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ORIGINAL ARTICLE
Year : 2019  |  Volume : 22  |  Issue : 6  |  Page : 790-795

Steroid response in primary childhood nephrotic syndrome in a tropical african environment


1 Department of Paediatrics, Paediatric Nephrology Unit, Ibadan, Oyo State, Nigeria
2 Department of Paediatrics, Paediatric Cardiology Unit, College of Medicine, University of Ibadan/University College Hospital, Ibadan, Oyo State, Nigeria

Date of Acceptance13-Feb-2019
Date of Web Publication12-Jun-2019

Correspondence Address:
Dr. A O Asinobi
Department of Paediatrics, Paediatric Nephrology Unit, College of Medicine, University of Ibadan/ University College Hospital, Ibadan, Oyo State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_206_16

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   Abstract 


Background: Earlier studies on childhood nephrotic syndrome (NS) in tropical Africa showed steroid resistance in the majority. More recent studies show a variable picture, necessitating a re-evaluation. This study was aimed at determining the current pattern of steroid response in childhood NS, in an environment known to be dominated by steroid resistance. Patients and Methods: This prospective study of consecutive children who received steroid therapy for primary NS was carried out at the University College Hospital, Ibadan, Nigeria between 2006 and 2013. The outcomes of interest were steroid sensitivity and death. The recruited patients received a 4-6 weeks' course of prednisolone at 60 mg/m2/day followed by alternate day doses of 40 mg/m2 up to total steroid therapy duration of 6 months in steroid sensitive patients. Statistical analysis was carried out using STATA version 12.0. P value <0.05 was considered significant. Results: Of 109 children that received steroids for at least 8 weeks, whose mean (SD) age was 7.9 (3.7) years, 69 (63.3%) were steroid sensitive. Those aged ≥6 years responded as well as those aged <6 years (P = 0.78). Boys were more likely to be steroid-sensitive than girls, 65.2% versus 34.8% (P = 0.039). There was zero mortality among the patients studied. Conclusion: This study has shown a better steroid sensitivity of 63.3% in children with primary NS compared with the previously reported 36.8-42.9% in patients with highly selective proteinuria. This improved steroid response and zero mortality show a remarkable departure from the past.

Keywords: Childhood, Ibadan Nigeria, negroid children, nephrotic syndrome, steroid sensitivity, steroid therapy, tropical environment


How to cite this article:
Asinobi A O, Ademola A D, Ogunkunle O O. Steroid response in primary childhood nephrotic syndrome in a tropical african environment. Niger J Clin Pract 2019;22:790-5

How to cite this URL:
Asinobi A O, Ademola A D, Ogunkunle O O. Steroid response in primary childhood nephrotic syndrome in a tropical african environment. Niger J Clin Pract [serial online] 2019 [cited 2019 Sep 17];22:790-5. Available from: http://www.njcponline.com/text.asp?2019/22/6/790/260030




   Introduction Top


The nephrotic syndrome (NS) is a common chronic childhood illness worldwide with a reported incidence of two to seven cases per 100,000 children and a prevalence of nearly 16 cases per 100,000.[1],[2] NS is currently the most common chronic childhood glomerular disorder seen in Nigeria.[3],[4],[5],[6],[7],[8],[9] Glucocorticoids have remained the mainstay of its treatment since their introduction in the 1950s,[10],[11] and steroid responsiveness is regarded as its most important prognostic indicator.[1]

Earlier studies on childhood NS at Ibadan[12],[13],[14],[15] and Kaduna[16],[17] both in Nigeria and other parts of tropical Africa[18],[19] showed predominance of steroid resistance, in contrast to their Caucasian counterparts.[20],[21] Earlier studies also from Ibadan[15] and South Africa[22],[23],[24] documented numerous adverse effects in children treated with steroids, resulting in the limitation of their use. It was therefore recommended then that steroids should be avoided in all African children with the disease.[23]

Presently in Nigeria, and in Africa generally, the pattern of steroid sensitivity appears to differ from place to place and vary with time,[12],[13],[14],[25],[26],[27],[28],[29],[30] necessitating a re-evaluation of the current pattern.

A patient's age at initial presentation has been noted to have an important impact on the disease distribution frequency in NS with focal segmental glomerulosclerosis (FSGS), usually associated with increased steroid resistance, developing at a median age of 6 years.[20],[21] Since the previous study on steroid responsiveness at our centre[25] was focused on NS children aged 5 years and below, the present study is targeted at both the young and older children. Aim: To determine the present pattern of steroid response in children with primary NS, especially in those aged 6 years and above, in an environment known to be dominated by steroid resistance.


   Patients and Methods Top


Study location

The study was performed at the Pediatric Nephrology Unit of the University College Hospital (UCH) Ibadan, a tertiary hospital in Southwest Nigeria, between January 2006 and December 2013. The children were initially admitted to the ward and later followed up in the children's outpatient department.

Study design

A prospective design was employed with recruitment of consecutive children presenting with primary NS who had no contraindications to steroid therapy. The outcomes of interest were steroid-sensitivity and death.

Ethical statement

Ethical approval for the study was obtained from the University of Ibadan/University College Hospital, Ibadan Joint Ethical Committee (UI/EC/15/0015).

Informed Consent Statement

The study was based on the unit's standard protocol for the treatment of NS and no additional written consent was obtained. Patients' individual data were made anonymous.

Inclusion Criteria

All consecutive primary NS patients aged 1-15 years presenting in our unit (in keeping with our hospital's cut-off age for first admission) who had no contraindications to steroid therapy were recruited into the study. Clinical and laboratory data that led to the establishment of the diagnosis of the NS in the studied patients were a combination of: 1. massive proteinuria (proteinuria of 3+ and above on dipstick urinalysis with a 24-hour urinary protein of >40 mg/m2/hour or spot urine protein/creatinine ratio >2.0); 2. hypoalbuminemia (serum albumin of <2.5 g/dl), and 3. oedema.[31] All the patients studied had both qualitative and quantitative assessment of proteinuria to enable determination of partial response.

Exclusion criteria were the following:

1. Patients with NS aged below 1 year who were most likely to have genetic mutations or the NS being a component of a syndrome and unlikely to be steroid sensitive,[32] 2. those with secondary NS, 3. overwhelming infections, 4. hypertensive crises, and 5. stage 4-5 chronic kidney disease (CKD). The usual causes of secondary NS in children were ruled out through clinical and laboratory evaluations.[1]

Patients' demography, clinical presentation, and laboratory diagnostic tests and results were recorded. Investigations routinely carried out on the patients and repeated as necessary were: dipstick urinalysis; urine microscopy, culture and sensitivity; 24-hour urinary protein estimation; spot urine protein; creatinine ratio estimation; creatinine clearance; lipid profile; serum electrolytes; blood urea and serum creatinine; full blood count; hemoglobin electrophoresis and blood film examination for malaria parasites especially for Plasmodium malariae (P. malariae). All children were also screened for Hepatitis B and C, HIV, anti-streptolysin O (ASO) titre, microscopy for ova of Schistosoma mansoni and haematobium in stool and urine, respectively, and they also underwent abdominal ultrasonography.

The recruited patients were initially placed on a 4-6 weeks' course of prednisolone at 60 mg/m2/day in divided doses (changed to single daily dosing in the latter part of the study), followed by alternate day doses of 40 mg/m2 up to total steroid therapy duration of 6 months, with tapering of dose in those that were steroid sensitive.[33] For children who were steroid resistant after 8 weeks of steroid treatment, renal biopsy was usually performed and other affordable immunosuppressive medications added.

To enable early detection of side effects and ensure early intervention, all the patients were admitted and strictly monitored for hypertension, infections, and other side effects for a minimum of 2 weeks and a maximum of 4 weeks on the average, depending on when they went into remission and the ability of individual parents to monitor their child effectively. Patients who were steroid resistant at 4 weeks were discharged after establishing prednisolone at 40 mg/m2 on alternate days. Before discharge, all caregivers were taught how to carry out and keep records of urinalysis and were instructed to report promptly if any adverse events were observed.

Steroid side effects were looked out for and angiotensin converting enzyme inhibitors (ACEI) were added when the children were noted to be hypertensive. Definitions of Terms:[33],[34]

Remission

Urine protein dipstick result of trace or negative for 3 consecutive days after commencement of prednisolone.

Steroid-Sensitive Nephrotic Syndrome (SSNS)

Remission was achieved in response to corticosteroid treatment.

Partial Remission

Reduction of proteinuria by ≥50% without complete remission within 8 weeks of steroid therapy.

Steroid-resistant nephrotic syndrome (SRNS)

Failure to achieve remission after 8 weeks of prednisolone therapy, i.e., after daily 60 mg/m2/day and alternate day treatment at 40 mg/m2.

Hypertension (HTN)

Blood pressure measurements > the 95th percentile for age, gender, and height.[35]

Data analysis

Statistical analysis was carried out using STATA version 12.0. Simple descriptive statistics such as mean ± SD were used for continuous variables. Percentages were used for categorical data. The results were analyzed for their statistical significance using Mann--Whitney U and Kruskal--Wallis test for continuous variables; Chi-square test was used for discrete variables. P value <0.05 was considered significant.


   Results Top


One hundred and nine children received steroids for at least 8 weeks out of whom 69 (63.3%) achieved complete remission, 7 (6.4%) had partial remission, whereas 33 (30.3%) showed no remission. [Table 1] shows that overall 69 (63.3%) were steroid sensitive, whereas 40 (36.7%) were steroid resistant and the age distribution is also shown in [Table 1]. Ninety percent of the SSNS responded within the first 4 weeks of steroid therapy.
Table 1: Comparison of children with steroid-sensitive and steroid-resistant idiopathic NS

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Boys were more likely to be steroid-sensitive than girls, 65.2% versus 34.8% (P = 0.039). Other factors associated with steroid sensitivity are shown in [Table 1]. Age stratification in the present study, as shown in the [Figure 1], illustrates that older children did as well as those less than 6 years.
Figure 1: Response to steroid treatment in relation to age

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Even though the median duration of illness before presentation was longer in the steroid-resistant group, the difference did not reach statistical significance.

None of the patients studied had P. malariae infection and if any P. falciparum infection was developed, it was promptly treated.

Four (3.7%) patients showed neuropsychiatric side effects of steroid use. Other notable side effects encountered (most of which resolved with steroid dose reduction) were cushingoid facies, hypertension, tinea capitis infection, thrombocytosis, glycosuria, and hypocalcemic tetany. The frequencies of occurrence of the side effects were not accurately documented but tinea capitis and cushingoid facies were the most prevalent with prolonged therapy.

Hypertension and infections were treated appropriately with antihypertensives and parenteral antibiotics. ACE-inhibitors (lisinopril or enalapril, whichever was available) were the first-line antihypertensives. There was zero mortality among the patients studied.


   Discussion Top


This study has shown better steroid sensitivity of 63.3% in primary NS patients managed at Ibadan compared with the previously reported overall response of 23.8% and later 36.8-42.9% in patients with highly selective proteinuria from same Centre in the 1970s.[12],[13],[14],[15] In addition, 6.4% of the treated patients had partial response, implying that the prognosis is expected to be good in about 69.7% of these children (with those that had partial remission inclusive). There seems to be no clear cut explanations for this improved steroid responsiveness but it may be postulated that there may have been a change in the etiology of NS. In addition, the institution of therapy was more prompt and the earlier studies probably involved treatment of both primary and secondary cases of NS, whereas the present study involved primary cases only.

With regards to a possible etiologic change, we have reported a changing trend in the histopathology of childhood NS in our centre,[36] which may point to a different etiology in recent times. In addition, the improved result may be partly attributable to the absence of P. malariae parasitemia in these patients. Adeniyi et al.[15] had previously highlighted the adverse effect of persistent P. malariae parasitaemia in patients who did not respond to treatment. Nondetection of P. malariae in our patients in present times may probably be because of easy access to antimalarials from pharmacy shops and street drug peddlers in our environment.

The fact that these patients were treated promptly irrespective of age, without waiting for a prior renal biopsy (which usually causes some delay in our practice due to its cost implications), might have contributed to the good outcome. A delay, with persistence of proteinuria, has the potential to cause more glomerular damage.

The present results compare favorably with the 60% sensitivity previously observed in nephrotic children aged 5 years and below in our centre.[27] Nevertheless, the result, though gratifying, falls far below the complete remission rates obtained in patients managed in Port Harcourt (80%)[26] and Lagos (82%)[29] (both in Nigeria) and the pattern seen among Caucasian children (averagely 80%).[21],[37] Genetic and geographic differences may account for the dissimilarity between tropical and temperate climates but the intracountry variation in Nigeria seems difficult to explain. Nigeria is the most populous country in Africa and is multitribal/ethnic and there is a possibility that the marked variation in steroid responsiveness may be partly genetic in origin and partly environmental. Predominant steroid resistance had been reported previously from the following centres in Nigeria: Ibadan and Ife both in Southwest Nigeria inhabited majorly by the Yorubas;[12],[13],[14],[15],[16],[17],[18],[38] ABUTH Zaria, Northern Nigeria predominantly Hausas and Fulanis.[17] From Enugu, South-eastern Nigeria where the population is predominantly Igbo, 30% sensitivity was reported with steroids but responses increased to 60% with the addition of cyclophosphamide.[28] In 2002, Ibadin et al.[27] working in Benin, South Nigeria reported 52% sensitivity, which was much better than many earlier reports from Nigeria but the patients were majorly Edos and Urhobos, minority tribes. Port Harcourt and Lagos children stand out in their results but their inhabitants are multiethnic and wealthier.[26],[29] It is plausible that the increased prevalence of APOL1 gene mutation documented among the Yorubas and Igbos with CKD may be a predisposing factor[39],[40] (among other genetic factors) to increased steroid resistance and progression to CKD in our children.

The results of this study are also similar to reports from Ghana where between 50 and 56% of their patients have been reported to be steroid sensitive.[30],[41] The reports on the prevalence of MCD and steroid responsiveness have varied widely in Africa and seems to be affected by the geographic location, race, environmental factors, and times. The whites in North Africa and South Africa have reports almost similar in steroid responsiveness to those from the Western world.[24],[42],[43] Earlier reports from East Africa showed predominant steroid resistance but there is a paucity of newer reports from that zone as regards this subject presently.[30] In West Africa and in Nigeria in particular, the picture is not uniform even though the patients are predominantly Negroid. Overall however, steroid sensitivity is far less than reported for Caucasians. In multiracial countries such as South Africa, the United States of America, and Great Britain, the increased prevalence of steroid-resistant NS in blacks compared with whites brings to the fore again the issue of genetic predisposition.[21],[24],[37],[44],[45]

Kim et al.[21] identified age at onset, hypertension, and decreased kidney function as predictors of initial steroid resistance. Older age at the time of initial presentation was associated with a higher risk of steroid resistance. The mean age of our patients at presentation in the present study was higher than the cohort included in the ISKDC study,[34] and the patients managed in Port Harcourt[26] and Lagos.[29] Many workers have shown that the probability of having FSGS or MPGN as the underlying cause of NS increases with increasing age, whereas the risk of having MCNS is inversely related to the age at presentation with NS.[21],[45],[46],[47] Older age should therefore be expected to be an important factor in the higher incidence of SRNS but surprisingly, age stratification in the present study showed that older children did as well as those below 6 years of age. Age has therefore not proven to be the only factor to consider in determining steroid responsiveness presently in our setting. Our observation that boys responded better than girls with NS is in keeping with reports from the United Kingdom and Egypt.[48],[49] The reason for this gender difference is not clear.

The management of NS with steroid in our centre in the 1960s and 70s[13],[14] showed a lot of adverse and life threatening side effects such as hypertension, encephalopathy, severe infections, and sudden death. This experience coupled with the loss of two children from overwhelming sepsis while being managed on outpatient basis, informed our decision to treat under direct observation. This included direct observation on the ward with meticulous monitoring, keeping home records, immediate reporting of adverse events when discharged, and short appointments. Although this decision, no doubt, entailed a lot of direct and indirect costs, it was gratifying that no patients died as a result of steroid use. We are therefore more confident that if appropriate measures are put in place, shorter duration of in-hospital management would be safe. In present times also, more potent antihypertensives and antibiotics are available to treat and prevent death among those that develop side effects of steroids compared with the past.

Patients treated in this study had prolonged steroid therapy but the previously suggested advantage of reduction in the frequency of relapses with prolonged steroid therapy for greater than 3 months is being queried, following recent reports of placebo-controlled parallel trials.[50] There may be need to reconsider this practice in the near future in view of newer evidences.


   Conclusion Top


This study has shown better steroid sensitivity of 63.3% in children with primary NS compared with the previously reported overall steroid response of 23.8% and later 36.8-42.9% in patients with highly selective proteinuria. This improved steroid response and zero mortality show a remarkable departure from the past. Pediatric nephrologists in our environs should be encouraged to carry out steroid trials in children presenting with primary NS, irrespective of older age, provided they are carefully monitored for infections and hypertension.

Abbreviations

NS - Nephrotic syndrome

SSNS - Steroid-sensitive nephrotic syndrome

SRNS - Steroid-resistant nephrotic syndrome

UCH - University College Hospital

SD - Standard deviation.

Acknowledgement

We are very grateful to Dr. Yaria JO for the data analysis and editing the manuscript. We appreciate the hard-working and caring pediatric resident doctors who passed through our unit over the years and looked after these patients, especially Dr. Yusuf BN and Dr. Alao MA. The dedicated nursing staff of SE2 ward are very much appreciated. We remain grateful to Dr. Ngozi Egejuru and Miss Omoshola Adenubi for their assistance with data management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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