|Year : 2022 | Volume
| Issue : 2 | Page : 78-85
Childhood nephrotic syndrome: A single center experience
Sherif Mohamed El-Desoky1, Dalal Abdullatif Alghamdi2, Mashael Mahmoud Abujabal1, Ghadeer Ghazi Alahmadi2, Jameela Abdulaziz Kari1
1 Pediatric Nephrology Center of Excellence; Department of Pediatrics, Collage of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2 Department of Pediatrics, Collage of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
|Date of Submission||21-Nov-2021|
|Date of Decision||21-Jul-2022|
|Date of Acceptance||28-Sep-2022|
|Date of Web Publication||31-Dec-2022|
Sherif Mohamed El-Desoky
Pediatric Nephrology Center of Excellence and Department of Pediatics, Collage of Medicine, King Abdulaziz University, Jeddah
Source of Support: None, Conflict of Interest: None
Background: Childhood nephrotic syndrome (NS) is the most frequently occurring chronic kidney disease (CKD) among children. Methods: This retrospective review aimed to determine the clinical profile, diagnostic procedures, therapeutic strategies, and outcomes of NS in children <18 years old diagnosed and followed up in the pediatric nephrology unit at King Abdulaziz University Hospital, Kingdom of Saudi Arabia, from 2000 to 2020. Children with an underlying secondary cause for NS were excluded. Results: Five hundred and sixteen children were enrolled into four groups of patients, including steroid-sensitive NS (SSNS, 276 patients), primary steroid resistant (SRNS, 138 patients), secondary SRNS (56 patients), and congenital and infantile NS (46 infants). The age at presentation was 5.29 ± 2.83 years and mean follow-up duration was 4 years. Kidney biopsy was indicated for 174 (33.7%) children, of whom 79 (45.4%) had focal segmental glomerulonephritis, 35 (20.1%) had IgM nephropathy, and 25 (14.3%) had minimal change disease. Seventy (13.5%) patients were found to have positive homozygous variants, chiefly in NPHS1 in 25 (35.27%), NPHS2 in 16 (22.8%), and LAMB2 in 6 (8.5%). Acute kidney injury and kidney failure were most commonly observed in patients with SRNS (P < 0.001), while sepsis and mortality were significantly predominant among patients with infantile NS (P < 0.001). Kidney failure was reported in 8.7% patients. Conclusion: NS in children remains a challenging chronic glomerular disorder with variable outcome. Progression of CKD is seen most commonly in children with SRNS, more so in those with genetic etiology. Patients with congenital NS have the highest mortality.
Keywords: Childhood, congenital, focal segmental glomerulosclerosis, idiopathic, infantile, steroid resistant nephrotic syndrome
|How to cite this article:|
El-Desoky SM, Alghamdi DA, Abujabal MM, Alahmadi GG, Kari JA. Childhood nephrotic syndrome: A single center experience. Asian J Pediatr Nephrol 2022;5:78-85
|How to cite this URL:|
El-Desoky SM, Alghamdi DA, Abujabal MM, Alahmadi GG, Kari JA. Childhood nephrotic syndrome: A single center experience. Asian J Pediatr Nephrol [serial online] 2022 [cited 2023 Mar 25];5:78-85. Available from: https://www.ajpn-online.org/text.asp?2022/5/2/78/366537
| Introduction|| |
Childhood NS, defined by nephrotic-range proteinuria (≥40 mg/m2/h or urine protein/creatinine ratio ≥200 mg/mL), hypoalbuminemia (<25 g/L), and edema, is the most frequent chronic kidney disease (CKD) in children. The incidence of childhood NS is reported as 4.7 (range 1.15–16.9) per 100,000 children, with substantial variability across ethnicity and geographical location.,,
Idiopathic NS can be classified on the basis of response to corticosteroid therapy (as steroid sensitive or steroid-resistant NS (SSNS or SRNS), the pattern of relapses, histopathology, or by genetic etiology. While the cause remains unknown, the pathogenesis of idiopathic NS is thought to involve immune dysregulation, systemic circulating factors, or inherited structural abnormalities of the podocyte. Approximately 80%–90% of patients with childhood idiopathic NS achieve remission with steroid therapy (SSNS). However, approximately 50% of children with SSNS develop frequently relapsing NS or steroid-dependent NS (SDNS). These patients may display complications, such as susceptibility to infection, thromboembolism, growth retardation, osteoporosis, and obesity secondary to steroid use.
The histological findings of idiopathic NS include minimal change disease, focal segmental glomerulosclerosis, which frequently shows steroid resistance and can progress to end-stage kidney failure. Genetic diagnosis is superior to histopathologic classification in predicting responsiveness to immunosuppression and clinical outcomes. Early identification of genetic causes for children with SRNS could allow discontinuation of immunosuppressive agents, aid in transplant management, and provide information for prenatal counseling.
| Methods|| |
We aimed to determine the clinical profile, diagnostic procedures, therapeutic strategies, and medium-term outcome for children with NS presenting to our tertiary care hospital.
A retrospective review was performed of the electronic medical records for all children diagnosed with NS, who were treated and followed up in the pediatric nephrology unit at King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia, from 2000 to 2020. The diagnosis of NS was based on clinical and laboratory findings of nephrotic range proteinuria (>40 mg/m2/hr) and hypoalbuminemia (serum albumin <25 g/L). We excluded children with an underlying secondary cause for NS, e.g., lupus nephritis, Henoch Schoenlein purpura, infections, or neoplasm. Permission to conduct the study was granted by the Ethics Research Committee of Faculty of Medicine of King Abdulaziz University (No. 290-22; nonintervention cohort).
Important definitions that were used to define disease course are as follows.
- Idiopathic NS: Refers to disease characterized by typical features, including age at onset 1-12 years, hypoalbuminemia (≤25 g/L), heavy proteinuria (>1 g/m2/day on 24-hr urine collection, spot urine protein/creatinine ratio >2 mg/mg, or persistent >2+ protein on urine dipstick), edema, transient microscopic hematuria, and no symptoms suggestive of systemic diseases
- Congenital NS: NS that presents within the first 3 months of life
- Infantile NS: NS that presents between 3 months and 1 year
- SSNS: Remission within 4 weeks of therapy with oral prednisolone at 60 mg/m2. It consists of 4 subcategories; no further relapses, infrequent relapses, frequent relapses and steroid dependence. Frequent relapses were defined as two or more relapses within 6 months of initial response, or four or more relapses in any 12-month period. SDNS was defined as two consecutive relapses during corticosteroid therapy withdrawal, or within 14 days of stopping therapy
- SRNS: Lack of complete remission after 4 weeks on daily dose of oral prednisolone (60 mg/m2) ± pulse intravenous methyl prednisolone 600 mg/m2/d for 3 days. Secondary or late SRNS refers to persistent proteinuria despite ≥4 weeks of prednisolone therapy of disease relapse, following one or more steroid-induced remissions, after ensuring no infection or nonadherence to medication.
Complete remission is defined as no proteinuria (urine protein <4 mg/m2/h or nil/trace on dipsticks for 3 consecutive early morning urine specimens, protein-to-creatinine ratio <0.2 mg/mg), serum albumin >35 g/L, no edema, normal renal function and normal blood pressure. Partial remission was defined as reduction in proteinuria by ≥50%, spot protein-to-creatinine ratio <2.0 mg/mg, serum albumin 25–35 g/L, no edema, stable renal function, and blood pressure.
Relapse was defined as recurrence of nephrotic-range proteinuria (>2 + by urine dipstick, urine protein >40 mg/m2/h, or spot urine protein-to-creatinine ratio >2.0 mg/mg for 3 consecutive days).
Our unit protocol of managing idiopathic NS follows the Kidney Disease Improving Global Outcome (KDIGO) guideline for management of idiopathic NS in children that was established in 2003 and updated subsequently. The management of patients with NS in children broadly followed the algorithm for management proposed by KDIGO 2021 clinical practice guideline for management of glomerular disease.
The standard dosing regimen for the initial episode of disease is daily oral prednisone/prednisolone at 60 mg/m2/d or 2 mg/kg/d (maximum 60 mg/d) for 4–6 weeks, followed by alternate days prednisone/prednisolone, 40 mg/m2 or 1.5 mg/kg (maximum of 50 mg) for another 4–6 weeks, then gradual tapering of dose to stop steroids in the next 2–3 months. For patients who present in late infancy (≥9 months old), we try a course of oral prednisolone as used for idiopathic NS.
Use of steroid-sparing agents
Noncorticosteroid immunosuppressive medications were considered in patients with steroid dependence, those with frequent relapses while on maintenance prednisolone dose of ≥0.5 mg/kg on alternate days, patients in whom there was evidence of steroid toxicity (including concerns over linear growth, Cushing habitus, ocular toxicity), those with poor adherence to steroid therapy, and in patients with SRNS.
Levamisole was indicated in patients who relapsed on prednisolone dose of 0.5–1 mg/kg on alternate days. If relapses occurred at prednisolone doses of >1 mg/kg on alternate days, other agents, such as cyclophosphamide, mycophenolate mofetil (MMF), cyclosporine (CsA), tacrolimus and rituximab, were preferred. The doses and monitoring of therapy for each of these agents followed standard guidelines. In the case of therapy with rituximab, repeat doses were given either electively after 6–12 months of the initial course or following relapse.
All patients with SRNS received pulse methylprednisolone, as per unit protocol, daily for three days as IV infusion at 600 mg/m2 per dose. Additional three doses were administered on alternate days in case heavy proteinuria persisted.
Patients with congenital or infantile onset disease, SRNS, and those with partial response also received therapy with anti-proteinuric agents, such as angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker. The dose was titrated gradually until proteinuria was minimized while maintaining acceptable blood pressure.
Management of congenital nephrotic syndrome
Since most such patients would require kidney transplantation during the first decade of life, as per unit protocol, these children were maintained on regular IV albumin infusions (Human albumin 20%, 1-4 g/kg/dose with IV furosemide given in a dose of 1 mg/kg midway or at end of the infusion), oral diuretics (furosemide 1 mg/kg/dose 2–3 times/day) as often as necessary, ACE-I, and supplements of thyroxine hormone once daily in the morning. Appropriate renal replacement therapy was initiated whenever indicated.
Infantile nephrotic syndrome
Patients with disease onset under 9-months of age were managed as congenital NS. Patients who presented in late infancy (≥9 months-old), particularly those in whom genetic testing did not yield a diagnosis, were managed as idiopathic childhood NS.
Kidney biopsy was indicated in children presenting with atypical features of idiopathic NS like; age <12 months or >12 years, hypocomplementemia, renal impairment without hypovolemia, persistent hypertension not induced by steroid therapy, gross hematuria, SRNS and secondary SRNS (late onset SRNS). Kidney biopsy was not performed in children with SSNS prior to initiation of CNI. The biopsy was performed under real-time ultrasound guidance after parental consent.
As per unit protocol, genetic testing was performed, following appropriate consents, for all patients with congenital or infantile NS, initial SRNS, SSNS and positive family history of similar condition, and patients with features suggesting a syndromic diagnosis. Only pathogenic variations were considered as disease-causing.
Management of chronic kidney disease
We follow the National Kidney Foundation Kidney Disease Outcome Quality Initiative (K/DOQI) classification to assign stages of CKD based on estimated glomerular filtration rate (eGFR), as follows: Stage 1: ≥90 ml/min/1.73 m2, stage 2: 60–89 ml/min/1.73 m2, stage 3: 30-59 ml/min/1.73 m2, stage 4: 15–29 ml/min/1.73 m2, and stage 5: <15 mL/min/1.73 m2. eGFR was calculated at initial presentation and at last follow up visit using the modified Schwartz formula in children, and the Modification of Diet in Renal Disease (MDRD) formula in adults (>18-year-old at last follow up).
Based on age at onset, response to steroids and disease course, patients are presented in four categories as shown in [Table 1]. All analyses were performed using STATA software (release 12; StataCorp LP, College Station, TX, USA). Continuous data is presented as mean ± standard deviation or median (range) based on the normality of its distribution. A P < 0.05 was considered statistically significant. The Kruskal–Wallis tests were used to compare polychotomous variables. The Chi-square test or Fisher exact test was used to compare categorical variables. For correlation, we used the Spearman correlation. Survival analysis was performed using the Kaplan–Meier analysis.
| Results|| |
Five hundred and sixteen children were enrolled in this study. [Table 1] shows that the age at presentation was 5.3 ± 2.8 years, and male: female ratio was 1.45. Patients were followed up for median duration of 4 years, and the age at last follow up was 9.3 ± 5.4 years. As shown in [Table 1], 276 patients had SSNS, 56 had secondary (late) SRNS, 138 had primary (initial) SRNS, and 46 had congenital and infantile NS (26 and 20 patients, respectively). Consanguinity was present in 57.5% cases, with highest prevalence among patients with congenital and infantile disease (91.3%), followed by patients with SRNS (32.6%). Hypertension was observed in 127 (24.6%) patients, chiefly among patients with initial and late SRNS (49.3 and 39.3%, respectively). Transient or persistent microscopic hematuria was most common in patients with initial SRNS (44.2%) and congenital and infantile NS (43.5%). The entire cohort was categorized by the decade of onset of disease, from 2000-2010 (first decade), and 2011-2020 (second decade), to compare the outcomes of CKD stage and mortality. [Table 1] shows the demographic, clinical and laboratory features of the studied groups. [Supplementary Table 1] provides these details for subcategories of patients with SSNS. Kidney biopsy was performed for 174 (33.7%) patients. [Figure 1] shows the frequency and distribution of histologies across the studied groups.
|Figure 1: Histopathological findings in various disease categories. Bars, from left to right for each stage, represent patients with secondary (late) steroid resistance, primary (initial) steroid resistance, and congenital or infantile NS, respectively. C1q: Complement 1q nephropathy, FSGS: Focal segmental glomerulosclerosis, IgA: IgA nephropathy, IgM: IgM nephropathy, MCD: Minimal change disease; MesPGN: Mesangioproliferative glomerulonephritis, MPGN: Membranoproliferative glomerulonephritis|
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[Table 2] provides the frequency and distribution of the different immunosuppressive and antiproteinuric medications that were used for patients with frequently relapsing, steroid-dependent and steroid-resistant disease. Pulse methylprednisolone was used in patients with refractory disease relapses in primary or secondary SRNS, prior to initiating other steroid-sparing medications.
[Table 3] shows the frequency of comorbidities among the studied groups. Overweight (body mass index (BMI) 25-29.9 kg/m2) was observed in 53 (9.4%) cases while severe obesity (BMI >30 kg/m2) was observed in 37 (6.6%) cases. However, the difference was not significant among the four studied groups. Acute kidney injury (AKI) and the acute need for kidney replacement therapy (KRT) was most frequent among patients with initial SRNS (P < 0.001); 12 (2.3%) patients needed acute KRT for AKI. While sepsis was significantly predominant among congenital NS (P < 0.001). Kidney failure was reported in 49 (8.7%) patients of whom 39 (7.5%) patients underwent KRT; this included regular hemodialysis in 17 (3.2%), automated peritoneal dialysis in 16 (3.1%), and kidney transplantation in 10 (1.9%).
|Table 3: Comorbidities and complications associated with disease or therapy|
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Genetic test results were available for 77 (14.9%) patients, variations in NPHS1 were the most frequent genetic changes found (25 [35.27%]), followed by NPHS2 (16 [22.8%]), LAMB2 (6 [8.5%]), SMARCAL1 (4 [5.7%]), ADCK4 (3 [4.3%]), two cases [2.8%] in each WT1, LAMA5, ITSN1, NUP205 variations, and, in one case each, NUP205, GAPVD1, SGPL1, CDK20, PLCE1, DLC1, OSGEP, ITNS2 and TRPC6 [Table 4] demonstrates the pathogenic genetic variants among the studied groups.
|Table 4: Genes in which pathogenic variants were found in the three groups of patients|
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At last follow up, the median eGFR was lower for patients with congenital and infantile nephrotic sydnrome and primary SRNS than those with SSNS or secondary SRNS [Table 1]. [Figure 2] shows that patients with initial SRNS and congenital/infantile NS had higher rates of advanced CKD stages. Patients with monogenic disease tended to have worse outcomes in terms of eGFR than monogenic disease, when examined within the subgroups of patients with histology of FSGS, and diagnosis of initial SRNS [P < 0.001 and P = 0.001, respectively; [Figure 3]]. [Figure 4] compares kidney survival among the patient groups, confirming the finding that rate of kidney survival was highest for SSNS group, and insignificantly worse for patients with initial SRNS (P = 0.05) and congenital/infantile NS (P = 0.26).
|Figure 2: Proportions of patients according to CKD stage at last follow up. Bars, from left to right for each stage, represent patients with steroid sensitive NS, secondary (late) steroid resistance, primary (initial) steroid resistance, and congenital or infantile NS, respectively. CKD: Chronic kidney disease, NS: Nephrotic syndrome|
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|Figure 3: Comparison of the eGFR at last follow up according to results of genetic testing, in patients with histology of FSGS, and diagnosis of initial SRNS. The lighter bar indicates eGFR in patients with monogenic disease. eGFR: Estimated glomerular filtration rate, FSGS: Focal segmental glomerulosclerosis, SRNS: Steroid resistant nephrotic syndrome|
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|Figure 4: Kaplan–Meier estimates of patient survival according to diagnosis. SRNS: Steroid resistant nephrotic syndrome, SSNS: Steroid sensitive nephrotic syndrome|
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Forty-two (8.1%) patients died. The highest mortality was in patients with congenital and infantile NS who usually succumbed within the first few months of life (n = 22, 47.8%), most commonly to sepsis. Seventeen (12.3%) deaths were reported among patients with initial SRNS, as a result of either sepsis, AKI or advanced CKD.
| Discussion|| |
We report the presentation and outcomes in 516 children with congenital, infantile and idiopathic NS from the west province of the Kingdom of Saudi Arabia from 2000 to 2020. In this study, findings were evaluated according to demographic, clinical characteristics, histopathology, genetic findings, and the response to steroid treatment. Kidney function and patient's survival were documented.
Steroid-sparing medications were required in 254 (54%) patients, with the choice guided by drug efficacy, adverse effects (AE) and the disease severity. Regional availability of medications and physician preferences greatly influence choice of such medication. In our study, MMF was often preferred to cyclophosphamide or CNI in patients with steroid-dependent SSNS since it allowed satisfactory reduction in relapses and had few gastrointestinal AE. Ogarek et al., have reported that MMF has fewer AE than cyclophosphamide and CNI while enabling long-term remission and reduced cumulative steroid requirement. Similarly, Xiang et al. observed that MMF is more effective than CNI and levamisole in reducing relapse frequency and cumulative prednisolone requirement in patients with frequently relapsing or steroid-dependent SSNS.
Levamisole has been suggested to be as effective as cyclophosphamide in frequently relapsing NS. However, we used the agent only infrequently due to its unavailability in Saudi Arabia. We have previously examined retrospectively the efficacy of cyclosphosphamide (n = 27) and rituximab (n = 19) as the first steroid-sparing agent in 46 patients with SDNS at two centers in Saudi Arabia. One-year relapse free survival was 58.6% and 84.2% for the respective agents, and both medications were associated with a significant reduction in steroid requirement.
Secondary (late onset) SRNS comprised 28.8% of all patients with SRNS, similar to what has been reported previously (13.8%-35.9% of cases of SRNS) and appeared to have better prognosis than primary SRNS. In our study, CNI s (cyclosporine or tacrolimus) were the first choice for patients with initial or late SRNS, used in 61 (44.2%) and 23 (41%) cases, respectively. This is consistent with current recommendations, based on evidence that 70% of patients achieving full or partial remission during therapy with CNI. While several series have reported efficacy of rituximab in patients with refractory SRNS, our results were less satisfactory, similar to findings of an open-label randomized trial that failed to find benefit with rituximab therapy in patients with CNI-refractory SRNS, and a report by Kari et al., on four patients with CNI-refractory SRNS who failed to achieve remission despite B cell depletion with a single dose of rituximab.
AKI is a common complication in NS, particularly among patients with initial SRNS, in whom it is attributed chiefly to intravascular volume depletion with severe proteinuria. AKI is recognized as the third most common complication in children with NS requiring hospital admission, affecting 58.6% such patients in a recent multicenter study from the USA; risk factors included concomitant infections, use of nephrotoxic medications and SRNS. Another complication of NS is a hypercoagulable state which predisposes to venous thromboembolism, including cerebral sinus venous thrombosis, pulmonary embolism, and renal vein thrombosis, observed in ~3% of cases of childhood-onset disease. Renal vein thrombosis was one of the earliest recognized complications of NS. We observed thrombotic complications in 0.6% cases, chiefly as deep vein thrombosis of femoral vein, in patients with SRNS. Similarly, a retrospective review on 326 children with NS during 1999-2006, found thromboembolism in 20.4 patients per 1000 patient-years, at median 70.5 days after diagnosis of NS. DVT was the most common (76%) thromboembolism and was frequently associated with the use of a central venous catheter (45%). Independent predictors of thromboembolism included older age (≥12 years), heavy proteinuria, and past history of thromboembolism.
We found causative genetic variations in 8.9% of patients presenting beyond infancy. IN comparison, an international registry reported monogenic cause in 14% of 1340 children with SRNS aged >1-year at onset. We found a monogenic cause most often (52.1% cases) in patients with congenital/infantile onset disease, with variations most commonly noted in NPHS1, NPHS2 and LAMB2. This is consistent with the findings of Sadowski et al., who report that variations in these three genes and WT1 explain 69%–85% of all cases of NS presenting as congenital NS, and 50-66% of cases presenting at 4-12 months age. An international renal genetic study found mutations in six new genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causative of NS in 17 families with partially treatment-sensitive nephrotic syndrome. Even so, overall immunosuppression is not recommended in patients with monogenic disease. Malakasioti et al., reviewed data of 178 patients with monogenic SRNS reported in 22 studies, and found that 35% had complete or partial response to therapy with CNI. Most responders had minimal change as the histology, and changes in WT1 were more common than other variations among responders. Patients with complete response had better kidney survival compared to those with partial or nonresponse (P < 0.01). Unlike our findings, a retrospective study found that a significant proportion of patients with SRNS progress to kidney failure regardless of short-term response to therapy with CNI therapy, often associated with recurrent episodes of AKI.
Expectedly, patient and kidney survival was most satisfactory among patients with SSNS (99% and 94%, respectively, at last follow up) and less satisfactory for primary SRNS (76% and 51%, respectively, at last follow up); over one-fourth of the patients with primary SRNS had progressed to kidney failure requiring KRT in the majority. SRNS is known to be associated with kidney failure in almost half the patients by 15 years. Similarly, Mekahli et al., when retrospectively reporting outcomes in 78 patients with SRNS at eight centers over 20-years, found kidney survival rates of 75%, 58% and 53% at 5, 10 and 15 years, respectively, and found older age at onset (>10-yr) as an independent predictor of kidney failure.
The primary goal in the management of patients with congenital NS in infancy and early childhood is to optimize nutrition and minimize complications, while ensuring adequate growth. Majority of these patients require kidney transplantation. None of our patients with congenital disease underwent kidney transplantation, chiefly due to difficulties in achieving body weight of ≥10 kg (considered a prerequisite for transplantation), high risk of sepsis and ensuing high mortality during infancy (55%). Long-term management of these patients is challenging even after transplant, with emphasis on close monitoring and management in the early posttransplant phase, particularly for graft vascular thrombus.
The major limitation of the study is its retrospective unicentric study design. Its strengths include the large sample size, relatively long duration of follow up, and reporting of outcomes in relation to results of genetic testing and histopathology.
| Conclusion|| |
NS in children represents a challenging chronic glomerular disorder with variable presentation and outcomes. Progression of CKD is more common in patients with primary SRNS, particularly in those with a monogenic cause. In contrast, mortality was highest in patients with congenital/infantile onset. Genetic testing in initial SRNS helps find the precise etiology, and has implications for therapy and prognosis.
The study was approved by the Intitutional ethical research committte at King Abdulaziz university (Approval ID 290-22).
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]