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Nephrotic syndrome (NS) in children includes a diverse group of diseases that range from genetic diseases without any immunological defects to causes that are primarily due to immunological effects. Recent advances in molecular and genomic studies have resulted in a plethora of genetic defects that have been localized to the podocyte, the basic str...
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Context 1
... causes of NS show some variations depending on the age of the child with early onset NS usually representing primary genetic or idiopathic causes, such as congenital NS, due to any of the known genetic defects or MCD and less often FSGS (Table 1) (2,6,7). As the age increases, the ratio of MCD and FSGS may vary with secondary causes becoming more common in the second decade. ...
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Background
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Background
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Citations
... Nephrotic syndrome (NS) is a clinical entity characterized by the triad of proteinuria, hypoalbuminemia, and edema [1]. It is a group of diseases composed of numerous etiologies, ranging from congenital, such as Finnish Type Nephropathy and Diffuse Mesangial Sclerosis, to primary renal diseases, including Minimal Change Nephrotic Syndrome (MCNS) and Focal Segmental Glomerulosclerosis (FSGS), or secondary forms due to systemic diseases such as, for instance, diabetes mellitus and lupus erythematosus [2]. The reported incidence of childhood NS is 2-7 per 100,000 children, with a prevalence of about 16 cases per 100,000 and variability among ethnic groups. ...
... The Finnish nephropathy gene is located on the long arm of chromosome 19 (19q13.1), which codes for nephrin [2]. The Finnish nephropathy gene is located on the long arm of chromosome 19 (19q13.1), ...
... Focal segmental glomerular sclerosis (FSGS) is responsible for 10 to 20% of NS cases in children [2]. The podocyte is the main site of injury in FSGS. ...
Nephrotic syndrome (NS) is a complex clinical entity characterized by proteinuria, hypoalbuminemia, and edema. In this review, we propose the view of NS as a podocytopathy, highlighting the importance of understanding the role of podocytes in the development of this condition. We discuss the various etiologies of NS, ranging from congenital to primary renal diseases, as well as secondary forms due to systemic diseases. We also delve into the mechanisms underlying podocyte injury, which plays a crucial role in the development of NS. By viewing NS as a podocytopathy, we suggest potential implications for the diagnosis and treatment of this condition, including the use of podocyte-specific biomarkers and targeted therapies. Our review provides a comprehensive overview of NS and its underlying mechanisms, emphasizing the importance of a multidisciplinary approach to the diagnosis and management of this condition. Further research is essential to better understand the complex interplay between podocyte injury and the development of NS, with the ultimate goal of improving patient outcomes.
... A characteristic feature of this glomerulopathy is the collapsing anatomy of the glomerulus when viewed under the microscope. The capillary loop collapses onto itself with marked enlargement of the glomerular tuft and prominent hyperplasia of the parietal epithelial cells (13,14). ...
Collapsing glomerulopathy is a rare and serious disease that is characterized by a rapid deterioration of kidney function and heavy proteinuria. This disease is a variant of focal segmental glomerulosclerosis (FSGS). The disease is more serious than other types of FSGS, with high risks of renal failure and poor prognosis. Collapsing glomerulopathy is often resistant to immunosuppressive therapy and can rapidly result in renal failure, making diagnosing and managing this disease an enormous challenge.
... HT suggest a diagnosis other than idiopathic NS (7). HT exists in one of every three patients in those individuals with MPGN, and the possibility of HT increases as the disease progresses (8). Macroscopic hematuria is a more common initial finding in patients with MPGN who were diagnosed in childhood compared to those diagnosed in their adulthood. ...
Aim:Nephrotic syndrome (NS) is the most common childhood glomerular disease manifested by proteinuria, edema and hypoalbuminemia. The aim of this study was to examine children with primary NS in terms of their clinical laboratory and histopathological features, and to evaluate their treatment responses.Materials and Methods:Thirty-eight (21 boys/17 girls) patients followed up with primary NS were included in this study.Results:The mean age at diagnosis was 6.4 years. The histopathological diagnoses were focal segmental glomerulosclerosis (FSGS) in 17 patients, minimal change disease (MCD) in 8, membranoproliferative glomerulonephritis (MPGN) in 3, and membranous glomerulonephritis in 1 patient. Those patients with MPGN were older than those with MCD and FSGS (p=0.035). Twenty-four patients were steroid sensitive. Steroid response rates were 88% in those patients with MCD, 41% in patients with FSGS and 33% in those with MPGN. At their last visit, three patients (7.9%) were diagnosed with chronic kidney disease.Conclusion:NS is the most common glomerular disease of childhood. Early diagnosis and the histopathological features of this disease have an important place in its prognosis. Knowing the demographic, clinical and pathological features of the disease is helpful in monitoring its progress and its prognosis.
... A correlation between increased podocyte lipid droplets and CPF-induced post-transplant recurrence of FSGS has not yet been reported. However, cholesterol deposition and foam cells are found in glomeruli of patients with FSGS or minimal change disease [18][19][20]. Furthermore, altered glomerular lipid metabolism and lipid accumulation has been previously shown in patients with diabetic nephropathy and glomerulosclerosis (reviewed in [21,22]). ...
Many patients with primary focal segmental glomerulosclerosis (FSGS) develop recurrence of proteinuria after kidney transplantation. Several circulating permeability factors (CPFs) responsible for recurrence have been suggested, but were never validated. We aimed to find proteins involved in the mechanism of action of CPF(s) and/or potential biomarkers for the presence of CPF(s). Cultured human podocytes were exposed to plasma from patients with FSGS with presumed CPF(s) or healthy and disease controls. Podocyte proteomes were analyzed by LC–MS. Results were validated using flow cytometry, RT-PCR, and immunofluorescence. Podocyte granularity was examined using flow cytometry, electron microscopy imaging, and BODIPY staining. Perilipin-2 protein expression was increased in podocytes exposed to presumed CPF-containing plasmas, and correlated with the capacity of plasma to induce podocyte granularity, identified as lipid droplet accumulation. Elevated podocyte perilipin-2 was confirmed at protein and mRNA level and was also detected in glomeruli of FSGS patients whose active disease plasmas induced podocyte perilipin-2 and lipid droplets. Our study demonstrates that presumably, CPF-containing plasmas from FSGS patients induce podocyte lipid droplet accumulation and perilipin-2 expression, identifying perilipin-2 as a potential biomarker. Future research should address the mechanism underlying CPF-induced alterations in podocyte lipid metabolism, which ultimately may result in novel leads for treatment.
... Infantile onset NS About 50% of children with infantile onset NS (age 3-12 months) have a genetic cause of NS which usually does not respond to PDN treatment [31,32]. The finding of DMS on kidney biopsy is highly suggestive for an underlying genetic defect, i.e., pathogenic variants in WT1, PLCE1, or PDSS2 genes [33][34][35][36]. Therefore, we suggest following one of three strategies for infantile NS without extrarenal manifestations ( Fig. 2): (i) primary genetic testing, if the results are rapidly available, with standard PDN treatment given if genetic testing is negative; (ii) primary kidney biopsy, followed by standard PDN treatment in the case of MCD and FSGS, genetic testing in the case of DMS, and specific treatment in the case of other underlying kidney histopathologies; and (iii) starting standard PDN treatment and then initiating genetic testing and kidney biopsy in case of SRNS. ...
Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, hypoalbuminemia, and/or concomitant edema. Approximately 85–90% of patients attain complete remission of proteinuria within 4–6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70–80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given.
... Podocyte damage is an initial step in the nephrotic syndrome known as podocytopathy, represented by minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) [1]. The podocyte is a terminally differentiated cell with distinct cell morphology that is primarily dependent on a highly dynamic underlying cytoskeletal network and that is critical for maintaining glomerular function and integrity in healthy kidneys [2]. ...
... Podocytes are differentiated epithelial cells of the glomerulus that play a critical role in the kidney filtration barrier. Podocyte damage inevitably leads to proteinuria and glomerular dysfunction [1]. Treatments for podocytes, on the other hand, are still quite restricted. ...
Proteinuria, an indication of kidney disease, is caused by the malfunction of podocytes, which play a key role in maintaining glomerular filtration. Angiopoietin-like 3 (ANGPTL3) has been documented to have a cell-autonomous involvement in podocytes, and deletion of Angptl3 in podocytes reduced proteinuria in adriamycin-induced nephropathy. Here, we developed a monoclonal antibody (mAb) against ANGPTL3 to investigate its effects on podocyte injury in an ADR nephropathy mouse model and puromycin (PAN) induced podocyte damage in vitro. The mAb against the human ANGPTL3-FLD sequence (5E5F6) inhibited the binding of ANGPTL3-FLD to integrin β3. Treatment with the 5E5F6 mAb in ADR nephropathy mice mitigated proteinuria and led to a significant decline in podocyte apoptosis, reactive oxygen species (ROS) generation and mitochondrial fragmentation. In PAN-induced podocyte damage in vitro, the 5E5F6 mAb blocked the ANPGPLT3-mediated activation of integrin αvβ3 and Rac1, which regulated the mitochondrial homeostasis. Altogether, anti-ANGPLT3-FLD mAb attenuates proteinuria and podocyte lesions in ADR mice models, as well as PAN-induced podocyte damage, in part through regulating mitochondrial functions. Our study provides a therapeutic approach for targeting ANGPTL3 in proteinuric kidney disease.
... Non-Finnish NS individuals, on the other hand, carry different mutations [16]. On chromosome 1q25-31, the NPHS2 gene was discovered [17]. This gene is 25 kb long and has a 1149 bp code region as well as eight exons [18], [19]. ...
... Kidney biopsies to make FSGS diagnosis should contain a minimum of eight glomeruli and a few glomeruli (ie, fewer than 15) cannot confidently exclude the diagnosis of FSGS [14]. Histological finding of even a single glomerulus with segmental sclerosis or hyalinosis is enough to warrant a diagnosis of FSGS [15,16]. ...
Introduction
The syndrome of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is one of the most common inherited mitochondrial disorders.
Presentation of case
A 33- year-old male was admitted due to edema, urinary retention, and reduce urinary output. The medical history included a pigmentary retinopathy (PR) at age of 22 and uveitis at age of 30, which were both treated with prednisolone. At age of 32, unapparent bilateral sensorineural hearing loss (SNHL) and symmetric basal ganglia calcifications were observed in neurologic study, and received prednisolone for the diagnosis of migraine and undefined vasculitis. Also, he described a right transient ischemic stroke (TIA) in the past 4 months. His family history included a dead brother, who had nearly similar components. Physical exam on admission corresponded with parkinsonism. The status points to MELAS but the genetic test was not available. Additional tests were applied, excluding all other disorders. Lactate was normal in serum and CSF. Kidney tests revealed a nephrotic syndrome and glomerulopathy, and the biopsy showed a single hyalinized glomerulus, which most likely suggests focal segmental glomerulosclerosis (FSGS). Muscle biopsy showed ragged red fibers.
Conclusion
Here, we report a challenging case of MELAS syndrome with rare manifestations including uveitis, PR, parkinsonism, and FSGS in the absence of lactic acidosis with unapparent muscle or hearing impairments. Since, clinicians might misdiagnose MELAS as vasculitis or other disorders due to its heterogeneous presentations, a proper investigations should guide the diagnosis of these conditions to reduce the delay of diagnosis and ineffective treatments.
... In adults, the disease is usually secondary while in children, it is usually primary or idiopathic. 1 MCD is more common in Asia and has a male predominance (approximately 2:1) in young children, difference that disappears in adolescents and adults. 1 MCD arises from a histopathologic lesion in the glomerulus featured by the absence of visible alterations in light microscopy and immunofluorescence, but with diffuse foot process effacement on electron microscopy. 2,3 The pathogenesis of proteinuria in MCD has not been fully understood. It is proposed that abnormal cytokines from T-cells and/or abnormal T-cell regulation by B-cells are implicated in the pathogenesis of this disease. ...
... Recently, it has been reported that podocytes play a key role. 2,3 The clinical course in children is often benign with a high rate of remission after corticosteroid treatment. The response rate in adults is lower, with 5%-30% of MCD adult patients not responding to initial steroid therapy. ...
... The response rate in adults is lower, with 5%-30% of MCD adult patients not responding to initial steroid therapy. 3 ANCA-associated vasculitis (AAV) is the most frequent cause of rapidly progressive glomerulonephritis in adults. 4 AAV occurs more commonly in Caucasians, has a male predominance and the typical age of disease onset is between the fifth and the seventh decade of life but it can be seen at any age. ...
Antineutrophil cytoplasmic antibodies (ANCA) are useful as markers for systemic vasculitis. PR3-ANCA antibodies have been also identified in
association with chronic inflammatory and infectious conditions, other autoimmune diseases, malignancy, and certain drugs. The association of
PR3 and minimal change disease (MCD) without vasculitis is not an expected finding. We report a case of MCD with PR3-ANCA positive title and
no histopathological findings of vasculitis. This reports to an 86-year-old Caucasian woman without relevant past medical history and a normal renal
function one month before presentation with sudden-onset nephrotic syndrome and rapidly progressive renal failure. Renal ultrasound was normal.
Autoimmune screening using enzyme-linked immunosorbent assay (ELISA) revealed PR3-ANCA high titers (238.7UQ). Renal biopsy did not show
vasculitis or crescentic glomerulonephritis. The glomeruli were normal. Autoimmune, inflammatory, infectious and malignant diseases were excluded.
MCD was assumed and she started prednisolone with clinical and analytical improvement. ANCA-associated glomerular disease can coexist with a
variety of other glomerular diseases including membranous nephropathy, lupus nephritis, IgA nephropathy, and bacterial infection-related glomerulonephritis. This association could be an incidental finding, but there may be an association with MCD not previously reported. Our case emphasizes
the importance of performing renal biopsies before embarking on a full-scale immunosuppression therapy based on ANCA title alone.
... regarding the degree of proteinuria reduction [57]. Maybe the great intensity of structural damage on podocytes impairs the favorable effects of ACEi and ARBs [67]. ...
Idiopathic Nephrotic Syndrome (INS) is the most frequent etiology of glomerulopathy in pediatric patients and one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in this population. In this review, we aimed to summarize evidence on the pathophysiological role and therapeutic potential of the Renin Angiotensin System (RAS) molecules for the control of proteinuria and for delaying the onset of CKD in patients with INS. This is a narrative review in which the databases PubMed, Web of Science, and SciELO were searched for articles about INS and RAS. We selected articles that evaluated the pathophysiological role of RAS and the effects of the alternative RAS axis as a potential therapy for INS. Several studies using rodent models of nephropathies showed that the treatment with activators of the Angiotensin-Converting Enzyme 2 (ACE2) and with Mas receptor agonists reduces proteinuria and improves kidney tissue damage. Another recent paper showed that the reduction of urinary ACE2 levels in children with INS correlates with proteinuria and higher concentrations of inflammatory cytokines, although, data with pediatric patients are still limited. The molecules of the alternative RAS axis comprise a wide spectrum, not yet fully explored, of potential pharmacological targets for kidney diseases. The effects of ACE2 activators and receptor Mas agonists show promising results that can be useful for nephropathies including INS.
