A Pattern of Glomerular Diseases in Egyptian Children: A Single-center Experience

BACKGROUND: Findings indicative of the glomerular disease are proteinuria, hematuria, nephrotic syndrome (NS), hypertension, and renal insufficiency. These presentations can be used to define different clinical patterns that resemble different underlying etiologies. METHODS: This study is a cross-sectional study enrolled in Children Hospital Cairo University. The study participants were recruited on two stages, retrospective and prospective stages. In the retrospective stage, all eligible patients across 5 years (between 2011 and 2015) with any glomerular disease were included in the study. In addition, prospectively, the new cases a long 6 months (from February 2016 till July 2016) with glomerular diseases were included in the study. RESULTS: A total of 594 cases with different glomerular diseases were identified. Cases were two groups: The retrospective group that involved 543 cases and the prospective group that included 51 cases. In the retrospective part of the study, the most common presentations were NS (68%), nephritis (16.4%), gross hematuria (10.5%), and nephrotic/nephritic syndrome (3.5%). The most common biopsies in the retrospective study were NS: MCNS (27.3%), NS: focal segmental glomerulosclerosis (FSGS) (23.4%), NS: Mesangioproliferative GN (9.4%), NS: Membranous GN (2.3%), Crescentric GN (3.9%), Membranous GN (0.8%), MPGN (0.8%), congenital nephrotic syndrome (CNS):Diffuse Mesangial Sclerosis (3.9%), CNS: Finnish type (2.3%), Alport (4.7%), IgA nephropathy (3.9%), IgM nephropathy (1.6%), lupus nephritis (LN) (3.1%), Thin basement membrane disease (3.1%), and others (9.4%) In the prospective study, the most common presentations were NS (76.5%), nephritis (11.8%), nephrotic/nephritic syndrome (7.8%), and gross hematuria (3.9%). The biopsies results were mainly NS: FSGS (33.3%) and NS: MCNS (33.3%). Other biopsies results in the prospective part were NS: Mesangioproliferative GN (16.7%), LN (8.3%), and IgA nephropathy (8.3%). CONCLUSION: The most common glomerular disease in childhood is NS. The most common pathology of glomerular diseases is minimal change NS.

Hereditary Congenital and Infantile Nephrotic Syndrome in Children: Strategy of Management with New Possibilities for Genetic Diagnosis and Therapy

Due to the worldwide genetic research, the fundamental information was obtained regarding the pathogenesis of the hormone-resistant congenital and infantile nephrotic syndrome in children. The mutations in the genes encoding the main components of the basement membrane of the kidney glomeruli, structural and functional podocyte proteins are responsible for the development of the congenital and infantile nephrotic syndrome with the typical histologic pattern of the diffuse mesangial sclerosis or focal segmental glomerulosclerosis. In accordance with the evidence-based international strategy, the clinical phenotyping combined with the targeted genetic analysis is the diagnosis standard for the hereditary nephrotic syndrome in children that are recommended to perform the genetic analysis prior to start of the steroid therapy and prior to the kidney biopsy. The early genetic diagnosis assures the personalized approach to the choice of the therapies considering the genotype and phenotype specifics of the congenital or infantile nephrotic syndrome in the particular child. The up-to-date strategy for the management of such children provides the carrying out of the conservative therapy and early transplantation of the related kidney when reaching 10-15 kg body weight (in this case, the kidneys are removed and transplanted during the same surgery), or the bilateral nephrectomy simultaneously or one stepped, then the second kidney and peritoneal dialysis, then kidney transplantation for the children reached 10-15 kg body weight. According to ESPN / ERA-EDTA register (2016), the 5-year survival rate of the children with the congenital nephrotic syndrome caused by NPHS1 gene mutation is 91% after kidney transplantation, 89% after allograft. The solutions for the pressing challenge of the domestic pediatrics are as the following: introduce the international strategy into the practice of the children management with the congenital and infantile nephrotic syndrome with the new possibilities of the genetic diagnosis and therapy replacing the kidney function; enhance the kidney transplantation and its availability; carry out the epidemiological studies of the hereditary nephrotic syndrome.

Podocytopathies

Podocytopathies include a wide spectrum of primary or secondary glomerular diseases that are the consequence of the podocyte injuries. The damage of podocytes can occur due to congenital or acquired disorders of podocyte transcriptional regulators, altered components of the slit diaphragm complex, abnormal assembly, or function of the actin-based cytoskeleton, dysfunction of membranes or cytoplasmic proteins, and mitochondrial injury. Podocytes reactions to injurious stimulus include FP effacement, apoptosis, and loss of podocyte, developmental arrest associated by mild proliferative activity, and dedifferentiation with moderated proliferation. Based on histopathological findings, podocytopathy may be diagnosed such as minimal change nephropathy; focal segmental glomerulosclerosis, diffuse mesangial sclerosis, or collapsing glomerulopathy while in relation to their etiology can be categorized as idiopathic, genetic, and reactive. Podocytopathies may be diagnosed due to podocyte morphological changes, immunohistochemistry, circulating and urine biomarkers, and genetic analysis. The primary clinical focus in prevention should be to reduce the factors that can damage the podocytes and cause hyperperfusion/hypertrophy of the glomerulus. Nowadays, control of systemic and intra glomerular hypertension by pharmacological blockade of angiotensin II is a central in the prevention strategy, while regeneration of podocytes by stem cells is therapeutic strategy of the future.

Long-term outcome in a case series of Denys–Drash syndrome

Background Denys–Drash syndrome (DDS) is a rare disease caused by mutations in exons 8 and 9 of the WT1 gene. It is characterized by the association of early onset steroid-resistant nephrotic syndrome (SRNS), Wilms’ tumour and, in some patients, intersex disorders, with increasing risk of gonadoblastoma. There are few published data concerning the long-term outcome of patients with DDS. The aim of this study was to report our experience. Methods Data were collected from five children (three boys) with confirmed DDS diagnosed from 1996 to 2017. The mean follow-up of these patients was 16 years. Results The patients presented with SRNS and diffuse mesangial sclerosis at renal biopsy. All patients were hypertensive and progressed to end-stage kidney disease, initiating dialysis at a mean age of 28 months. Three patients developed Wilms’ tumour 9 months after the SRNS was identified, which was treated by nephrectomy and chemotherapy. All five patients received kidney transplantation. SRNS did not recur after transplantation in any of the patients and graft survival was similar to that of other kidney transplant recipients in our programme. All three boys had ambiguous genitalia and cryptorchidism but a confirmed male karyotype (46, XY). One girl presented with gonadal agenesis, whereas the other one had normal female ovarian tissue and external genitalia. Both girls had a female karyotype (46, XX). Gonadoblastoma was not observed at any case. Conclusions Early DDS recognition in patients with SRNS is crucial due to its low prevalence, the specific treatment approach required and early detection of Wilms’ tumour. Few data are available regarding long-term outcomes.

Laminin-521 Protein Therapy for Glomerular Basement Membrane and Podocyte Abnormalities in a Model of Pierson Syndrome

Background Laminin α5β2γ1 (LM-521) is a major component of the GBM. Mutations in LAMB2 that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of Lamb2 mutant mice and restore glomerular permselectivity.Methods We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of Lamb2−/− pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture.Results Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the foot process effacement observed in untreated pups. Moreover, treatment with hLM-521 delayed the onset of proteinuria but did not prevent nephrotic syndrome, perhaps due to its absence from the podocyte aspect of the GBM.Conclusions These studies show that GBM composition and function can be altered in vivovia vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired.