Materiały źródłowe

• #1 Nephrotic Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470444/

  Nephrotic syndrome (NS) is a clinical syndrome defined by massive proteinuria (greater than 40 mg/m^2 per hour) responsible for hypoalbuminemia (less than 30 g/L), with resulting hyperlipidemia, edema, and various complications. It is caused by increased permeability through the damaged basement membrane in the renal glomerulus. It results from an abnormality of glomerular permeability that may be primary with a disease-specific to the kidneys or secondary to congenital infections, diabetes, systemic lupus erythematosus, neoplasia, or certain drug use. […] Nephrotic syndrome (NS) is a clinical syndrome defined by massive proteinuria responsible for hypoalbuminemia, with resulting hyperlipidemia, edema, and various complications. It is caused by increased permeability through the damaged basement membrane in the renal glomerulus, especially infectious or thrombo-embolic. It results from an abnormality of glomerular permeability that may be primarily due to an intrinsic renal disease in the kidneys or secondary due to congenital infections, diabetes, systemic lupus erythematosus, neoplasia, or certain drug use.

• #2 Immunopathogenesis of childhood idiopathic nephrotic syndrome

  https://www.chikd.org/journal/view.php?number=778

  Pediatric nephrotic syndrome (NS) is a clinical syndrome characterized by massive proteinuria, hypoalbuminemia, and generalized edema. […] Although the exact pathogenesis of INS has not been fully clarified, traditional therapeutic approaches based on immunosuppressive agents largely support the key role of the immune system, especially in SSNS. […] Most previous studies have suggested that the main pathogenesis of INS is T cell dysfunction and/or abnormal secretion of certain glomerular permeability factors. […] However, recent studies have suggested that the pathogenesis may also be related to B cell dysfunction. […] Currently, INS is considered an immune-mediated disorder caused by a complex interplay between T cells, B cells, soluble factors, and podocytes, which may vary among patients. […] A more in-depth investigation of the pathogenic pathways of INS is required to define precise targets for therapeutic intervention and to lead to a more effective personalized therapeutic approach.

• #3 Nephrotic Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470444/

  The glomerular capillaries are lined by fenestrated endothelium, which sits on the glomerular basement membrane, covered by glomerular epithelium, or podocytes, which envelop the capillaries with the capillaries’ cellular extensions called foot processes. These processes interdigitate with special cell-cell junctions called the slit diaphragm, which together form the glomerular filter. Normally, larger proteins (greater than 69 kD) are excluded from filtration. The destruction of podocytes above a critical mass also leads to irreversible glomerular damage. […] Increased glomerular permeability causes albuminuria, eventually leading to hypoalbuminemia. Consequently, hypoalbuminemia results in a decline in plasma colloid osmotic pressure, in turn causing increased transcapillary filtration of water in the body. Subsequently, this process leads to the development of edema. […] An alternative hypothesis states that an intrinsic defect in the renal tubules leads to a decline in sodium excretion. This might occur if the intraluminal protein directly causes renal epithelial sodium reabsorption.

• #4 Nephrotic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Nephrotic_syndrome

  Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. […] The underlying mechanism typically involves damage to the glomeruli of the kidney. […] In nephrotic syndrome, the glomeruli are affected by an inflammation or a hyalinization that allows proteins such as albumin, antithrombin or the immunoglobulins to pass through the cell membrane and appear in urine. […] As a response to hypoproteinemia the liver commences a compensatory mechanism involving the synthesis of proteins, such as alpha-2 macroglobulin and lipoproteins. An increase in the latter can cause the hyperlipidemia associated with this syndrome.

• #5 Causes and Pathophysiology of Nephrotic Syndrome in Childhood | IntechOpen

  https://www.intechopen.com/chapters/69943

  Nephrotic syndrome is a general type of kidney disease seen in children. Nephrotic syndrome starts develops due functional and structural changes in the GFB, consequential difficulty to control protein in the urine. The etiology of nephrotic syndrome is also age reliant. Most cases reported in the first 3 months of life are referred to as congenital nephrotic syndrome (CNS) and are due to genetic diseases. Congenital nephrotic syndrome is the type of nephrotic syndrome which occurs in first 3 months of life and is due to genetic causes mostly by alterations in the gene encrypting nephrin, a podocyte opening diaphragm protein. The most important possible functions of the kidney is the filtration of blood and blood products at glomeruli, which permits the fluid and dirty products while retaining the greater part of blood proteins and all blood cells within the vasculature. These types of process of filtration is made potential by the (GFB), which is made up of specific glomerular epithelial cells (podocytes), endothelial cells, and GBM these distal bottom actions are attached to the GBM. Loss of negative charge of the GBM occurs in nephrotic syndrome. The confirmation, swelling and diffusion podocyte binds to bottom actions, dislocation of opening diaphragms, occurrence of filling junctions, vacuole formation, and deficiency of inclusion of podocytes from the GBM, these type of morphologic changes in podocytes that occur during progress of nephrotic syndrome. Some of soluble mediators that may alter capillary wall permeability in nephrotic syndrome proved by investigational data to carry the existence show to be true for this includes scared decrease of proteinuria subsequent treatment with protein A immunoadsorption in of primary nephrotic syndromes. For more than 30 years nephrotic syndrome may be because of abnormalities of the immune system has existed. Both the humoral and cellular immune responses are abnormal during relapse of nephrotic syndrome. In children with nephrotic syndrome facial or general edema, is the basic symptom due to accumulation of fluid in the interstitial compartment. In nephrotic syndrome the edema is usually causes disproportionate proteinuria, which leads to retention of sodium and water, hypoalbuminemia to recompense for intravascular volume depletion. The pathogenesis of edema can be well explained by analysis of the classic Starling equation, which explains the regulation of fluid movement across capillary walls.

• #6 The View of Pediatric Nephrotic Syndrome as a Podocytopathy

  https://www.mdpi.com/2673-8236/3/4/30

  Nephrotic syndrome (NS) is a complex clinical entity characterized by proteinuria, hypoalbuminemia, and edema. […] 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. […] The main pathophysiological alteration in NS is the impairment of the glomerular filtration barrier. Therefore, its permeability becomes non-selective, and urinary protein loss occurs. […] Podocytes are highly differentiated epithelial cells with a large cell body and elongated cellular extensions, the foot processes, that interdigitate along the outer wall of the glomerular capillary and, among other functions, provide structural support and control the filtration process.

• #7 The View of Pediatric Nephrotic Syndrome as a Podocytopathy

  https://www.mdpi.com/2673-8236/3/4/30

  Being the final barrier to protein loss in the glomerulus, alterations in podocyte structure can explain why injuries in these cells, such as the effacement of their foot processes, are typically related to proteinuria and hypoalbuminemia and, therefore, to the conditions under the NS umbrella. […] The mechanisms that underlie FP effacement and podocytes’ response to injury are important to determine the clinical manifestations of NS and prognosis. […] The understanding of podocyte-specific protein alterations and the dynamic changes of glomerular permeability and selectivity are also relevant for the management and treatment of NS. […] The protein composition of SD justifies the importance of this cellular junction for glomerulus permeability. […] The unique zipper-like architecture of the SD is essential to the glomerulus permeability; therefore, podocyte depletion due to detachment, apoptosis, or necrosis is a critical step in the development of NS.

• #8 Nephrotic Syndrome: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/244631-overview

  There are two current hypotheses for the formation of edema in nephrotic syndrome. The underfill hypothesis holds that the loss of albumin leading to lower plasma colloid pressure is the cause. The overfill hypothesis states that the edema is due to primary renal sodium retention. […] An increase in glomerular permeability leads to albuminuria and eventually to hypoalbuminemia. In turn, hypoalbuminemia lowers the plasma colloid osmotic pressure, causing greater transcapillary filtration of water throughout the body and thus the development of edema. […] An alternative hypothesis is an intrinsic defect in the renal tubules which cause a decrease in sodium excretion. This could occur if the filtered intraluminal protein directly stimulated renal epithelial sodium reabsorption. […] A third possible mechanism is an enhanced peripheral capillary permeability to albumin, as shown by radioisotopic technique in human studies of 60 patients with nephrotic syndrome.

• #9 Symptomatic management of nephrotic syndrome in children – UpToDate

  https://www.uptodate.com/contents/symptomatic-management-of-nephrotic-syndrome-in-children

  The nephrotic syndrome (NS) is caused by renal diseases that increase the permeability across the glomerular filtration barrier. It is classically characterized by nephrotic-range proteinuria, hypoalbuminemia, and edema. The first two features are diagnostic. […] Idiopathic NS is the most common form of NS in children, representing more than 90 percent of cases before 10 years of age and 50 percent after 10 years of age. The majority of children with NS will respond to steroid therapy. However, symptomatic treatment is important in the early course of therapy as response to steroid therapy may take several weeks. […] Symptomatic treatment also becomes the mainstay of therapy in children who fail to respond to steroids, especially in those with genetic mutations that cause their NS. […] Despite a total increase in body water, children with NS may have a decreased intravascular volume. Serious intravascular volume depletion may be observed at onset of the NS with severe hypoalbuminemia and may be aggravated by diarrhea or diuretics. […] Edema is treated by salt restriction because renal retention of sodium is one of two principal mechanisms that lead to edema in the NS. Dietary salt intake should be restricted to less than 2 to 3 mEq/kg per day.

• #10 Nephrotic syndrome | PPT

  https://www.slideshare.net/slideshow/nephrotic-syndrome-38928706/38928706

  Hypoalbunemia is due to both the proteinuria and due to the increase renal catabolism (in tubules). […] Metabolic consequences of the nephrotic syndrome include the following: Infection, Hyperlipidemia and atherosclerosis, Hypocalcemia and bone abnormalities, Hypercoagulability, Hypovolemia. […] Hypocalcemia is common in the nephrotic syndrome, but rather than being a true hypocalcemia, it is usually caused by a low serum albumin level. […] Hypovolemia occurs when hypoalbuminemia decreases the plasma oncotic pressure, resulting in a loss of plasma water into the interstitium and causing a decrease in circulating blood volume. […] Symptoms and signs include anorexia, malaise, puffy eyelids, retinal sheen, abdominal pain, wasting of muscles, and edema. […] Management involves treating any underlying causes, controlling edema and hyperlipidemia, and using corticosteroids or other immunosuppressive drugs to induce remission in frequent relapsers or steroid-dependent patients.

• #11 Nephrotic Syndrome in Paediatrics – Mind The Bleep

  https://mindthebleep.com/nephrotic-syndrome/

  Nephrotic syndrome consist of a triad of oedema, hypoalbuminaemia and proteinuria. […] The glomerular filtration barrier consists of fenestrated endothelium of the capillary, the glomerular basement membrane and podocyte foot processes. The connection between foot processes are called slit diaphragms. This barrier usually excludes proteins from filtration. […] Proteinuria occurs as a result of disease disrupting the filtration barrier, resulting in increased glomerular permeability. The podocyte is usually the component of the barrier that is targeted by pathological processes. […] Children develop hypoalbuminaemia due to the loss of protein in the urine. This causes a positive feedback mechanism with the liver producing more albumin. As well as synthesising more albumin, the liver also increases its production of LDL and VDL and lipoprotein which causes hypercholesterolaemia and hypertriglyceridaemia.

• #12 Nephrotic Syndrome in Paediatrics – Mind The Bleep

  https://mindthebleep.com/nephrotic-syndrome/

  Children become hypercoagulable and are at an increased risk of thrombosis, particularly renal vein thrombosis, but also deep vein thrombosis and pulmonary emboli. This occurs due to loss of anti thrombin III, protein C and protein S in the urine, secondary to proteinuria. There is also increased hepatic synthesis of pro coagulant factors and increased platelet activation. […] Oedema occurs as a result of decreased oncotic pressure secondary to hypoalbuminaemia which means more water is filtered through the capillaries and urine output increases. This leads the kidneys to retain sodium in the collecting tubules in order to retain fluid. […] Children are also immunocompromised due to loss of immunoglobulins and complement in the urine. Treatment with steroids and biologics compound an infection risk. They are most prone to encapsulated organisms e.g. Strep. pneumoniae, H. influenzae.

• #13 Diagnosis and Management of Nephrotic Syndrome in Adults | AAFP

  https://www.aafp.org/pubs/afp/issues/2016/0315/p479.html

  Nephrotic syndrome (NS) consists of peripheral edema, heavy proteinuria, and hypoalbuminemia, often with hyperlipidemia. […] The mechanism of edema formation in NS is unclear. The primary defect seems to be increased glomerular permeability to albumin and other plasma proteins. Primary renal sodium retention and decreased oncotic pressure from hypoalbuminemia lead to increased extravasation of fluid from the intravascular space into the interstitial space, resulting in edema. […] The pathophysiology of thrombogenesis in NS is also not completely understood but seems to be multifactorial, involving loss of coagulation regulatory proteins and a shift in the hemostatic balance toward a prothrombotic milieu. Patients with NS and prothrombotic genetic mutations have a further increased risk of thrombosis.

• #14 Systemic Complications In Childhood Nephrotic Syndrome | IJNRD

  https://www.dovepress.com/disease-associated-systemic-complications-in-childhood-nephrotic-syndr-peer-reviewed-fulltext-article-IJNRD

  Cardiovascular complications of NS include increased risk of atherosclerosis and thromboembolism, due to dysregulated lipid metabolism and dyslipidemia. […] The pathogenesis of the increased infection frequency is linked to defects in cell-mediated immunity, urinary loss of immunoglobulins, properdin factor band B, and complement factors. […] Metabolic abnormalities, such as deranged coagulation, immunodeficiency from immunoglobulin and complement loss, and anemia from erythropoietin and transferrin deficiency, are linked with low molecular weight proteins, including some binding proteins, that are excreted in patients with NS. […] One of the important and alarming complications of idiopathic NS is acute kidney injury (AKI). […] Disturbance of calcium homeostasis in NS is linked with hypocalcemia, reduced vitamin D metabolites in serum, weakened intestinal absorption of calcium, and raised levels of parathyroid hormone, which lead to abnormal bone histology.

• #15 The role of the immune system in idiopathic nephrotic syndrome | Molecular and Cellular Pediatrics | Full Text

  https://molcellped.springeropen.com/articles/10.1186/s40348-021-00128-6

  Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. […] Several lines of evidence strongly indicate a role of the immune system in the pathogenesis of non-genetic INS. […] Soluble factors, different immune cells, recently even immunologic properties of podocytes are potentially implicated in the pathogenesis of the disease, but the precise role of the immune system in INS has not yet been completely elucidated. […] Shalhoub et al. hypothesized that INS represents the renal manifestation of a systemic T-cell dysregulation (deficient suppression) resulting in the production of a circulating mediator, which modifies podocyte structure, leads to foot-process effacement and results in so-called lipoid nephrosis.

• #16 Pathogenesis of Minimal Change Nephrotic Syndrome: A Review of the Underlying Molecular Mechanisms

  https://chikd.org/journal/view.php?number=696

  Nephrotic syndrome (NS) is the most common glomerular disorder in childhood, and a vast majority of cases are idiopathic. […] Idiopathic NS has been considered a disorder of T-cell function mediated by a circulating factor that alters podocyte function resulting in massive proteinuria since the last four decades. […] The candidate molecules as pathological mediators of steroid-dependent NS are CD80 (also known as B7-1), hemopexin, and angiopoietin-like 4. […] Recent studies suggest that not only T cells but also other immune cells and podocytes are involved in the pathogenesis of MCNS. […] Shalhoub, in 1974, proposed that the increased glomerular permeability to plasma protein in MCNS is due to a circulating factor released by T-cells; however, until date the search for the circulating factor has been unsuccessful.

• #17 Steroid-sensitive nephrotic syndrome in children: triggers of relapse and evolving hypotheses on pathogenesis | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/s13052-015-0123-9

  Nephrotic syndrome remains the most common manifestation of glomerular disease in childhood. Minimal change nephropathy is the most common cause of the syndrome in children. […] This review seeks to appraise the common triggers of relapse and to highlight the evolving hypotheses about the pathogenesis of the syndrome. […] Hypotheses on pathogenesis of the syndrome have evolved from the concepts of immune dysregulation, increased glomerular permeability to podocytopathy. […] The pathogenesis of nephrotic syndrome remains incompletely resolved despite the strong evidence of immune dysregulation, mainly involving cell-mediated immunity. […] The tendency of the disease to manifest and relapse after viral infections or an atopic episode, the association with HLA antigens and Hodgkins lymphoma, and the therapeutic response to steroids and cyclosporine support the immune dysregulation hypothesis.

• #18

  https://link.springer.com/article/10.1007/s00467-021-05401-4

  The pivotal role of prednisolone and the efficacy of immunosuppressive agents in SSNS treatment strongly implicate the immune system in the pathogenesis of the disease. […] The involvement of T cells in nephrotic syndrome (NS) was reported in the 1970s. […] The main basis of this T cell theory is as follows: (1) there is an absence of routine deposition of immunoglobulins or complement in the glomeruli, suggesting the involvement of humoral factors; (2) immunosuppressants that suppress T cell function (corticosteroids, ciclosporin, and cyclophosphamide) are effective; and (3) some cases achieve remission following measles infection, which impairs T-cell function. […] Based on the highly effective therapeutic effects of B cell-depleting monoclonal antibody rituximab (RTX), the hypothesis that B cells are associated with disease was proposed in the 2010s.

• #19 The role of the immune system in idiopathic nephrotic syndrome | Molecular and Cellular Pediatrics | Full Text

  https://molcellped.springeropen.com/articles/10.1186/s40348-021-00128-6

  Different subsets of T-cells have been implicated in the pathogenesis of INS in the last decades. […] The Immune dysregulation Polyendocrinopathy, Enteropathy, and X-linked (IPEX) syndrome with concomitant nephrotic syndrome provides strong evidence for the crucial role of regulatory T-cells (Tregs) in INS. […] Treg number in physiological states is low, but they can be rapidly generated from immature CD4+ T-cells, that expand in response to stimulation. […] Interestingly, Shimada et al. showed that Tregs have the potential to turn off CD80 expression on podocytes once it is induced. […] Finally, Treg dysregulation can amplify the neutrophil-induced oxidative burst triggered by an infection, potentially leading to INS relapse. […] Another important cell type, Th17 cells also derive from the naive CD4+ progenitor cells, as do Tregs.

• #20 Pathogenesis of minimal change nephrotic syndrome: an immunological concept

  https://www.e-cep.org/journal/view.php?doi=10.3345/kjp.2016.59.5.205

  The importance of the association between Tregs and nephrotic syndrome is highlighted by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome with concomitant nephrotic syndrome. IPEX syndrome is a rare disorder of the immune regulatory system caused by mutations of FOXP3, which is a transcription factor responsible for the generation and maturation of Tregs, and the development of MCNS in IPEX syndrome can be explained by Treg dysfunction. […] Some studies have shown an association between various cytokines and proteinuria, and stated that glomerular permeability factors can be responsible for nephrotic syndrome in patients or in animal models of the proteinuric disease. […] Recent studies have identified that increased IL-13 expression can lead to podocyte injury and can induce a MCNS-like phenotype. An increase in IL-13 production by CD3+, CD4+, and CD8+ T cells was shown to mediate SSNS.

• #21 A review of nephrotic syndrome and atopic diseases in children – Zheng – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/57201/html

  A previous study revealed that the pathogenesis of NS might be correlated to Th2 activation. Furthermore, NS patients commonly exhibit the downregulation of Th1 cells and the upregulation of Th2 cells, resulting in a Th1/Th2 imbalance, and this may be one of the important mechanisms of NS occurrence and development. […] In addition, as important immunoregulatory cells, Treg also plays an important role in autoimmune diseases, transplant rejection, and tumors. Normally, Treg cells and Th17 cells maintain a balance between them. In NS, Treg expression decreases, and Th17 expression increases, and the Th17/Treg imbalance is involved in the development of NS. […] This suggests that the atopic process is also involved in the development of NS. […] Therefore, it was speculated that NS and atopic diseases may be the same kind of disease, have a similar pathogenesis, and only exhibit different clinical manifestations due to different affected parts of the disease.

• #22 The role of the immune system in idiopathic nephrotic syndrome | Molecular and Cellular Pediatrics | Full Text

  https://molcellped.springeropen.com/articles/10.1186/s40348-021-00128-6

  Among Teffs, the Th2 subset was traditionally indicated as a major player in the pathogenesis of INS, because MCD is often associated with atopy and allergy, which in turn are caused by Th2 immunologic responses. […] The disproportion between CD4+ and CD8+ T-cells seems to play a relevant role in INS, too. […] Although INS has been traditionally considered to be a T-cell mediated disease, recently the view shifted towards a potential role of B-cells in the pathogenesis of INS. […] Recent findings indicate that podocytes can act as antigen-presenting cells and be part of the adaptive immune system. […] Podocytes have attracted particular attention as a key player in the pathogenesis of INS.

• #23 Pathogenesis of minimal change nephrotic syndrome: an immunological concept

  https://www.e-cep.org/journal/view.php?doi=10.3345/kjp.2016.59.5.205

  Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia. Minimal change nephrotic syndrome (MCNS) is the most common form of INS in children. The pathogenesis of MCNS still remains unclear, however, several hypotheses have been recently proposed. For several decades, MCNS has been considered a T-cell disorder, which causes the impairment of the glomerular filtration barrier with the release of different circulating factors. Increased levels of several cytokines are also suggested. Recently, a „two-hit” theory was proposed that included the induction of CD80 (B7-1) and regulatory T-cell (Treg) dysfunction, with or without impaired autoregulatory functions of the podocyte. […] More than four decades ago, MCNS was considered as an exclusive systemic disorder of T cells and cell-mediated immunity. Increased levels of various cytokines were also suggested as one aspect of the pathogenesis. Recently, Shimada et al. proposed a „two-hit” theory that included the induction of CD80 (or B7-1) and regulatory T-cell (Treg) dysfunction, with or without impaired autoregulatory function of the podocytes.

• #24 Clinical and Experimental Pediatrics

  https://www.e-cep.org/m/journal/view.php?number=20125550538

  The precise pathophysiology of MCNS still remains elusive. We hereby discuss immunological insights and recent findings on the pathogenesis of MCNS. […] Recently, Shimada et al. proposed a „two-hit” theory that included the induction of CD80 (or B7-1) and regulatory T-cell (Treg) dysfunction, with or without impaired autoregulatory function of the podocytes. […] The importance of the association between Tregs and nephrotic syndrome is highlighted by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome with concomitant nephrotic syndrome. […] However, the reason behind children with MCNS having Treg impairment and/or podocyte autoregulation is still unknown. […] The initial hit is the induction of CD80 on the podocyte, resulting in an alteration in shape with actin disruption that causes increased glomerular permeability and proteinuria. The second hit is usually caused by the ineffective censoring of podocyte CD80 due to Treg dysfunction or impaired podocyte autoregulation and reduced CTLA-4, IL-10, or TGF- response.

• #25 Clinical and Experimental Pediatrics

  https://www.e-cep.org/m/journal/view.php?number=20125550538

  CD80 expression may result from either direct binding of the podocyte by activated T-cell cytokines such as IL-13, or by activation of podocyte TLR by microbial products or allergens. […] In normal circumstances, CD80 expression on podocytes is terminated by Treg cytokines or CTLA-4 and IL-10 by podocytes. However, if a second hit occurs in MCNS and abnormal censoring of podocyte CD80 expression continues due to a defective autoregulatory response by Tregs or by the podocyte itself, CD80 expression persists and results in MCNS. […] The implicated role of circulatory factors in the etiopathogenesis of MCNS has long been postulated. […] In contrast to the well-established involvement of T cells in MCNS, the role of B cells is not yet certain. […] B-cell biology, however, has attained more attention lately, since treatment with rituximab, a monoclonal antibody directed against CD20 bearing cells, has shown good therapeutic responses in the treatment of both childhood and adulthood MCNS.

• #26 Steroid-sensitive nephrotic syndrome in children: triggers of relapse and evolving hypotheses on pathogenesis | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/s13052-015-0123-9

  Although the pathogenic mechanism for nephrotic syndrome has traditionally focused on dysregulation of T cells, there is increasing evidence that B cells also play a role given the efficacy of rituximab in treating the disorder. […] The exact mechanism of action remains unclear but it has been proposed that induction of regulatory T cells may lead to a late effect on decreasing proteinuria long after completion of therapy. […] For pediatricians and pediatric nephrologists, there is a strong evidence to institute relapse-specific interventions in children with SSNS. […] The recognition of the crucial role of podocyte injury in nephrotic syndrome has resulted in many new studies which have identified several important molecular pathways that can regulate podocyte injury; giving new evidence that indicates that the disease results from podocyte dysfunction. […] Development of drugs which can affect these pathways holds prospects for targeted and effective treatments for nephrotic syndrome in future.

• #27

  https://link.springer.com/article/10.1007/s00467-021-05401-4

  The parallel occurrence of B cell depletion and a decrease in disease activity in NS strongly suggests a direct involvement of B cell pathology. […] Moreover, the lymphocyte subset most associated with relapse after RTX administration are switched memory B cells. […] Additionally, mycophenolate mofetil, useful in preventing the recurrence of SSNS, suppresses switched memory B cells dominantly, suggesting that B cells are also involved in its pathogenesis. […] Podocytes express human leukocyte antigen (HLA) class II and function as immune cells. […] Aberrant expression of HLA class II causes autoimmune diseases in antigen-presenting cells and various organs. […] These facts suggest that podocytes can act as immune cells in the pathogenesis of NS. […] The pathophysiological role of circulating factors in NS has been suggested, especially in patients with focal segmental glomerulosclerosis.

• #28 Pediatric Nephrotic Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/982920-overview

  The hallmark of idiopathic nephrotic syndrome (INS) is massive proteinuria, leading to decreased circulating albumin levels. […] However, strong evidence suggests that INS, at least in part, has an immune pathogenesis. […] The effect of glucocorticoids on inducing remission in INS implicates the immune system, and Shalhoub proposed that dysfunction of T lymphocytes contributed to the pathogenesis of the condition. […] A circulating factor may also play a role in the development of proteinuria in INS as seen by the rapid development of proteinuria in the recurrence of nephrotic syndrome after kidney transplantation in some patients with FSGS. […] More recent data point to a paradigm shift about the role of the immune system in the pathogenesis of MCNS in some patients. […] The interaction of the extracellular domain of nephrin molecules bridging the gap between foot processes of neighboring podocytes is critical for the sieving property of the slit diaphragm.

• #29 The View of Pediatric Nephrotic Syndrome as a Podocytopathy

  https://www.mdpi.com/2673-8236/3/4/30

  The presence of a systemic circulating factor, likely podocyte-derived, has also been suggested. […] The immune system may be involved in the pathogenesis of NS, particularly a dysfunction or dysregulation of T lymphocytes. […] A hypothetical cause of NS is the existence of a circulating permeability factor that disturbs the glomerular permeability. […] The existence of a circulating factor was further corroborated by the possibility of maternal transmission of FSGS. […] Some molecules have been investigated as potential permeability factors, including hemopexin, heparanase, angiopoietin-like 4 (ANGPTL4), cardiotrophin-like cytokine-1, and suPAR. […] The early identification of genetic causes for SRNS allows for more appropriate management of the disease. […] Specific mutations in the genes NPHS1, NPHS2, LAMB2, and WT1 explain 69 to 85% of NS cases starting in the first three months of life.

• #30 Immune Mediators in Idiopathic Nephrotic Syndrome: Evidence for a Relation Between Interleukin 8 and Proteinuria | Pediatric Research

  https://www.nature.com/articles/pr2008257

  The pathogenesis of idiopathic nephrotic syndrome (INS) remains unknown. Several findings suggest a role for the immune system. […] The pathogenesis of INS is not yet fully understood. Many studies have proposed a role for the immune system, and this hypothesis is supported by a favorable response to anti-inflammatory drugs, a relation between relapses and viral infections or allergic reactions, the recurrence of the disease in transplanted patients, and an association with immunologic disorders. […] More recently, it has been proposed that alterations in the cytokine and chemokine profile of INS patients might contribute to proteinuria and glomerular damage. […] One of the actions of TGF- is to induce the accumulation of monocytes and stimulation of fibroblasts by increasing the expression of two CC-chemokines: monocyte chemoattractant protein-1 (MCP-1/CCL2) and regulated on activation normal T-cell expressed and secreted (RANTES/CCL5).

• #31 Immune Mediators in Idiopathic Nephrotic Syndrome: Evidence for a Relation Between Interleukin 8 and Proteinuria | Pediatric Research

  https://www.nature.com/articles/pr2008257

  Another mediator of interest when studying the INS pathogenesis is IL-8 (IL-8/CXCL8), a chemokine produced by endothelial cells and macrophages that attracts neutrophils and lymphocytes to the inflammation site, and may be involved in the pathogenesis of proteinuria in INS. […] Our findings suggest that IL-8/CXCL8 and TGF-1 are involved in the pathogenesis of INS: IL-8/CXCL8 associated with local changes in glomerular permeability and TGF-1 could be related to worse response to corticosteroids.

• #32 Pediatric Nephrotic Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/982920-overview

  The current consensus is that injury or dysfunction of podocytes plays a primary role in the development of proteinuria. […] Various forms of INS have been described with genetic mutations affecting the podocyte. […] Podocyte biology and genetics have greatly expanded the understanding of the pathophysiology of proteinuria in renal diseases.

• #33 Take a look at the Recent articles

  https://www.oatext.com/Pathogenesis-of-idiopathic-nephrotic-syndrome-in-children-molecular-mechanisms-and-therapeutic-implications.php

  The podocytopathies are characterized by changes in the podocytes, which may be at the structural or molecular levels. […] The changes at the molecular levels have recently assumed prominence as a new paradigm on the pathogenesis of idiopathic nephrotic syndrome in children. […] In a nut-shell, idiopathic nephrotic syndrome has been defined as a T-cell disorder associated with a functional renal impairment in which the molecular mechanisms leading from the stimulation of the immune system to the clinical expression of the renal disease can be analyzed according to five biological events: a Th 2 activation of T cells by interleukin-13; a yet unresolved glomerular permeability factor of immune origin; a molecular disorientation of slit diaphragms or glomerular basement membrane responsible for proteinuria; a podocyte cytoskeleton rearrangement responsible for foot process effacement; and renal avidity for sodium and edema formation resulting from a primary stimulation of tubular sodium, K+-ATPase and an increase of endothelial permeability.

• #34 Take a look at the Recent articles

  https://www.oatext.com/Pathogenesis-of-idiopathic-nephrotic-syndrome-in-children-molecular-mechanisms-and-therapeutic-implications.php

  At the molecular level, focal adhesion kinase (FAK) is prominently involved in the effacement of the foot processes commonly seen in podocytopathies. […] Changes in podocyte proteins such as nephrin and nephrin homologue- Neph1, CD2-associated protein (CD2AP) and podocin, all play an important role in the pathogenesis of podocytopathies. […] Thus, in the nephrotic syndromes, there are changes in the podocytes which manifest as effacement of the podocyte foot processes, as well as structural alterations in the cytoskeleton and molecular reorganization of the slit diaphragm. […] The new knowledge about these molecular mechanisms has established the role of immunosuppressive drugs on podocytopathies and holds prospects for novel treatment approaches.

• #35 Take a look at the Recent articles

  https://www.oatext.com/Pathogenesis-of-idiopathic-nephrotic-syndrome-in-children-molecular-mechanisms-and-therapeutic-implications.php

  The conventional paradigm on the pathogenesis of nephrotic syndrome revolves around the concept of a glomerular disorder which is characterized by massive proteinuria with consequent hypoalbuminemia, generalized edema and hyperlipidemia. […] However, the changes at structural and molecular levels of the podocytes have recently assumed prominence as a new paradigm on the pathogenesis of pediatric idiopathic nephrotic syndrome. A number of complex molecular pathways with inter-related nexus result in a molecular disorientation of the slit diaphragm or the glomerular basement membrane leading to proteinuria, as well as in a rearrangement of the podocyte cytoskeleton which is responsible for foot process effacement. […] In acquired podocytopathies such as focal segmental glomerulosclerosis and minimal change disease, the molecular changes observed in proteins from the cytoskeleton, cell transmembrane, and the slit diaphragm induce foot process effacement and changes in negative charges which eventuates in massive proteinuria.

• #36

  https://link.springer.com/article/10.1007/s00467-021-05401-4

  The role of infection as a trigger for the onset or relapse of SSNS has been suggested. […] Many studies have investigated the association between SSNS and allergic diseases such as asthma, atopic dermatitis, or hay fever. […] The prevailing view is that common pathogenesis exists between allergic disease and SSNS rather than NS caused solely by allergic diseases. […] Advances in genetics have played a major role in the pathogenesis of NS. […] A combination of linkage analysis and whole-exome sequencing identified EMP2 mutations in SSNS. […] GWAS is a research method for clarifying single-nucleotide polymorphisms (SNPs) related to disease susceptibility genes by comprehensively examining and comparing SNPs as polymorphic markers between case and control groups. […] Gbadegesin et al., using hypothesis-free exome-wide study methods, first showed that the HLA-DQ region was significantly associated with SSNS in children in a South Asian population.

• #37 Genetics of Childhood Nephrotic Syndrome | Duke Molecular Physiology Institute | Duke Molecular Physiology Institute

  https://dmpi.duke.edu/studies/genetics-childhood-nephrotic-syndrome

  Studies of hereditary steroid resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) have generated data to improve our understanding of the pathogenesis of nephrotic syndrome (NS); however, little progress has been made in identifying genetic factors associated with the predominant form of NS, childhood onset steroid sensitive nephrotic syndrome (SSNS). […] The locus provided an unbiased genetic evidence that adaptive immunity is important in the pathogenesis of NS. […] The body of work from these International collaborations have reinforced our initial findings that childhood nephrotic syndrome is largely due to perturbation of adaptive immunity, and these findings has now set the stage for discovery of novel and specific therapeutics for nephrotic syndrome.

• #38

  https://link.springer.com/article/10.1007/s00467-021-05401-4

  The HLA-DR/DQ gene encodes an HLA class II molecule required for antigen presentation by antigen-presenting cells or B cells. […] The mechanism by which these alterations cause NS is unclear, but the immune balance may be altered. […] Although the pathogenesis of SSNS has not been clarified, the autoantibody hypothesis has recently been a focus. […] As mentioned above, NPHS1 encoding nephrin is a susceptibility gene; therefore, anti-nephrin antibodies may be involved in some patients with SSNS. […] Recently, Watts et al. reported that circulating autoantibodies against nephrin were detected in approximately 30% of patients with minimal change disease.

• #39 STEROID THERAPY FOR CHILDREN WITH IDIOPATHIC NEPHROTIC SYNDROME: IS A SHORT-TERM OR LONG-TERM TREATMENT PLAN MORE EFFECTIVE? – Turkish Medical Student Journal

  https://turkmedstudj.com/articles/steroid-therapy-for-children-with-idiopathic-nephrotic-syndrome-is-a-short-term-or-long-term-treatment-plan-more-effective/doi/tmsj.galenos.2023.2022-12-2

  Idiopathic nephrotic syndrome is one of the most common glomerular diseases in childhood. Corticosteroids are the first line of treatment for this disease. […] The exact pathogenesis of childhood nephrotic syndrome is not fully understood, but recently, immune system dysregulation has been the focus, and many other diverse factors, such as genetic factors and environmental factors, are thought to play a role in podocyte dysfunction. Infections have also been suggested to play a role in disease onset or recurrence. […] In recent years, it has been stated that the presence of autoantibodies against the protein called nephrin, which is expressed on the surface of podocytes and has a critical role in preventing proteinuria, is important in minimal change disease. […] It is thought that diffuse podocytopathy, which is seen frequently in children with nephrotic syndrome, is caused by the damage of podocytes due to an autoimmune response.

• #40 The View of Pediatric Nephrotic Syndrome as a Podocytopathy

  https://www.mdpi.com/2673-8236/3/4/30

  The presence of mutations in these genes decreases to 50 to 66% when NS starts between 4 and 12 months of life. […] The early identification of genetic causes supports the discontinuation of immunosuppressive agents and provides more information for prenatal counseling. […] The morphological picture of glomerulopathies is of great practical importance since, among all kidney diseases, they are the most diagnosable with a renal biopsy. […] The same form of clinical presentation can relate to very different morphological lesions with different pathogenic mechanisms, prognosis, and therapeutic approaches. […] Although kidney biopsy is the gold standard for NS diagnosis, this kind of invasive procedure is not routinely performed in children. […] The advances in this research field might improve the clinical outcomes and therapeutic approaches of patients with NS.

• #41 Nephrotic syndrome in children

  https://www.nhs.uk/conditions/nephrotic-syndrome/

  The main treatment for nephrotic syndrome is steroids, but additional treatments may also be used if a child develops significant side effects. […] Most children respond well to treatment with prednisolone, with the protein often disappearing from their urine and the swelling going down within a few weeks. This period is known as remission. […] If your child has congenital nephrotic syndrome, they’ll need frequent albumin infusions to help them grow and develop normally. This often requires a stay in hospital. […] In some cases, your doctor may recommend surgery to remove 1 or both of your child’s kidneys. This will stop proteins being lost in your child’s urine and reduce their risk of potentially serious problems, such as blood clots.

• #42 Prevalence and associated factors of infection in children with nephrotic syndrome aged 2-18 years in the northwest and east Amhara region, Ethiopia: a multi-center cross-sectional retrospective study | BMC Public Health | Full Text

  https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-024-19408-7

  Serum albumin level, presence of hematuria, and rural residence were significantly associated with infection. […] The proposed mechanism of infection in children with nephrotic syndrome-related hypoalbuminemia was that hypoalbuminemia was an indicator of urinary loss of immunoglobulins and complement factors required for opsonization, phagocytosis, and host defense. […] The presence of hematuria as an independent factor for children with nephrotic syndrome. Hematuria (blood in the urine) was an important clinical manifestation of a urinary tract infection. […] The other associated factor for infection in children with nephrotic syndrome was residence. Children in rural areas were 3.3 times more likely to have infection than children lived in urban areas.

• #43 A review of nephrotic syndrome and atopic diseases in children – Zheng – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/57201/html

  Pediatric nephrotic syndrome (NS) is a common and recurrent glomerular disease in childhood. […] The pathogenesis of this disease is not clear. However, in recent years, with the improvement of medical technology and more in-depth research, it was found that 50-70% of children with NS have increased total IgE in peripheral blood, and have clinical manifestations, such as airway hyperresponsiveness, skin pruritus, repeated eczema, and skin allergy. Hence, NS has many similarities with atopic diseases. […] The pathogenesis of minimal changes in NS children is not clear. To date, no single theory can completely explain its entire pathophysiological process. At present, it is considered that NS is mainly correlated to immune dysfunction, especially T cell dysfunction, which leads to the abnormal secretion of osmotic factors, such as cytokines or specific antibodies, and attacks podocytes, resulting in glomerular filtration membrane damage.

• #44 A review of nephrotic syndrome and atopic diseases in children – Zheng – Translational Andrology and Urology

  https://tau.amegroups.org/article/view/57201/html

  A previous study revealed that the pathogenesis of NS might be correlated to Th2 activation. Furthermore, NS patients commonly exhibit the downregulation of Th1 cells and the upregulation of Th2 cells, resulting in a Th1/Th2 imbalance, and this may be one of the important mechanisms of NS occurrence and development. […] In addition, as important immunoregulatory cells, Treg also plays an important role in autoimmune diseases, transplant rejection, and tumors. Normally, Treg cells and Th17 cells maintain a balance between them. In NS, Treg expression decreases, and Th17 expression increases, and the Th17/Treg imbalance is involved in the development of NS. […] This suggests that the atopic process is also involved in the development of NS. […] Therefore, it was speculated that NS and atopic diseases may be the same kind of disease, have a similar pathogenesis, and only exhibit different clinical manifestations due to different affected parts of the disease.

• #45 Pathogenesis of Minimal Change Nephrotic Syndrome: A Review of the Underlying Molecular Mechanisms

  https://chikd.org/journal/view.php?number=696

  Although the pathophysiology of NS has not been completely explained until now, it is considered a complex multifactorial disease with an immunological component. […] The pathogenesis leading to podocyte effacement is not clear. […] As immunosuppression with corticosteroids is the mainstay of NS therapy, it is logical to suspect immune dysregulation as a pathogenic factor in disease development. […] CD80, also known as B7-1, is a transmembrane molecule present on the surface of both antigen presenting cells and activated B-cells, and acts as a co-stimulatory signal for T-cell activation. […] In 2004, Reiser et al. reported that under certain conditions, podocytes can express CD80, and its expression results in the development of a proteinuric condition. […] The pathophysiology of NS is still far from being fully explained, although recent advances in podocyte biology have provided novel insights into the possibility of NS being a podocytopathy. […] MCNS is regarded as a multifactorial disease. It is hypothesized that MCNS is a podocytopathy and that CD80 or other circulatory factors are the triggers for proteinuria.

• #46 Steroid-sensitive nephrotic syndrome in children: triggers of relapse and evolving hypotheses on pathogenesis | Italian Journal of Pediatrics | Full Text

  https://ijponline.biomedcentral.com/articles/10.1186/s13052-015-0123-9

  Another hypothesis that evolved was the role of a systemic circulating factor which might result in increased glomerular permeability in patients with minimal change nephropathy and focal segmental glomerulosclerosis. […] However, recent evidence suggests that the primary defect in idiopathic nephrotic syndrome might be at the level of podocytes (the glomerular visceral epithelial cell). […] A hypothesis to unify these concepts of immune dysregulation, increased glomerular permeability and podocytopathy is yet to be proposed, but the speculation that critical podocyte proteins are probably potential targets for T cell cytokines or vascular permeability factors still needs further confirmation. […] Nevertheless, the podocyte evidently plays a key role both in the maintenance of the glomerular filtration barrier and structural integrity, as its injury and loss contribute to proteinuria and progressive sclerosis.

• #47 Department of Defense Funds $1.5 Million Grant to Dr. Tarak Srivastava to Study Immunopathogenesis of Nephrotic Syndrome in Children | Children’s Mercy Kansas City

  https://www.childrensmercy.org/childrens-mercy-research-institute/news-and-stories/department-of-defense-funds-1-5-million-grant-to-dr-tarak-srivastava-to-study-immunopathogenesis-of-nephrotic-syndrome-in-children/

  Nephrotic syndrome is a common kidney disease in children that causes protein loss from the blood into the urine leading to proteinuria from damage to the kidney filter. […] Treatment involves steroids and other immunosuppressive drugs, but it remains empirical due to a lack of understanding of the immune dysregulation of the disease. […] Dr. Srivastava explains that recent studies with human genetic data have shown significantly increased gene expression levels of a protein called SH3BP2 and its associated binding proteins in kidney biopsies of patients with nephrotic syndrome. […] SH3BP2 serves as a binding scaffold for other proteins that regulate immune signaling pathways, making it a master regulator of immune mechanisms. […] This study aims to investigate how the scaffold protein SH3BP2, along with its binding partners VAV2 and PLCG2, contributes to both innate and adaptive immune activation, playing a central role in nephrotic syndrome’s pathogenesis.

• #48 Department of Defense Funds $1.5 Million Grant to Dr. Tarak Srivastava to Study Immunopathogenesis of Nephrotic Syndrome in Children | Children’s Mercy Kansas City

  https://www.childrensmercy.org/childrens-mercy-research-institute/news-and-stories/department-of-defense-funds-1-5-million-grant-to-dr-tarak-srivastava-to-study-immunopathogenesis-of-nephrotic-syndrome-in-children/

  Dr. Srivastava and his team hypothesize that immune-mediated injury and structural damage to podocytes in nephrotic syndrome are mediated by downstream signaling involving SH3BP2-PLCG2 and SH3BP2-VAV2. […] Our long-term goal is to understand the process of disease development in nephrotic syndrome and develop targeted therapy with an SH3BP2 inhibitor to replace empirical treatment, said Dr. Srivastava.

• #49

  https://link.springer.com/article/10.1007/s40124-024-00333-7

  This review aims to provide an updated overview of nephrotic syndrome (NS) in children, with a focus on its prevalence, incidence, classification, pathogenesis, molecular mechanisms, prognosis, current treatments, and gene testing. […] Recent research in NS has highlighted several advancements. […] NS is a common pediatric glomerular disease where genetic mutations, particularly in NPHS1 and NPHS2, play a significant role. […] Genetic testing is essential for identifying these mutations, allowing for personalized treatment strategies, especially in cases of congenital and steroid-resistant NS. […] However, the complexity of genetic testing and the availability of resources can be limiting factors, particularly in regions with less access to advanced diagnostic tools. […] Despite these advances, challenges remain in treating steroid-resistant nephrotic syndrome (SRNS). […] Further research is needed to overcome these hurdles, aiming to develop more precise treatments and improve prognosis for SRNS patients.

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