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. […] 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.

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

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

  In a healthy individual, less than 0.1% of plasma albumin may traverse the glomerular filtration barrier. […] The glomerular structural changes that may cause proteinuria are damage to the endothelial surface, the glomerular basement membrane, or the podocytes. One or more of these mechanisms may be seen in any one type of nephrotic syndrome. Albuminuria alone may occur or, with greater injury, leakage of all plasma proteins (ie, proteinuria) may take place. […] 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.

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

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

  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.

• #1 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 molecular changes observed in proteins from the cytoskeleton, cell transmembrane, and slit diaphragm induce foot process effacement and changes in negative charges resulting in massive proteinuria seen in these podocytopathies. […] The new knowledge about these molecular mechanisms has established the role of immunosuppressive drugs on podocytopathies and holds prospects for novel treatment approaches.

• #1 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.

• #1 An Overview of Molecular Mechanism of Nephrotic Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3401527/

  Evidences suggested that podocytes may succumb the epithelial-mesenchymal transition (EMT) after antigenic encounter. […] Elevated TGF-1 production might induce the expression of integrin-linked kinase (ILK), a protein that is related to the pathogenesis of many nephropathies that course with proteinuria. […] Podocytes of patients with FSGS and membranous nephropathy present lower expression of nephrin mRNA than cells from patients with MCD. […] The nephrotic syndromes are known by their changes in podocytes as the effacement of podocyte foot processes, as well as structural changes in cytoskeleton and molecular reorganization of slit diaphragm. […] The main pathogenic mechanism involved in MN is the deposition of immune complexes, in subepithelial regions that leads to a progressive thinning of the glomerular capillary.

• #1 Immunopathogenesis of childhood idiopathic nephrotic syndrome

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

  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. […] However, recent studies have suggested that the pathogenesis may also be related to B cell dysfunction. […] In this review, an overview of the immunopathogenesis and a detailed review of the emerging autoimmune-mediated etiology of INS are described. […] These observations have prompted studies to identify circulating permeability factors, focusing on T cell products. […] Several candidate molecules have been identified, including T-helper 1 (Th1) cytokines (tumor necrosis factor- [TNF-], interleukin [IL]-2, and IL-18), T-helper 2 (Th2) cytokines (IL-4 and IL-13), and T-helper 17 (Th17)-related cytokines (IL-17, IL-1, IL-6, and IL-23).

• #1

  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.

• #1 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. […] The two-hit hypothesis proposes that the expression of CD80 on podocytes and ineffective inhibition of podocyte CD80 due to regulatory T-cell dysfunction or impaired autoregulation by podocytes results in NS. […] Recent studies suggest that not only T cells but also other immune cells and podocytes are involved in the pathogenesis of MCNS.

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

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

  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. […] Shalhoub postulated that MCNS is a disorder of T-cell function, resulting in increased plasma levels of lymphocyte-derived permeability factor. […] Of the various factors presumed to increase glomerular permeability to serum proteins, the most likely pathogenic factors are considered to be cytokines. […] The induction of Treg led to a marked reduction in proteinuria in animal models, and most patients with MCNS showed decreased levels of Treg. […] Shimada et al. reported that abnormal censoring of podocyte CD80 expression could underlie Treg dysfunction or impaired autoregulation by podocytes.

• #1 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. […] Another important cell type, Th17 cells also derive from the nave CD4+ progenitor cells, as do Tregs. […] 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. […] Similar to the dichotomy of Tregs/Th17, some findings indicate that the ratio of the Th2/Th1 subsets is much more important in the pathomechanism of INS rather than their absolute count.

• #1 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. […] Traditional therapeutic approaches based on immunosuppressive agents largely support the key role of the immune system in idiopathic NS (INS), especially in the steroid-sensitive form. […] Although most previous studies have suggested the main role of T cell dysfunction and/or the abnormal secretion of certain glomerular permeability factors, recent studies have emphasized the role of B cells since the therapeutic efficacy of B cell depletion therapy in inducing and/or maintaining prolonged remission in patients with INS was confirmed. […] 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.

• #1

  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. […] CD80 (B7-1), important for B-cell and T-cell interaction, has attracted considerable attention because of its association with SSNS. […] Podocytes express human leukocyte antigen (HLA) class II and function as immune cells. […] 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. […] 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.

• #1 Immunopathogenesis of childhood idiopathic nephrotic syndrome

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

  Podocytes have attracted attention as a novel key player in the immunopathogenesis of INS. […] The „first hit” is induction of podocyte expression of CD80 in response to a circulating factor (such as a cytokine, allergen, or microbial product). […] If dysfunctional Tregs in patients with MCD cannot turn off podocyte CD80 expression by secretion of soluble CTLA-4, IL-10, and transforming growth factor-beta, proteinuria may persist. […] In 2004, sustained remission of NS in a boy treated with rituximab, a B cell-depleting anti-CD20 monoclonal antibody, for recurrent idiopathic thrombocytopenic purpura was observed by chance. […] These findings support a key role for B cells in INS pathogenesis. […] An increased amount of serum CD23, a marker of B-cell activation, has been reported in pediatric SSNS.

• #1 Immunopathogenesis of childhood idiopathic nephrotic syndrome

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

  Increased levels of serum B-cell activating factor and IL-21, which contribute to B-cell activation, have been observed in adult patients with MCD. […] Recently, several large transethnic genome-wide association studies in large pediatric cohorts, including Korean patients, revealed specific risk alleles in the HLA region that play a crucial role in antigen presentation to T cells. […] These findings suggest that memory B cells play a key role in the pathogenesis of pediatric SSNS, and that the reappearance of memory B cells can predict relapse following B cell depletion therapy in childhood SSNS. […] Although the pathogenesis of INS is not completely understood, it seems likely that INS is an immune-mediated disorder caused by a complex interplay between immunoregulatory cells, soluble factors, and podocytes, which may vary between patients.

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

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

  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. […] Increased CD80 levels in urine are observed in patients with MCNS with relapse compared to those in remission and with other glomerular diseases. […] 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.

• #1 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 dysregulation of Tregs has been shown to be important in the pathogenesis of several autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Recently, it has also been suggested that Tregs play an important role in the pathogenesis of MCNS. […] 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. […] Therefore, these findings can further strengthen the hypothesis that IL-13 may increase podocyte permeability through the modulation of SD proteins, resulting in nephrotic-range proteinuria, namely MCNS, and also provide an explanation for the plausible connection among Th2 cytokines, MCNS, and atopy.

• #1 Minimal-Change Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/243348-overview

  Interleukin-13 (IL-13) has been implicated in the pathogenesis of MCD. In a study on Chinese children in Singapore, it was shown that IL-13 genetic polymorphisms correlate with the long-term outcome of MCD. An animal study by Lai et al suggested that IL-13 overexpression can cause podocyte foot process fusion and proteinuria. […] In patients who develop acute kidney injury (AKI), endothelin 1 expression is greater in the glomeruli, vessels, and tubules than in the non-AKI group. The glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play a primary role in the development of proteinuria. […] Nephrin is a major component of the slit diaphragm and is critical for preserving the glomerular capillary barrier to protein. The slit diaphragm is often missing in MC nephrotic syndrome (MCD) kidneys.

• #1 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 implicated role of circulatory factors in the etiopathogenesis of MCNS has long been postulated. Vascular permeability factor, elaborated from concanavalin A-stimulated lymphocytes obtained from patients with MCNS, acts on systemic capillaries and on the glomerular permeability barrier. […] In contrast to the well-established involvement of T cells in MCNS, the role of B cells is not yet certain. Despite an observed association between allergic diathesis and the onset of MCNS, an elevation of IgM, IgE, B-lymphocytes, and their subsets, surface IgM-, IgG-, and IgE-positive cells (B, B, and B) were already described in an earlier study. […] Here, we reviewed the pathogenesis of MCNS from an immunological perspective. Recent studies propose that the pathogenesis of MCNS could involve both lymphocytes and podocytes. Further studies are required to elucidate the exact pathophysiology of MCNS, and the development of novel drugs that target podocytes and immunosuppressants for lymphocytes are also needed.

• #1 Clinical Pathology Glossary: Nephrotic Syndrome & Key Pathologies | ditki medical & biological sciences

  https://ditki.com/course/pathology/glossary/pathophysiologic-disorder/nephrotic-syndrome-key-pathologies

  Nephrotic syndrome is the result of podocyte injury, which can be caused by toxins, viral infections, antigens to podocyte antigens, and other factors. Podocyte damage, effacement, and detachment from the basement membrane allows proteins to leak through the filtration membrane and enter the urine. […] The pathophysiology of minimal change disease is uncertain, but researchers think T-cell dysfunction and/or autoantibodies to the slit diaphragm are involved. […] Focal segmental glomerulosclerosis (FSGS) is characterized by podocyte detachment and death, which „denudes” the glomerular basement membrane and leads to scarring. […] Membranous nephropathy is characterized by immune complex deposition between the podocytes and basement membrane. The immune complexes activate the complement system and other immune responses. […] Amyloidosis can affect multiple parts of the nephron, nephrotic syndrome occurs when the glomerulus is damaged. […] Metabolic and hemodynamic changes in diabetes lead to sclerosis and fibrosis.

• #1 Minimal-Change Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/243348-overview

  It is postulated that MCD is a disorder of T cells, which release a cytokine that injures the glomerular epithelial foot processes. This, in turn, leads to a decreased synthesis of polyanions. The polyanions constitute the normal charge barrier to the filtration of macromolecules, such as albumin. When the polyanions are damaged, leakage of albumin follows. The identity of this circulating permeability factor is uncertain, although it is postulated that it may be hemopexin. […] Some of the cytokines that have been studied in MCD are interleukin-12 (IL-12) and interleukin-4 (IL-4). IL-12 levels have been found to be elevated in peripheral blood monocytes during the active phase and normalized during remission. Interleukin-18 (IL-18) can synergize with IL-12 to selectively increase the production of vascular permeability factor from T cells. In addition, levels of IL-4 and CD23 (a receptor for immunoglobulin E [IgE]) have been found to be elevated in peripheral blood lymphocytes.

• #1 Nephrotic Syndrome: Causes, Symptoms, Diagnosis, Treatment

  https://www.webmd.com/a-to-z-guides/what-is-nephrotic-syndrome

  Nephrotic syndrome isn’t a disease. It’s a group of symptoms that can appear if your kidneys aren’t working right. […] When they’re damaged, too much protein slips through the filters into your urine. The result is nephrotic syndrome. […] Some of the conditions that can damage your glomeruli include: Minimal change disease. Minimal change disease is the main cause of nephrotic syndrome in children. […] Focal segmental glomerulosclerosis is a disease that scars the glomeruli. It’s the most common primary cause of nephrotic syndrome in adults. […] Membranous nephropathy. This condition causes the membranes of the glomeruli to thicken. […] Diabetes is the most common secondary cause of nephrotic syndrome in adults. […] Lupus is a chronic disease of the immune system, can seriously damage the kidneys.

• #1 An Overview of Molecular Mechanism of Nephrotic Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3401527/

  Podocytopathies (minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS)) together with membranous nephropathy are the main causes of nephrotic syndrome. […] Considering the pathogenesis of proteinuria, some elucidations have been directed towards the involvement of epithelial-mesenchymal transition. […] The pathogenesis of glomerular sclerosis seen in FSGS might to be caused by an increase in glomerular profibrotic cytokines, such as IL-13 and IL-4, whereas other studies suggested the increase of TGF- levels in this process. […] The TGF- pathway controls cellular responses to many chronic glomerular injuries, thereby leading to an increase in the production of extracellular matrix, an increase in podocyte number and area, and apoptosis. […] Some studies have shown that higher renal expression of TGF-1 would be observed in children with FSGS in comparison to patients with MCD.

• #1 Evaluation of nephrotic syndrome – Differential diagnosis of symptoms | BMJ Best Practice US

  https://bestpractice.bmj.com/topics/en-us/356

  Nephrotic syndrome is defined as the presence of proteinuria (3.5 g/24 hours), hypoalbuminemia (3.0 g/dL), and peripheral edema. […] Nephrotic syndrome is not a single disease; it is a constellation of several symptoms that can be caused by several renal diseases. The challenge is to determine the underlying etiology causing the nephrotic syndrome in any given patient. […] Glomerular proteinuria develops when the components of the filtration barrier are disrupted by disease. The podocyte is the major target of pathologic processes resulting in the development of high-grade glomerular proteinuria. […] In focal segmental glomerulosclerosis (FSGS), the podocyte is often the target of an unknown circulating factor. In idiopathic membranous nephropathy, the podocyte is the target of an antibody response, and in genetic causes of steroid-resistant nephrotic syndrome (SRNS), the genetic mutation affects the podocyte or the filtration barrier.

• #1 Nephrotic syndrome – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/nephrotic-syndrome/

  FSGS is classically not associated with immune complex deposition. […] Structural damage of glomerular filtration barrier massive renal loss of protein (hyperproteinuria) reactively increased hepatic protein synthesis. […] Loss of negative charge of glomerular basement membrane loss of selectivity of barrier (especially for negatively charged albumin). […] Podocyte damage and fusion nonselective proteinuria (except in minimal change disease, which manifests with selective glomerular proteinuria). […] If protein loss exceeds hepatic synthesis (usually with a loss of protein 3.5 g/24 hours) hypoproteinemia/hypoalbuminemia, initially with both normal GFR and creatinine. […] Loss of antithrombin III, protein C, and protein S, increased synthesis of fibrinogen, and loss of fluid into the extravascular space hypercoagulability.

• #1 An Overview of Molecular Mechanism of Nephrotic Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3401527/

  The role played by the complement system seems to be essential for the development of the disease. […] Podocyte lesion might increase the expression of matrix metalloproteinase-9 (MMP-9) in these cells, which might induce collagen IV degradation and alterations in nephrin expression. […] In primary membranous glomerulopathy, some molecules such as megalin and phospholipase A2 receptor have been considered as being the antigens responsible for subepithelial immune complexes, which change the glomerular permeability. […] In both FSGS and MCD podocytopathies, the molecular changes observed in proteins from the cytoskeleton, cell transmembrane, and slit diaphragm induce foot process effacement and changes in negative charges, resulting in strong proteinuria.

• #1 Nephrotic syndrome – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/nephrotic-syndrome/

  Nephrotic syndrome may be caused by primary glomerular disorders (8090% of cases) and/or systemic diseases and toxic exposures (1020% of cases). […] Damage of glomerular filtration barrier: Minimal change disease: cytokine-mediated damage of podocytes. […] Focal segmental glomerulosclerosis: sclerosis of glomeruli damage and loss of podocytes. […] Membranous nephropathy: Anti-phospholipase A2 receptor antibodies (anti-PLA2R antibodies) bind to PLA2R (an autoantigen in glomerular podocytes) and thereby form immune complexes that activate the complement system, leading to podocyte injury. […] Amyloid nephropathy: Deposition of amyloid (e.g., AL amyloidosis, AA amyloidosis) in various organs (the kidney is the most commonly involved organ). […] Amyloid deposition in glomeruli mesangial expansion nodular sclerosis.

• #1 Nephrotic syndrome – Wikipedia

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

  Nephrotic syndrome is characterized by large amounts of proteinuria (3.5 g per 1.73 m2 body surface area per day, or 40 mg per square meter body surface area per hour in children), hypoalbuminemia ( 3.5 g/dl), hyperlipidaemia, and edema that begins in the face. […] 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 (the formation of a homogenous crystalline material within cells) 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.

• #1 Nephrotic syndrome – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/nephrotic-syndrome/

  Loss of transport proteins. […] Loss of plasma proteins plasma protein binding increase in free plasma drug concentration, but drug toxicity is usually not increased. […] Plasma levels of cholesterol, LDL, triglycerides, and lipoproteins (mainly LPA) to compensate for the loss of albumin lipiduria (fatty casts). […] Loss of immunoglobulins increased risk of infection, especially Streptococcus pneumoniae infection. […] Sodium retention possible hypertension.

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

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

  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.

• #1 Nephrotic Syndrome in Paediatrics – Mind The Bleep

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

  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.

• #1 Nephrotic syndrome | PPT

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

  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. […] Nephrotic syndrome is characterized by nephrotic range proteinuria, hypoalbuminemia, hyperlipidemia, and edema. It can be primary, caused by diseases limited to the kidney, or secondary, caused by diseases involving other organ systems. […] 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.

• #1 New insights into the pathophysiology of oedema in nephrotic syndrome | Nefrología

  https://revistanefrologia.com/en-new-insights-into-pathophysiology-oedema-articulo-X2013251411051700

  In nephrotic syndrome, a defective glomerular filtration barrier allows the passage of proteolytic enzymes or their precursors, which have the ability to activate the epithelial sodium channel, thereby causing the subsequent sodium retention and oedema. […] Contrary to the classic hypothesis, the alternative hypothesis (also called the overfill hypothesis) postulates that sodium retention in many NS patients is a primary renal phenomenon and may be caused by an intrinsic renal defect in sodium excretion, which in turn causes an expansion in plasma volume (hence the term overfill). […] Most of our understanding of the molecular mechanisms of sodium retention in NS has come from the use of animal models that induced NS by puromycin aminonucleoside (PAN). […] The cortical collecting tubule is the reabsorption point for sodium in nephrotic syndrome.

• #1 New insights into the pathophysiology of oedema in nephrotic syndrome | Nefrología

  https://revistanefrologia.com/en-new-insights-into-pathophysiology-oedema-articulo-X2013251411051700

  Ichikawa also performed micropuncture studies of superficial nephron tubular segments in the unilateral NS model in rats, and showed that the amount of sodium at the end of the distal convoluted tubule is the same in the proteinuric kidney as in the normal kidney. […] Despite the findings of Ichikawa et al, other studies have postulated that sodium retention in NS may occur in other nephron segments. […] Another sodium transporter that has been reported to be involved in sodium retention in NS is the Na+/K+-ATPase pump. […] Another sodium transporter that has been reported to be strongly involved in sodium retention in NS is the epithelial sodium channel or amiloride-sensitive sodium channel (ENaC). […] The first observations on ENaC activation by serine proteases in proteinuric states were made by Kastner et al.

• #1 New insights into the pathophysiology of oedema in nephrotic syndrome | Nefrología

  https://revistanefrologia.com/en-new-insights-into-pathophysiology-oedema-articulo-X2013251411051700

  Plasmin is known to come from the activation of plasminogen through the enzymatic action of urokinase, which is normally present in the collecting tubule. […] To summarise, the plasminogen present in plasma is probably filtered through NS’s own defective glomerular barrier and is then converted into plasmin by the action of urokinase present in the collecting tubule. Plasmin would then activate ENaC, resulting in sodium retention with the subsequent appearance of oedema.

• #1

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

  Advances in genetics have played a major role in the pathogenesis of NS. […] Approximately 30% of patients with SRNS have a single causative gene associated with podocytes. […] SSNS and SRNS appear to be on the same spectrum and overlap because patients with SSNS may develop steroid resistance during the disease and may partially respond to immunosuppressant therapy, even if genetic abnormalities are identified. […] 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.

• #1

  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. […] In addition to identifying the relevant SNPs, identifying the actual disease susceptibility alleles may be essential for clarifying the subsequent pathophysiology. […] The next challenge is to clarify the significance of disease susceptibility variants detected by GWAS, that is, the direct mechanism causing the disease. […] 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. […] Conclusively, future research to clarify the pathogenesis of SSNS is expected based on the knowledge derived from hypothesis-free genetic techniques.

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

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

  Loss of negative charge of the GBM occurs in nephrotic syndrome. […] Mutations in genes encoding some of the opening diaphragms proteins or their transcription factors can cause SRNS and/or FSGS. […] Some of soluble mediators that may alter capillary wall permeability in nephrotic syndrome proved by investigational data to carry the existence. […] 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.

• #1 Disease mechanism and pharmacological approaches for TBC1D8B-induced steroid resistant nephrotic syndrome

  https://www.telethon.it/en/what-we-do/research/projects-funded/disease-mechanism-and-pharmacological-approaches-for-tbc1d8b-induced-steroid-resistant-nephrotic-syndrome/

  Nephrotic syndromes (NS) are a combinations of symptoms that can lead, in both children and young adults, to kidney dysfunction and increased risk to progress toward end-stage kidney disease. […] However, for the remaining 10% such therapeutic treatment is useless, thus indicating the occurrence of the steroid-resistant nephrotic syndrome (SRNS). […] Extensive research in the SRNS pathogenesis have proven that in over 30% of people affected by SRNS symptomatology the cause of the disease is hereditary (i.e., dysfunctional genes transmitted from parents to their children). […] Such pathogenic genetic variants comprise proteins expressed by specialized kidney cells named podocytes which are responsible to maintain the structural integrity of the kidney filtering apparatus. […] Despite several advances, the understanding of the biological role of genetic alterations causing SRNS is still difficult, thus limiting the identification of novel therapeutic options for SRNS.

• #1 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

  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. […] Previous data had already pointed to a possible role of immunoglobulins as a binding partner to a circulating permeability factor. […] In conclusion, an active role of B-cells in INS pathogenesis gains more and more evidence, challenging the standpoint of INS as a disease only driven by T-cell dysfunction and RTX and other anti-CD20 antibodies pose as promising alternatives to other steroid-sparing agents. […] Recent findings indicate that podocytes can act as antigen-presenting cells and be part of the adaptive immune system.

• #1 Rituximab therapy in nephrotic syndrome: implications for patients’ management | Nature Reviews Nephrology

  https://www.nature.com/articles/nrneph.2012.289

  Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. […] A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A2 receptor autoantibodies, which are implicated in the pathogenesis of this disorder. […] Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events.

• #2 Nephrotic Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/25713

  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. […] 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.

• #2 Nephrotic Syndrome – StatPearls – NCBI Bookshelf

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

  In a healthy person, the loss of plasma albumin through the glomerular filtration barrier is less than 0.1%. Filtration of plasma water and solutes occurs extracellularly and through the filtration slits and endothelial fenestrae. The glomerular changes that may lead to proteinuria are damage to the glomerular basement membrane, the endothelial surface, or the podocytes. Albumin is the main constituent in proteinuria, accounting for 85%. Albumin carries a net negative charge. The loss of glomerular membrane negative charge plays an important role in causing albuminuria. A generalized defect in glomerular permeability is associated with nonselective proteinuria causing a glomerular leakage of various plasma proteins. This phenomenon does not allow a clear-cut separation of causes of proteinuria.

• #2 Nephrotic Syndrome – StatPearls – NCBI Bookshelf

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

  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.

• #2 An Overview of Molecular Mechanism of Nephrotic Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3401527/

  The role played by the complement system seems to be essential for the development of the disease. […] Podocyte lesion might increase the expression of matrix metalloproteinase-9 (MMP-9) in these cells, which might induce collagen IV degradation and alterations in nephrin expression. […] In primary membranous glomerulopathy, some molecules such as megalin and phospholipase A2 receptor have been considered as being the antigens responsible for subepithelial immune complexes, which change the glomerular permeability. […] In both FSGS and MCD podocytopathies, the molecular changes observed in proteins from the cytoskeleton, cell transmembrane, and slit diaphragm induce foot process effacement and changes in negative charges, resulting in strong proteinuria.

• #2

  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.

• #2 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.

• #2 The Role of TNF-α in the Pathogenesis of Idiopathic Nephrotic Syndrome and Its Usefulness as a Marker of the Disease Course

  https://www.mdpi.com/2077-0383/13/7/1888

  The pathogenesis of idiopathic nephrotic syndrome (INS) has not been fully explained. […] Despite many studies, the pathogenesis of INS remains unclear. Undoubtedly, the immune system dysregulation plays a crucial role. The first hypothesis pointed to a circulating permeability factor from dysfunctional T-cells, and, among many candidates, several cytokines have been considered, including TNF-α. […] TNF-α is a pleiotropic and proinflammatory cytokine, produced mainly by activated macrophages and monocytes as a prohormone, constituting 233 amino acids. […] Some experimental studies confirm the involvement of TNF-α in glomerular damage in various types of glomerulopathy. […] It has long been suggested that TNF-α is one of the circulatory permeability factors involved in the pathogenesis of nephrotic syndrome.

• #2 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 dysregulation of Tregs has been shown to be important in the pathogenesis of several autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Recently, it has also been suggested that Tregs play an important role in the pathogenesis of MCNS. […] 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. […] Therefore, these findings can further strengthen the hypothesis that IL-13 may increase podocyte permeability through the modulation of SD proteins, resulting in nephrotic-range proteinuria, namely MCNS, and also provide an explanation for the plausible connection among Th2 cytokines, MCNS, and atopy.

• #2 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. […] Another important cell type, Th17 cells also derive from the nave CD4+ progenitor cells, as do Tregs. […] 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. […] Similar to the dichotomy of Tregs/Th17, some findings indicate that the ratio of the Th2/Th1 subsets is much more important in the pathomechanism of INS rather than their absolute count.

• #2

  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. […] CD80 (B7-1), important for B-cell and T-cell interaction, has attracted considerable attention because of its association with SSNS. […] Podocytes express human leukocyte antigen (HLA) class II and function as immune cells. […] 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. […] 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.

• #2 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

  A new paradigm for the pathogenesis of proteinuria in nephrotic syndrome has emerged after the discovery by Kestila et al. that mutations in the gene NPHS1, which encodes the podocyte-expressed nephrin, cause congenital NS in humans. […] Shimada et al. proposed the two-hit podocyte immune disorder underlying MCD. The first hit is induction of podocyte expression of CD80 in response to a circulating factor such as cytokines, allergens, or microbial products. The second hit represents dysfunction of the auto-regulatory mechanisms (secretion of soluble CTLR-4, IL-10, and TGF- by Tregs or downregulation of CD80 by podocytes itself), resulting in persistent CD80 expression and proteinuria. […] In spite of the numerous experimental and clinical studies performed in the last decades, the immune pathogenesis of the non-genetic, idiopathic nephrotic syndrome is still not completely understood.

• #2 Minimal-Change Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/243348-overview

  Interleukin-13 (IL-13) has been implicated in the pathogenesis of MCD. In a study on Chinese children in Singapore, it was shown that IL-13 genetic polymorphisms correlate with the long-term outcome of MCD. An animal study by Lai et al suggested that IL-13 overexpression can cause podocyte foot process fusion and proteinuria. […] In patients who develop acute kidney injury (AKI), endothelin 1 expression is greater in the glomeruli, vessels, and tubules than in the non-AKI group. The glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play a primary role in the development of proteinuria. […] Nephrin is a major component of the slit diaphragm and is critical for preserving the glomerular capillary barrier to protein. The slit diaphragm is often missing in MC nephrotic syndrome (MCD) kidneys.

• #2 History of Research on Pathogenesis of Idiopathic Nephrotic Syndrome | Clinical Gate

  https://clinicalgate.com/history-of-research-on-pathogenesis-of-idiopathic-nephrotic-syndrome/

  Although nephrotic syndrome (NS) is a common kidney disease, its pathogenesis remains unclear. […] The pathogenesis of idiopathic nephrotic syndrome (INS) remains elusive. […] In the past decade, advances in molecular biology have both improved our understanding of the pathogenesis of INS and created confusion. […] The candidate active molecules in INS, other than cytokines, include: reactive oxygen species, nuclear factor-kappa B, hemopexin, CD80 (also known as B7.1), and angiopoietin-like 4; mammalian target of rapamycin complex 1 in MCNS; cardiotrophin-like cytokine-1 and soluble urokinase-type plasminogen activator receptor in FSGS; and M-type phospholipase A2 receptor and cationic bovine serum albumin in IMN. […] The pathogenesis of INS, that is, MCNS, primary FSGS, and IMN, remains elusive despite many years of research.

• #2 Nephrotic Syndrome: Causes, Symptoms, Diagnosis, Treatment

  https://www.webmd.com/a-to-z-guides/what-is-nephrotic-syndrome

  Nephrotic syndrome isn’t a disease. It’s a group of symptoms that can appear if your kidneys aren’t working right. […] When they’re damaged, too much protein slips through the filters into your urine. The result is nephrotic syndrome. […] Some of the conditions that can damage your glomeruli include: Minimal change disease. Minimal change disease is the main cause of nephrotic syndrome in children. […] Focal segmental glomerulosclerosis is a disease that scars the glomeruli. It’s the most common primary cause of nephrotic syndrome in adults. […] Membranous nephropathy. This condition causes the membranes of the glomeruli to thicken. […] Diabetes is the most common secondary cause of nephrotic syndrome in adults. […] Lupus is a chronic disease of the immune system, can seriously damage the kidneys.

• #2 Nephrotic Syndrome Pathophysiology: its Complications, Risk Facto

  https://www.longdom.org/open-access/nephrotic-syndrome-pathophysiology-its-complications-risk-factors-and-symptoms-99625.html

  The kidney’s glomeruli are often damaged as part of the underlying mechanism. […] When glomeruli are affected by inflammation or hyalinization, which is the formation of a homogenous crystalline material inside of cells, proteins like albumin, antithrombin, or immunoglobulins can pass through the cell membrane and end up in the urine. This condition is known as nephrotic syndrome. […] The primary blood protein responsible for maintaining an oncotic pressure, which prevents fluid leaking into the extracellular media and the subsequent development of edoemas, is albumin. […] The liver starts a compensatory mechanism in response to hypoproteinemia that involves the creation of proteins such alpha-2 macroglobulin and lipoproteins. The hyperlipidemia linked to this disease may be brought on by an increase in the latter.

• #2 Nephrotic Syndrome in Paediatrics – Mind The Bleep

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

  Nephrotic syndrome consist of a triad of oedema, hypoalbuminaemia and proteinuria. […] 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. (Tapia C, 2023) […] 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. […] 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.

• #2 New insights into the pathophysiology of oedema in nephrotic syndrome | Nefrología

  https://www.revistanefrologia.com/en-new-insights-into-pathophysiology-oedema-articulo-X2013251411051700

  The cortical collecting tubule is the reabsorption point for sodium in nephrotic syndrome. […] Ichikawa also performed micropuncture studies of superficial nephron tubular segments in the unilateral NS model in rats, and showed that the amount of sodium at the end of the distal convoluted tubule is the same in the proteinuric kidney as in the normal kidney. […] Another sodium transporter that has been reported to be strongly involved in sodium retention in NS is the epithelial sodium channel or amiloride-sensitive sodium channel (ENaC). […] The first observations on ENaC activation by serine proteases in proteinuric states were made by Kastner et al. […] Plasmin is known to come from the activation of plasminogen through the enzymatic action of urokinase, which is normally present in the collecting tubule.

• #2 New insights into the pathophysiology of oedema in nephrotic syndrome | Nefrología

  https://www.revistanefrologia.com/en-new-insights-into-pathophysiology-oedema-articulo-X2013251411051700

  To summarise, the plasminogen present in plasma is probably filtered through NS’s own defective glomerular barrier and is then converted into plasmin by the action of urokinase present in the collecting tubule. Plasmin would then activate ENaC, resulting in sodium retention with the subsequent appearance of oedema.

• #2 Disease mechanism and pharmacological approaches for TBC1D8B-induced steroid resistant nephrotic syndrome

  https://www.telethon.it/en/what-we-do/research/projects-funded/disease-mechanism-and-pharmacological-approaches-for-tbc1d8b-induced-steroid-resistant-nephrotic-syndrome/

  To this end, we will focus on mutations of TBC1D8B, a gene with unknown function that was recently described to cause hereditary SRNS. […] By finding both novel genes and pathways involved in function of pathogenic TBC1D8B variants, we will provide insight into alternative signaling routes that may be targeted for future SRNS therapies.

• #2 Immunopathogenesis of childhood idiopathic nephrotic syndrome

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

  Increased levels of serum B-cell activating factor and IL-21, which contribute to B-cell activation, have been observed in adult patients with MCD. […] Recently, several large transethnic genome-wide association studies in large pediatric cohorts, including Korean patients, revealed specific risk alleles in the HLA region that play a crucial role in antigen presentation to T cells. […] These findings suggest that memory B cells play a key role in the pathogenesis of pediatric SSNS, and that the reappearance of memory B cells can predict relapse following B cell depletion therapy in childhood SSNS. […] Although the pathogenesis of INS is not completely understood, it seems likely that INS is an immune-mediated disorder caused by a complex interplay between immunoregulatory cells, soluble factors, and podocytes, which may vary between patients.

• #2 Rituximab therapy in nephrotic syndrome: implications for patients’ management | Nature Reviews Nephrology

  https://www.nature.com/articles/nrneph.2012.289

  Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. […] A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A2 receptor autoantibodies, which are implicated in the pathogenesis of this disorder. […] Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events.

• #2 Minimal-Change Disease: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/243348-overview

  CD80 is a protein expressed on the surface of several antigen-presenting cells. It is also expressed on podocytes, and increased expression of CD80 has resulted in a reduced expression of nephrin. Urinary levels of CD80 are increased in patients with MCD but not in patients with FSGS. Thus, this may have clinical applicability in distinguishing these two entities. […] B-cell depleting agents have shown efficacy in the treatment of MCD, which suggests that B-cells may have a role in the pathogenesis of MCD. Additionally, anti-nephrin antibodies may also play a role in the pathogenesis of MCD.

• #3 Nephrotic Syndrome in Adults: Diagnosis and Management | AAFP

  https://www.aafp.org/pubs/afp/issues/2009/1115/p1129.html

  Nephrotic syndrome may be caused by primary (idiopathic) renal disease or by a variety of secondary causes. […] The underlying pathophysiology of nephrotic syndrome is not completely clear. […] Massive proteinuria causes renal tubulointerstitial inflammation, with resulting increased sodium retention that overwhelms the physiologic mechanisms for removing edema. […] Patients may have an overfilled or expanded plasma volume in addition to expanded interstitial fluid volume.

• #3 New insights into the pathophysiology of oedema in nephrotic syndrome | Nefrología

  https://revistanefrologia.com/en-new-insights-into-pathophysiology-oedema-articulo-X2013251411051700

  Oedema is a common clinical manifestation of nephrotic syndrome. However, the pathophysiological mechanism of sodium retention in nephrotic syndrome has been intensely debated for decades. Several clinical and experimental observations argue against the classic or „underfill” hypothesis of oedema formation in nephrotic syndrome. […] In many patients, oedema formation in nephrotic syndrome is due to the kidney being intrinsically unable to excrete salt and is unrelated to systemic factors (i.e. hypoalbuminaemia, decreased effective arterial blood volume, and secondary hyperaldosteronism). The cortical collecting duct is the nephron site of sodium retention in nephrotic syndrome. Activation of the epithelial sodium channel in the cortical collecting duct is responsible for sodium retention in nephrotic syndrome.

• #3 Rituximab therapy in nephrotic syndrome: implications for patients’ management | Nature Reviews Nephrology

  https://www.nature.com/articles/nrneph.2012.289

  Rituximab offers an alternative to current immunosuppressive therapies for difficult-to-treat nephrotic syndrome. […] A substantial proportion of rituximab-treated patients with idiopathic membranous nephropathy show complete or partial remission of proteinuria, and reduced levels of phospholipase A2 receptor autoantibodies, which are implicated in the pathogenesis of this disorder. […] Successful rituximab therapy induces prolonged remission and enables discontinuation of other medications without substantially increasing the risk of infections and other serious adverse events.

• #3 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

  A new paradigm for the pathogenesis of proteinuria in nephrotic syndrome has emerged after the discovery by Kestila et al. that mutations in the gene NPHS1, which encodes the podocyte-expressed nephrin, cause congenital NS in humans. […] Shimada et al. proposed the two-hit podocyte immune disorder underlying MCD. The first hit is induction of podocyte expression of CD80 in response to a circulating factor such as cytokines, allergens, or microbial products. The second hit represents dysfunction of the auto-regulatory mechanisms (secretion of soluble CTLR-4, IL-10, and TGF- by Tregs or downregulation of CD80 by podocytes itself), resulting in persistent CD80 expression and proteinuria. […] In spite of the numerous experimental and clinical studies performed in the last decades, the immune pathogenesis of the non-genetic, idiopathic nephrotic syndrome is still not completely understood.

• #3

  https://journals.lww.com/kidney360/fulltext/2024/08000/minimal_change_disease_and_fsgs_are_a_spectrum_of.20.aspx

  Minimal change disease (MCD) and FSGS are podocytopathies that are common causes of nephrotic syndrome (NS). Patients with MCD and FSGS demonstrate clinical heterogeneity that reflects the underlying pathogenic mechanism(s). […] MCD and primary FSGS as histologic descriptors reflect a common disease pathophysiology often referred to as immune-mediated FSGS (IM-FSGS) or presumed permeability factor-related FSGS. […] IM-FSGS is also postulated to be due to a systemic circulating factor leading to podocyte dysfunction. […] One possible circulating factor is the discovery of autoantibodies directed at the critical podocyte slit diaphragm protein, nephrin. […] Targeted binding of antinephrin autoantibodies may disrupt nephrin structure (e.g., nephrin tyrosine phosphorylation) and/or function and lead to loss of slit diaphragm integrity, podocyte injury, and proteinuria. […] Several lines of preclinical, translational, and clinical evidence collectively support the hypothesis that immune-mediated NS can manifest histologically as MCD and/or FSGS, likely reflecting different stages of disease.

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