The importance of genetic study in steroid-resistant nephrotic syndrome

Steroid-resistant nephrotic syndrome (SRNS) is a challenging clinical task. It has heterogeneous etiology and extremely variable clinical outcomes and generally progresses to end-stage renal disease (ESRD). Different gene mutations in podocyte’s slit diaphragm, mitochondria, and cytoskeleton proteins, as well as glomerular basement membrane (GBM) have been associated with SRNS. These proteins regulate the function of the glomerular filtration barrier. Advances in genetic approaches and podocytology have led to discover the SRNS-causing genes that lead to a better understanding of the drug resistance. More than 45 genetic mutations have been recognized in the hereditary form of SRNS. This review offers an update on the current knowledge of steroid resistance-causing gene mutations in podocytes. Understanding the specific genes involved in SRNS would guarantee an optimum therapeutic benefit of steroid treatment.

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The New Compound Heterozygous Mutation of NUP Nephropathy: Report of Two Cases and Literature Review

10.21203/rs.3.rs-238609/v1 ◽

2021 ◽

Author(s):

Yuxin Pei ◽

Liping Rong ◽

Mengjie Jiang ◽

Zhilang Lin ◽

Cheng Cheng ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Literature Review ◽

End Stage Renal Disease ◽

Compound Heterozygous ◽

Founder Mutations ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Renal Manifestation ◽

Stage Renal Disease ◽

End Stage

Abstract Backgrounds: NUP nephropathy is identified as a rare monogenic cause of steroid-resistant nephrotic syndrome recently. To explore the relationship between NUP mutation and renal disorders, we provide two cases and a literature review of the genotypical and phenotypical features in patients with NUP nephropathy.Results: We reported two patients with newly diagnosed NUP nephropathy who carried a compound heterozygous mutations in NUP107 and NUP93 gene respectively. Both patients were diagnosed steroid-resistant nephrotic syndrome and progressed to end-stage renal disease in childhood. While the mutation c.1537+1G>A in NUP93 gene was previously described, the mutations c.460A>G and c.1085C>T in NUP107 gene and c.1472A>T in NUP93 gene were novel. We also summarized the phenotypic and genetic spectrum of NUP nephropathy in eighty-six reported patients who carried 50 different mutations in 6 NUP genes (NUP107, NUP93, NUP205, NUP85, NUP133, NUP160). The majority of them were Asians (66/86, 76.7%). The mutation c.2492A>C and c.1079-1083del in NUP107 had been identified as the founder mutations in East Asian[1-3], while c.1772G>T and c.1886A>G in NUP93 might be the founder mutations in Western Europe and Turkish respectively. Nephrotic syndrome was the most common renal manifestation (68/86, 79.1%). Although the renal prognosis was poor that 80.8% (59/73) of them developed end-stage renal disease within the first two decades, the outcome of renal transplantation in NUP nephropathy is better than patients with other steroid-resistant nephrotic syndrome. Focal segmental glomerulosclerosis was the most prevalent renal biopsy pathologic type (56/65, 86.1%). Various extra-renal manifestations were found in 44.8% (26/58) of patients. Neurological involvement was the most common extra-renal presentation (22/26, 84.6%), including microcephaly (13/22, 59.1%), intellectual disability (12/22, 54.5%), and global developmental delay (10/22, 45.5%). Diverse abnormalities of the facial appearance (8/26, 30.8%), short stature (5/26, 19.2%),and contain convergent strabismus (4/26, 15.4%) had also been reported. There are significant differences in extra-renal manifestations between different genomics. Conclusions: The renal manifestation of NUP nephropathy is highly consistent that most patients suffered early-onset SRNS with FSGS. More than half of the patients had extra-renal symptom concomitantly. Asians showed potential susceptibility to NUP nephropathy. Despite the limited reports, some genotype-phenotype correlations have been gradually revealed.

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Prediction of steroid resistance and steroid dependence in nephrotic syndrome children

Journal of Translational Medicine ◽

10.1186/s12967-021-02790-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Katarzyna Zaorska ◽

Piotr Zawierucha ◽

Monika Świerczewska ◽

Danuta Ostalska-Nowicka ◽

Jacek Zachwieja ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Multiple Logistic Regression Analysis ◽

Kidney Injury ◽

Steroid Resistance ◽

Neural Network Approach ◽

Steroid Resistant ◽

Steroid Dependence ◽

Steroid Dependent ◽

Stage Renal Disease ◽

End Stage

Abstract Background Steroid resistant (SR) nephrotic syndrome (NS) affects up to 30% of children and is responsible for fast progression to end stage renal disease. Currently there is no early prognostic marker of SR and studied candidate variants and parameters differ highly between distinct ethnic cohorts. Methods Here, we analyzed 11polymorphic variants, 6 mutations, SOCS3 promoter methylation and biochemical parameters as prognostic markers in a group of 124 Polish NS children (53 steroid resistant, 71 steroid sensitive including 31 steroid dependent) and 55 controls. We used single marker and multiple logistic regression analysis, accompanied by prediction modeling using neural network approach. Results We achieved 92% (AUC = 0.778) SR prediction for binomial and 63% for multinomial calculations, with the strongest predictors ABCB1 rs1922240, rs1045642 and rs2235048, CD73 rs9444348 and rs4431401, serum creatinine and unmethylated SOCS3 promoter region. Next, we achieved 80% (AUC = 0.720) in binomial and 63% in multinomial prediction of SD, with the strongest predictors ABCB1 rs1045642 and rs2235048. Haplotype analysis revealed CD73_AG to be associated with SR while ABCB1_AGT was associated with SR, SD and membranoproliferative pattern of kidney injury regardless the steroid response. Conclusions We achieved prediction of steroid resistance and, as a novelty, steroid dependence, based on early markers in NS children. Such predictions, prior to drug administration, could facilitate decision on a proper treatment and avoid diverse effects of high steroid doses.

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Novel Mutations in NPHS2 Detected in Both Familial and Sporadic Steroid-Resistant Nephrotic Syndrome

Journal of the American Society of Nephrology ◽

10.1681/asn.v132388 ◽

2002 ◽

Vol 13 (2) ◽

pp. 388-393 ◽

Cited By ~ 1

Author(s):

Stephanie M. Karle ◽

Barbara Uetz ◽

Vera Ronner ◽

Lisa Glaeser ◽

Friedhelm Hildebrandt ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Renal Disease ◽

End Stage Renal Disease ◽

Positional Cloning ◽

Mutational Analysis ◽

Causative Gene ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Stage Renal Disease ◽

End Stage

ABSTRACT. Autosomal recessive steroid-resistant nephrotic syndrome (SRINS) belongs to the heterogeneous group of familial nephrotic syndrome and represents a frequent cause of end-stage renal disease in childhood. This kidney disorder is characterized by early onset of proteinuria, progression to end-stage renal disease, and histologic findings of focal segmental glomerulosclerosis, minimal change nephrotic syndrome, or both. A causative gene, NPHS2, has been mapped to chromosome 1q25-q31 and was recently identified by positional cloning. This study reports five novel NPHS2 mutations: A284V, R196P, V290M, IVS4-1G→T, and 460-467insT in 12 (46%) of 26 multiplex families and in 7 (28%) of 25 single patients with the clinical diagnosis of a SRINS. Because NPHS2 mutations were found in nearly 30% of these patients with “sporadic” SRINS, mutational analysis should also be performed in these patients. Besides better classification of the disease entity, identification of NPHS2 mutations may save some of these patients from unnecessary steroid treatment and also permit the prediction of absence of disease recurrence after kidney transplantation.

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NPHS2 gene mutation, atopy, and gender as risk factors for steroid-resistant nephrotic syndrome in Indonesians

Paediatrica Indonesiana ◽

10.14238/pi51.5.2011.272-6 ◽

2011 ◽

Vol 51 (5) ◽

pp. 272 ◽

Cited By ~ 1

Author(s):

Dedi Rachmadi ◽

Danny Hilmanto ◽

Ponpon Ijradinata ◽

Abdurahman Sukadi

Keyword(s):

Risk Factors ◽

Nephrotic Syndrome ◽

Gene Mutation ◽

Significant Risk ◽

Gene Mutations ◽

Male Gender ◽

Amplification Refractory Mutation System ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Nphs2 Gene

Background Steroid-resistant nephrotic syndrome (SRNS) often develops into end stage renal disease. Previous studies have reported that NPHS2 gene mutation, gender, and atopic history are risk factors associated with SRNS. Interethnic, sociocultural, and environmental differences have also been suggested to affect these mutations.Objective To analyze possible risk factors for SRNS, including NPHS2 gene mutations (412C→T and 419delG), gender and atopic history, in Indonesian subjects with SRNS.Methods A case-control study with 153 subjects, consisting of 88 SRNS patients and 65 control subjects, was undertaken in 10 Indonesian teaching centre hospitals from September 2006 to December 2007. Analysis of the NPHS2 gene mutation in 412 C→T was performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), while that for the NPHS2 gene mutation in 419delG was performed by restriction fragment length polymorphism (RFLP). Data was analyzed by multiple logistic regression.Results In our Indonesian subjects, the significant risk factors for SRNS were male gender (OR=2.21; CI 95%:1.07-4.56, P=0.036), NPHS2 412C→T gene mutation (OR=18.07; CI 95%:6.76-48.31, P<0.001), and NPHS2 419delG gene mutation (OR=4.55; CI 95%:1.66-12.47, P=0.003). However, atopic history was not a significant risk factor for SRNS (OR=1.807; CI 95%:0.642-5.086, P=0.262).Conclusion NPHS2 412C→T and 419delG gene mutations, as well as male gender are risk factors for SRNS in Indonesian subjects. Atopic history was not significantly associated with SRNS in our subjects. [Paediatr Indones. 2011;51:272-6].

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

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2016.76 ◽

2010 ◽

Vol 53 (3) ◽

pp. 157-159 ◽

Cited By ~ 3

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.

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A novel biomimetic nanomedicine system with anti-inflammatory and anti-osteoporosis effects improves the therapy efficacy of steroid-resistant nephrotic syndrome

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01165-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jian Li ◽

Mingyi Zhao ◽

Xinying Xiang ◽

Qingnan He ◽

Rong Gui

Keyword(s):

Nephrotic Syndrome ◽

Glycyrrhizic Acid ◽

Immune Escape ◽

Platelet Membrane ◽

Steroid Resistance ◽

Inflammatory Factors ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Anti Inflammatory

AbstractClinically, steroid-resistant nephrotic syndrome (SRNS) is always prolonged and difficult to treat and easily develops into end-stage renal disease, resulting in a low survival rate. Strategies to reverse steroid resistance and reduce the long-term use of high doses of steroid medicines are urgently needed. In this study, a novel nanoparticle drug system (Pm-GCH) with a core–shell structure was designed. Metal–organic frameworks, synthesized by glycyrrhizic acid (G) and calcium ions (Ca2+) loaded with hydrocortisone (H) were the core of the nanoparticles. Platelet membrane vesicles were the shells. The natural platelet membrane endows Pm-GCH with good biocompatibility and the ability to promote immune escape. In addition, under the chemotaxis of inflammatory factors, platelet membranes assist Pm-GCH in nonspecific targeting of the inflammatory sites of the kidney. Under an inflammatory acid environment, GCH slowly degrades and releases glycyrrhizic acid and hydrocortisone. Glycyrrhizic acid inhibits the inactivation of hydrocortisone, jointly inhibits the activity of phospholipase A2 (PLA2) and the classic activation pathway of complement C2, blocks the production of inflammatory factors, plays an anti-inflammatory role, and enhances the efficacy of hydrocortisone in the treatment of SRNS. Moreover, glycyrrhizic acid alleviates osteoporosis induced by long-term use of glucocorticoids. These results indicate that Pm-GCH is a promising treatment strategy for SRNS. Graphical Abstract

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Wilms′ tumour 1 gene mutations in south Indian children with steroid-resistant nephrotic syndrome

The Indian Journal of Medical Research ◽

10.4103/0971-5916.195044 ◽

2016 ◽

Vol 144 (2) ◽

pp. 276 ◽

Cited By ~ 2

Author(s):

Prabha Senguttuvan ◽

AravindSelvin Kumar ◽

R Srilakshmi ◽

SMK Karthickeyan ◽

K Balakrishnan ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Gene Mutations ◽

Wilms Tumour ◽

Indian Children ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

South Indian

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

Journal of the American Society of Nephrology ◽

10.1681/asn.v132400 ◽

2002 ◽

Vol 13 (2) ◽

pp. 400-405 ◽

Cited By ~ 1

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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The podocin V260E mutation predicts steroid resistant nephrotic syndrome in black South African children with focal segmental glomerulosclerosis

Communications Biology ◽

10.1038/s42003-019-0658-1 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Melanie A. Govender ◽

June Fabian ◽

Errol Gottlich ◽

Cecil Levy ◽

Glenda Moonsamy ◽

...

Keyword(s):

Nephrotic Syndrome ◽

South African ◽

Focal Segmental Glomerulosclerosis ◽

Steroid Resistance ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Black South African ◽

African Children ◽

Segmental Glomerulosclerosis ◽

South African Children

AbstractIn black African children with focal segmental glomerulosclerosis (FSGS) there are high rates of steroid resistance. The aim was to determine genetic associations with apolipoprotein L1 (APOL1) renal risk variants and podocin (NPHS2) variants in 30 unrelated black South African children with FSGS. Three APOL1 variants were genotyped and the exons of the NPHS2 gene sequenced in the cases and controls. APOL1 risk alleles show a modest association with steroid sensitive nephrotic syndrome (SSNS) and steroid resistant nephrotic syndrome (SRNS). The NPHS2 V260E variant was present in SRNS cases (V/V = 5; V/E = 4; E/E = 11), and was absent in SSNS cases. Haplotype analysis suggests a single mutation origin for V260E and it was associated with a decline in kidney function over a 60-month period (p = 0.026). The V260E variant is a good predictor of autosomal recessive SRNS in black South African children and could provide useful information in a clinical setting.

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Comparison of oral and intravenous cyclophosphamide in children with steroid-resistant nephrotic syndrome

Paediatrica Indonesiana ◽

10.14238/pi51.5.2011.266-71 ◽

2011 ◽

Vol 51 (5) ◽

pp. 266

Author(s):

Eka Laksmi Hidayati ◽

Sudung O. Pardede ◽

Partini P. Trihono

Keyword(s):

Nephrotic Syndrome ◽

Oral Route ◽

Steroid Resistance ◽

Intravenous Route ◽

Intravenous Cyclophosphamide ◽

Steroid Resistant ◽

Steroid Resistant Nephrotic Syndrome ◽

Number Of Patients ◽

The Mean ◽

A Prospective Study

Background There are variations in remission rates following treatment of steroid-resistant nephrotic syndrome (SRNS) with cyclophosphamide.Objective To compare the efficacy of oral versus intravenous cyclophosphamide (CPA) in the management of pediatric SRNS.Methods This was a prospective study of 41 children with SRNS treated with CPA. One group received oral CPA at a dose of 2 mg/kg body weight/day for 8-12 weeks, while the other group received intravenous CPA at a dose of 500mg/m2 body surface area (BSA) monthly for 6 months. All patients were concomitantly treated with prednisone on alternate days. The primary outcome was the number of patients attaining remission.Results The study was comprised of 20 children receiving oral CPA and 21 children receiving intravenous CPA. There were 29 boys and 12 girls. The mean age of children at the onset of nephrotic syndrome (NS) was 47 ± 40 months old (range 12 months – 13 years), and the mean duration of NS before initiation of CPA therapy was 15 ± 28 months (range 1 – 129 months). Remission was achieved in 29 (70.7%) patients, with no difference between oral and intravenous route of CPA administration. The mean time to achieve remission was 22.7 weeks (about 5 months). The oral route group required less time in achieving remission than the intravenous route group. No association was found between remission and other factors, such as onset of steroid resistance, route of CPA, hypertension and hematuria. Side-effects included infection, anemia, nausea/vomiting, and alopecia. None of the patients required discontinuation of the medication.Conclusion Oral CPA was as effective as intravenous CPA for children with steroid-resistant nephrotic syndrome. [Paediatr Indones. 2011;51:266-71].

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