scholarly journals A Novel Model for Nephrotic Syndrome Reveals Associated Dysbiosis of the Gut Microbiome and Extramedullary Hematopoiesis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1509
Author(s):  
Jasmin I. Maier ◽  
Manuel Rogg ◽  
Martin Helmstädter ◽  
Alena Sammarco ◽  
Gerd Walz ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Disease ◽  
Mouse Model ◽  
Gut Microbiome ◽  
Extramedullary Hematopoiesis ◽  
Glomerular Sclerosis ◽  
Protein Loss ◽  
Adult Mice ◽  
Focal Segmental Glomerular Sclerosis ◽  
Significant Enrichment

Glomerular kidney disease causing nephrotic syndrome is a complex systemic disorder and is associated with significant morbidity in affected patient populations. Despite its clinical relevance, well-established models are largely missing to further elucidate the implications of uncontrolled urinary protein loss. To overcome this limitation, we generated a novel, inducible, podocyte-specific transgenic mouse model (Epb41l5fl/fl*Nphs1-rtTA-3G*tetOCre), developing nephrotic syndrome in adult mice. Animals were comprehensively characterized, including microbiome analysis and multiplexed immunofluorescence imaging. Induced knockout mice developed a phenotype consistent with focal segmental glomerular sclerosis (FSGS). Although these mice showed hallmark features of severe nephrotic syndrome (including proteinuria, hypoalbuminemia and dyslipidemia), they did not exhibit overt chronic kidney disease (CKD) phenotypes. Analysis of the gut microbiome demonstrated distinct dysbiosis and highly significant enrichment of the Alistipes genus. Moreover, Epb41l5-deficient mice developed marked organ pathologies, including extramedullary hematopoiesis of the spleen. Multiplex immunofluorescence imaging demonstrated red pulp macrophage proliferation and mTOR activation as driving factors of hematopoietic niche expansion. Thus, this novel mouse model for adult-onset nephrotic syndrome reveals the significant impact of proteinuria on extra-renal manifestations, demonstrating the versatility of this model for nephrotic syndrome-related research.

scholarly journals Integrin, Exosome and Kidney Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
An-Ran Shen ◽  
Xin Zhong ◽  
Tao-Tao Tang ◽  
Cui Wang ◽  
Jing Jing ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Cell Communication ◽  
Transforming Growth Factor Β ◽  
Cellular Adhesion ◽  
Glomerular Sclerosis ◽  
Urokinase Plasminogen Activator Receptor ◽  
Focal Segmental Glomerular Sclerosis

Integrins are transmembrane receptors that function as noncovalent heterodimers that mediate cellular adhesion and migration, cell to cell communication, and intracellular signaling activation. In kidney, latency associated peptide-transforming growth factor β (TGF-β) and soluble urokinase plasminogen activator receptor (suPAR) were found as the novel ligands of integrins that contribute to renal interstitial fibrosis and focal segmental glomerular sclerosis glomerulosclerosis (FSGS). Interestingly, recent studies revealed that integrins are the compositional cargo of exosomes. Increasing evidence suggested that exosomal integrin played critical roles in diverse pathophysiologic conditions such as tumor metastasis, neurological disorders, immunology regulation, and other processes. This review will focus on the biology and function of exosomal integrin, emphasizing its potential role in kidney disease as well as its implications in developing novel therapeutic and diagnosis approaches for kidney disease.

Long-Term Evaluation of Children with Nephrotic Syndrome and Focal Segmental Glomerular Sclerosis

Nephron ◽  
1983 ◽  
Vol 35 (4) ◽  
pp. 225-231 ◽  
Author(s):  
Amir Tejani ◽  
Anthony D. Nicastri ◽  
Dilip Sen ◽  
C.K. Chen ◽  
Kishore Phadke ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Glomerular Sclerosis ◽  
Focal Segmental Glomerular Sclerosis ◽  
Term Evaluation ◽  
Segmental Glomerular Sclerosis

scholarly journals Effective cholesterol lowering after myocardial infarction in patients with nephrotic syndrome may require a multi-pharmacological approach: a case report

2021 ◽  
Vol 5 (5) ◽  
Author(s):  
Simon Sjuls ◽  
Ulf Jensen ◽  
Karin Littmann ◽  
Annette Bruchfeld ◽  
Jonas Brinck
Keyword(s):  
Myocardial Infarction ◽  
Nephrotic Syndrome ◽  
Sglt2 Inhibitor ◽  
Lipid Lowering ◽  
Glomerular Sclerosis ◽  
Lipid Lowering Therapy ◽  
Inhibitory Antibody ◽  
Pcsk9 Inhibitors ◽  
Focal Segmental Glomerular Sclerosis ◽  
Lowering Therapy

Abstract Background Nephrotic syndrome causes severe hypercholesterolaemia due to increased production and altered clearance of lipoproteins from the liver. It is challenging for patients with nephrotic syndrome and coronary heart disease to meet LDL-cholesterol (LDL-C) goals for secondary prevention with conventional lipid-lowering therapy. Case summary We present a man with nephrotic syndrome caused by focal segmental glomerular sclerosis (FSGS) and hypercholesterolaemia. He presented at the emergency room (ER) with an ST-elevation myocardial infarction at the age of 26. On follow-up, the patient had persistent hypercholesterolaemia [LDL-C 3.9 mmol/L and lipoprotein(a) 308 nmol/L] despite a combination of lipid-lowering therapy with atorvastatin 80 mg/day and ezetimibe 10 mg/day. Addition of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitory antibody evolocumab 140 mg bi-monthly did not improve cholesterol levels. However, after addition of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin 10 mg/day on top of other anti-proteinuric treatments, the patient’s proteinuria was reduced and a dramatic drop in LDL-C level by 3.2–0.6 mmol/L (−81%) was observed when evolocumab was re-introduced. Discussion We show that target LDL-C levels were obtained in this patient with therapy-resistant FSGS and hypercholesterolaemia following multi-pharmacological treatment with SGLT2 and PCSK9 inhibitors on top of conventional lipid-lowering therapy. The SGLT2-inhibitor reduced proteinuria and, speculatively, also reduced urinary loss of PCSK9-antibody. Therefore, in patients with nephrotic syndrome and cardiovascular disease novel therapeutic options to manage proteinuria could be considered to improve the efficacy of the lipid-lowering therapy, especially when the protein-based PCSK9 inhibitors are used.

scholarly journals Terapia della sindrome nefrosica idiopatica: ruolo delle tecniche aferetiche

2013 ◽  
Vol 25 (4_suppl) ◽  
pp. S41-S45
Author(s):  
Luigi Moriconi
Keyword(s):  
Nephrotic Syndrome ◽  
Idiopathic Nephrotic Syndrome ◽  
Sono State ◽  
Minimal Change ◽  
Glomerular Sclerosis ◽  
Minimal Change Nephropathy ◽  
Focal Segmental Glomerular Sclerosis ◽  
Segmental Glomerular Sclerosis ◽  
State Identificate

La Sindrome Nefrosica Idiopatica (Idiopathic Nephrotic Syndrome, INS) ricorre essenzialmente in presenza di due glomerulopatie: la MCN (Minimal Change Nephropathy) e la FSGS (Focal Segmental Glomerular Sclerosis). La prima ha un decorso più benigno ed è più frequente nei bambini, mentre la seconda ha un decorso più severo, può portare a Insufficienza Renale Cronica Terminale e può re-cidivare nel trapianto. Soprattutto per la FSGS sono state identificate possibili eziologie virali o genetiche, oltre a forme secondarie in corso di altre malattie, per cui non è semplice classificare queste glomerulopatie. Le forme ricorrenti nel rene trapiantato costituiscono un gruppo più omogeneo. I fattori che sembrano essere comuni alla MCN e alla FSGS, anche se maggiormente espressi e studiati nella seconda, sono la lesione glomerulare caratterizzante a carico dei podociti, e il frequente riscontro di sostanze circolanti, definite fattori di permeabilità (PFs), capaci di indurre proteinuria. Corticosteroidi e Immunosoppressori sono la terapia standard della INS. Tuttavia, la presenza di casi farmaco-resistenti e l'identificazione di alcuni PFs circolanti hanno consentito di utilizzare nuove terapie dirette a bloccare la sintesi o l'azione di queste molecole e hanno fornito un ulteriore razionale alla loro rimozione mediante plasmaferesi convenzionale (PEX) o aferesi selettiva.

Therapeutic Response and Long-Term Renal Outcomes in Childhood Idiopathic Steroid-Resistant Nephrotic Syndrome: A Single-Center Study

Nephron ◽  
2021 ◽  
pp. 1-8
Author(s):  
Jiwon Jung ◽  
Joo Hoon Lee ◽  
Young Seo Park
Keyword(s):  
Renal Function ◽  
Nephrotic Syndrome ◽  
Therapeutic Response ◽  
Glomerular Sclerosis ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Renal Outcomes ◽  
Focal Segmental Glomerular Sclerosis

<b><i>Purpose:</i></b> We aimed to evaluate therapeutic response and long-term renal outcomes of childhood idiopathic steroid-resistant nephrotic syndrome (iSRNS). <b><i>Methods:</i></b> We retrospectively reviewed treatment regimens, especially calcineurin inhibitor (CNI), pathologic diagnoses, and long-term renal outcomes of iSRNS patients for 30 years. <b><i>Results:</i></b> Of 516 patients with idiopathic NS, 52 (10.1%) had iSRNS. Renal biopsies from 48 patients showed minimal change disease (MCD) in 23 (47.9%), focal segmental glomerulosclerosis in 24 (50.0%), and mesangioproliferative glomerulonephritis in 1 (2.1%). The median follow-up period was 66.5 (range, 4–275) months, and 90.4% of them were treated with a CNI. CNI induced remission in 70.2% within 50.4 ± 43.5 days. Of the patients with MCD and focal segmental glomerular sclerosis (FSGS), 86.4% (19/22) and 45.0% (9/20) (<i>p =</i> 0.005) responded to CNI, respectively. Mean time until remission after using CNI was longer with FSGS (90.4 ± 54.0 days) than with MCD (29.6 ± 26.3 days) (<i>p =</i> 0.010). CNI-responsive patients with FSGS or MCD showed preserved renal function, and CNI nonresponsive MCD patients also showed preserved renal function during follow-up. However, end-stage renal disease (ESRD) progressed in 8 out of 11 patients with FSGS nonresponsive to the CNI for an average of 44.9 ± 18.4 months after diagnosis. <b><i>Conclusion:</i></b> Different response rates and times for remission were achieved with the CNI according to the pathology of iSRNS. All MCD patients regardless of CNI response and all CNI-responsive patients with FSGS showed excellent renal outcomes, while almost all FSGS patients nonresponsive to CNI eventually progressed to ESRD.

Mycosis fungoides with focal segmental glomerular sclerosis and nephrotic syndrome

1998 ◽  
Vol 38 (2) ◽  
pp. 301-305 ◽  
Author(s):  
Jennifer Clay Cather ◽  
Clotilde Jackow ◽  
James Yegge ◽  
Frederick Hagemeister ◽  
Madeleine Duvic
Keyword(s):  
Nephrotic Syndrome ◽  
Mycosis Fungoides ◽  
Glomerular Sclerosis ◽  
Focal Segmental Glomerular Sclerosis ◽  
Segmental Glomerular Sclerosis

Transgenic mouse model of kidney disease: Insertional inactivation of ubiquitously expressed gene leads to nephrotic syndrome

Cell ◽  
1990 ◽  
Vol 62 (3) ◽  
pp. 425-434 ◽  
Author(s):  
Hans Weiher ◽  
Tetsuo Noda ◽  
Douglas A. Gray ◽  
Arlene H. Sharpe ◽  
Rudolf Jaenisch
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Disease ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Transgenic Mouse Model ◽  
Insertional Inactivation

scholarly journals Frasier syndrome: A rare syndrome with WT-1 gene mutation

2017 ◽  
Vol 4 (3) ◽  
pp. 1101
Author(s):  
Vindhiya Kadambavana Sundaram ◽  
Sundari Subramanian ◽  
Lakshmi Charan Chinumuthu ◽  
Aishwarya Dharmanathan
Keyword(s):  
Nephrotic Syndrome ◽  
Wilms Tumor ◽  
Immunosuppressive Agents ◽  
External Genitalia ◽  
Female Child ◽  
Suppressor Gene ◽  
Glomerular Sclerosis ◽  
Frasier Syndrome ◽  
Sex Development ◽  
Focal Segmental Glomerular Sclerosis

Frasier syndrome is a rare disorder of sex development. It is caused by mutation in Wilms’ tumor suppressor gene (WT-1) located in 11p23. This gene encodes a transcription factor involved in the development of kidney and gonads. The syndrome is characterized by female external genitalia in 46, XY patients, streak gonads with a higher risk of gonadal tumors, mainly gonadoblastoma. Nephropathy consists of nephrotic syndrome (NS) mainly due to focal segmental glomerular sclerosis (FSGS). NS presents early in childhood and responds poorly to steroid and immunosuppressive agents. Progression to End Stage Renal Disease (ESRD) usually occurs by second or third decade of life. We present a 6 years old female child with insignificant past medical history diagnosed as steroid resistant nephrotic syndrome. Renal biopsy showed FSGS. CT Abdomen showed streak gonads with rudimentary uterus. Further genotype showed WT-1 mutation with Karyotype of 46XY. Elective bilateral gonadectomy was done and histopathology showed bilateral dysgerminoma. After a year, her disease progressed to ESRD and she succumbed to the illness.

scholarly journals Rituximab treatment for steroid dependent or steroid resistant nephrotic syndrome in adult patients

2020 ◽  
Author(s):  
Jing Huang ◽  
Ping Wang ◽  
Zhao Cui ◽  
Yimiao Zhang ◽  
Fang Wang ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
B Cell ◽  
Kidney Function ◽  
Adult Patients ◽  
Cell Depletion ◽  
Glomerular Sclerosis ◽  
B Cell Depletion ◽  
Steroid Resistant ◽  
Focal Segmental Glomerular Sclerosis ◽  
Steroid Dependent

Abstract Background: Minimal change disease (MCD) and focal segmental glomerular sclerosis (FSGS) are major causes of nephrotic syndrome (NS). The patients of steroid-dependent (SD) or steroid-resistant (SR) NS are exposed to high doses of steroid, more adverse effects, and worse outcomes. This study applied B cell-oriented rituximab therapy in MCD or FSGS adult patients with SD or SR, to investigate its efficiency and safety. Methods: Eight patients with steroid-dependent and frequent-relapsing (SD/FR) NS and six patients with steroid-resistant (SR) NS were enrolled. B-cell-oriented (<5 cells/mm 3 ) rituximab administration was used with single dose of 375 mg/m 2 adjusted according to eGFR. Results: During the follow-up period of 15.0 (8.8-18.0) months, B-cell depletion was achieved and maintained in all the 14 patients. Four, two, seven, one patients received two, three, four, five infusions of rituximab respectively. No adverse event was observed. All the eight SD/FR patients maintained complete remission without relapse. Six of them stopped steroid in 10 (2.3-12.3) months and four of them further stopped immunosuppressants. All of them maintained stable kidney function (eGFR 107.4 ± 27.4 vs. 111.0 ± 31.5 mL/min/1.73m 2 , P=0.600). All the six SR patients showed no response and presented with severe nephrotic syndrome. Five of them presented with kidney function deterioration (eGFR 49.6 ± 35.7 vs. 15.9 ± 11.5 ml/min/1.73m 2 , P=0.047) and three of them went into ESRD. Conclusion: B cell depletion-oriented regimen of rituximab was effective and safe for MCD or FSGS adult patients with SD/FR nephrotic syndrome, which could reduce drug doses and adverse events. This regimen showed no therapeutic effect for SR patients.

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