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Clinical Journal of the American... Jun 2017Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic nephrotic syndrome in nondiabetic white adults. About 80% of cases... (Review)
Review
Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and 20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN. Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels (15%), or serum anti-THSD7A (3%-5%). The remaining 10% without demonstrable anti-PLA2R/THSd7A antibody or antigen likely have PMN probably secondary to a different, still unidentified, anti-podocyte antibody. Considerable clinical and experimental data now suggests these antibodies are pathogenic. Clinically, 80% of patients with PMN present with nephrotic syndrome and 20% with non-nephrotic proteinuria. Untreated, about one third undergo spontaneous remission, especially those with absent or low anti-PLA2R levels, one-third progress to ESRD over 10 years, and the remainder develop nonprogressive CKD. Proteinuria can persist for months after circulating anti-PLA2R/THSD7A antibody is no longer detectable (immunologic remission). All patients with PMN should be treated with supportive care from the time of diagnosis to minimize protein excretion. Patients with elevated anti-PLA2R/THSD7A levels and proteinuria >3.5 g/d at diagnosis, and those who fail to reduce proteinuria to <3.5 g after 6 months of supportive care or have complications of nephrotic syndrome, should be considered for immunosuppressive therapy. Accepted regimens include steroids/cyclophosphamide, calcineurin inhibitors, and B cell depletion. With proper management, only 10% or less will develop ESRD over the subsequent 10 years.
Topics: Autoantibodies; Biomarkers; Disease Progression; Glomerulonephritis, Membranous; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Receptors, Phospholipase A2; Remission Induction; Risk Factors; Thrombospondins; Time Factors; Treatment Outcome
PubMed: 28550082
DOI: 10.2215/CJN.11761116 -
Nature Reviews. Nephrology Apr 2021Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by nephrotic-range proteinuria, hypoalbuminaemia and oedema, which manifest in...
Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by nephrotic-range proteinuria, hypoalbuminaemia and oedema, which manifest in utero or during the first 3 months of life. The main cause of CNS is genetic defects in podocytes; however, it can also be caused, in rare cases, by congenital infections or maternal allo-immune disease. Management of CNS is very challenging because patients are prone to severe complications, such as haemodynamic compromise, infections, thromboses, impaired growth and kidney failure. In this consensus statement, experts from the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) summarize the current evidence and present recommendations for the management of CNS, including the use of renin-angiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis. Therapeutic management should be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, while preventing complications and preserving central and peripheral vessels. We do not recommend performing routine early nephrectomies but suggest that they are considered in patients with severe complications despite optimal conservative treatment, and before transplantation in patients with persisting nephrotic syndrome and/or a WT1-dominant pathogenic variant.
Topics: Albumins; Antibiotic Prophylaxis; Anticoagulants; Combined Modality Therapy; Diuretics; Fluid Therapy; Genetic Markers; Genetic Testing; Humans; Infections; Nephrectomy; Nephrotic Syndrome; Thrombosis
PubMed: 33514942
DOI: 10.1038/s41581-020-00384-1 -
Clinical Journal of the American... Dec 2022Idiopathic nephrotic syndrome often responds to immunosuppressive treatment. Nevertheless, this syndrome-and the drugs used to treat it-remain important causes of... (Review)
Review
Idiopathic nephrotic syndrome often responds to immunosuppressive treatment. Nevertheless, this syndrome-and the drugs used to treat it-remain important causes of patient morbidity. Idiopathic nephrotic syndrome is usually caused by minimal change disease or FSGS, diseases that primarily affect the podocytes. In spite of decades of research, the underlying causes of both diseases remain incompletely understood. There is, however, a large body of observational and experimental data linking the immune system with both minimal change disease and FSGS, including associations with systemic infections and hematologic malignancies. Perhaps most compellingly, many different immunomodulatory drugs are effective for treating idiopathic nephrotic syndrome, including biologic agents that have well-defined immune targets. In fact, the unexpected efficacy of targeted therapeutic agents has provided important new insights into the pathogenesis of these diseases. Given the large number of drugs that are available to deplete or block specific cells and molecules within the immune system, a better understanding of the immunologic causes of idiopathic nephrotic syndrome may lead to better diagnostic and therapeutic approaches.
Topics: Humans; Nephrotic Syndrome; Nephrosis, Lipoid; Glomerulosclerosis, Focal Segmental; Immune System
PubMed: 36198505
DOI: 10.2215/CJN.07180622 -
Development (Cambridge, England) May 2022Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo...
Nephrotic syndrome (NS) is characterized by severe proteinuria as a consequence of kidney glomerular injury due to podocyte damage. In vitro models mimicking in vivo podocyte characteristics are a prerequisite to resolve NS pathogenesis. The detailed characterization of organoid podocytes resulting from a hybrid culture protocol showed a podocyte population that resembles adult podocytes and was superior compared with 2D counterparts, based on single-cell RNA sequencing, super-resolution imaging and electron microscopy. In this study, these next-generation podocytes in kidney organoids enabled personalized idiopathic nephrotic syndrome modeling, as shown by activated slit diaphragm signaling and podocyte injury following protamine sulfate, puromycin aminonucleoside treatment and exposure to NS plasma containing pathogenic permeability factors. Organoids cultured from cells of a patient with heterozygous NPHS2 mutations showed poor NPHS2 expression and aberrant NPHS1 localization, which was reversible after genetic correction. Repaired organoids displayed increased VEGFA pathway activity and transcription factor activity known to be essential for podocyte physiology, as shown by RNA sequencing. This study shows that organoids are the preferred model of choice to study idiopathic and congenital podocytopathies.
Topics: Female; Humans; Kidney; Male; Nephrotic Syndrome; Organoids; Pluripotent Stem Cells; Podocytes
PubMed: 35417019
DOI: 10.1242/dev.200198 -
Clinical Journal of the American... Jan 2018Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome....
BACKGROUND AND OBJECTIVES
Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.
RESULTS
In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. , , , and were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.
CONCLUSIONS
Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.
Topics: Adolescent; Adult; Age of Onset; Child; Child, Preschool; DNA Mutational Analysis; Female; Genetic Association Studies; Genetic Markers; Genetic Predisposition to Disease; Heredity; Humans; Infant; Male; Mutation; Mutation Rate; Nephrotic Syndrome; Pedigree; Phenotype; Predictive Value of Tests; Prognosis; Exome Sequencing; Young Adult
PubMed: 29127259
DOI: 10.2215/CJN.04120417 -
Journal of the American Society of... Apr 2014The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and... (Clinical Trial)
Clinical Trial
The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.
Topics: Adolescent; Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal, Murine-Derived; Child; Female; Glomerulonephritis, Membranoproliferative; Glomerulosclerosis, Focal Segmental; Humans; Male; Middle Aged; Nephrosis, Lipoid; Nephrotic Syndrome; Recurrence; Rituximab
PubMed: 24480824
DOI: 10.1681/ASN.2013030251 -
Pediatric Nephrology (Berlin, Germany) Nov 2009Congenital nephrotic syndrome (CNS) is a rare kidney disorder characterized by heavy proteinuria, hypoproteinemia, and edema starting soon after birth. The majority of... (Review)
Review
Congenital nephrotic syndrome (CNS) is a rare kidney disorder characterized by heavy proteinuria, hypoproteinemia, and edema starting soon after birth. The majority of cases are caused by genetic defects in the components of the glomerular filtration barrier, especially nephrin and podocin. CNS may also be a part of a more generalized syndrome or caused by a perinatal infection. Immunosuppressive medication is not helpful in the genetic forms of CNS, and kidney transplantation is the only curative therapy. Before the operation, management of these infants largely depends on the magnitude of proteinuria. In severe cases, daily albumin infusions are required to prevent life-threatening edema. The therapy also includes hypercaloric diet, thyroxin and mineral substitution, prevention of thrombotic episodes, and prompt management of infectious complications. The outcome of CNS patients without major extrarenal manifestations is comparable with other patient groups after kidney transplantation.
Topics: Humans; Intracellular Signaling Peptides and Proteins; Kidney Transplantation; Membrane Proteins; Nephrotic Syndrome; Podocytes
PubMed: 17968594
DOI: 10.1007/s00467-007-0633-9