accurate measurement of blood pressure in children, (2) criteria for diagnosis of hypertension in children, (3) assessment of overall cardiovascular risk in hypertensive children, (4) routine laboratory tests for the investigation of children with hypertension, (5) ambulatory blood pressure measurement in children, and (6) the role of echocardiography. We discuss the rationale for the recommendations and present additional supporting material for the clinician, including tables with standardized techniques for blood pressure measurement and determination of normative blood pressure values for children. Hypertension Canada's Canadian Hypertension Education Program Guidelines Task Force will update the recommendations annually and develop future evidence-based recommendations to guide prevention and treatment of pediatric hypertension.
Nous vous présentons les toutes premières recommandations fondées sur des données probantes relatives à la prise de la pression artérielle chez l’enfant et au diagnostic et à l’évaluation de l’hypertension infantile. Puisque l’incidence de l’hypertension infantile s’accroît à mesure de l’augmentation de l’obésité infantile, on se rend compte de l’importance de mesurer la pression artérielle des enfants. Les présentes recommandations ont ainsi été élaborées pour combler une importante lacune en matière de soins pédiatriques. En 2016, nous vous présentons, selon un ordre semblable à celui prévu pour les patients adultes, 15 recommandations traitant 1) de la mesure précise de la pression artérielle chez l’enfant, 2) des critères du diagnostic de l’hypertension infantile, 3) de l’évaluation du risque cardiovasculaire global chez l’enfant hypertendu, 4) des examens de laboratoire courants du suivi de l’hypertension chez l’enfant, 5) de la mesure ambulatoire de la pression artérielle chez l’enfant et 6) du rôle de l’échocardiographie. Nous fournissons les motifs justifiant les présentes recommandations et nous offrons des ressources additionnelles à l’intention des médecins, notamment des tableaux présentant des techniques normalisées de mesure de la pression artérielle et de détermination des valeurs de pression artérielle normative chez l’enfant. Le groupe de travail chargé du PECH d’Hypertension Canada veillera désormais chaque année à mettre à jour ses recommandations fondées sur des données probantes afin de promouvoir la prévention et le traitement de l’hypertension infantile.
Charcot-Marie-Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, the common mechanisms underlying the neuropathy and ...FSGS remain unknown. Mutations in INF2 were recently identified in patients with autosomal dominant FSGS. INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance. We therefore hypothesized that INF2 may be responsible for cases of Charcot-Marie-Tooth neuropathy associated with FSGS.
We performed direct genotyping of INF2 in 16 index patients with Charcot-Marie-Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively. Histologic and functional studies were also conducted.
We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2. Patients presented with an intermediate form of Charcot-Marie-Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. The INF2 mutants perturbed the INF2-MAL-CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42.
INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function. (Funded by the Agence Nationale de la Recherche and others.).
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