scholarly journals C1q Nephropathy: The Unique Underrecognized Pathological Entity

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Joe Devasahayam ◽  
Gowrishankar Erode-Singaravelu ◽  
Zeenat Bhat ◽  
Tony Oliver ◽  
Arul Chandran ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Minimal Change Disease ◽  
Clinical Presentation ◽  
Immunofluorescence Microscopy ◽  
Immunosuppressive Agents ◽  
Adverse Outcomes ◽  
C1q Nephropathy ◽  
Steroid Resistant ◽  
Microscopic Lesion ◽  
Microscopic Features

C1q nephropathy is a rare glomerular disease with characteristic mesangial C1q deposition noted on immunofluorescence microscopy. It is histologically defined and poorly understood. Light microscopic features are heterogeneous and comprise minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and proliferative glomerulonephritis. Clinical presentation is also diverse, and ranges from asymptomatic hematuria or proteinuria to frank nephritic or nephrotic syndrome in both children and adults. Hypertension and renal insufficiency at the time of diagnosis are common findings. Optimal treatment is not clear and is usually guided by the underlying light microscopic lesion. Corticosteroids are the mainstay of treatment, with immunosuppressive agents reserved for steroid resistant cases. The presence of nephrotic syndrome and FSGS appear to predict adverse outcomes as opposed to favorable outcomes in those with MCD. Further research is needed to establish C1q nephropathy as a universally recognized distinct clinical entity. In this paper, we discuss the current understanding of pathogenesis, histopathology, clinical features, therapeutic options, and outcomes of C1q nephropathy.

scholarly journals Intravenous Cyclophosphamide Induces Remission in Children with Difficult to Treat Steroid Resistant Nephrotic Syndrome from Minimal Change Disease

2021 ◽  
Author(s):  
Maha Haddad ◽  
Arun Kale ◽  
Lavjay Butani
Keyword(s):  
Nephrotic Syndrome ◽  
North American ◽  
Minimal Change Disease ◽  
Immunosuppressive Agents ◽  
Laboratory Data ◽  
Minimal Change ◽  
Indian Children ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
American Children

Abstract Background: Steroid resistant nephrotic syndrome (SRNS), while uncommon in children, is associated with significant morbidity. Calcineurin inhibitors (CNIs) remain the first line recommended therapy for children with non-genetic forms of SRNS, but some children fail to respond to them. Intravenous (IV) cyclophosphamide (CTX) has been shown to be effective in Asian-Indian children with difficult to treat SRNS (SRNS-DTT). Our study evaluated the outcome of IV CTX treatment in North American children with SRNS-DTT.Methods: Retrospective review of the medical records of children with SRNS-DTT treated with IV CTX from January 2000 to July 2019 at our center. Data abstracted included demographics, histopathology on renal biopsy, prior and concomitant use of other immunosuppressive agents and serial clinical/laboratory data. Primary outcome measure was attainment of complete remission (CR). Results: Eight children with SRNS-DTT received monthly doses (median 6; range 4-6) of IV CTX. Four (50%) went into CR, 1 achieved partial remission and 3 did not respond. Three of the 4 responders had minimal change disease (MCD). Excluding the 1 child who responded after the 4th infusion, the median time to CR was 6.5 (range 0.5-8) months after completion of IV CTX infusions. Three remain in CR at a median of 8.5 years (range: 3.7-10.5 years) after completion of CTX; one child relapsed and became steroid-dependent. No infections or life-threatening complications related to IV CTX were observed.Conclusions: IV CXT can induce long term remission in North-American children with MCD who have SRNS-DTT.

scholarly journals Intravenous cyclophosphamide induces remission in children with difficult to treat steroid resistant nephrotic syndrome from minimal change disease

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Maha Haddad ◽  
Arundhati Kale ◽  
Lavjay Butani
Keyword(s):  
Nephrotic Syndrome ◽  
North American ◽  
Minimal Change Disease ◽  
Immunosuppressive Agents ◽  
Laboratory Data ◽  
Minimal Change ◽  
Indian Children ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
American Children

Abstract Background Steroid resistant nephrotic syndrome (SRNS), while uncommon in children, is associated with significant morbidity. Calcineurin inhibitors (CNIs) remain the first line recommended therapy for children with non-genetic forms of SRNS, but some children fail to respond to them. Intravenous (IV) cyclophosphamide (CTX) has been shown to be effective in Asian-Indian children with difficult to treat SRNS (SRNS-DTT). Our study evaluated the outcome of IV CTX treatment in North American children with SRNS-DTT. Methods Retrospective review of the medical records of children with SRNS-DTT treated with IV CTX from January 2000 to July 2019 at our center. Data abstracted included demographics, histopathology on renal biopsy, prior and concomitant use of other immunosuppressive agents and serial clinical/laboratory data. Primary outcome measure was attainment of complete remission (CR). Results Eight children with SRNS-DTT received monthly doses (median 6; range 4–6) of IV CTX. Four (50%) went into CR, 1 achieved partial remission and 3 did not respond. Three of the 4 responders had minimal change disease (MCD). Excluding the 1 child who responded after the 4th infusion, the median time to CR was 6.5 (range 0.5–8) months after completion of IV CTX infusions. Three remain in CR at a median of 8.5 years (range: 3.7–10.5 years) after completion of CTX; one child relapsed and became steroid-dependent. No infections or life-threatening complications related to IV CTX were observed. Conclusions IV CXT can induce long term remission in North-American children with MCD who have SRNS-DTT.

scholarly journals P1802EVALUATION OF THE GENETICAL FEATURES AFFECTING THE RENAL OUTCOMES IN CHILDREN WITH STEROID RESISTANT NEPHROTIC SYNDROME

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Elif Comak ◽  
Aslı Toylu ◽  
Ugur Bilge ◽  
Gülsah Kaya Aksoy ◽  
Mustafa Koyun ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Target Genes ◽  
Immunosuppressive Agents ◽  
Gene Panel ◽  
Sequencing Analysis ◽  
Single Nucleotide Variants ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Genes Encoding ◽  
Renal Prognosis

Abstract Background and Aims Nephrotic syndrome in childhood is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Although most children respond to glucocorticoid therapy, approximately 10% of patients turn out to be steroid resistant (steroid-resistant nephrotic syndrome [SRNS]). Although several studies in children with SRNS have shown that mutations in genes encoding proteins in the podocyte skeleton may be responsible for the etiology in only one-third of cases, the genetic features related with renal prognosis and response to immunosuppressive agents are not fully recognized. The aim of this study was to investigate the genomic alterations associated with renal prognosis and resistance to immunosuppression in children with SRNS. Method The children with SRNS were enrolled in this study. Custom gene panel was designed for next-generation sequencing analysis of more than 20 target genes (ABCB1, ABCC2, CTLA4, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, FOXP3, GSTP1, IMPDH1, IMPDH2, NOS3, NR3C1, SLCO1B1, SLCO1B3, TPMT, UGT1A9, UGT2B7) and 200 single nucleotide variants (SNVs) which were reported as implicated in renal prognosis of nephrotic syndrome. The target gene panel was enriched for drug metabolism regulating transporters and enzymes. Results A total of 25 children, 16 boys (64%), median age at last visit 17.5 years (13-18 years), median age at diagnosis 7.5 years (2-15), median follow-up 9.58±4.54 years, were included in the study. All patients were diagnosed focal segmental glomerulosclerosis on renal biopsy.

scholarly journals P0338CRUMBS HOMOLOG2-EZRIN SIGNALING INDUCED PODOCYTE INJURY, LEADING TO MINIMAL-CHANGE DISEASE(MCD) AND FOCAL SEGMENTAL GLOMERULOSCLEROSIS(FSGS)

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Ichiro Hada
Keyword(s):  
Electron Microscopy ◽  
Nephrotic Syndrome ◽  
Cell Line ◽  
Focal Segmental Glomerulosclerosis ◽  
Minimal Change Disease ◽  
Immunofluorescence Microscopy ◽  
Minimal Change ◽  
Podocyte Injury ◽  
Heavy Proteinuria ◽  
Foot Process

Abstract Background and Aims The etiology and cellular pathogenesis of podocyte injury leading to minimal-change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remain largely obscure. Genetic mutation of crumbs homolog 2 (CRB2) is a cause of congenital nephrotic syndrome. Type-1 transmembrane proteins including CRB2 transduce outside-in signals that are involved in various cellular events including changes in the cytoskeletal network. The aim of the present study is to determine whether alteration of CRB2-mediated signaling in podocytes causes MCD and FSGS. Method Mice were immunized with a partial recombinant protein including the extracellular part of mouse CRB2. Urinalysis was obtained, and the kidney was subjected to histopathology. Kidney samples were also subjected to immunofluorescence microscopy and glomerular isolation to determine whether activation of the ezrin/radixin/moesin (ERM) family of cross-linkers between plasma membrane proteins and the actin cytoskeleton is involved in the pathogenesis of this nephrotic model. A CRB2-expressing mouse podocyte cell line was generated and incubated with anti-CRB2 antibody, and cell lysates were subjected to immunoblot analysis of ERM phosphorylation. The presence of anti-CRB2 antibody in the serum was determined by Western blot analysis. Results Apparent anti-CRB2 antibody was detected in the serum from 4 weeks onward. Immunized mice developed proteinuria at 4 weeks, which continued at least until 29 weeks. Mice developing extremely heavy proteinuria also developed hematuria from 18 weeks onward. Light microscopy revealed MCD in mice with proteinuria alone and FSGS in mice with heavy proteinuria and hematuria. Immunofluorescence microscopy revealed positive granular IgG staining in podocyte foot processes, but not complement C3. Electron microscopy and immuno-electron microscopy revealed alteration of actin organization associated with prominent foot process effacement. Strong phosphorylation of ezrin was observed in the glomerulus from the proteinuric stage and in the cellular lysates from the CRB2-expressing podocyte cell line incubated with anti-CRB2 antibody. Conclusion The current data revealed that binding of anti-CRB2 antibody to the extracellular domain of CRB2 on the podocyte foot process activated the ezrin-cytoskeleton network, leading to podocyte injury. Our data also indicated that signaling by this one molecular can induce two different phenotypes of glomerular injury: MCD and FSGS. In our model, the signaling was activated by anti-CRB2 antibody, but in patients with nephrotic syndrome the CRB2 ligands remain unknown. Therefore, it will be important to identify the soluble factors interacting with CRB2, which may be novel factors contributing to the pathogenesis of MCD and FSGS.

scholarly journals Case Report: Corneal Leucoma as a Novel Clinical Presentation of Nail-Patella Syndrome in a 5-Year-Old Girl

2021 ◽  
Vol 9 ◽  
Author(s):  
Ling Hou ◽  
Yue Du ◽  
Yubin Wu ◽  
Yue Zeng ◽  
Chengguang Zhao
Keyword(s):  
Nephrotic Syndrome ◽  
Clinical Presentation ◽  
De Novo ◽  
Autosomal Dominant Disorder ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Psychomotor Delay ◽  
Bilateral Absence ◽  
Patient Reported ◽  
Nail Patella Syndrome

Nail-patella syndrome (NPS) is a rare autosomal-dominant disorder characterized by the classic tetrad of absent or hypoplastic finger and toe nails, absent or hypoplastic patella, skeletal deformities involving the elbow joints, and iliac horns. This disease is caused by heterozygous pathogenic variations in the LMX1B gene, which encodes the LIM homeodomain transcription factor protein (LMX1B). We report a case of corneal leucoma and dysplasia prior to overt steroid-resistant nephrotic syndrome (SRNS) in a patient with NPS. At presentation, the parents of a 5-year-old female patient reported their daughter had corneal leucoma, psychomotor delay and speech defect. We also noted the presence of bilateral edema of the lower extremities, hypertension, nail dystrophy, and the bilateral absence of patella. She developed steroid-resistant nephrotic syndrome. Lowe oculocerebrorenal syndrome and NPS were the conditions considered in differential diagnosis. Trio-based whole genome sequencing indicated a heterozygous de novo likely pathogenic variation in the LMX1B gene (c.805A>C [p.Asn269His]). Patients with NPS often develop nail, ocular, or orthopedic symptoms prior to nephrotic syndrome. Corneal leucoma may be a novel clinical presentation of NPS.

scholarly journals Plasmapheresis-induced Clinical Improvement in a Patient with Steroid-Resistant Nephrotic Syndrome Due to Podocin (NPHS2) Gene Station

2010 ◽  
Vol 53 (3) ◽  
pp. 157-159 ◽  
Author(s):  
Sylva Skálová ◽  
Miroslav Podhola ◽  
Karel Vondrák ◽  
Gil Chernin
Keyword(s):  
Nephrotic Syndrome ◽  
Clinical Improvement ◽  
Combined Therapy ◽  
Immunosuppressive Agents ◽  
Gene Mutations ◽  
First Year ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Heterozygous Form ◽  
First Year Of Life

Podocin mutations (NPHS2 gene) are mostly responsible for steroid-resistant nephrotic syndrome (SRNS) of childhood onset. Patients with NPHS2 gene mutations do not respond to corticoids and other immunosuppressive agents; partial remission can be rarely induced by cyclosporin A. We present a boy, where SRNS was diagnosed within first year of life. By the age of 15 years, proteinuria reached 9000 mg/24 h, cholesterolemia 15 mmol/L, albuminemia 19.6 g/L, in spite of combined therapy with cyclosporine A, methylprednisolone, enalapril and losartan. At that time a combined heterozygous form of two NPHS2 gene mutations (p.R138Q and p.V290M) was diagnosed, methylprednisolone was discontinued and patient underwent ten plasmapheresis procedures. This resulted in clinical improvement (proteinuria 3000 mg/24 h, S-cholesterol 6 mmol/L, albumin 30g/L) lasting for three years. In conclusion, plasmapheresis can result in clinical improvement and stabilization of SRNS caused by podocine mutation, before renal replacement therapy is initiated.

scholarly journals Mutations in NPHS2 Encoding Podocin Are a Prevalent Cause of Steroid-Resistant Nephrotic Syndrome among Israeli-Arab Children

2002 ◽  
Vol 13 (2) ◽  
pp. 400-405 ◽  
Author(s):  
Yaacov Frishberg ◽  
Choni Rinat ◽  
Orli Megged ◽  
Eli Shapira ◽  
Sofia Feinstein ◽  
...  
Keyword(s):  
Renal Failure ◽  
Nephrotic Syndrome ◽  
Immunosuppressive Agents ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
End Stage Renal Failure ◽  
Arab Children ◽  
Presenting Symptoms ◽  
End Stage ◽  
Arab Descent

ABSTRACT. Steroid-resistant nephrotic syndrome (SRNS) represents a heterogeneous group of kidney disorders that are often resistant to other immunosuppressive agents and tend to progress to end-stage renal failure. Mutations in the gene NPHS2 that encode a protein named podocin have recently been found in a recessive form of SRNS. Ten children from two inbred families of Israeli-Arab descent presented with SRNS. Renal histologic findings were of diffuse mesangial proliferation. Six patients reached end-stage renal failure, but nephrotic syndrome did not recur after renal transplantation. Mutation analysis of NPHS2 revealed that they were homozygous for the C412T mutation (R138X). Eighteen children were subsequently analyzed with SRNS due to biopsy-proven focal segmental glomerulosclerosis (FSGS) from unrelated families of Israeli-Arab descent. Analysis disclosed six additional patients (33%) bearing the same mutation in a homozygous pattern. Three of them had no affected relatives, although they came from large families. Taken together, of the 27 patients tested (familial and nonfamilial), 15 patients (55%) were homozygous for the mutation (R138X). They all shared the same haplotype and were homozygous for the A1023G polymorphism, thus pointing to a possible founder effect. Thirteen children of Israeli-Jewish origin with SRNS and biopsy-proven FSGS and 15 children of both ethnic groups with steroid-responsive FSGS were tested, and none was found to have mutations in NPHS2. The results of this study demonstrate that mutations in NPHS2 are a common cause of SRNS in Israeli-Arab children. Mutations in NPHS2 may cause SRNS in nonfamilial cases. The interethnic differences in the occurrence of NPHS2 mutations may explain, in part, the previous observation that Arab patients with FSGS in Israel have a worse prognosis as compared with Jewish patients, despite similar presenting symptoms and medical management. Identifying the causing mutation will enable clinicians to avoid unnecessary immunosuppressive therapeutic trials in newly diagnosed patients and to provide prenatal diagnosis to families at risk.

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