Sudan Journal of Medical Sciences Volume 13, Issue no. 3, DOI 10.18502/sjms.v13i3.2952 Production and Hosting by Knowledge E Research Article Childhood Steroid-sensitive Nephrotic Syndrome: Characteristics and Predictors of Relapses (A Study at a Single Center in Khartoum) Eltigani M. A. Ali, Nahla Mohamed Elhadi, Mohamed B Abdelraheem, and Rashid A Ellidir Pediatric Renal Unit, Soba University Hospital, Khartoum, Sudan Abstract Background: Childhood steroid-sensitive nephrotic syndrome (SSNS) usually has a favorable outcome in spite of its relapsing course. The objective of the authors was to study the demographic and clinical characteristics, outcome and risk factors for relapses in children with SSNS at a single center in Khartoum, Sudan. Material and Methods: In this cross-sectional, facility-based study, the authors retrospectively reviewed all the records of children with SSNS, followed at the Pediatric Renal Unit, Soba University Hospital, Khartoum between 2001 and 2014. SSRNS was defined as the remission of proteinuria within 4–6 weeks of corticosteroids. Relapse is the recurrence of proteinuria after remission; frequent if ≥ 2 within initial six months or ≥ 4 within one year, and steroid dependence if 2 during therapy or within 14 days after stopping it. Results: 330 children (males 220; 66.7%) with SSNS were studied with a mean age of 5.2 ± 3.5 years of whom 42.4% aged 1–5 years. At the presentation, hypertension was detected in 31.8% and hematuria in 19.1%. Serum cholesterol was elevated in all patients (mean 347.34 ± 117.87 mg/dl) and serum creatinine in 7.27% (mean 1.4 ± 0.35 mg/dl). Renal histology showed mesangioproliferative glomerulonephritis (MesPGN) in 57.5%, minimal change disease (MCD) in 35.5%, and focal segmental glomerulosclerosis (FSGS) and IgM nephropathy in 3.5% each. During the course of the illness, 10.3% achieved long-term remission, 89.7% relapsed— of whom 52.3% had frequent relapsing/steroid-dependent (FR/SD) course and 37.7% had infrequent relapses. Risk of frequent relapses were age of onset and low/moderate socioeconomic status (P = 0.015 and 0.019, respectively). Infections were recorded in 71.8%, but not significantly associated with the risk of frequent relapses (P > 0.05). Conclusions: The majority children with SSNS at this single center in Khartoum had a relapsing course with the majority being FR or SD. Predictors of frequent relapses were young age at onset and low socioeconomic status. Keywords: nephrotic syndrome, steroid sensitive, relapse, children, Sudan How to cite this article: Eltigani M. A. Ali, Nahla Mohamed Elhadi, Mohamed B Abdelraheem, and Rashid A Ellidir (2018) “Childhood Steroid- sensitive Nephrotic Syndrome: Characteristics and Predictors of Relapses (A Study at a Single Center in Khartoum),” Sudan Journal of Medical Sciences, vol. 13, issue no. 3, pages 133–143. DOI 10.18502/sjms.v13i3.2952 Page 133 Corresponding Author: Eltigani M. A. Ali; email: eltigani_ali@yahoo.com Received 20 July 2018 Accepted 10 September 2018 Published 24 September 2018 Production and Hosting by Knowledge E Eltigani M. A. Ali et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Editor-in-Chief: Prof. Mohammad A. M. Ibnouf http://www.knowledgee.com mailto:eltigani_ali@yahoo.com https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Sudan Journal of Medical Sciences Eltigani M. A. Ali et al 1. Introduction The majority of children with nephrotic syndrome (NS) are steroid responsive referred to as steroid-sensitive nephrotic syndrome (SSNS) [1]. More than 90% of these SSNS patients have minimal change pathology and therefore have favorable long-term renal outcome [1]. In Africa, children have a different pattern of NS with a paucity of minimal change disease (MCD), with the majority being steroid resistant with a higher risk of progression to CKD [2]. About 80–90% of SSNS children experience one or more subse- quent relapses that can be infrequent or frequent relapses (FR) or steroid dependence (SD) [3, 4]. The age of onset of the disease [5], time to respond to steroids [6], length of treatment [6, 7], infections [8, 9], rapid steroid tapering [10] were reported to be the predictors of the relapses and their frequency. Prolonged use of steroids increases the risk of steroid toxic effects and infections with subsequent high morbidity and mortality. Therefore, Alkylating agents, Levamisole, Calcineurin inhibitors, Mycophe- nolate mofetil and Rituximab have been used as steroid-sparing agents. Complications of SSNS, occurring with variable frequencies were infections [11] (bacterial or viral), thromboembolism [12] (arterial or venous), renal insufficiency [13], hypovolemia [13], and drugs-related side effects. There are limited data on the long-term outcome of SSNS, but multivariate analysis showed that renal function remains normal in adult- hood and that long-term sequels are generally related to side effects of medications [14]. The aim of this study was to identify the demographic and clinical characteris- tics, and predictors of relapse and outcome of SSNS in children at a Single center in Khartoum. 2. Material and Methods In this cross-sectional, facility-based study, the authors retrospectively reviewed the hospital records of all children (age > 1–18 years) with SSNS who had been followed-up in the pediatric nephrology unit, Soba University Hospital, Khartoum, between August 2001 and January 2012. The criteria for diagnosis of NS were serum albumin < 2.5 gm/dl) and urine albumin–creatinine ratio [UACR] ≥ 200 mg/mmol [15]. The inclusion criteria were: response to steroids (prednisolone 60 mg/m2/day) within 4–6 weeks [16], onset > 1 year, and follow-up ≥ 6 months. The exclusion criteria were: congenital or syndromic forms, family history of NS, NS with systemic disease and incomplete records. Data were abstracted from the records using standard data collection sheet. Demographic features, blood pressure, height and weight, and socioeconomic status DOI 10.18502/sjms.v13i3.2952 Page 134 Sudan Journal of Medical Sciences Eltigani M. A. Ali et al were recorded. Laboratory data—urinalysis and culture, UACR, blood urea, serum crea- tinine, electrolytes, albumin, cholesterol, and kidney biopsy histology—were recorded. Treatment protocols and responses, complications, and outcome were also recorded. 3. Definitions Definitions of remission, relapse, frequent relapse and steroid dependence were as per the International Study of Kidney Disease in Children (ISKDC) [17]. Remission: protein- uria < 4 mg/m2/hr or albumin negative or trace on urine dipsticks for three consecutive days. Sustained remission: no relapse for at least six months. Relapse: proteinuria > 40 mg/m2/hr or albumin 3+ on urine dipsticks for three consecutive days after having been in remission. Infrequent relapse: less than two relapses in six months of response or less than four in twelve months. Frequent relapse (FR): two or more relapses within six months of response or more than three in any twelve months. Steroid dependence (SD): two consecutive relapses while on alternate-day steroids or within 14 days of its discontinuation. Long-term remission: no relapse for at least three years. Estimated glomerular filtration rate (e GFR) was calculated using the Schwartz formula [18]. CKD was defined as GFR < 60 ml/min/1.73m2 for ≥ 3 months and CKD5 requiring renal replacement therapy (RRT) as GFR < 15 ml/min/1.73 m2 [19]. Hypertension was defined as blood pressure above 95𝑡ℎ percentile for age [20]. Hematuria was defined as > 3 RBCs/HPF in urine sediment [21]. 4. Treatment Protocols NS was treated with prednisolone 60 mg/m2/day divided doses for 4–6 weeks and then tapered to 40 mg/m2/day (single dose) on alternate days for 4–6 weeks [1]. In FR and SD NS, Cyclophosphamide (CPM), Levamisole, Cyclosporine (CSA), or Mycophe- nolate Mofetil (MMF) were used after induction of remission with prednisolone. Doses and treatment durations were as follows: CPM: 2.5 mg/kg/day for 8–12 weeks, oral CSA: 4–5 mg/kg/day in two divided doses for twelve months), MMF: 600 mg/m2 twice daily for 12 months and levamisole: 2 mg/kg/day for 12 months. Outcome measures were remission (sustained, long-term), relapses (infrequent, FR, SD), CKD. DOI 10.18502/sjms.v13i3.2952 Page 135 Sudan Journal of Medical Sciences Eltigani M. A. Ali et al 5. Data Analysis Data were organized into a master sheet using the Statistical Package for Social Sci- ences (SPSS), version 19. Data were presented using frequencies and percentages for categorical variables and means ± standard deviation (SD) for numerical continuous variables. Variables were compared using independent t-test for independent vari- ables. For all statistical analysis, P-value less than 0.05 was considered as statistically significant. 6. Results Out of 460 children admitted with idiopathic NS, 330 (71.7%) had steroid-sensitive NS (SSNS). Of them, 220 (66.7%) were males and 110 (33.3%) females, with a male to female ratio of 2:1. The mean age at presentation was 5.2 ± 3.5 (range 1.5–16) years. The age spectrum was variable with 42.4% of patients being in the age range of 1–5 years. The mean age of onset of the disease was 5.4 ± 3.57 years with 62.7% being in the age range of 1–5 years. Hypertension was detected in 105 patients (31.8%) and hematuria in 63 (19.1%). Serum cholesterol was elevated in all patients (100%) with mean serum levels of 347.34 ± 117.87 (range 224–687) mg/dl. Serum creatinine was elevated in 24 (7.3%) with a mean of 1.4 ± 0.35 (range 0.9–2) mg/dl, respectively. Serum albumin was less than 2 gm/dl in 264 patients (80%) with a mean level of 2.18 ± 0.68 (range 0.9–3.3 GM/dl). Renal biopsies were performed in 84 patients (25%), and indications were shift to CSA in 44 FR/SD cases (52.4%), macroscopic hematuria 11 (13.1%), late age at onset 8 (9.5%) and persistent elevated serum creatinine in 4 (4.7%). Types of histological lesions are shown in Table 1. Non-MCD lesions were the commonest types. During the follow-up period (mean 3.2 ± 2.6, range 1.5–13 years), 34 patients (10.3%) achieved long-term remission, 123 (37.3%) had FR/SD, and 173 (52.4%) had infrequent relapses. Predictors of frequent relapses are shown in Table 2. Age of onset less than five years and low socioeconomic status were significantly associated with the risk of FR/SD course (P = 0.015 and 0.019, respectively). Infections were recorded in 237 (71.8%) patients with SSNS and in 232 (78.4%) with relapsing NS; 49.3% respiratory, 28% UTI and 1.1% peritonitis. But infections were not significantly associated with frequency of relapses (P > 0.005). In about 87 (70.7%) patients with FR/SD nephrotic syndrome, steroid-sparing drugs were used, whereas in 36 (29.3%) small-dose alternate-day steroids were used. Types and frequency of use of these drugs are shown in Table 3. Non-infectious complications were recorded in 32 (9.7%) DOI 10.18502/sjms.v13i3.2952 Page 136 Sudan Journal of Medical Sciences Eltigani M. A. Ali et al patients with SSNS. Frequency and types of these complications are shown in Table 4. Lastly, follow-up visit after a mean follow-up period of 3.2 ± 2.6 years (range 1.5– 13 years), 235 patients with SSNS (71.2%) were in remission, 68 (20.6%) in relapse, 3 (0.9%) developed CKD, and 24 (7.3%) were lost to follow-up; Table 5. T 1: Types of histopathology lesions in studied patients with SSNS underwent renal biopsy. Histopathology lesion Number Percentage Mesangial-proliferative glomerulonephritis 48 57.5% Minimal Change Disease 30 35.5% Focal segmental glomerulosclerosis 3 3.5% IgM nephropathy 3 3.5% Total 84 100.0% T 2: Risk factors for relapses in studied children with SSNS (frequent versus infrequent relapsing). Risk factor FR/SD (n = 123) Infrequent relapsing (n = 173) P-value Gender Male 85 (69.1%) 115 (66.5%) Female 38 (30.9%) 58 (33.5%) 0.061 Age at onset < 5 years 104 (84.6%) 86 (52.5%) > 5 years 9 (15.4%) 58 (47.5%) 0.015* Time to initial response < 2 weeks 53 (43.1%) 71 (41%) > 2 weeks 70 (46.9%) 102 (59%) 0.091 Socioeconomic status Low 89 (64.2%) 78 (45.1%) High 5 (4.1%) 9 (5.2%) 0.019* Initial mean serum albumin 1.17 ± 0.72 1.2 ± 0.64 0.588 Infections Respiratory 70 (47.9%) 76 (52.1%) 0.281 UTI 40 (48.2%) 43 (51.8%) 0.211 * P-value is statistically significant. 7. Discussion In developed countries, over 80% of children with idiopathic NS are steroid-sensitive [1]. In this series, children with steroid-sensitive NS (SSNS) constituted 71.7% of all children with idiopathic NS who were followed in the center. In contrast, in developing DOI 10.18502/sjms.v13i3.2952 Page 137 Sudan Journal of Medical Sciences Eltigani M. A. Ali et al T 3: Types of treatment used in studied children with relapsing NS. Treatment Number Percentage Cyclophosphamide (CPM) 42 34.2% Alternate-day steroids 36 29.3% Cyclosporine A (CSA) 18 14.6% CPM followed by CSA 14 11.4% Mycophenolate Mofetil (MMF) 7 5.7% Levamisole 6 4.8% T 4: Frequency and types of complications in studied children with SSNS. Complication Number Percentage Cushingoid features 12 37.5% Hypertension 8 25.0% Glucosuria 5 15.6% Short stature 4 12.50% CKD 3 9.40% Total 32 100.00% T 5: Outcome of studied children with SSNS on last follow-up. Outcome Number Percentage Sustained remission 57 17.30% Non-sustained remission 178 53.90% Relapse 68 20.60% CKD 4 0.90% Lost to follow-up 24 7.30% Total 32 100.00% countries, especially in Africa, the majority tend to have steroid-resistant disease [2, 22], which could be related to the predominance of non-MGD lesions among these populations. In this study, males were predominantly affected, which is consistent with the finding reported by the ISKDC [23]. The mean age of presentation of children in this study was 5.2 years with 42.4% being in the age group 1–5 years. Hypertension, hematuria, and elevated serum creatinine were recorded at presentation in 31.8%, 19.1% and 7.3% of them, respectively. Similar finding was reported in other studies [24]. Earlier and recent studies showed that about 80–90% of SSNS children experi- ence one or more subsequent relapses that can be infrequent or frequent relapses or steroid-dependent [3, 4]. Among them, 35 to 50% relapse frequently [4, 26]. Our series showed similar finding, as only 10.3% achieved sustained remission in the first 12 months, whereas the majority (89.7%) experienced relapses; among them 37.3% had DOI 10.18502/sjms.v13i3.2952 Page 138 Sudan Journal of Medical Sciences Eltigani M. A. Ali et al frequent relapses. However, other studies reported lower rate of infrequent and fre- quent relapses; Om P. Mishra et al. reported that 59.3% had relapses (52% infrequent, 7.3% frequent, and 0.6% steroid-dependent) [25]. Noer reported 63.6% had relapsing NS, including 50.5% infrequent and 13.3% frequent relapses [26]. These variations in the frequency of relapses have been related to many factors. Younger age at the onset of the disease was reported to be correlated with the frequency of relapse, with more frequent relapses in children younger than 4 years [27, 28]. The authors found that children in the age group 1–5 years had significantly more relapses in comparison to other age groups (P = 0.015). About 50–70% of relapses in NS are precipitated by a viral upper respiratory tract infection [29–31]. This is likely due to non-specific host response to infection rather than to viral antigen or antibody response [30]. Therefore, other infections such as UTI, peritonitis, and skin infections have also been reported as triggers of relapses [29, 32]. We found that the majority (71.8%) of relapses fol- lowed infections; upper respiratory (45.7%), UTI (25.1%), and peritonitis (1%), and this association was statistically significant (P < 0.05). However, there was no statisti- cally significant difference between patients with frequent and those with infrequent relapses regarding the frequency of infections (P = 0.211). Low socioeconomic status was another risk factor for frequent relapses in this series (P = 0.019). This could be related to the fact that such children are vulnerable to infection and hence more likely to relapse. In this study, potential risk factors for relapse such as gender, time to initial response to steroids, and initial serum albumin, were not significantly associated with frequency of relapses (P = 0.061, 0.091 and 0.588, respectively) as reported in other studies. In conclusion, in a population of Sudanese children, SSNS is characterized by a relaps- ing course in the majority of patients. Predictors of relapse were young at onset and had low socioeconomic status. Although infections were documented in the majority of relapsing patients, they did predict the frequency of relapses. High rate of relapse and non-sustained remission on last follow-up despite the use of a wide spectrum of steroid-sparing drugs reflects the need for effective therapy to prevent morbidity and mortality. Conflict of Interests Authors declare no conflict of interests. DOI 10.18502/sjms.v13i3.2952 Page 139 Sudan Journal of Medical Sciences Eltigani M. A. Ali et al Ethical Clearance The authors declare that the research protocol has been approved by the Sudan Medi- cal Specialization Board Research Committee and Soba Hospital Research Committees, and that an informed consent was then obtained. They also declare that the results of this study have not been published before, except for the abstracts. Acknowledgements This work is a part of a thesis submitted for partial fulfillment of Clinical MD in Pedi- atrics, University of Khartoum (2014). The authors would like to thank the staff at the Pathology and Medical Records Departments, Soba University Hospital, for their cooperation and help during data collection. They are also grateful to the staff in Health Statistics Department, University of Khartoum, for their help with data analysis. Author Contributions The authors declare that they all had significant contributions to the study and that they all agree with the content of the study. 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