Loading

Journal of Clinical Nephrology and Research

Combined Immunosuppressive Treatment in Children with Primitive Steroid Resistant Nephrotic Syndrome

Research Article | Open Access
Article DOI :

  • 1. Department of pediatric nephrology, Charles Nicolle Hospital, Tunisia
+ Show More - Show Less
Corresponding Authors
Sayari Taha, Department of pediatric nephrology, Charles Nicolle Hospital, 9 April 1938 Boulevard, Tunis–Tunisia
CONCLUSION

SRNS is a rare and challenging condition that affects a subset of children with nephrotic syndrome. The management of SRNS requires the use of one or more IA, including CsA, MMF, and RTX. While these agents have shown efficacy, there is still controversy regarding the optimal use and combination these drugs. We described the disease course of children who received combination therapy with multiple associated IA. Our findings suggest that this combination therapy may be a viable treatment option. However, further studies are needed to determine the most effective and safe combination therapy for this challenging condition. The results of our study may provide insights into the use of IA for the management of SRNS and may guide the development of future treatment strategies.

REFERENCES
  1. Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int. 2021; 100: 753-779.
  2. Chanchlani R, Parekh RS. Ethnic Differences in Childhood Nephrotic Syndrome. Front Pediatr. 2016; 4: 39.
  3. Lee JM, Kronbichler A, Shin JI, Oh J. Current understandings in treating children with steroid- resistant nephrotic syndrome. Pediatr Nephrol. 2021; 36: 747-761.
  4. Niaudet P. Treatment of childhood steroid-resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. French Society of Pediatric Nephrology. J Pediatr. 1994; 125: 981-986.
  5. Pottel H, Mottaghy FM, Zaman Z, Martens F. On the relationship between glomerular filtration rate and serum creatinine in children. Pediatr Nephrol. 2010; 25: 927-934.
  6. Echeverri CV, Valencia GA, Higuita LM, Gayubo AK, Ochoa CL, Rosas LF, et al. Immunosupressive therapy in children with steroidresistant nephrotic syndrome: single center experience. J Bras Nefrol. 2013; 35: 200-205.
  7. Kamei K, Ishikura K, Sako M, Ito S, Nozu K, Lijama K, et al. Rituximab therapy for refractory steroid-resistant nephrotic syndrome in children. Pediatr Nephrol. 2020; 35: 17-24.
  8. Kim JH, Park SJ, Yoon SJ, Lim BJ, Jeong HJ, Lee JS, et al. Predictive factors for ciclosporin-associated nephrotoxicity in children with minimal change nephrotic syndrome. J Clin Pathol. 2011; 64: 516-519.
  9. El-Husseini A, El-Basuony F, Mahmoud I, Sheashaa H, Sabry A, Hassan R, et al. Long-term effects of cyclosporine in children with idiopathic nephrotic syndrome: a single-centre experience. Nephrol Dial Transplant. 2005; 20: 2433-2438.
  10. Prasad N, Manjunath R, Rangaswamy D, Jaiswal A, Agarwal V, Bhadauria V, et al. Efficacy and Safety of Cyclosporine versus Tacrolimus in Steroid and Cyclophosphamide Resistant Nephrotic Syndrome: A Prospective Study. Indian J Nephrol. 2018; 28: 46-52.
  11. Sachdeva S, Khan S, Davalos C. Management of Steroid-Resistant Nephrotic Syndrome in Children. Cureus. 2021; 13: e19363.
  12. Zhao J, Liu Z. Treatment of nephrotic syndrome: going beyond immunosuppressive therapy. Pediatr Nephrol. 2020; 35: 569-579.
ABBREVIATIONS

CKD: Chronic Kidney Disease; CSA: Cylosporine A; IA: Immunosuppressive Agents; MMF: Mycofenolate Mofetil; RTX: Rituximab; SRNS: Steroid Resistant Nephrotic Syndrome

INTRODUCTION

Steroid Resistant Nephrotic Syndrome (SRNS) is a rare but serious condition defined as the lack of complete remission at 4 weeks daily prednisolone therapy [1]. Its prevalence varies depending on the population and geographical region studied. However, it is estimated that 10-20% of children with nephrotic syndrome will be steroid-resistant [2]. The management of SRNS often requires the use of immunosuppressive agents (IA) including Cyclosporine A (CsA), Mycophenolate Mofetil (MMF), and rituximab (RTX) [3]. CsA is a calcineurin inhibitor that inhibits T-cell signaling in lymphocytes and also has direct non-immune effects on the podocyte actin cytoskeleton. MMF inhibits inosine monophosphate dehydrogenase, a key enzyme in purine biosynthesis, suppressing DNA replication in T and B lymphocytes to modulate the immune response. RTX is a chimeric monoclonal antibody that targets CD20 on B lymphocytes, depleting them to regulate the immune system. It also stabilizes SMPDL-3b, preventing podocyte actin remodeling, although this is not related to the immune system [2,3,12]. While these IA have shown efficacy in the treatment of SRNS, there is still much controversy about the optimal use and combination of these drugs. In particular, the use of therapy with two or more simultaneous IA, has been suggested as a potential strategy to improve the outcomes of patients with SRNS. The aim of this study is to describe the characteristics and disease course of SRNS in children who have received combination therapy with CsA, MMF, and RTX. This study seeks to provide insights into the use of IA in the management of this challenging condition.

METHODS

The study design was that of a retrospective single-center chart including patients < 18 years with SRNS, who were treated at a pediatric tertiary care department between January 2008 and December 2020. Subjects with congenital or infantile or secondary nephrotic syndrome were excluded as well as those with systemic disease, vasculitis or glomerulonephritis. Were included those who were treated with an association of at least two IA including CsA, MMF, or RTX, with a minimal required follow-up period of one year. Data were collected for IA initiation time, duration of use, response rate and toxicity for each treatment. Drug response was recorded for those with 2 or more months of immunosuppressant treatment.

Definitions: The cases were defined according to Kidney Disease Improving Global Outcome (KDIGO) nomenclature of glomerular disease [1]:

- Steroid resistance was defined as lack of response to a course of corticosteroid therapy: prednisone or prednisolone at a dose of 60 mg/m² of body surface area per day for 4 weeks.

- Complete remission is defined as a urinary protein excretion of ≤ 0.3 g/24 hours, with normal serum albumin levels and resolution of edema.

- Partial remission is defined as a urinary protein excretion of ≤ 3.5 g/24 hours, with a reduction of at least 50% from baseline proteinuria, and stable or improved serum albumin levels.

- Relapse is defined as a return of protein excretion ≥ 50mg/kg/24 hours or more in a patient who previously achieved complete or partial remission for at least three consecutive days after reduction or discontinuation of immunosuppressive therapy.

- CsA resistance was defined as lack of response to CsA after 6 months of treatment

The following clinical data were recorded: gender, family history of nephrotic syndrome, age of disease onset, clinical and biological characteristics at the diagnosis of nephrotic syndrome, renal function, histopathological type and genetic findings, age of CsA initiation, relapses while on CsA and adverse effects, time to initiation of the second and/or third IA and adverse effects, and disease course using two or more IA. All patients were treated according to the protocol of the French Society of Pediatric Nephrology [4]. Children presenting with SRNS were initially treated with Cs A at a dose of 150-200 mg/m² of body surface area per day, with a target residual level between 100 and 300 ng/mL, along with prednisone at a dose of 30 mg/m² of body surface area per day for 1 month, followed by 30 mg/m² of body surface area on alternate days for five months.

The response to therapy was evaluated at the 4-month mark following the initiation of treatment. If complete or partial remission had not been achieved, the treatment was discontinued. In cases where remission was obtained, the dosage of prednisone was gradually decreased and discontinued within the next 3 months, while that of CsA was tapered and terminated in the following 3 months (with a total treatment duration of 12 months). The dose of CsA was adjusted according to the residual rate and any adverse effects. After treating or excluding any chronic infection and verifying treatment observance and genetics result, nephrotic syndrome was defined as refractory. So, second-line agents were introduced MMF and/or RTX. MMF was used at the dose of 600mg/m² of body surface/day in two divided doses for 12-36 months [1]. RTX was used at the dose of 375mg/m² of body surface/ injection twice [1].

Statistical analysis

Qualitative data were compared Pearson chi-square test. Means of quantitative data were compared using t-test. Cumulative rates were compared using Kaplan Meier survival function with log rank. A P value of < 0.05 was considered as significant. The primary outcome variable was the number of patients who went into remission (complete or partial). The secondary outcome variables were mean time to remission (after treatment initiation), toxicity rates relative to each immunosuppressive regimen and renal function (estimated glomerular filtration calculated with the modified Schwartz equation).

RESULTS

A total of 26 patients were included in the study, all of whom were on at least two IA. Corticosteroid resistance was noted at diagnosis in 36.4% of patients, while 63.6% became resistant later on. Demographic and clinical data of the cohort are shown in Table I. Renal biopsy was performed in 72% of patients. The most common histological finding was minimal change disease, observed in 36.4% of cases, followed by focal segmental glomerulosclerosis in 31.8% and diffuse mesangial proliferation in 4.5%. Genetic testing was performed in 40.9% of cases, with only one patient found to have the NPHS2 mutation.

The mean time of CsA initiation was 205 days: 67 days for those who presented with initially SRNS versus 287 days for those who were secondary SRNS. The mean initial CsA dosage was 160.80 ± 22.01 mg/day, and the mean residual level was 221.63 ± 109.93 ng/mL. The mean number of relapses under CsA was 2.53 ± 0.99. The time to initiation of a second IA was 48 months after the diagnosis of nephrotic syndrome. All patients in this study were treated with the combination of CsA and MMF, and two patients received the combination of CsA, MMF and RTX. The difference between mean delays to remission, after initiating CsA alone and under combined treatment with CsA and MMF or RTX; were respectively 6.71 ± 3 versus 4 ± 1.41 months (t-statistic=3.88; 95%CI: 1.3-4.11; P<10-3). Thus, cumulative remission rates who were detailed in survival curves in Figure 1, showed no significant difference between CsA and combined treatment (P=0.08).

Patients with SRNS who were treated by combined IA were compared a group of subjects under CsA (n=51): regrouping children on CsA alone before combining IA (n=26) and those who received exclusively CsA. The two groups were comparable. Different profiles of response to CsA and to combined IA were detailed in Table 2. The two patients treated with the combination of CsA, MMF and RTX achieved complete remission.

Treatment with IA was associated with toxicity in 65.5% of cases. CsA side effects were hypertrichosis in 63.6% of cases, gingival hypertrophy in 36.4% of cases, hypertension 40.9% of cases, and CKD in 31.8% of cases, side effects of MMF were mainly gastrointestinal disorders, noted in 43%. The patient who received the combination of CsA, MMF and RTX presented moderate lymphopenia. Thirteen patients developed severe renal disease which means stage 3, 4 or 5, among whom 23% (n=3) went to end-stage CKD. The mean time to progression to severe CKD was 45 ± 36 months after diagnosis. Overall, the mean creatinine at the end of the follow-up was up to 65.35 ± 23.17 µmol/L, which gave a mean estimated glomerular filtration rate of 76.40 ±37.38 ml/min/1.73m². This was significantly lower compared to the initial rates (t-statistic =6.69; 95% CI: 39.20-72.79; P <10-3) Figure 2.

DISCUSSION

The management of SRNS remains a clinical challenge due to the lack of consensus regarding optimal treatment strategies. Our study aimed to evaluate the efficacy and safety of a combination of two or more IA in the treatment of SRNS. Our results showed that all patients included in the study were on at least two immunosuppressive agents. The most commonly used IA was CsA, with MMF being the second-line most commonly used treatment. In a similar Colombian study testing multiple immunosuppressant therapies in SRNS, MMF was the most used (100%), followed by CsA (69.2%), Cyclophosphamide 23.1%, and RTX 23% [6].

The study demonstrated that a combination of CsA + MMF can lead to significant remission rates in patients with SRNS. In our cohort, 34.6% of patients achieved complete remission, which is consistent with the results of previous studies: Notably, patients who received the combination of CsA with both MMF and RTX achieved complete remission, suggesting that this combination may be a promising option for refractory cases of SRNS [3, 4]. In a recent review, Kamei and al reported that remission rates in patients with initial steroid resistance were 43.9% and late steroid resistance were 57.7%, while combining other secondline IA to RTX [7]. However, our study also revealed that the use of IA was associated with a significant rate of toxicity, particularly with the use of CsA alone or combined to MMF. Similar results were described in an Egyptian review, where these rates reached respectively 70.1%, 32.5 and 10.3%. [9] Others noted less frequent side effects with CsA: hypertrichosis in only 18 to 20% of cases and gingival hypertrichosis in only 7 to 15% [10].

Renal failure due to the use of CsA have been well described in literature. Ji Hong and al concluded that the median CsA residual level was an independent and significant risk factor for the development of CsA associated nephrotoxicity in children with nephrotic syndrome [8]. The time to progression to renal disease in this review underscores the importance of early detection and treatment of SRNS to prevent or delay CKD progression. Moreover, regular monitoring of renal function and blood pressure is crucial for patients with SRNS to detect and manage potential complications early on.

Despite the efficacy of the combination of CsA and MMF, a significant proportion of patients (15.38%) remained resistant to treatment. The reasons for treatment resistance are multifactorial and may include genetic factors, disease severity, and non-adherence to medication. In our cohort, genetic testing was performed in only 40.9% of cases, highlighting the need for broader genetic testing in patients with SRNS. Research has demonstrated that monogenic SRNS cases are associated with an increased resistance to immunosuppressive therapy. Therefore, genetic testing helps avoid these drugs and prevent potential adverse effects. This results in an added advantage of personalized treatment and the avoidance of renal biopsy [11].

Our study provides further evidence that a combination of CsA and MMF can lead to significant remission rates in patients with SRNS, although it is associated with a high rate of adverse effects. Future studies are needed to explore the efficacy and safety of newer IA and combination therapies in the treatment of SRNS. Recent studies has shown that the detection of individual genetic variations in SRNS has highlighted the importance of podocyte damage in causing the disease. Focusing on treating podocyte damage is crucial, and drugs that specifically target podocytes, along with immunosuppressants, are preferable as the primary treatment for SRNS [12].

Received : 23 May 2023
Accepted : 11 May 2023
Published : 13 May 2023
Journals
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X