Childhood Steroid-sensitive Nephrotic Syndrome: Characteristics and Predictors of Relapses (A Study at a Single Center in Khartoum)

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.


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 subsequent 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, Mycophenolate 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 adulthood 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 characteristics, and predictors of relapse and outcome of SSNS in children at a Single center in Khartoum.

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/m 2 /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.
Treatment protocols and responses, complications, and outcome were also recorded.

Definitions
Definitions of remission, relapse, frequent relapse and steroid dependence were as per the International Study of Kidney Disease in Children (ISKDC) [17].Remission: proteinuria < 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/1.73m2for ≥ 3 months and CKD5 requiring renal replacement therapy (RRT) as GFR < 15 ml/min/1.73m 2 [19].Hypertension was defined as blood pressure above 95 ℎ percentile for age [20].Hematuria was defined as > 3 RBCs/HPF in urine sediment [21].

Data Analysis
Data were organized into a master sheet using the Statistical Package for Social Sciences (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 variables.For all statistical analysis, P-value less than 0.05 was considered as statistically significant.
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.

Histopathology lesion Number Percentage
Mesangial

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 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 experience 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] [29][30][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 followed infections; upper respiratory (45.7%),UTI (25.1%), and peritonitis (1%), and this association was statistically significant (P < 0.05).However, there was no statistically 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 relapsing 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.

T 1 :
Types of histopathology lesions in studied patients with SSNS underwent renal biopsy.
Risk factors for relapses in studied children with SSNS (frequent versus infrequent relapsing).
Types of treatment used in studied children with relapsing NS.Outcome of studied children with SSNS on last follow-up.