Long-Term Outcomes in Children with Steroid-Resistant Nephrotic Syndrome Treated with Calcineurin Inhibitors

Pathogenic Variants ◽

Nail Patella Syndrome

Abstract Background and Aims Monogenic causes of steroid-resistant nephrotic syndrome (SRNS) have been reported for up to one-third of children depending on age of the disease onset. Immunosuppressive treatment of genetic SRNS with calcineurin inhibitors (CNIs) is still controversial. The aim of the study was to investigate the efficacy of CNIs with focus on inducing remission and long-term kidney function in children with monogenic SRNS. Method Retrospective analysis of efficacy CNIs in five children (2M/3F) with monogenic SRNS was performed. Kidney biopsy prior CNIs revealed FSGS (n=4) and MCD (n=1). The initial cyclosporine (CsA) dose was 5 mg/kg/24h to keep a target level of 80-150 ng/ml and tacrolimus (TAC) - 0.1 mg/kg/24h to achieve a target level of 5-10 ng/ml. CsA took all 5 patients with subsequent switching to TAC in 2 children due to cosmetic side effects. The median follow-up period was 165.0 (IQR: 59.0; 185.5) months. Next generation sequencing (NGS) was used for identification of pathogenic variants in all patients. Results The median age at onset of monogenic SRNS was 33.0 (IQR: 16.5; 63.0) months. 2/5 (40%) patients presented with acute SRNS, 1/5 (20%) child with infantile NS, 1/5 (20%) - with isolated nephrotic range proteinuria with hypoalbuminemia and 1/5 (20%) - with NS and extrarenal features of Nail-Patella syndrome. NGS identified previously described pathogenic variants in all 5 children, including NPHS2 homozygous c.28dup (p.Glu87Ter) (n=1), NPHS2 compound heterozygous c.868G>A (p.Val290Met) in combination with c.686G>A (p.Arg229Gln) (n=1), LMX1B heterozygous c.788T>G (p.Val263Gly) (n=1), LMX1B heterozygous c.737G>A (p.Arg246Gln) (n=1), and COL4A3 heterozygous c.2962G>A (p.Gly988Arg) variant (n=1). The median time from diagnosis to initiation of CNIs treatment was 72.0 (IQR: 33.0; 93.0) months. CNIs induced complete remission in 2/5 (40%) patients, presented with acute SRNS, including one girl with MCD due to NPHS2 compound heterozygous variants with mutation-dependent pathogenicity of one (p.R229Q) of them and one boy with FSGS due to COL4A3 heterozygous variant (n=1). Partial remission was induced by CNIs in 2/5 (40%) girls with FSGS due to LMX1B heterozygous variants with isolated SRNS (n=1) and Nail-Patella syndrome (n=1). The median duration of CNIs treatment to obtain complete or partial remission was 13.5 (IQR: 6.8; 15.8) months. Acute CNIs-associated nephrotoxicity had 2 patients with LMX1B variants. At the last follow up full and partial responders to CNIs treatment aged of 16.5 (IQR: 11.8; 17.5) years had CKD-1 (n=3) and CKD-2 (n=1). 1/5 (20%) boy with NPHS2-associated infantile NS was CNI resistant and developed CKD-5 at the age of 6.5 years with subsequent living related kidney transplantation. Conclusion We found that 4/5 (80%) children with monogenic SRNS demonstrated partial or full response to CNIs treatment with stable long-term kidney function. We assume that CNIs might improve podocyte function by stabilization of their cytoskeleton disrupted in patients with monogenic SRNS.

Long-term outcomes after early treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome

Pediatric Nephrology ◽

10.1007/s00467-018-4145-6 ◽

2018 ◽

Vol 34 (2) ◽

pp. 353-357 ◽

Cited By ~ 9

Author(s):

Shuichiro Fujinaga ◽

Tomohiko Nishino ◽

Chisato Umeda ◽

Yuji Tomii ◽

Yoshitaka Watanabe ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Early Treatment ◽

Long Term Outcomes ◽

Japanese Children ◽

Steroid Resistant ◽

Baseline characteristics and long-term outcomes of steroid-resistant nephrotic syndrome in children: impact of initial kidney histology

Pediatric Nephrology ◽

10.1007/s00467-020-04760-8 ◽

2020 ◽

Vol 35 (12) ◽

pp. 2377-2381

Author(s):

Yoshitaka Watanabe ◽

Shuichiro Fujinaga ◽

Amane Endo ◽

Shota Endo ◽

Mayu Nakagawa ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Long Term Outcomes ◽

Steroid Resistant ◽

Baseline Characteristics

Long-term outcome of idiopathic steroid-resistant nephrotic syndrome in children

Pediatric Nephrology ◽

10.1007/s00467-015-3174-7 ◽

2015 ◽

Vol 31 (3) ◽

pp. 425-434 ◽

Cited By ~ 12

Author(s):

Aya Inaba ◽

Yuko Hamasaki ◽

Kenji Ishikura ◽

Riku Hamada ◽

Tomoyuki Sakai ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Term Outcome ◽

Long Term Outcome ◽

Steroid Resistant ◽

Long-term outcome of children with steroid-resistant nephrotic syndrome treated with tacrolimus

Pediatric Nephrology ◽

10.1007/s00467-010-1471-8 ◽

2010 ◽

Vol 25 (6) ◽

pp. 1117-1124 ◽

Cited By ~ 42

Author(s):

Isabel Roberti ◽

Shefali Vyas

Keyword(s):

Nephrotic Syndrome ◽

Term Outcome ◽

Long Term Outcome ◽

Steroid Resistant ◽

Long-Term Outcome of Steroid-Resistant Nephrotic Syndrome in Children

Journal of the American Society of Nephrology ◽

10.1681/asn.2016101121 ◽

2017 ◽

Vol 28 (10) ◽

pp. 3055-3065 ◽

Cited By ~ 56

Author(s):

Agnes Trautmann ◽

Sven Schnaidt ◽

Beata S. Lipska-Ziętkiewicz ◽

Monica Bodria ◽

Fatih Ozaltin ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Term Outcome ◽

Long Term Outcome ◽

Steroid Resistant ◽

The Unique Difference Between Serum Level of Soluble Urokinase Plasminogen Activator Receptor (suPAR) in Steroid-Resistant Nephrotic Syndrome Children Treated with an Alkylating Agent and Calcineurin Inhibitors

Journal of Comprehensive Pediatrics ◽

10.5812/compreped.109912 ◽

2021 ◽

Vol In Press (In Press) ◽

Author(s):

Ahmedz WIdiasta ◽

Kurnia Wahyudi ◽

Husna Nugrahapraja ◽

Yunia Sribudiani ◽

Dedi Rachmadi

Keyword(s):

Nephrotic Syndrome ◽

Plasminogen Activator ◽

Calcineurin Inhibitors ◽

Urokinase Plasminogen Activator ◽

Urokinase Plasminogen Activator Receptor ◽

Steroid Resistant ◽

The Third ◽

Supar Level ◽

Plasminogen Activator Receptor

Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading contributor to chronic kidney disease (CKD), and calcineurin inhibitors (CNIs) or monoclonal antibodies are currently the best identified therapy. Meanwhile, some developing countries still use alkylating agents (AA) such as cyclophosphamide (CPA) to treat SRNS due to economic reasons. Objectives: This study aims to determine the employability of soluble urokinase plasminogen activator receptor (suPAR) as a biomarker for monitoring therapy in SRNS children and compare the clinical improvement with those treated with an AA and CNIs. Methods: This was a retrospective cohort study conducted at Hasan Sadikin Hospital, Indonesia. The data was collected from July 2019 to July 2020 from 70 children with FSGS. Clinical signs were evaluated monthly, and serum suPAR level was measured at the third and sixth months following therapy. Two-way repeated measures ANOVA was carried out to compare the differences in suPAR level at baseline with the third and sixth months in SRNS patients who received AA and CNIs. Results: The mean age was nearly similar between the two groups based on the t-test (P = 0.140). Steroid-resistant nephrotic syndrome was more frequent in boys than in girls (P = 0.020), according to the Chi-square test. Baseline serum suPAR level was not significantly different between the two groups. In the third month, the daily urinary protein level was higher in SRNS patients that received the AA compared to the CNIs group (P < 0.001). There was a significant interaction between time and treatment (F(2,138) = 7.203, P = 0.001), with higher suPAR level in SRNS patients that received the AA compared to those administered with CNIs at the 3rd and 6th months, but this difference was not statistically significant (P > 0.05). Conclusions: As a noninvasive tool, suPAR is a promising modality in monitoring SRNS therapy, and CNIs have a tendency to achieve faster remission than the AA.

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 ◽

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

Use of Cyclosporine Therapy in Steroid Resistant Nephrotic Syndrome (SRNS): A Review

Global Journal of Health Science ◽

10.5539/gjhs.v8n4p136 ◽

2015 ◽

Vol 8 (4) ◽

pp. 136 ◽

Cited By ~ 10

Author(s):

Syed Raza Shah ◽

Areeba Altaf ◽

Mohammad Hussham Arshad ◽

Anum Mari ◽

Sahir Noorani ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Side Effects ◽

Immunosuppressive Treatment ◽

Pediatric Nephrology ◽

Calcineurin Inhibitors ◽

Symptomatic Treatment ◽

Steroid Resistant ◽

Cyclosporine Therapy ◽

Difficult Challenge

<p>A chronic, progressive disorder Steroid Resistant Nephrotic Syndrome (SRNS) accounts for 10-20% of all children with Nephrotic Syndrome. It is a heterogeneous disorder comprised of persistent edema, proteinuria, hypoalbuminemia and hyperlipidemia. Treatment for steroid-resistant nephrotic syndrome (SRNS) is challenging and children who suffer from SRNS require aggressive treatment to achieve remission. Calcineurin inhibitors have been used more in an empirical manner than on the basis of clear rationale. It was in 1984 when cyclosporine was first considered for the treatment of steroid resistant nephrotic syndrome. Cyclosporin is a calcineurin inhibitor that suppresses immune response by downregulating the transcription of various cytokine genes. Till now many studies have been conducted to determine dosages, duration of therapy, side effects and advantages of cyclosporine. Treatment of SRNS remains a difﬁcult challenge in pediatric nephrology. Treatment should be individualized according to the underlying histopathology, and clinical and environmental conditions of the children. There is an urgent need to distinguish as soon as possible those patients who may beneﬁt from prolonged immunosuppressive treatment from those who will not beneﬁt from such treatment and who will just suffer from its major side effects. The emerging evidence that the majority of genetic forms of SRNS should receive symptomatic treatment only, should also be clinically tested and studies baring its significance should be evaluated in the future.</p>