Frequent Steroid Research Articles

Steroid Sensitive Nephrotic Syndrome: Revised Guidelines

JustificationSteroid sensitive nephrotic syndrome (SSNS) is one of the most common chronic kidney diseases in children. These guidelines update the existing Indian Society of Pediatric Nephrology recommendations on its management.ObjectiveTo frame revised guidelines on diagnosis, evaluation, management and supportive care of patients with the illness.ProcessThe guidelines combine evidence-based recommendations and expert opinion. Formulation of key questions was followed by review of literature and evaluation of evidence by experts in two face-to-face meetings.RecommendationsThe initial statements provide advice for evaluation at onset and follow up and indications for kidney biopsy. Subsequent statements provide recommendations for management of the first episode of illness and of disease relapses. Recommendations on the use of immunosuppressive strategies in patients with frequent relapses and steroid dependence are accompanied by suggestions for step-wise approach and plan of monitoring. Guidance is also provided regarding the management of common complications including edema, hypovolemia and serious infections. Advice on immunization and transition of care is given. The revised guideline is intended to improve the management and outcomes of patients with SSNS, and provide directions for future research.

Safety of anti-inflammatory drugs in children with asthma.

Inhaled corticosteroids (ICS) are widely used as the first-line treatment of asthma. When the disease is not controlled by standard doses of ICS, other anti-inflammatory drugs should be considered. The aim of this report is to review the main adverse events induced by anti-inflammatory drugs in children with asthma and discuss possible actions to prevent or mitigate these effects. Proper interpretation of ICS safety studies requires knowledge of the pharmaceutical properties and delivery device systems of the different ICS available. Genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression were found in children and adults who use ICS to treat their asthma. There is evidence of the association between montelukast use and neuropsychiatric events. Benefits of ICS, properly prescribed and used, outweigh their potential adverse effects. There is substantial evidence that the combination of ICS with long-acting beta2 agonists is safe for asthmatic children. Awareness of the potential risks of neuropsychiatric events in children taking montelukast should inform the clinicians' prescribing practices. Omalizumab is generally well-tolerated, but the evidence on the safety of other biologic agents in children is scanty. The risk of systemic adverse events with anti-inflammatory drugs must be balanced against the risks of uncontrolled asthma and/or frequent oral steroid use.

Steroid sensitive nephrotic syndrome: Revised guidelines

Justification: Steroid-sensitive nephrotic syndrome (SSNS) is one of the most common chronic kidney diseases in children. These guidelines update the existing Indian Society of Pediatric Nephrology recommendations on its management. Objective: To frame revised guidelines on diagnosis, evaluation, management, and supportive care of patients with the illness. Process: The guidelines combine evidence-based recommendations and expert opinion. Formulation of key questions was followed by review of literature and evaluation of evidence by experts in two face-to-face meetings. Recommendations: The initial statements provide advice for evaluation at onset and follow-up and indications for kidney biopsy. Subsequent statements provide recommendations for the management of the first episode of illness and of disease relapses. Recommendations on the use of immunosuppressive strategies in patients with frequent relapses and steroid dependence are accompanied by suggestions for step-wise approach and plan of monitoring. Guidance is also provided regarding the management of common complications including edema, hypovolemia, and serious infections. Advice on immunization and transition of care is given. The revised guideline is intended to improve the management and outcomes of patients with SSNS and provide directions for future research.

Randomized clinical trial to compare efficacy and safety of repeated courses of rituximab to single-course rituximab followed by maintenance mycophenolate-mofetil in children with steroid dependent nephrotic syndrome

BackgroundApproximately 30% of children with idiopathic nephrotic syndrome develop a complicated course with frequent relapses or steroid dependency. Rituximab, a B cell depleting monoclonal antibody, is a safe and effective alternative to steroids or other immunosuppressants for achieving and maintaining remission in this population at short term. Despite the good initial response relapses inevitably occur after regeneration of B lymphocytes, necessitating either repeat courses of rituximab or addition of another steroid-sparing immunosuppressant.MethodsThis is a prospective, single-center, open-label, two-parallel-arm randomized controlled phase III study among children with steroid dependent nephrotic syndrome who are maintained in remission with oral steroids. One hundred children will be randomized to either Rituximab and maintenance Mycophenolate mofetil (A) or repeated courses of prophylactic Rituximab only (B). In arm A, mycophenolate mofetil (1200 mg/m2 per day) will be started 3 months after Rituximab administration. In arm B, Rituximab infusions will be administered at 0, 8 and 16 months if B cell count normalize at the given time points. Prednisolone will be discontinued in both groups 2 weeks following first course of rituximab. Primary aim is to evaluate the difference in 24-month relapse-free survival. Main secondary endpoints are cumulative prednisolone dose, frequency of relapses and changes in anthropometry. Circulating B lymphocyte populations will be studied as biomarkers or predictors of rituximab responsiveness and adverse events will be analysed.DiscussionThe study will provide evidence as to the comparative safety and efficacy of two alternative steroid-sparing therapeutic options in children suffering from steroid dependent nephrotic syndrome. The two-year study design will address the long-term results obtained with the alternative treatment protocols.Trial registrationThis trial was prospectively registered to the Clinicaltrial.gov (NCT03899103 dated 02/04/2019; https://clinicaltrials.gov/) and Clinical Trials Registry of India (CTRI/2019/04/018517 dated 09/04/2019).

Is there any role of renin-angiotensin system inhibitors in modulating inflammatory bowel disease outcome?

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been associated with improved outcomes in inflammatory bowel disease. We aimed to investigate any possible effect of antihypertensive medications on inflammatory bowel disease course. One hundred and fifty inflammatory bowel disease patients with hypertension were compared using a 1:1 ratio with age- and gender-matched control patients with inflammatory bowel disease. The class of antihypertensive medication, traditional risk factors for atherosclerosis, inflammatory bowel disease characteristics, and history (surgery, hospitalizations, and treatment) were retrospectively analyzed. Of 150 (44.7% Crohn's disease) patients with hypertension, 46.7% were on angiotensin receptor blockers, 30.6% on angiotensin-converting enzyme inhibitors, 40% on β-blockers, and 40.7% on calcium channel blockers. Univariate analysis revealed significantly higher rates of traditional risk factors for atherosclerosis among antihypertensive users. When analyzing by class of antihypertensive medication, angiotensin receptor blockers were significantly associated with milder course as indicated by less frequent immunomodulator (P = 0.039) and steroid use (P = 0.041). Rates of lifetime steroids were statistically significantly lower among angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (odds ratio = 1.191, 95% confidence interval, 1.005-1.411). After adjustment with confounding factors, only angiotensin receptor blockers were associated with milder inflammatory bowel disease course (P = 0.037) and lower rates of immunomodulator use (P = 0.038). Our study suggests a possible protective effect of angiotensin receptor blockers on overall inflammatory bowel disease course by targeting the renin-angiotensin system. Their effect on inflammatory bowel disease needs to be studied in larger cohorts.

A 10-year-old girl with acute shortness of breath

A 10-year-old girl with known allergies and asthma presented with a 2-year gradual worsening of asthma symptoms and recent dramatic escalation, including multiple exacerbations requiring emergency department treatment but no intubation or ICU admission. Her asthma was well controlled on minimal treatment until age 8. Presenting symptoms included shortness of breath, chest tightness, audible wheeze, abnormal voice quality, and frequent rapid-onset attacks with hoarse voice and inspiratory difficulty unresponsive to short-acting bronchodilators. She also had significant shortness of breath on exertion resulting in restricted activity. Respiratory symptoms at school, particularly in one area, caused severe anxiety resulting in home-schooling, social isolation, and agoraphobia. Over 2 years, her asthma therapy had been escalated from low-dose inhaled corticosteroid (ICS) to combined anti-IgE antibody, very high-dose ICS, long-acting bronchodilator, leukotriene receptor antagonist, and short-term oral steroids more than monthly for breakthrough symptoms. Additional medications included nasal steroid, oral antihistamine, proton pump inhibitor, and an oral contraceptive. Side effects of frequent oral steroids included weight gain (body mass index > 95th percentile) and comorbidities included gastroesophageal reflux. Spirometry and physical examination were normal. An additional investigation revealed the diagnosis.

P1800RITUXIMAB ENHANCES THE EXPRESSION OF INTERLEUKIN-6 VIA TOLL-LIKE RECEPTOR 3 SIGNALING IN HUMAN PODOCYTE

Abstract Background and Aims The etiology of idiopathic nephrotic syndrome (INS) in children remains unclear, but it is well known that viral infections often cause relapses of INS. Since toll-like receptor 3 (TLR3), a ligand of viral dsRNA exists in podocytes, dysregulation of TLR3 signaling in podocytes may be involved in the pathogenesis of INS. Recently, rituximab (RTX) a specific antibody to human CD20, has been successfully used to treat children with intractable nephrotic syndrome (frequent relapse nephrotic syndrome, FRNS, and steroid dependent nephrotic syndrome, SDNS). It has been reported that depletion of B cell is main mechanism of RTX treatment. However, some patients experienced recurrence before peripheral blood B cell recovery, whereas selected patients have sustained remission even after peripheral blood B cell recovery. Considering that dramatic effects of RTX in the treatment of INS, it is speculated that some B cell-independent mechanisms of RTX exist. In this context, some recent studies have reported a direct effect of RTX on podocyte, targeting sphingomyelinase phosphodiesterase acid-like 3b (SMPDL3b), but detailed mechanisms remain to be determined. In this study, we examined whether RTX influences TLR3 signaling in cultured human podocyte. Method Immortalized human podocytes in culture were treated with polyinosinic-polycytidylic acid (poly IC), a synthetic analogue of viral dsRNA. RTX were added before or after the treatment of poly IC. Then, expression of interleukin (IL)-6 were measured using real time RT-PCR and ELISA. Direct binding of RTX to podocyte were confirmed by immunofluorescence. Results Poly IC induced the expression of IL-6 in cultured human podocyte in a concentration and time-dependent manner. IL-6 expression induced by poly IC were enhanced in both mRNA and protein level by pretreatment of RTX. RTX itself were apparently stained on podocyte by immunofluorescence. Conclusion RTX binds directly to cultured human podocyte and enhances the IL-6 expression induced by poly IC. Since IL-6 from podocyte was reported to be engaged in regulating glomerular inflammation by cross-talk with endothelial cells, exploring the role of enhanced IL-6 from podocyte by RTX, at least in a part, suggests a direct mechanism of RTX in treating intractable nephrotic syndrome in children.

P0401RITUXIMAB VESUS CYCLOPHOSPHAMIDE AS FIRST STEROID SPARING AGENT IN CHILDHOOD FREQUENTLY RELAPSING OR STEROID DEPENDENT NEPHROTIC SYNDROME

Abstract Background and Aims Approximately 50% of children with steroid sensitive nephrotic syndrome (SSNS) will suffer from frequent relapses or steroid dependency, prompting the use of so-called steroid-sparing drugs. In this pilot study, we compare the efficacy and safety of rituximab to oral cyclophosphamide as first-line steroid-sparing medications Method A prospective open label randomized study of children with frequent relapsing or steroid-dependant SSNS. Exclusion criteria were steroid-resistant disease, prescription of immunosuppressive agents other than prednisolone or levamisole, evidence of impaired kidney function, leucopenia or active infection. The recruited children were allocated either to the oral cyclophosphamide (3mg/kg/day for 8 weeks) or intravenous rituximab treatment (two doses of 375 mg/m2/dose, 2 weeks apart) and were monitored for relapses and side effects for 12 months Results 46 subjects were included from two centers; 27 received cyclophosphamide and 19 received rituximab. One-year relapse-free survival was reached in 17 (58.6%) patients treated with cyclophosphamide compared to 16 (84.2%) with rituximab (adjusted HR: 0.36; 95% CI: 0.09 – 1.45; p=0.151). The mean interval to relapse was 6.9 months in the cyclophosphamide group (N=10) and 6.3 months in the rituximab group (N=3). Both treatments were associated with a significant (p=?) reduction in prescribed dose of oral alternate days steroid from 1.02 to 0.36mg/kg (Cyclophoshamide) and 0.86 to 0.08mg/kg (Rituximab). Importantly, a significantly (P = 0.003) higher percentage of patients achieved complete withdrawal of steroid within 3 months of commencing study treatment in the rituximab (73.7%) versus cyclophosphamide (29.6%) group. Transient leucopenia was the most frequent adverse effect observed in the cyclophosphamide group (18.5%) and one patient (3.4%) had acute hepatotoxicity beside severe leucopenia and neutropenia on the 7th week of treatment although she showed complete recovery with withdrawal of cyclophosphamide and maintained remission. A minor infusion related reaction was observed in 1 patient (5%) in the rituximab group. Conclusion Rituximab is non-inferior to cyclophosphamide and safe as a first-line steroid-sparing agent in children with SSNS. A larger multicenter study is required to assess superiority over cyclophosphamide

The combined use of Adrenocorticotropic hormone (ACTH) and Calcineurin inhibitor (CNI) in the treatment of Refractory Nephrotic Syndrome in a child

Background: Primary podocytopathies including Focal Segmental Glomerulosclerosis (FSGS) have been recognized to show variable responses to conventional treatment and overall prognosis. Persistent failure to respond to therapies remains a vexing problem for clinicians. ACTH has recently resurged as a therapy for treatment-resistant podocytopathies. We describe a case of steroid-resistant NS in a 10-year-old boy with a history of multiple failed secondary therapies, who showed partial response to biweekly ACTH therapy. Further clinical improvement was observed with the addition of the calcineurin inhibitor (CNI), tacrolimus. Case description: A 10-year-old Hispanic boy, diagnosed with frequently-relapsing steroid sensitive NS at the age of 2, and was largely relapse-free for 5 years on Cyclosporine A (CsA). Within two months after a trial off CsA, he relapsed. His course was complicated by more frequent relapses and steroid resistance. Renal biopsy performed at this time showed early focal segmental glomerulosclerosis (FSGS) and no signs of CsA-induced nephropathy. Whole exome sequencing revealed a heterozygous variant of uncertain significance in PLCE1 (Phospholipase C Epsilon 1). Trials of the steroid sparing agents tacrolimus and mycophenolate mofetil, both with and without steroids, were ineffective. He had several prolonged hospitalizations due to poorly controlled relapse. He became dependent on biweekly 25% albumin infusions. His renal function deteriorated from a baseline creatinine of 0.3 mg/dl to 0.7 mg/dl due to multiple episodes of acute kidney injury. ACTH initiated at a low dose of 40 units/1.73 m² biweekly was ineffective. Three months later, the dose was increased to 80 units/1.73 m² biweekly and he achieved partial remission and renal function returned to baseline. Tacrolimus was added at 6 months for synergy with trough levels maintained between 3-5 ng/ml. He achieved partial remission, and avoided further hospitalizations. Conclusion: ACTH alone or in combination with calcineurin inhibitor (CNI) can be a viable alternative for children who are resistant to other therapies. Variability in renal phenotype has been implicated with the PLCE1 (Phospholipase C Epsilon 1) gene. In this case, we suspect the role of his heterozygous variant PLCE1 mutation, or likely a compound heterozygous state with another unidentified mutation or modifiers or environmental factors, plays a role in the progression to a refractory NS state.

High serum FSH is not a risk factor for low bone mineral density in infertile men.

Male infertility is associated with a higher long-term morbidity and mortality risk. However, it is not clear which diseases are contributing to this risk. Osteoporosis is a possible factor, as it is a frequent disease and sex steroids regulate both fertility and bone health. Furthermore, there are data indicating that high FSH levels in women are related to low bone mineral density (BMD), independent of estradiol levels. As infertile men often have increased FSH, already from a young age, this could be a risk factor for impaired bone health in later life. One hundred and thirty-seven men with a history of male factor infertility due to spermatogenic failure (SgF men) as well as a control group of 70 men from couples treated with IVF for female factor infertility (non-SgF men) were included in a long-term follow-up study. Men with explained infertility, including testosterone deficiency, were not included. Data from baseline fertility investigations were retrieved from the patient files of the SgF men. At follow-up hormonal and semen analysis were performed and axial, femoral and total body BMD was measured by dual X-ray absorptiometry in all men. Multiple linear regression was used to assess differences between SgF and non-SgF men and to study associations between FSH levels and BMD. Median follow-up time was 14.8years (5th-95th percentile 11.3-18.2) after fertility assessment for SgF men and 15.6years (12.1-18.5) for non-SgF men (p=0.033). When comparing the two groups, no significant differences in total T, free T or E2 levels were apparent at follow-up. As expected, LH and FSH were higher in SgF men ((median (5th-95th percentile)) for LH (IU/L): 4.3 (2.2-13.6) for SgF men and 3.0 (1.4-5.8) for non-SgF men (p<0.001); FSH (IU/L): 9.8 (2.8-35.5) versus 3.7 (1.6-8.7); p<0.001), and inhibin B and semen parameters were lower in SgF men. There were no differences in BMD between the two groups at follow-up. Furthermore, both groups had median Z-scores close to zero at all sites, indicating that BMD is not different when compared to age-matched healthy men. In SgF men, neither baseline FSH, nor FSH at follow-up, was associated with BMD at the different sites at follow-up. Men with spermatogenic failure are not at increased risk for impaired bone health when middle aged. Furthermore, infertile men with high FSH levels do not have lower BMD.

Efficacy of Levamisole in children with Frequent Relapsing and Steroid Dependent Nephrotic Syndrome at Tertiary Care Center-Karachi.

Objectives:To determine the effectiveness of levamisole in maintaining remission of proteinuria in children with frequent relapsing and steroid dependent nephrotic syndrome (FR/SDNS).Methods:This observational study on 81 children with FR /SDNS was carried out from June 2007 - June 2017 at The Kidney Center-Postgraduate Training Institute, Karachi-Pakistan. Levamisole (leva) along with low dose prednisolone on alternate day (AD) was used after induction of remission with daily oral prednisolone in children with FR/ SDNS for 6-36 months. Patients with steroid resistance were excluded. Data was analyzed using descriptive statistics.Results:Eighty-one patients with FR (66) or SD (15) received levamisole treatment. Mean age at diagnosis was 3.72 ±2.33 years. Levamisole was used on AD in 59.25% and daily in 40.74% of cases. Twenty-four could not complete six months and were excluded, 57 patients completed treatment duration of 15.68±9.93 months and 51 post-leva follow-up of 11.70±11.23 months. Mean leva-dose was 1.73±0.67 mg/kg/ patient. Mean cumulative prednisolone dose per patient before, on-leva and post-leva was 3389.81±2785.22, 2471.97±2024.98 and 661.37± 905.37 mg respectively. Mean relapse rate per year before leva, on -leva and post -leva was 3.30 ±0.50,0.98± 1.1and 0.79±1.27 respectively. Levamisole was effective in 90% of patients. During post-leva follow up, 76.4% patients, maintained remission, whereas 23.5% behaved as FR/SD and require further immunosuppressive therapy.Conclusions:Levamisole was effective in maintaining remission in 90% while on treatment, whereas it maintained remission after discontinuation in 76.4% cases. Levamisole may be used as first steroid sparing agent before other immunosuppressive therapies in children with FR/SDNS. Further studies are required for optimal duration and dosage schedule.

Significant Burden and Psychological Distress Among Caregivers of Children With Nephrotic Syndrome: A Cross-Sectional Study.

Background:Childhood nephrotic syndrome (NS) follows a chronic course in most children. However, little is known about the psychosocial burden of NS on the caregivers despite evidence that caregiver burden or impairment in their well-being may alter the outcome of chronic childhood illnesses.Objectives:To determine the frequency and predictors of significant caregiver burden and psychological distress among caregivers of children with NS.Design:A cross-sectional study.Setting:Two pediatric nephrology clinics in Lagos, Nigeria.Patients:We included primary caregivers of children with idiopathic NS for at least 6 months.Measurements:The primary outcomes were psychological distress and significant caregiver burden among caregivers.Methods:We interviewed caregivers using the 12-item General Health Questionnaire (GHQ-12) and the 6-item Zarit Burden Interview (ZBI-6). The GHQ-12 scores ≥ 3 and ZBI-6 scores ≥ 6 indicated psychological distress and significant caregiver burden, respectively.Results:The caregivers were mostly mothers (77.9%) and married (92.4%), whereas the children (n = 172) were mainly male (65.1%). Most of the children (n = 152; 88.4%) had steroid-sensitive NS including 24 (14%) children with frequent relapses or steroid dependence and 20 (11.6%) with steroid-resistant NS. Of the 172 caregivers, 53 (30.8%) and 30 (17.4%) reported psychological distress and significant burden, respectively. Caregivers of children in relapse had adjusted an odds ratio (aOR) with 95% confidence interval (CI) of 2.45 (1.05-5.67) and 3.30 (1.22-8.92) of psychological distress and significant caregiver burden, respectively. Furthermore, caregivers of male children and those who needed help paying for health care had an aOR of 4.61 (1.34-15.68) and 3.06 (1.06-8.87) of significant caregiver burden, respectively.Limitations:The study was limited by its cross-sectional design and the use of generic rather than disease-specific instruments.Conclusion:One in every 6 caregivers of children with idiopathic NS reported significant caregiver burden, and it was associated with psychological distress. Our findings underscore the need for psychosocial support for caregivers of children with NS, especially those with identifiable vulnerability.

Review on long‐term non‐renal complications of childhood nephrotic syndrome

Nephrotic syndrome (NS) is the most common glomerular childhood disease. A body of literature has described the long-term renal prognosis of childhood-onset idiopathic NS. However, the nonrenal outcomes have not been studied as much. We aimed to discuss the long-term non-renal outcomes of childhood NS, highlighting studies with a follow-up period of more than 10 years. We reviewed the literature and found that a number of immunosuppressive agents have stopped inflammation, stabilised the podocyte cytoskeleton and reduce proteinuria. However, prolonged treatment has frequently been associated with a high risk of renal and non-renal complications in patients with a complicated disease course, defined as frequent relapses or steroid dependency. Non-renal complications may include impaired longitudinal growth and pubertal development, undesirable fertility outcomes, ocular complications, bone mineral diseases and potential malignancies. This review discusses and summarises the non-renal outcomes of idiopathic childhood NS.

Bone mineral density and its influencing factors in children with idiopathic nephrotic syndrome: a prospective observational study

Glucocorticoids are first-line therapy for children with idiopathic nephrotic syndrome (INS). These children are at risk of deranged bone metabolism and low bone mineral density (BMD). We studied 60 children with INS and divided them into two groups. Group 1 included 21 children (initial and infrequent relapsing) and group 2 included 39 children (frequent relapsing, steroid dependent and steroid resistant). Dual-energy X-ray absorptiometry of the lumbar spine was performed to assess BMD. Mean BMD Z-score was compared in both groups; this correlated significantly on univariate analysis with cumulative steroid dose, serum vitamin D levels and calcium supplementation. However, on multivariate analysis, serum vitamin D level was the only factor significantly predictive of low z-score.

Prevention of relapses with levamisole as adjuvant therapy in children with a first episode of idiopathic nephrotic syndrome: study protocol for a double blind, randomised placebo-controlled trial (the LEARNS study)

IntroductionIdiopathic nephrotic syndrome (INS) is characterised by a high relapse rate up to 80% after initial response to standard therapy with corticosteroids. Steroid toxicity is common and causes a great...

Rituximab versus cyclophosphamide for the treatment of children with steroid resistance nephrotic syndrome; a clinical trial study

Introduction: The most common complications of the nephrotic syndrome (NS) are the frequent relapses, steroid resistance, and long-term steroid administration. Objectives: This study aimed to compare the therapeutic effect of rituximab versus cyclophosphamide in the prevention of relapses and the complications of treatment in children with steroid-resistant NS. Patients and Methods: This clinical trial study was performed on 50 patients with resistant steroidal NS referred to Masoumeh hospital in Qom, Iran. Patients were randomly divided into the two groups including intervention (n=20) and control groups (n=30). In addition to the prednisolone, the intervention group received 375 mg/m2/weekly rituximab intravenously for 4 weeks. The control group received oral doses of cyclophosphamide 2 mg/kg/d for 3 months. During treatment, the frequency of relapses, the mean dose of steroid and the complications of treatment were compared with a paired t-test, independent t-test, and chi-square test. Results: A significant decrease in the mean dose of steroids and the mean number of relapses were seen in patients after administration of rituximab and cyclophosphamide (P&lt;0.001). However, rituximab reduced the dose of steroid administration by 12.25 mg/d, while cyclophosphamide reduced only 2.83 mg/d (P&lt;0.001). Rituximab reduced the relapse rate two times on average, while cyclophosphamide reduced only 0.5 times (P&lt;0.001). The incidence of complications in the cyclophosphamide group was found to be more severe than the rituximab group. Conclusion: To compare rituximab versus cyclophosphamide regarding lower the frequency of recurrence after treatment, we found rituximab is a more suitable drug for the treatment of steroid-resistant NS than cyclophosphamide.

Immunosuppressive therapy in children with primary nephrotic syndrome: single center experience, Karachi, Pakistan

BackgroundMajority of children with nephrotic syndrome are steroid sensitive, but treatment of difficult to treat nephrotic (frequent relapsing, steroid dependent and steroid resistant) syndrome is challenging. Low dose steroid, levamisole, cyclophosphamide (CPM), mycophenolate mofetil (MMF) and calcineurin inhibitors (CNIs) are the common options of treatment.Objective of the study was to determine the response to steroid and alternative immunosuppressive agents (ISAs) in children with difficult nephrotic syndrome (DNS).MethodsThis is a retrospective cohort study of 176 children with DNS, managed over 12 years at The Kidney Center-Postgraduate Training Institute, Karachi- Pakistan from 2005 to 2017.Initial episode was treated with daily oral prednisolone (OP) for 4–8 weeks followed by alternate day OP for 12–24 weeks. Subsequently low dose OP, levamisole (Leva)and cyclophosphamide was used for frequent relapsing (FR)/ steroid dependent (SD). All with initial steroid resistance and non- responders to leva and or cyclophosphamide were biopsied and treated with CNIs and MMF. Data was analyzed using descriptive statistics.ResultsThere were 130(73.86%) children with FR/SD and 46(26.13%) with SRNS. All children with SR (46) and 86 with FR/SD were biopsied. Minimal change disease (60.60%) and focal segmental glomerulosclerosis (FSGS 23%) were the two common lesions. Majority (73.86%) received single OP whereas divided doses were administered in 26.13% cases. Daily OP was used for 4, 6 and 8 weeks in 61.36,28.4 and10.22% respectively. Steroids were tapered over 3 (31.81%),4 (52.27%) and 6 months (15.90%). Levamisole, CPM, cyclosporin (CS) and MMF were used sequentially in 45, 54.23, 50 and 20% respectively. Combination of MMF and CS was used in 11.29% of cases.Levamisole was effective in 80%, CPM induced complete remission (CR, 57.77%) or partial remission (PR, 22.22%), CS induced CR 46.59% and PR 39.77%. MMF showed PR and CR 69 and 12.82% respectively. At last follow up, 46% were maintaining remission while off treatment, whereas 35% are maintaining remission on therapy,10.23% lost- to-follow, 5.68% progressed to chronic kidney disease. Mortality was 2.84% and it was due to infection and uremia.ConclusionMajority had steroid sensitive MCD. Levamisole and cyclophosphamide were effective in maintaining remission in FR/ SD. FSGS was responsible for resistance to steroid and alternative ISAs. Cyclosporin was effective in inducing remission in SRNS. Mortality was less than 3%.

Levamisole in Children with Idiopathic Nephrotic Syndrome: Clinical Efficacy and Pathophysiological Aspects.

Steroid sensitive nephrotic syndrome is one of the most common pediatric glomerular diseases. Unfortunately, it follows a relapsing and remitting course in the majority of cases, with 50% of all cases relapsing once or even more often. Most children with idiopathic nephrotic syndrome respond initially to steroid therapy, nevertheless repeated courses for patients with relapses induce significant steroid toxicity. Patients with frequent relapses or steroid dependency thus require alternative treatment, such as cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, levamisole, or rituximab. To reduce the relapse rate, several drugs have been used. Among these, levamisole has been considered the least toxic and least expensive therapy. Several randomized controlled trials (RCT) showed that levamisole is effective in reducing the relapse risk in steroid sensitive forms of nephrotic syndrome with a low frequency of side effects. Levamisole is a synthetic imidazothiazole derivative with immune-modulatory properties. In this article, we review recent data from randomized trials and observational studies to assess the efficacy of levamisole in frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome.

Abstract #115 Adrenal Insufficiency Due to Frequent Steroid Injections

Abstract #115 Adrenal Insufficiency Due to Frequent Steroid Injections

Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome: an open-label randomized controlled trial

Both levamisole and mycophenolate mofetil (MMF) prevent relapses in patients with frequently relapsing nephrotic syndrome; however, their efficacy has not been compared prospectively. This single-center, randomized, open-label trial enrolled 149 children ages 6-18 years with frequently relapsing or steroid-dependent nephrotic syndrome. Participants were randomized in a 1:1 ratio to receive therapy with MMF (750-1000 mg/m2 daily) or levamisole (2-2.5 mg/kg on alternate days) for 1 year; prednisolone was discontinued by 2-3 months. In intention-to-treat analyses, the frequency of relapse was similar between participants treated with MMF and levamisole (mean difference -0.29 relapses/patient-year; 95% confidence interval -0.65, 0.08). Relapse rates declined to almost one-third of baseline for both treatment groups. Therapy with MMF was not superior to levamisole in terms of the proportions of participants with sustained remission (40.8% vs. 34.2%), frequent relapses (14.5% vs. 16.4%), or treatment failure, a composite outcome of frequent relapses, steroid resistance, or significant steroid toxicity (15.8% vs. 20.6%). These outcomes were also similar in time to event analyses. Changes in anthropometry and blood pressure were similar between the groups, and the rates of adverse effects were low in both groups. Flow cytometry in 32 participants demonstrated similar proportions of B cells and CD4+, CD8+, T helper (Th)1, Th2, Th17, and T regulatory (Treg) cells during follow-up. Therapy with MMF was not superior to levamisole in the frequency of relapses, likelihood of sustained remission or corticosteroid sparing in children with frequently relapsing or steroid-dependent nephrotic syndrome. Registration CTRI/2012/02/002394.