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Christer Holmberg - One of the best experts on this subject based on the ideXlab platform.
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Congenital Nephrotic Syndrome nphs1 features resulting from different mutations in finnish patients
Kidney International, 2000Co-Authors: Jaakko Patrakka, Christer Holmberg, Marjo Kestilä, Minna Männikkö, Ulla Lenkkeri, Jorma Wartiovaara, Vesa Ruotsalainen, Paivi Tissari, Ilona Visapaa, Juhani RapolaAbstract:Congenital Nephrotic Syndrome (NPHS1): Features resulting from different mutations in Finnish patients. Background Congenital Nephrotic Syndrome (NPHS1) is a rare disease inherited as an autosomally recessive trait. The NPHS1 gene mutated in NPHS1 children has recently been identified. The gene codes for nephrin, a cell-surface protein of podocytes. Two mutations, named Fin-major and Fin-minor, have been found in over 90% of the Finnish patients. In this study, we correlated the NPHS1 gene mutations to the clinical features and renal findings in 46 Finnish NPHS1 children. Methods Clinical data were collected from patient files, and kidney histology and electron microscopy samples were re-evaluated. The expression of nephrin was studied using immunohistochemistry, Western blotting, and in situ hybridization. Results Nephrotic Syndrome was detected in most patients within days after birth regardless of the genotype detected. No difference could be found in neonatal, renal, cardiac, or neurological features in patients with different mutations. Nephrin was not expressed in kidneys with Fin-major or Fin-minor mutations, while another slit diaphragm-associated protein, ZO-1, stained normally. In electron microscopy, podocyte fusion and podocyte filtration slits of various sizes were detected. The slit diaphragms, however, were missing. In contrast to this, a Nephrotic infant with Fin-major/R743C genotype expressed nephrin in kidney had normal slit diaphragms and responded to therapy with an angiotensin-converting enzyme inhibitor and indomethacin. Conclusions The most common NPHS1 gene mutations, Fin-major and Fin-minor, both lead to an absence of nephrin and podocyte slit diaphragms, as well as a clinically severe form of NPHS1, the Finnish type of Congenital Nephrotic Syndrome.
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Congenital Nephrotic Syndrome
Kidney International, 1996Co-Authors: Christer Holmberg, Jarmo Laine, Kai Ronnholm, Marja Alahouhala, Hannu JalankoAbstract:Congenital Nephrotic Syndrome (CNS) can be caused by neonatal infections, renal diseases which exceptionally occur in early infancy and Syndromes with a renal histology of DMS. The most common CNS is the Finnish-type (CNF), an autosomal recessively inherited disease characterized by intrauterine onset of massive proteinuria. The CNF gene has been localized to the long arm of chromosome 19, but the pathogenesis remains unclear. Forty-six CNF patients have been treated at our institution. The diagnosis was based on family history, severe proteinuria of intrauterine onset (serum albumin 20 g/liter when serum albumin was corrected to > 15 g/liter), a large placenta (> 25% of birth wt), exclusion of other CNS-types and normal glomerular filtration rate during the first six months. Treatment included i.v. albumin substitution, optimal nutrition, thyroxine and anticoagulation. Forty-one patients had been nephrectomized bilaterally at a mean age of 1.2 years and after 3 to 25 months on peritoneal dialysis renal transplantation (Tx) had been performed on 34 who were a mean age of 2.2 years. Growth and development has been normal. Patient survival after Tx was 97%, graft survival 94%, 81% and 81% one, three and five years after Tx was (50% cadaver grafts). Mean GFR was 75 ml/min/1.73 m2 after three years, mean height SDS -1.42, and the nine oldest patients attend school in a normal class.
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Glomerular anionic charge in Congenital Nephrotic Syndrome of the Finnish type
The Histochemical Journal, 1995Co-Authors: Päivi Ljungberg, Juhani Rapola, Christer Holmberg, Harry Holthöfer, Hannu JalankoAbstract:Decrease of the anionic charge of the glomerular basement membrane and especially the reduced amount of heparan sulphate proteoglycan in the lamina rara externa has been suggested to be the basic pathogenetic defect in Congenital Nephrotic Syndrome. In the present study the anionic charge of glomeruli was examined in the Congenital Nephrotic Syndrome of the Finnish type and in controls using cationic stains (polyethyleneimine, Ruthenium Red) in electron microscopy. Chondroitinase and heparinase treatments were used to characterize further the anionic elements detected. Scanning electron microscopy (SEM) was used in addition to transmission electron microscopy (TEM) to examine the tridimensional structure and secondary changes of podocytes in this Syndrome. The number (mean ± SD) of polyethyleneimine granules per 1 μm length of lamina rara externa of the glomerular basement membrane was 24.9 ± 4.5 in control and 2.32 ± 4.3 in Congenital Nephrotic Syndrome subjects. The Ruthenium Red staining pattern was closely similar in Syndrome and control kidneys. The granules evident after staining with either cationic stain were seen after chondroitinase but not after heparinase treatment in control as well as in Syndrome patient kidney samples. No denuded areas of basement membrane in 42 glomeruli from four Syndrome patients were found in SEM. In conclusion, the amount of anionic sites in the lamina rara externa as detected by either cationic stain was comparable to controls. These results do not support the hypothesis of decreased anionic sites in the lamina rara externa of the glomerular basement membrane in Congenital Nephrotic Syndrome of the Finnish type.
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Congenital Nephrotic Syndrome of the finnish type is not associated with the Pax-2 gene despite the promising transgenic animal model
Genomics, 1994Co-Authors: Marjo Kestilä, Christer Holmberg, Karl Tryggvason, Minna Männikkö, Leena PeltonenAbstract:Congenital Nephrotic Syndrome of the Finnish type (CNF) is an autosomal recessive disease with an incidence of 1 in 8000 in Finland. CNF is characterized by massive proteinuria and Nephrotic Syndrome at birth. In a recent report, deregulation of expression of the gene coding for the Pax-2 DNA-binding protein was shown to generate severe kidney abnormalities in transgenic mice resembling the clinical and pathological findings in Congenital Nephrotic Syndrome, making it a candidate gene for CNF. However, in this study, we have unequivocally excluded the Pax-2 gene locus as a causative for Congenital Nephrotic Syndrome of the Finnish type.
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Post-transplantation nephrosis in Congenital Nephrotic Syndrome of the Finnish type
Kidney International, 1993Co-Authors: Jarmo Laine, Juhani Rapola, Harry Holthöfer, Hannu Jalanko, Leena Krogerus, Eeva Von Willebrand, Irmeli Lautenschlager, Kaija Salmela, Christer HolmbergAbstract:Post-transplantation nephrosis in Congenital Nephrotic Syndrome of the Finnish type. Congenital Nephrotic Syndrome of the Finnish type (CNF) is an autosomal recessively inherited disease manifesting as massive proteinuria, edema and ascites in the neonatal period. The disease is believed to be limited to the kidneys and recurrences after renal transplantation have not been reported. At our center 29 transplantations have been performed on 28 CNF patients. One to 33 months after transplantation, seven grafts (24%) of six patients have developed a steroid-resistant Nephrotic Syndrome. The clinical data and renal histology of these patients were analyzed in order to elucidate the cause of the proteinuria. At the onset of six of the seven episodes of nephrosis, the patient had evidence of a preceding CMV- or EBV-infection and the remaining patient had sinusitis. Upon light and electron microscopy examination, endothelial swelling of the glomerular capillaries resembling transplant glomerulopathy (TG) was seen, but unlike TG, the glomerular basement membranes were normal. The response of proteinuria to steroid or cyclophosphamide therapy was poor, with total remission in only two patients and partial remission in one patient, all treated with methylprednisolone and cyclophosphamide immediately after the diagnosis. Four grafts have been lost. Our data show that CNF patients have an increased tendency for post-transplantation nephrosis.
Hannu Jalanko - One of the best experts on this subject based on the ideXlab platform.
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Congenital Nephrotic Syndrome
Pediatric Nephrology, 2009Co-Authors: Hannu JalankoAbstract: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.
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Congenital Nephrotic Syndrome
Kidney International, 1996Co-Authors: Christer Holmberg, Jarmo Laine, Kai Ronnholm, Marja Alahouhala, Hannu JalankoAbstract:Congenital Nephrotic Syndrome (CNS) can be caused by neonatal infections, renal diseases which exceptionally occur in early infancy and Syndromes with a renal histology of DMS. The most common CNS is the Finnish-type (CNF), an autosomal recessively inherited disease characterized by intrauterine onset of massive proteinuria. The CNF gene has been localized to the long arm of chromosome 19, but the pathogenesis remains unclear. Forty-six CNF patients have been treated at our institution. The diagnosis was based on family history, severe proteinuria of intrauterine onset (serum albumin 20 g/liter when serum albumin was corrected to > 15 g/liter), a large placenta (> 25% of birth wt), exclusion of other CNS-types and normal glomerular filtration rate during the first six months. Treatment included i.v. albumin substitution, optimal nutrition, thyroxine and anticoagulation. Forty-one patients had been nephrectomized bilaterally at a mean age of 1.2 years and after 3 to 25 months on peritoneal dialysis renal transplantation (Tx) had been performed on 34 who were a mean age of 2.2 years. Growth and development has been normal. Patient survival after Tx was 97%, graft survival 94%, 81% and 81% one, three and five years after Tx was (50% cadaver grafts). Mean GFR was 75 ml/min/1.73 m2 after three years, mean height SDS -1.42, and the nine oldest patients attend school in a normal class.
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Glomerular anionic charge in Congenital Nephrotic Syndrome of the Finnish type
The Histochemical Journal, 1995Co-Authors: Päivi Ljungberg, Juhani Rapola, Christer Holmberg, Harry Holthöfer, Hannu JalankoAbstract:Decrease of the anionic charge of the glomerular basement membrane and especially the reduced amount of heparan sulphate proteoglycan in the lamina rara externa has been suggested to be the basic pathogenetic defect in Congenital Nephrotic Syndrome. In the present study the anionic charge of glomeruli was examined in the Congenital Nephrotic Syndrome of the Finnish type and in controls using cationic stains (polyethyleneimine, Ruthenium Red) in electron microscopy. Chondroitinase and heparinase treatments were used to characterize further the anionic elements detected. Scanning electron microscopy (SEM) was used in addition to transmission electron microscopy (TEM) to examine the tridimensional structure and secondary changes of podocytes in this Syndrome. The number (mean ± SD) of polyethyleneimine granules per 1 μm length of lamina rara externa of the glomerular basement membrane was 24.9 ± 4.5 in control and 2.32 ± 4.3 in Congenital Nephrotic Syndrome subjects. The Ruthenium Red staining pattern was closely similar in Syndrome and control kidneys. The granules evident after staining with either cationic stain were seen after chondroitinase but not after heparinase treatment in control as well as in Syndrome patient kidney samples. No denuded areas of basement membrane in 42 glomeruli from four Syndrome patients were found in SEM. In conclusion, the amount of anionic sites in the lamina rara externa as detected by either cationic stain was comparable to controls. These results do not support the hypothesis of decreased anionic sites in the lamina rara externa of the glomerular basement membrane in Congenital Nephrotic Syndrome of the Finnish type.
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Post-transplantation nephrosis in Congenital Nephrotic Syndrome of the Finnish type
Kidney International, 1993Co-Authors: Jarmo Laine, Juhani Rapola, Harry Holthöfer, Hannu Jalanko, Leena Krogerus, Eeva Von Willebrand, Irmeli Lautenschlager, Kaija Salmela, Christer HolmbergAbstract:Post-transplantation nephrosis in Congenital Nephrotic Syndrome of the Finnish type. Congenital Nephrotic Syndrome of the Finnish type (CNF) is an autosomal recessively inherited disease manifesting as massive proteinuria, edema and ascites in the neonatal period. The disease is believed to be limited to the kidneys and recurrences after renal transplantation have not been reported. At our center 29 transplantations have been performed on 28 CNF patients. One to 33 months after transplantation, seven grafts (24%) of six patients have developed a steroid-resistant Nephrotic Syndrome. The clinical data and renal histology of these patients were analyzed in order to elucidate the cause of the proteinuria. At the onset of six of the seven episodes of nephrosis, the patient had evidence of a preceding CMV- or EBV-infection and the remaining patient had sinusitis. Upon light and electron microscopy examination, endothelial swelling of the glomerular capillaries resembling transplant glomerulopathy (TG) was seen, but unlike TG, the glomerular basement membranes were normal. The response of proteinuria to steroid or cyclophosphamide therapy was poor, with total remission in only two patients and partial remission in one patient, all treated with methylprednisolone and cyclophosphamide immediately after the diagnosis. Four grafts have been lost. Our data show that CNF patients have an increased tendency for post-transplantation nephrosis.
Larisa Kovacevic - One of the best experts on this subject based on the ideXlab platform.
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management of Congenital Nephrotic Syndrome
Pediatric Nephrology, 2003Co-Authors: Larisa Kovacevic, Christopher Reid, Susan P A RigdenAbstract:We reviewed the medical records of seven children with Congenital Nephrotic Syndrome (CNS) treated by unilateral nephrectomy, captopril, and indomethacin since 1990. Clinical response to the treatment was analyzed using the Students' t-test. After a median period of 54 months (range 36–88 months) follow-up, five patients were alive at a median age of 74 (range 43–88) months. Median (range) plasma albumin rose from 11 (6–17) g/l at the start of treatment to 18 (15–22) g/l and 21 (18–25) g/l after 6 and 12 months treatment, respectively (P=0.001 and P=0.0006). Albumin infusions per patient per month decreased from 7 (0–18) to 0 (0–30) in the 6 months post treatment (P=0.017). The median (range) height standard deviation scores at 12 months and 30 months from onset of treatment were –1.56 (−2.96 to 0.41) and –1.43 (−2.40 to 0.90), respectively. In conclusion, management of CNS with captopril and indomethacin therapy in combination with unilateral nephrectomy achieves significant improvements in plasma albumin and reduces the need for albumin infusions and time in hospital, while growth is maintained. Second nephrectomy, dialysis, and transplantation can be delayed until the 3rd year of life or longer.
Jutta Gellermann - One of the best experts on this subject based on the ideXlab platform.
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Article Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort
2016Co-Authors: Agnes Trautmann, Monica Bodria, Fatih Ozaltin, Alaleh Gheisari, Anette Melk, Marta Azocar, Ali Anarat, Salim Caliskan, Francesco Emma, Jutta GellermannAbstract:Background and objectives Steroid-resistant Nephrotic Syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for Congenital Nephrotic Syndrome and childhood-onset steroid-resistant Nephrotic Syndrome. Design, setting, participants, & measurements Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant Nephrotic Syndrome, Congenital Nephrotic Syndrome, or persistent subneph-rotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. Results Steroid-resistant Nephrotic Syndrome manifested in the first 5 years of life in 64 % of the patients. Congenital Nephrotic Syndrome accounted for 6 % of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a geneti
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Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort
Clinical Journal of the American Society of Nephrology, 2015Co-Authors: Agnes Trautmann, Monica Bodria, Fatih Ozaltin, Alaleh Gheisari, Anette Melk, Marta Azocar, Ali Anarat, Salim Caliskan, Francesco Emma, Jutta GellermannAbstract:Background and objectives Steroid-resistant Nephrotic Syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for Congenital Nephrotic Syndrome and childhood-onset steroid-resistant Nephrotic Syndrome. Design, setting, participants, & measurements Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant Nephrotic Syndrome, Congenital Nephrotic Syndrome, or persistent subNephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. Results Steroid-resistant Nephrotic Syndrome manifested in the first 5 years of life in 64% of the patients. Congenital Nephrotic Syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 ( n =138), WT1 ( n =48), and NPHS1 ( n =41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in Congenital Nephrotic Syndrome to 15%–16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%–45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% ( n =4) of patients with a genetic diagnosis. Conclusions The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.
Agnes Trautmann - One of the best experts on this subject based on the ideXlab platform.
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Infants with Congenital Nephrotic Syndrome have comparable outcomes to infants with other renal diseases.
Pediatric Nephrology, 2018Co-Authors: Stephanie Dufek, Agnes Trautmann, Elisa Ylinen, Harika Alpay, Gema Ariceta, Christoph Aufricht, Justine Bacchetta, Sevcan A. Bakkaloglu, Aysun Karabay Bayazit, Salim CaliskanAbstract:Background Children with Congenital Nephrotic Syndrome (CNS) commonly develop end stage renal failure in infancy and require dialysis, but little is known about the complications and outcomes of dialysis in these children.
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Article Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort
2016Co-Authors: Agnes Trautmann, Monica Bodria, Fatih Ozaltin, Alaleh Gheisari, Anette Melk, Marta Azocar, Ali Anarat, Salim Caliskan, Francesco Emma, Jutta GellermannAbstract:Background and objectives Steroid-resistant Nephrotic Syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for Congenital Nephrotic Syndrome and childhood-onset steroid-resistant Nephrotic Syndrome. Design, setting, participants, & measurements Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant Nephrotic Syndrome, Congenital Nephrotic Syndrome, or persistent subneph-rotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. Results Steroid-resistant Nephrotic Syndrome manifested in the first 5 years of life in 64 % of the patients. Congenital Nephrotic Syndrome accounted for 6 % of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a geneti
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Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort
Clinical Journal of the American Society of Nephrology, 2015Co-Authors: Agnes Trautmann, Monica Bodria, Fatih Ozaltin, Alaleh Gheisari, Anette Melk, Marta Azocar, Ali Anarat, Salim Caliskan, Francesco Emma, Jutta GellermannAbstract:Background and objectives Steroid-resistant Nephrotic Syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for Congenital Nephrotic Syndrome and childhood-onset steroid-resistant Nephrotic Syndrome. Design, setting, participants, & measurements Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant Nephrotic Syndrome, Congenital Nephrotic Syndrome, or persistent subNephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. Results Steroid-resistant Nephrotic Syndrome manifested in the first 5 years of life in 64% of the patients. Congenital Nephrotic Syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 ( n =138), WT1 ( n =48), and NPHS1 ( n =41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in Congenital Nephrotic Syndrome to 15%–16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%–45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% ( n =4) of patients with a genetic diagnosis. Conclusions The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.