Patterns, triggers, and predictors of relapses among children with steroid-sensitive idiopathic nephrotic syndrome at the University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria

Anigilaje E Ademola; Ishola Ibraheem

doi:10.4103/jesnt.jesnt_36_21

ORIGINAL ARTICLE

Year : 2022 | Volume : 22 | Issue : 2 | Page : 117-127

Patterns, triggers, and predictors of relapses among children with steroid-sensitive idiopathic nephrotic syndrome at the University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria

Anigilaje E Ademola, Ishola Ibraheem
Nephrology Unit, Department of Paediatrics, University of Abuja Teaching Hospital, Abuja, Nigeria

Date of Submission	08-Nov-2021
Date of Acceptance	10-Jan-2022
Date of Web Publication	19-May-2022

Correspondence Address:
Dr. Anigilaje E Ademola
Nephrology Unit, Department of Paediatrics, University of Abuja Teaching Hospital, Abuja
Nigeria

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jesnt.jesnt_36_21

Abstract

Background Childhood steroid-sensitive idiopathic nephrotic syndrome (SSINS) is plagued with relapses that contribute to its morbidity and the cost of treatment.
Patients and methods This is a retrospective review of relapses among children with SSINS at the University of Abuja Teaching Hospital from January 2016 to July 2020. Triggers related to relapse incidents were noted. χ² test was deployed for predictors (factors at the first clinical presentations that associate with subsequent relapses) of relapses. Predictors with P values of less than 0.05 were considered significant, and 95% confidence intervals (CI) and odd ratio (OR) were described.
Results A total of 60 patients with SSINS, comprising 52 (86.7%) males, aged 23 months to 18 years, with a mean age of 7.04±4.16 years, were studied. A total of 38 (63.3%) participants had 126 relapses, including infrequent relapses in 30 (78.9%) and frequent relapses in eight (21.1%). The commonest triggers were acute upper respiratory tract infections (68, 53.9%) and urinary tract infections in 25 (19.8%) relapses. In four (3.2%) relapses, no trigger was identified. The time-to-first relapse ranged 14–365 days, with a median time of 60 days. The significant predictors were hypertension (OR=3.4, 95% CI; 1.04–11.09, P=0.038), urinary tract infections (OR=9.9, 95% CI; 1.16–80.71, P=0.014), malaria fever (OR=8.0, 95% CI; 2.45–26.38, P<0.001), microhematuria (OR=4.9, 95% CI; 11.58–15.16, P=0.004), elevated serum creatinine (OR=12.3, 95% CI; 1.48–101.20, P=0.005), and hypercholesterolemia (OR=4.1, 95% CI; 1.35–12.63, P=0.011).
Conclusion Although the pathogenesis of relapses remains unknown, it is prudent to consider relapse-specific preventive strategies against triggers and predictors of relapses in our setting.

Keywords: Nigeria, patterns, predictors, relapses, steroid-sensitive idiopathic nephrotic syndrome, triggers

How to cite this article:
Ademola AE, Ibraheem I. Patterns, triggers, and predictors of relapses among children with steroid-sensitive idiopathic nephrotic syndrome at the University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria. J Egypt Soc Nephrol Transplant 2022;22:117-27

How to cite this URL:
Ademola AE, Ibraheem I. Patterns, triggers, and predictors of relapses among children with steroid-sensitive idiopathic nephrotic syndrome at the University of Abuja Teaching Hospital, Gwagwalada, Abuja, Nigeria. J Egypt Soc Nephrol Transplant [serial online] 2022 [cited 2023 Jun 10];22:117-27. Available from: http://www.jesnt.eg.net/text.asp?2022/22/2/117/345440

Introduction

Nephrotic syndrome (NS) characterized by massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia has steroid as its main therapy [1],[2]. Thus, steroid responsiveness is the most important indicator of disease resolution or progression to end-stage kidney disease [3].

Steroid responsiveness also varies across geographical regions reflecting histopathological lesions and ethnogenetic and environmental factors [4]. In Europe and North America, minimal change disease (MCD) represents 85% of the cases, with steroid responsiveness seen in more than 90% of the MCD cases [5]. In Africa, MCD NS with good treatment outcome to steroids also predominates in temperate regions [6]. In tropical Africa, and from the 1960s to 1980s, steroid-resistant non-MCD including quartan malaria nephropathy was the dominant histopathology type [6]. However, in the years after 1989, proliferative glomerulonephritis, MCD, and focal segmental glomerulosclerosis have predominated [6].

In Nigeria, earlier reports with steroid therapy among children with NS appear not to be favorable; [7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19] however, our study [4] and those of others [20],[21],[22],[23] have documented high and increasing rates of steroid-sensitive nephrotic syndrome (SSNS).

Up to 50% of children with SSNS have frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent NS [24],[25]. FRNS and its retreatment with steroid is associated with adverse effects, including obesity, short stature, effects on bone mineral density, cataracts, hypertension, hearing impairment, and infertility [26],[27]. In addition, relapse-related admissions are not without economic, social, and emotional burden because of hospital stay, service payments, and low quality of life of the family [27]. FRNS/steroid-dependent NS may also warrant steroid-sparing immunosuppressant with its attendant toxicities. Thus, parents and nephrologists are keen at knowing predictors of relapses at the first presentation of NS. This inquisition had identified predictors of relapses to include male sex [28],[29], age younger than 5 years at onset of NS [29],[30], the duration from initial steroid therapy to remission, hypoalbuminemia, hematuria, and predilection in children of South Asian or East/Southeast Asian ancestry compared with European ancestry [31],[32],[33],[34],[35]. In addition, most relapses have been triggered by viral upper respiratory tract infection (URTI) and intercurrent infections that include both upper and lower respiratory tract and gastroenteritis [36],[37],[38],[39]. Unfortunately, the effectiveness of daily low-dose prednisolone in reducing relapses from intercurrent infections in Indian subcontinent [36],[37],[38],[39] was not confirmed by a large-size multi-center PREDNOS 2 study in the United Kingdom [40]. This contradiction probably reflects different responses to low-dose prednisolone as a preventer of relapse in populations of children with different ethnic background [40]. As it is, identifying triggers and predictors of relapses among SSNS would continue to be a topic of interest among pediatric nephrologists as the search continues for targeted interventions that will ameliorate disease course and morbidity [41].

Curiously, few studies have been done on relapses among Nigerian children with SSNS [42],[43],[44].

This study discusses the patterns, triggers, and predictors of relapses among children with steroid-sensitive idiopathic nephrotic syndrome (SSINS) at the University of Abuja Teaching Hospital (UATH), Abuja, Nigeria, from January 2016 to July 2020.

Patients and methods

Ethical consent

Ethical consideration followed the Helsinki Declaration of 1975, as revised in 1983. Consent to abstract retrospective data contained in patients’ medical records was obtained from the Research and Ethics Committee of the UATH, Abuja.

Inclusion criteria

All cases of SSINS in children aged 1 month to 18 year from January 2016 to July 2020 at the UATH were noted. INS is a NS that is not congenital, infantile, or secondary [1],[4],[45],[46]. SSINS is an INS that attains remission within the initial 4 weeks of steroid therapy as defined by the International Study of Kidney Disease in Children (ISKDC) [46]. We have previously published the details of management of childhood NS at UATH, Abuja. [4]

Exclusion criteria

The study excluded congenital, infantile, and secondary NS. Congenital NS refers to a NS diagnosed in the first 3 months of life. [1],[4] Infantile NS is seen in children from 3 to 12 months of life. [1],[4] Secondary NS refers to a proven etiology extrinsic to the kidney [1],[4]. Thus, secondary NS includes NS secondary to autoimmune and vasculitic diseases, such as systemic lupus erythematosus; infectious diseases such as malaria, HIV, and hepatitis B and C; and sickle cell anemia. [1],[4],[45],[46].

The following operational terms and diagnosis were applied:

NS was the presence of edema, massive proteinuria of spot urine protein–creatinine ratio more than or equal to 200 mg/mmol, hypoalbuminemia (serum albumin ≤25 g/l), and hypercholesterolemia (serum cholesterol >5.2 mmol/l) [1],[4],[45].

Complete remission/steroid sensitivity was when urine dipstick albumin becomes negative or shows a trace for 3 consecutive days [46].

A partial remission was proteinuria level of 1+/2+ proteinuria by dipstick for 3 consecutive days [46].

SSNS was an attainment of remission within the initial 4 weeks of steroid therapy as defined by the ISKDC [46]. Steroid-resistant NS was the failure to achieve complete remission after 8 weeks of steroid therapy as defined by the ISKDC [46].

A relapse was stated when there is more than or equal to 3+ protein on urine dipstick for 3 consecutive days [46]. FR was stated when there are more than or equal to 2 relapses in the first 6 months after the presentation or more than or equal to 4 relapses within any 12-month period [46].

Infrequent relapse (IR) was stated when children experience less relapses than FR.

Steroid-dependent NS was stated when children relapsed while on steroid therapy or within 14 days of discontinuation of steroid therapy [46].

The ISKDC steroid regimen used was 60 mg/m² once daily (single morning dose) for 28 days, followed by 40 mg/m² given on an alternate day for a further 28 days [47]. We extended the alternate-day prednisolone from 28 to 56 days (8 weeks) for patients who had partial remission to prednisolone after 28 days of induction prednisolone.

The ISKDS steroid regimen for IR was prednisolone 60 mg/m² daily until urinary remission (three consecutive days of zero or trace proteinuria), followed by 40 mg/m² on an alternate day for 14 doses over a 28-day period [47].

Steroid resistance was treated with alternate-day steroid at 30 mg/m² with cyclosporine or mycophenolate. We used cyclosporine rather than mycophenolate except in children with a reduced estimated glomerular filtration rate at presentation. Supportive treatment included the use of cimetidine and omeprazole while on steroid therapy, diuretics (low-salt intravenous albumin, frusemide, metolazone or hydrochlorothiazide, and spironolactone) for edema, intravenous hydralazine and nifedipine/amlodipine for hypertension, and angiotensin-converting enzyme inhibitors for steroid-resistant NS.

Urinary tract infection (UTI) was diagnosed when there was a positive test result for pyuria by either microscopy (≥5 white blood cells per high-power field in uncentrifuged urine specimen) or dipstick test (positive leukocyte esterase test) and a positive growth on culture of at least 50 000 colony-forming unit/ml of a single uropathogen in urine specimen obtained by catheterization or greater than 100 000 colony-forming unit/ml of a single uropathogen in clean-catch urine specimen or any uropathogen growth in urine obtained suprapubically [48].

Diarrheal disease was defined as the passage of three or more stools a day, with a recent change in consistency and with or without blood in stools [49].

Spontaneous bacterial peritonitis was a bacterial infection of ascitic fluid which occurs in the absence of any other source of intra-abdominal infection. It is assumed in a child with NS who has fever, generalized abdominal pain and tenderness, and full blood count picture in keeping with bacterial infection, and clinical improvement following appropriate antibiotics. We do not routinely do ascitic fluid microscopy, biochemistry, and culture to confirm spontaneous bacterial peritonitis [50].

Malaria infection was an acute febrile illness caused by Plasmodium falciparum characterized by chills, fever, sweating, headache, myal, characterized by chills, fever, sweating, headache, myalgia, arthralgia, nausea, vomiting, and abdominal pain; it is confirmed using parasite-based diagnostic testing through either microscopy or a rapid diagnostic test. Other Plasmodium species were not detected [51].

URTI is defined as self-limited irritation and swelling of the upper airways (nose, sinuses, pharynx, larynx, and large airways) with associated fever, cough, rhinitis, dysphagia, earache, myalgia, or malaise and no signs of pneumonia in a patient with no other condition that would account for their symptoms or with no history of chronic obstructive pulmonary disease, emphysema, or chronic bronchitis [52],[53].

Cellulitis was an acute inflammatory condition of the dermis and subcutaneous tissue, spreading and pyogenic in nature, and characterized by localized pain, erythema, swelling, and heat. It is confirmed by Gram’s stain and bacterial culture of open drainage or needle aspirate [54].

Hypertension was defined as systolic and or diastolic blood pressures greater than the 95th centile for age, sex, and length using normogram published in the fourth report of the National High Blood Pressure Education Group [4].

Significant microhematuria represented red blood cells more than or equal to 5/high power field. [4].

Socioeconomic status (SES) stratification was done using the one proposed by Oyedeji [55], which employs the educational status and occupation of parents. SES was classified into high, medium, and low based on the occupation and level of education of the parents. Predictors of relapse were factors (infections and noninfections) that are present in a child with NS at the first clinical presentations that could be related with subsequent relapse(s). Triggers are factors that were related to occurrence of a relapse incident.

Statistical analysis

Statistical analysis was done with the SPSS, version 20 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0, Armonk, NY: IBM Corp.). Characteristics were summarized using means and SDs for normally distributed variables and medians and interquartile range for those that were not. The relationship of predictor variables with subsequent relapses (FR and IR) was compared using χ² or Fisher’s exact as appropriate. Predictors of relapses that achieved P values of less than 0.05 were considered statistically significant and were described for odd ratios and confidence intervals (CI) set at 95% level.

Results

[Figure 1] is the schematic diagram of the 88 children with NS seen over the study period from January 2016 to July 2020. Only 60 children with SSINS were included in this study. Reasons for the exclusion of the remaining 28 children are as shown in [Figure 1].

Figure 1 Schematic diagram of 88 children with NS seen over the study period from January 2016 to July 2021. NS, nephrotic syndrome.

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The 60 SSINS were followed up over a median period of 34 months. This included the respective 7, 12, 16, 16, and 9 seen in 2016, 2017, 2018, 2019, and 2020. [Table 1] depicts the baseline sociodemographic characteristics of children with SSINS. It comprised 52 (86.7%) males and eight (13.3%) females, with a male-to-female ratio of 6.5 : 1, with age range of 23 months to 18 years and a mean age of 7.04±4.16 years. A majority of patients (36, 60%) were within 0–5-year age group. The Igbo ethnic group constituted the majority, with 18 (30%) patients, followed by the Fulanis (14, 28.3%) and the Yorubas (eight, 13.3%). Almost half (29, 48.3%) of the patients belonged to the low socioeconomic class.

Table 1 Baseline sociodemographic characteristics of patients with steroid-sensitive idiopathic nephrotic syndrome

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[Table 2] shows the baseline clinicolaboratory characteristics of patients with SSINS. The following comorbidities were identified at baseline including hypertension in 24 (40%), peritonitis in eight (13.3%), UTIs in 13 (21.7%), P. falciparum malaria fever in 37 (61.7%), gross hematuria in four (6.7%), microscopic hematuria in 36 (60%), anemia in eight (13.3%), elevated serum creatinine in 15 (25%), hypoalbuminemia in 51 (85%) and hypercholesterolemia in 34 (56.7%). [Table 3] depicts the pattern and triggers of relapses among SSINS. The time to first remission ranged from 5 to 42 days, with a median time of 15 days (interquartile range=16). Among the 60 patients with SSINS, 22 (36.7%) were nonrelapsing and 38 (63.3%) were relapsing. IR was documented in 30 (78.9%) patients, whereas eight (21.1%) were FR (21.1%). Of the eight FR, three (37.5%) were also steroid dependent. A total of 126 relapses were observed. The commonest trigger of relapse was acute URTIs, noted for 68 (53.9%) relapses. The relapse-associated URTIs also included 61 (48.4%) patients who were coinfected with P. falciparum malaria fever and 25 (19.8%) coinfected with UTIs. After URTIs, the other common triggers of relapses included UTIs in 25 (19.8%), followed by peritonitis in 11 (8.7%), diarrheal disease and P. falciparum malaria fever in seven (5.6%) relapses each, and cellulitis in four (3.2%) relapses. In four (3.2%) relapses, no trigger could be identified. [Table 4] describes the baseline predictors of SSINS. The time range to the first relapse was 14–365 days, with a median time of 60 days (interquartile range of 60 days). The predictors of subsequent relapses were hypertension, UTIs, P. falciparum malaria fever, microhematuria, elevated serum creatinine, and hypercholesterolemia. Compared with those without hypertension, those with hypertension were thrice as likely to have relapses (95% CI; 1.04–11.09, P=0.038). UTIs were significantly associated with relapses, with the odds of relapses increased by nine times (95% CI; 1.16–80.71, P=0.014). The presence of P. falciparum malaria at presentation was eight times as likely to have relapses compared with patients without P. falciparum malaria (95% CI; 2.45–26.38, P˂0.001). The odds of relapse in patients with microscopic hematuria were four times as likely compared with those without microscopic hematuria (95% CI; 11.58–15.16, P=0.004). An elevated serum creatinine at presentation increased the odds of relapses by 12 times (95% CI; 1.48–101.20, P=0.005). Lastly, hypercholesterolemia increased the risk of relapses by four times compared with not having hypercholesterolemia at the first presentation (95% CI; 1.35–12.63, P=0.011).

Table 2 Baseline clinicolaboratory characteristics of patients with steroid-sensitive idiopathic nephrotic syndrome

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Table 3 Pattern and triggers of relapses among patients with steroid-sensitive idiopathic nephrotic syndrome

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Table 4 Baseline predictors of relapses among patients with steroid-sensitive idiopathic nephrotic syndrome

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Discussion

In this study involving 60 SSINS cases, 126 relapses were seen among 38 (63.3%) relapsing patients, including 30 (78.9%) with IR and eight (21.1%) with FR. Infectious triggers of relapses predominated in 122 (96.8%) relapses. Acute URTIs were the commonest trigger noted for 68 (53.9%) relapses. Other triggers were UTIs in 25 (19.8%), peritonitis in 11 (8.7%), diarrheal disease and malaria fever (P. falciparum) in seven (5.6%) relapses each, and cellulitis in four (3.2%) relapses. In four (3.2%) relapses, no trigger was identified. A priori predictors [28],[29],[30],[31],[32],[33],[34],[35] of relapses like age, sex, SES, gross hematuria, hypoalbuminemia, duration of steroid therapy, time-to-first remission, and time-to-first relapse were not found to be significantly associated with relapses in this study. Rather, the predictors of subsequent relapses noted in this study included hypertension, UTIs, malaria fever, microhematuria, elevated serum creatinine, and hypercholesterolemia.

At foremost, it is prudent to note that there is no consistency in predictors observed for subsequent relapses among children with NS in all studies, possibly owing to variation in sample size, sociodemographic and clinical characteristics of patients, variable follow-up time, or variability in the defined outcomes of what relapses are [23,27–31, 33, 35, 41–43].

Although age was not an independent predictor of relapses in this study and those of others [28],[42],[56], Mishra et al. [57] and Sinha et al. [58] documented younger age of onset as a pointer toward relapse in NS in their own series. Furthermore, Sureshkumar et al. [28] and Andersen et al. [29] reported male sex as a risk factor for subsequent relapses; however, this study and those of others [56],[58] did not find such a relationship. Regarding the duration of steroid therapy on risk of relapse, Sinha et al. [58] reported a reduction in the risk of FRs by 30% with an initial steroid therapy of more than or equal to 12 weeks. On the contrary, this study and the one by Ali et al. [59] did not report any effect of the duration of steroid therapy of first episode of NS on future disease pattern. In fact, some authors have demonstrated no benefit of prolonging therapy beyond 12 weeks on the risk of future relapse [58],[60]. We also did not find time-to-first remission as a predictor of relapse, whereas longer time to achieve remission was reported to be a significant risk factor of relapse by other authors [28],[32],[33],[59]. Time-to-first relapse within the first 6 months of steroid therapy was found to be associated with relapse in some studies [61],[62], but this association was not observed in this cohort. Low SES relating to a higher risk of infection-related relapses was reported by Ali et al. [63] but not in this study. Furthermore, an association between presence of hematuria at initial presentation and future relapse has been reported earlier [33],[62],[64] but not in this study. In addition, hypoalbuminemia noted for risk of relapse by some authors [27],[64] was not associated with relapse among our patients with SSINS. Hypoalbuminemia as a risk of relapse would suggest that the initial proteinuria and the proteinuria of subsequent relapses in NS may be occurring via a similar mechanism.

This study depicts a larger proportion of IR (78.9%) compared with higher burden of FR noted by other authors [28],[29],[58]. A plausible explanation would be a differential higher occurrence of relapses among white [29] and Asian [28],[58] children compared with the ethnically black Africans in this study. Another explanation could be that our patients with FR are already defaulting from follow-up because of retreatment fatigue.

In this study, the main trigger of relapse was acute URTI (53.9%) followed by UTI (19.8%), peritonitis (8.7%), diarrheal disease (5.6%), malaria fever (5.6%), and cellulitis (3.2%). RTI consistently ranks as the most prominent trigger of relapses regardless of the geographical setting [36],[52],[65],[66]. In these studies [52],[65],[66], RTI was responsible for 66.9% of relapse cases. Although the effectiveness of daily low-dose prednisolone in reducing the risk of relapse from intercurrent infections in Indian subcontinent [36],[37],[38],[39] was not confirmed by a larger-size multicenter PREDNOS 2 study in the United Kingdom [40], our anecdotal observation would support that a daily 5-mg prednisolone throughout the course of an acute URTI tends to prevent relapse in our children with SSINS. However, we look forward to having a randomized control study that will establish the effectiveness of daily low-dose prednisolone and zinc supplementation in preventing relapses during acute URTIs in our own setting. The role of vaccinations in preventing infectious diseases, including URTI caused by influenza, has not been clear cut [67]. Although the number of relapses was not increased in influenza-vaccinated children with NS, unfortunately, there were cases of relapse that followed inactivated influenza vaccine [67].

Although UTI ranked second as a trigger of relapse in this study, it assumes a more frequent role in the report of Uwaezuoke et al. [43] and other authors [68],[69]. Although the prevalence of diarrhea in developing countries is still quite high [70], diarrhea was responsible for only 5.6% relapses in this study, 6% in an Indian study [52], and 14% in a Pakistani study [65]. Similar to this study, the Pakistani study also documented other infections like peritonitis and cellulitis as common triggers of relapses in childhood NS [65].

An important trigger of relapse that has been reported rarely in literature is the one caused by malaria fever. In this study and the one by Uwaezuoke et al. [43], malarial fever was identified as a common trigger of relapses among children with SSINS. This finding is noteworthy in settings where malarial fever is endemic, as control of malaria infestations could mean a lesser risk of relapse among children with NS.

Although the precise pathophysiological mechanisms leading to childhood NS and its relapses is still unknown [41], the infectious origin of relapses has been linked to releases of cytokines [52]. When exposed to infections, there is an up-regulation of interleukin-13 and interleukin-4 expression on T cells. These cytokines stimulate monocytes to release vascular permeability factors that are involved in the pathogenesis of proteinuria of NS [71]. Binding of vascular permeability factors with receptors expressed on podocytes tends to disrupt glomerular permeability with a consequent proteinuria [72]. However, it remains to be proven if acute URTI or UTI as a commoner trigger of relapse compared with diarrheal disease are because of a lesser T-cell cytokines production in diarrheal disease [70].

In this study, no trigger was identified for four (3.2%) relapses. We are not sure if the trigger in these four relapse episodes is due to psychological stress. Psychological stress has been noted to be a trigger of relapse and proteinuria in children with NS owing to a dysregulation of cortisol caused by psychological stress, causing immune system disorders and subsequent relapses [73].

For this study, we re-emphasize predictors of relapse to mean factors (infections and noninfections) present at the first clinical presentations of NS that could be related with subsequent relapse(s). We identified predictors of relapses to include hypertension, UTIs, malaria fever, microhematuria, elevated serum creatinine, and hypercholesterolemia.

Hypertension found in 40% of the SSINS cases increases the odds of relapse by three times. Similarly, Imbusi et al. [74] also documented hypertension to be a predictor of relapse in NS. Hypertension is seen in up to 59.1% of different populations of children with NS [75]. Hypertension in NS could result from fluid shifts, sodium retention, medication adverse effects (steroids), obesity, increased arterial stiffness, dysglycemia, dyslipidemia, renal fibrosis, impaired glomerular filtration rate, and progression of chronic kidney disease [75].

Furthermore, UTIs found in 21.7% of our patients significantly increased the odds of relapses by nine times. UTIs have also been noted to be responsible for poor response to steroid [68],[69]. Children with NS are prone to UTIs because of increased urinary loss of immunoglobulin and factor B, defective T-cell function, relative malnutrition, and immunosuppressive agents [76]. Measures to prevent UTIs include adequate hydration, avoidance of constipation, regular voiding, second voiding, hygienic wiping of the perineum, and cotton underpants [77]. It will be beneficial if children with SSINS are also routinely screened for UTIs.

Of our 10 patients, six (61.7%) had malarial fever at presentation, and those with malarial fever were eight times more likely to develop relapses subsequently. We tend to agree with Stevenson and Riley [78], who suggest immediate ‘nonspecific’ immune response induced by acute malarial infection to be responsible for malaria-induced relapses. Natural killer cells induce the production of the pro-inflammatory cytokine, interleukin-8, which in turn helps in the recruitment and activation of other cells during malaria infestation [78]. Thus, relapse-specific interventions like intermittent preventive therapy for malaria fever may be beneficial for childhood NS in geographical areas where malaria infection is endemic [43].

Overall, 25% of the patients had elevated serum creatinine at the first episode of NS. We also found that the odds of subsequent relapse increased by 12 times in patients with elevated serum creatinine. Elevated serum creatinine in keeping with acute kidney injury was also reported by Welegerima et al. [79] to be a predictor of relapse. The possible etiopathogenesis of acute kidney injury in NS includes acute tubular necrosis from hypovolemia and infection, renal interstitial edema with vascular congestion, bilateral renal vein thrombosis, acute pyelonephritis, rapid progression of the original glomerular disease, and exposure to nephrotoxic medications [80].

Hypercholesterolemia was found in 56.7% of patients at the first episode of NS, and it increases the risk of subsequent relapses by four times. Hypercholesterolemia was also reported to be a risk factor of relapse in the studies of Gebrehiwot et al. [27] and Suresh et al. [81]. A putative explanation is that hypercholesterolemia is a cause of podocytopathy, with its attendant proteinuria [27]. Hyperlipidemia in NS results from increased hepatic synthesis of triglycerides and cholesterol as a result of hypoalbuminemia stimulus on the liver [27].

Microscopic hematuria was present in 60% of the patients at the first presentation, and patients who had microscopic hematuria are four times more likely to have relapses compared with those who did not have microscopic hematuria. Similarly, microscopic hematuria enjoys an inconsistent relationship with subsequent relapses, FR or SD, in the published literature [28],[82].

Limitations of the study

A single-center tertiary health institution-based study might have omitted some SSINS managed for IR at the peripheral hospitals that were not referred to us. It is also possible that some patients with FR are already defaulting from follow-up because of retreatment fatigue.

Being a retrospective study, some medical interviews were not conducted at clinical presentations and at the time of relapse, so variables like history of atopy, family history of kidney diseases, and weights at births were largely missing.

Conclusion

This study would sum up to indicate that IF was commoner than FR among children with SSINS. It shows that acute URTIs and UTIs are common triggers of relapses. It demonstrates that some variables at first diagnosis of NS are capable of predicting subsequent relapses. These predictors include hypertension, UTIs, malaria fever, microhematuria, elevated serum creatinine, and hypercholesterolemia. Although the exact pathogenesis of relapses remains unknown, it is prudent to consider relapse-specific interventions against triggers and predictors of relapses. These efforts would include daily low-dose steroid at the onset of URTIs, intermittent preventive therapy against malaria fever, prevention of UTIs, and management of hypertension and hypercholesterolemia.

Acknowledgements

If any, the authors are grateful to all children and parents who made up the patients of this study.

Authors’ contribution: both authors participated in the conceptualization and design of the study, data acquisition, and interpretation; participated in the drafting and critical revision for important intellectual content; and approved the final version of the manuscript to be published.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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