| Abstract|| |
Prevalence, clinicopathological features, and outcome of childhood idiopathic steroid-resistant nephrotic syndrome (ISRNS) vary in different countries. We report on these parameters in a single center in Khartoum. We retrospectively reviewed all the records of children with idiopathic nephrotic syndrome (INS) followed up in the pediatric renal unit, Soba Hospital, Khartoum between 2001 and 2012. ISRNS was defined as no remission within four weeks of daily prednisolone at a dose of 60 mg/m2. In 430 children with INS 130 (28%) had SRNS with a mean age of 7.7 ± 4.12 years. Males were 78 (60%). At presentation, hematuria was recorded in 57%, hypertension was recorded in 48%, and renal impairment in 15%. Histopathology showed focal segmental glomerulosclerosis in 40.8%, mesangioproliferative glomerulonephritis (22.3%), mesangiocapillary glomerulonephritis (16.9%), minimal change disease (MCD) (16.2%), and membranous glomerulonephritis (3.8%). Therapy included cyclosporine in 38.5%, additional therapy with cyclophosphamide, mycophenolate mofetil or tacrolimus in 20.8%, and steroids ± diuretics ± angiotensin converting enzyme (ACE) inhibitors in 40.7%. After 3.64 ± 2.84 years, 26.8% had complete remission (CR), 18.6% partial remission (PR), 26.8% were unremitting, 21.5% had chronic kidney disease (CKD), 1.6% died, and 4.6% were lost to follow-up. Non-MCD cases had significantly lower CR and higher CKD rates than MCD (P = 0.047 and 0.041, respectively). Cyclosporine ± additional therapy was significantly associated with higher rate of CR than steroids ± ACE inhibitors ± diuretics (P = 0.001), but the prevalence of CKD between the two groups was not significantly different (P = 0.604). Impaired renal function and hypertension at presentation were risk factors for CKD (P = 0.001 and 0.001, respectively). In Sudanese children with ISRNS, non-MCD lesions were the most common lesions. This pattern in addition to the lack of adequate therapy may explain the relatively lower CR and higher CKD rates. Impaired renal function and hypertension at presentation were risk factors for progression to CKD.
|How to cite this article:|
Ali ETM, Makki HF, Abdelraheem MB, Makke SO, Allidir RA. Childhood idiopathic steroid-resistant nephrotic syndrome at a Single Center in Khartoum. Saudi J Kidney Dis Transpl 2017;28:851-9
|How to cite this URL:|
Ali ETM, Makki HF, Abdelraheem MB, Makke SO, Allidir RA. Childhood idiopathic steroid-resistant nephrotic syndrome at a Single Center in Khartoum. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2020 Aug 7];28:851-9. Available from: http://www.sjkdt.org/text.asp?2017/28/4/851/211348
| Introduction|| |
Although most children with the idiopathic nephrotic syndrome (INS) are steroid responsive, 20% are classified as steroid-resistant. The prevalence of idiopathic steroid-resistant nephrotic syndrome (ISRNS) varies in different parts of the world. The prevalence was estimated to be 10–20% and tends to be higher in African Americans.,,, ISRNS has many underlying pathologies such as focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) with FSGS being the most common type.,,, Treatment of the ISRNS remains a therapeutic challenge with considerable variation in management plans and outcomes. Progression to chronic kidney disease (CKD) is inevitable in nonresponders with a high risk of up to 50%. ISRNS accounts for less than 10% of children who progressed to CKD5 requiring renal replacement therapy (RRT), but the rates of progression are variable in different populations. Renal impairment at presentation and failure to respond to treatment are predictors of poor outcome and progression to CKD. Studying clinicopathologic characteristics and treatment outcomes of ISRNS can be helpful in determining the etiology, outcome, and predictors for prognosis. Published data about ISRNS in children in Sudan are scanty. The aim of this study was to define these parameters in children with ISRNS who have been managed in a single pediatric renal center in Khartoum which is the biggest and main tertiary center in the country and receives cases from all parts of Sudan.
| Materials and Methods|| |
We retrospectively reviewed all the records of children (age >1–18 years) with INS who had been followed up in the pediatric nephrology unit, Soba Hospital, Khartoum between August 2001 and January 2012.
Criteria for diagnosis of nephrotic syndrome (NS) were edema, hypoalbuminemia (albumin <2.5 g/dL) and nephrotic range proteinuria [urinary albumin-creatinine ratio (UACR) ≥200 mg/mmol12 or dipstick proteinuria >300 mg/dL].
Inclusion criteria were resistance to steroids (prednisolone at a dose of 60 mg/m2 daily for 4–6 weeks), onset >1 year, and follow-up ≥6 months. Exclusion criteria were; congenital or syndromic forms, family history of NS, and NS with systemic disease. Data were abstracted from the records using standard data collection sheet. Demographic features, blood pressure, height, and weight were recorded. Laboratory data including urine tests (urinalysis, cultures, and UACR), blood tests (urea, creatinine, albumin, and electrolytes), serology (C3 and C4, antinuclear antibody, anti-double-stranded DNA, hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus), and kidney histology were retrieved. Treatment protocols and responses, complications, and outcome were recorded. Complete remission (CR) was defined as proteinuria negative or trace (<30 mg/dL) on dipsticks for three consecutive days and partial remission (PR) as the persistence of urine dipstick proteinuria of 30–100 mg/dL with normalization of serum albumin. Sustained remission is considered if no relapse for at least six months. Steroid resistance (SR) is considered primary if no response to initial steroid course, or secondary if NS became steroid-resistant after the initial response. Renal impairment was defined as serum creatinine above the upper limit of normal for age. Estimated glomerular filtration rate (e GFR) was calculated from the Schwartz formula. CKD was defined as GFR <60 mL/min/ 1.73 m2 for ≥3 months and CKD5 requiring RRT as GFR <15 mL/min/1.73 m2., Hypertension was defined as blood pressure above 95th percentile for age. Hematuria was defined as >3 red blood cells/high power field in urine sediment., Oral Cyclosporine (CSA); 4–5 mg/kg/day with a trough level of 100–150 ng/mL was used as 2n line and titrated to achieve CR or PR. Prednisolone was added, tapered, and continued with alternate day dose of 10 mg/m2. Oral cyclophosphamide (CPD); 2–3 mg/kg/day for 8–12 weeks, tacrolimus (TAC); 0.15 mg/kg/day with trough level of 5–9 ng/mL and mycophenolate mofetil (MMF);600 mg/m2 twice daily were used mainly as 3rd line therapy in CSA-resistance. When 2nd and 3rd line drugs are not available, prednisolone was used (40 mg/m2 alternate days, tapered to 10 mg/m2 alternate days for 1–2 years). If no remission, Lisinopril (2.5–5 mg/day) and oral diuretics were added. Patients were followed in the outpatient clinic for every one to three months depending on their response. The follow-up included BP, weight and height assessment, dipstick for proteinuria and drug monitoring. Serum creatinine and GFR were estimated at baseline and thereafter checked according to the changes of serum creatinine levels. Outcome measures were CR, PR, unremitting disease, progression to CKD, and death. Informed consent was obtained from Soba Hospital Research Committee and Hospital Director.
| Statistical Analysis|| |
Data entry and analysis was performed using a Statistical package for social sciences (SPSS) version 18.0 (SPSS Inc., Chicago, IL, USA). Descriptive statistics such as means ± standard deviation (SD) were used for variables such as age and clinical and laboratory features. Percentages were used for categorical data. Variables were compared using Student’s t-test. Chi-square test was used to examine the association between risk factors at presentation and adverse outcomes on follow-up. The value of P <0.05 was considered statistically significant. Kaplan–Meier survival analysis was used for evaluating renal survival.
| Results|| |
Out of 430 children admitted with INS, 130 (28%) had ISRNS. Males were 78; 6% and females 21.4%. The mean age at diagnosis was 7.72 ± 4.12 (range 2.2–16.8) years. The age spectrum was variable with 46.9% being between 5 and 10 years [Table 1]. At presentation, hematuria was detected in 57%, hypertension in 48%, and impaired renal function (mean serum creatinine ± SD, 1.44 ± 0.35, range 0.9–2.0 mg/dL) in 15%. The mean serum albumin ± SD was 1.99 ± 0.48 (range 1.2–3) g/dL. SR was primary in 59% and secondary in 41% but with no statistically significant difference between them regarding age or gender (P = 0.25 and 0.30, respectively). Biopsy findings are shown in [Table 2]; FSGS was the most common lesion (40.8%) followed by mesangioproliferative glomerulonephritis (MesPGN) (22.3%), MPGN (16.9%), MCD (16.2 %), and membranous glomerulonephritis (MGN) in (3.8%). Non-MCD lesions were significantly more common in age ≥5 than <5 years (P = 0.043). Treatments regimens used are shown in [Table 3].
|Table 1: Age distribution of children with ISRNS in the study (n = 130).|
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|Table 2: Histological types of ISRNS in children in the study (n = 130).|
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|Table 3: Drug treatment regimens used in children with ISRNS in the study (n = 130).|
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During the study period, 38.5% received CSA (2nd line therapy), 20.8% had additional (3rd line therapy) with CPD, MMF, or TAC, and 40.7% received steroids ± diuretics ± ACE inhibitors, [Table 3]. Complications were recorded in 26%; 13% were infections-related and 13% drug-related. Infections were respiratory (6.1%), urinary tract infections (5.4%) and peritonitis (1.5%). Drug-related complications were cushioned appearance (9.2%), short stature (1.5%), and hirsutism and gingival hypertrophy (2.3%). After a mean follow-up period of 3.4 ± 2.8 (range 0.9–12) years, 26.8% achieved CR, 18.6% PR, 26.8% were unremitting, 21.5% progressed to CKD, 1.6% died, and 4.7% were lost to follow-up [Table 4]. Non-MCD was associated with the statistically significant lower rate of CR and higher prevalence of CKD than MCD (P = 0.047 and 0.041 respectively). Patients who received 2nd ± 3rd line therapy had statistically significant higher rate of CR than those who received steroids ± angiotensin converting enzyme inhibitors (ACEI) ± diuretics (P = 0.001). However, the prevalence of CKD was not statistically different between the two treatment groups (P = 0.604). Risk factors for CKD were hypertension and renal impairment at presentation (P = 0.00, relative risk (RR) 6.19; 95% Confidence interval (CI); 2.40–15.90 and P = 0.01, RR 7.10; 95% CI; 2.50–20.12 respectively). Twenty-two (16.9%) reached CKD5 requiring RRT and the mean time to reach CKD5 requiring RRT was 4.45 ± 2.95 years. Using Kaplan–Meier method, renal survival was 65% and 36% at 5 and 10 years respectively, [Figure 1]. Renal survival at 5 and 10 years was not significantly different between patients treated with 2nd and 3rd line therapy and those with steroids ± ACEI ± diuretics [Figure 2].
|Table 4: Treatment outcomes of ISRNS in children in the study (n = 130).|
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|Figure 1: Renal survival rates at 5 and 10 years in children with idiopathic steroid-resistant nephrotic in the study.|
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|Figure 2: Renal survival rates at 5 and 10 years in children with idiopathic steroid-resistant nephrotic syndrome in the study (2nd ± 3rd line therapy versus steroids ± angiotesin converting enzyme inhibitors ± diuretics).|
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| Discussion|| |
ISRNS has many underlying pathologies, poor renal outcome, and yet has no optimal treatment. We report on our experience in the management of ISRNS in a single center in Khartoum, Sudan over ten years from multiethnic population. In this study, the prevalence of ISRNS (28%) is higher than in Caucasians (20%),, but lower than in USA and some African countries (39%, 54.8%, and 34% res-pectively).,, Prevalence of SRNS has been related to prevalence of non-MCD pathology.,, However, this does not explain our results. This is because we had a higher prevalence of non-MCD compared to other countries (83.8% versus 74%, 86.5% and 95.7%, respectively),, but in contrast, we had a lower prevalence of ISRNS than in these countries (28% versus 39%, 353%, 54.8% respectively). Therefore this variation in prevalence of ISRNS may be also related to genetic factors rather than pathology alone. Discovery of specific genes mutations causing SRNS have provided basic insights into the mechanism of the disease. Some studies concluded that recent gene mutations discoveries would have strong impact on practice, diagnostics, understanding of pathogenesis, and treatment of the disease.,
The mean age of presentation (7.7 years) of our children was comparable to other studies.,, However, Saudi study reported younger age. This age variation may be related to pathology as MCD patients tend to be younger than those with non-MCD.,, This finding is consistent with our results as 81/91 (89%) of our patients with non-MCD were aged ≥5 years. Male predominance in this study was similar to other studies.,
We reported primary SR in 59% of cases. which is comparable to reports from USA (47%), Europe (58%)., In contrast, International Study of Kidney Disease in Children study reported 14%. This variation could be related to the duration of initial steroid therapy.
In this study, hematuria, hypertension, and renal impairment were common presenting features of ISRNS as shown in other studies. ,,,,.
Recent studies have shown an increasing prevalence of FSGS with variable rates (30-65%),,,,,,,, which are consistent with our finding (40.8%). The relatively higher prevalence of MesPGN (22.3%) and MPGN (16.9%) in this study are probably related to the high rate of infection-related GN. Data from several tropical and subtropical countries have shown comparable results. ,,,, Focal MesPGN was suggested to be an early marker of FSGS. Therefore, our prevalence of FSGS might have been higher than we reported if we reconsider this fact. MGN in our patients accounted for only 4% of lesions. Other studies have shown similar findings.,,,
Western data did not include these immune complex glomerular diseases. In this study, IgA histology was not seen as a cause of SRNS as in some studies. This may be due to lack of diagnostic facilities.
The treatment outcome of ISRNS varied with the pattern of histopathology and drug regimens used. CSA is effective but the high rate of relapse, nephrotoxicity, and dependence were limiting factors.,, Variable rates of remissions (14.8%–80%) have been reported in many studies.,,,,,,,, In this study, we report a relatively lower rate of remission [CR (26.8%) and PR (18.6%)]. This could be due to the predominance of non-MCD or lack of effective drug therapy (e.g., CSA, TAC, or MMF) in about two-thirds of our patients. However, our CR is comparable to studies using pulse CPD (Nigeria; 33.3% and India; 29.2%) or IV dexamethazone with methyl prednisolone (India; 35%).,, In contrast, other studies using mainly CSA, reported higher CR (45%–82%).,,,,
Nonresponders usually progress to CKD or CKD5 requiring RRT with a risk of as high as 50%. Most of our patients who progressed to CKD (78.6%; 22/28 cases) had aggressive non-MCD lesions. Lack of effective drug therapy may be another risk factor for CKD since most of our patients with CKD (64%; 18/28) had no access to 2nd ± 3rd line therapy. However, our results showed no statistically significant difference in prevalence of CKD between patients receiving 2nd ± 3rd therapy and those receiving steroids ± ACEI line despite the significantly higher CR in the first group. In this study, 16.9% reached CKD5 requiring RRT. This figure is much higher than that in USA (3.5%), KSA (10%), and Egypt (9%),, but lower than in Tunisia (50%), and Iran (26%)., This variation may be related to availability of adequate management facilities. The mean time to reach CKD5 requiring RRT is comparable to that in some developing countries (4.45 ± 2.95 versus 4.9 ± 3.7 years). Predicted renal survival rates were 85%, and 36% at 5 and 10 years respectively. These rates are lower than reports in Europe and other Asian counties, but higher than in Nigeria., In this study, hypertension and renal impairment at presentations were significantly associated with risk of progresssion to CKD (P = 0.003 and 0.001, respectively).
In conclusion, in a population of Sudanese children with ISRNS, common presenting features were later age, hypertension and hematuria and later age at presentation. Non-MCD, mainly FSGS were the most common lesions. The lower rate of CR and higher prevalence of CKD may be due to the predominance of Non-MCD lesions and/or lack of effective therapy. However, due to the relatively short period of follow-up, we could not conclude on the role of such therapy in prevention of CKD. Hypertension and renal impairment at presentation were risk factors for CKD.
Oral CSA, oral IV CPD, MMF, and TAC are now provided for free in Sudan for patients with SRNS. This would hopefully improve remission rates and reduce the risk of CKD. The ongoing program of transplantation that we have recently started would hopefully offer hope of survival to those with advanced CKD.
| Disclosure|| |
The authors declare that the research protocol has been approved by Soba Hospital Research Committee and an informed consent was then obtained. They also declare that the results of this study have not been published before except as abstracts.
Conflict of interest: None declared.
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El-Tigani M. A Ali
Department of Pediatrics and Child Health, Soba University Teaching Hospital, Khartoum
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]