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

Focal Segmental Glomerular Sclerosis

Renal Outcomes ◽

Purpose: We aimed to evaluate therapeutic response and long-term renal outcomes of childhood idiopathic steroid-resistant nephrotic syndrome (iSRNS). Methods: We retrospectively reviewed treatment regimens, especially calcineurin inhibitor (CNI), pathologic diagnoses, and long-term renal outcomes of iSRNS patients for 30 years. Results: 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) (p = 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) (p = 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. Conclusion: 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.

MO1027EFFICACY OF CALCINEURIN INHIBITORS IN CHILDREN WITH MONOGENIC STEROID-RESISTANT NEPHROTIC SYNDROME

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab108.0024 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Larisa Prikhodina ◽

Svetlana Papizh ◽

Inna Povolotskaya

Keyword(s):

Nephrotic Syndrome ◽

Calcineurin Inhibitors ◽

Compound Heterozygous ◽

Target Level ◽

Steroid Resistant ◽

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 Follow-Up in Children with Steroid-Resistant Nephrotic Syndrome

Clinical Pediatrics ◽

10.1177/000992289203100504 ◽

1992 ◽

Vol 31 (5) ◽

pp. 283-288 ◽

Cited By ~ 6

Author(s):

Nesrin Besbas ◽

Rezan Topaloglu ◽

Omit Saatci ◽

Aysin Bakkaloglu

Keyword(s):

Nephrotic Syndrome ◽

Steroid Resistant ◽

Long Term Follow Up

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 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 ◽

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 ◽

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