ABSTRACT
Introduction
Nephrotic syndrome (NS) is one of the most common childhood kidney diseases. Thromboembolic (TE) events are among the most serious complications of NS in children, with a reported prevalence of 1.8–5%. Venous thromboembolism (VTE) is the predominant type. Most cases of TE are clinically symptomatic, but some may be subclinical, thus, their true incidence may be underestimated. Studies on TE in childhood onset NS are few and varied, this prompted us to conduct the present study.
Objective
To study the pattern of thromboembolism in childhood INS.
Patients and Methods
This descriptive retrospective study included 225 pediatric patients with idiopathic NS (11 with TE events and 214 with no TE events) regularly following up in Alexandria University Children’s Hospital, Egypt from 2013 to 2023. Diagnosis of thromboembolism was based on clinical diagnosis and appropriate diagnostic imaging.
Results
The frequency of TE among our cohort was 4.9%.The median age of onset of the first TE event was 5.5 years. Most of the TE events (63.6%) occurred during the 1st 6 months of NS diagnosis. The total number of TE events was 15 events, and the most common site was cerebral sino-venous thrombosis (CSVT). The triglyceride levels were significantly higher in the TE event group. The median urinary protein/creatinine ratio was slightly higher in the TE event group. In the TE event group, 4 patients (36.4%) were steroid-resistant and only one of the 11 patients died.
Conclusion
In conclusion, TE events are not uncommon among INS children and most of the events occurred early during the disease. There was no significant relationship between the degree of proteinuria, serum albumin level, and the occurrence of TE events, while the level of triglycerides was significantly higher in patients who developed TE events.
1. Introduction
Nephrotic syndrome (NS) is one of the most common childhood kidney diseases, characterized by nephrotic range proteinuria, hypoalbuminemia, generalized edema, and hyperlipidemia [Citation1,Citation2].
The prevalence of childhood NS worldwide is approximately 16 cases per 100,000 children, with an incidence of two to seven per 100,000 children. Idiopathic NS (INS) can affect children of any age from infancy to adolescence and predominantly occurs in those aged 1–6 years [Citation2]. Thromboembolic (TE) events are among the most serious complications of NS [Citation3,Citation4].
Venous thromboembolism (VTE) is the predominant type of TE in INS children. Although most reported cases of VTE in NS children were clinically symptomatic and diagnosis was confirmed by imaging, it should be noted that subclinical VTE may still be more common in childhood NS than is previously thought [Citation5]. Arterial thrombosis is less common in NS [Citation6]. Thrombosis can occur in any vessel in patients with NS, but the most common sites are deep vein thrombosis (DVT) of the lower limbs, renal vein thrombosis (RVT) and pulmonary embolism (PE) [Citation7]. The incidence of cerebral sino-venous thrombosis (CSVT) in children is much lower than that in adults, though the true incidence may be underestimated for many events that are asymptomatic, mildly symptomatic or had a delay in diagnosis [Citation2].
Although reports, observational studies and systematic reviews carried out on the frequency and risk factors of TE events in NS are few and varied, and most have been done on adult patients [Citation6,Citation8–15], the reported prevalence of TE in childhood NS is 1.8–5% and the mortality of NS due to TE in children is reported to be approximately 8.5%, and is especially high for cerebral venous thrombosis, being as high as 10% [Citation9,Citation11,Citation16–19].
Data on TE in childhood INS are still limited. This prompted us to conduct the present study.
2. Patients and methods
This was a descriptive retrospective study including 225 pediatric patients with idiopathic nephrotic syndrome regularly following up from 2013 to 2023. Patients included 2 groups, the first group (NS patients with TE events) including 11 patients, and the second group (NS patients with no TE events) including 214 patients.
Nephrotic syndrome was diagnosed according to the International Pediatric Nephrology Association (IPNA) criteria [Citation20]. Diagnosis of thromboembolism (e.g. cerebral sino-venous thrombosis [CSVT], renal vein thrombosis [RVT], deep vein thrombosis [DVT], pulmonary embolism [PE], intracardiac thrombosis and internal carotid artery [ICA] thrombosis) was based on clinical diagnosis and confirmed by appropriate diagnostic imaging.
Data collected from the patients were the age of onset of NS, age of the first TE event, age at the time of the study, sex, and the type and site of the TE event.
2.1. Statistical analysis
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp). Qualitative data were described using numbers and percentages. The Kolmogorov-Smirnov test and Shapiro-Wilk test were used to verify the normality of distribution. Quantitative data were described using range (minimum and maximum), mean, standard deviation, median and interquartile range (IQR). The significance of the obtained results was judged at the 5% level.
2.2. The used tests were
1 - Chi-square test
For categorical variables, to compare between different groups
2 - Fisher’s Exact or Monte Carlo correction
Correction for chi-square when more than 20% of the cells have expected count less than 5.
3 - Student t-test
For normally distributed quantitative variables, to compare between two studied
4 - Mann Whitney test
For not normally distributed quantitative variables, to compare between two studied groups
3. Results
A total of 225 patients diagnosed with INS were studied of which 11 patients developed TE events during the study period, with a frequency of 4.9% ().
Table 1. Distribution of the studied cases according to the occurrence of TE events (n = 225).
The demographic and anthropometric data of the studied patients are presented in (). At the onset of the disease, the median age of the patients was 4 years for both groups, and at the time of enrollment in the study, their ages ranged from 1.5 to 21 years with median of 10 years for the TE event group and 10.5 years for the no TE event group. The male: female ratio was 2.3:1.Thus, no statistically significant difference between the 2 studied groups as regards the age of onset of the disease, the age at the time of enrollment of the study nor the gender could be detected.
Table 2. Comparison between the two studied groups according to the demographic data.
In the TE event group, the duration from the diagnosis of NS till the onset of the first TE event varied from 1 to 48 months with a mean of 10.82 ± 14.08 months. The age onset of the first TE event ranged from 1.25 to 10.08 years with a median of 5.5 years. Most of the TE events (63.6%) occurred during the early course of the disease (1st 6 months of NS diagnosis) ().
Table 3. Distribution of the studied cases according to the age of the event and the duration till the onset of thrombosis in the event group (n = 11).
The total number of TE events was 15 events (all occurred during active proteinuria [some at the onset and some at relapses of NS]), their sites are shown in . The most common site was CSVT (6 events), followed by PE (3 events) and DVT (3 events), other sites of thrombosis included intracardiac thrombosis (1 event), RVT (1 event) and ICA thrombosis (1 event). Four patients (36.4%) developed more than one TE event, one developed DVT followed by intracardiac thrombus 2 years later, the second developed DVT followed by PE, the third developed PE and CSVT simultaneously, and the fourth developed DVT and CSVT simultaneously.
Table 4. Distribution of the studied cases according to the site of thrombosis in the event group (n = 11).
The lipid profile during proteinuria (some at the onset and some at subsequent relapses of NS) showed that triglycerides (TG) were elevated in about 88% of the patients, and the total cholesterol level was elevated in about 94% of the patients. All patients with TE events showed elevated TG and cholesterol levels, the mean TG level was higher in the TE event group than the no TE event group and this difference was statistically significant, while the mean cholesterol level was higher in the no TE event group than the TE event group, but this difference was not statistically significant ().
Table 5. Comparison between the two studied groups according to the lipid profile and the serum albumin.
Serum albumin was low in all patients during proteinuria (with the diagnosis of NS or with subsequent relapses), with no statistically significant difference in the albumin levels between the 2 groups ().
The median urinary protein/creatinine ratio was 7.69 mg/mg during proteinuria (some at the onset and some at relapses of NS), the level of proteinuria was slightly higher in the TE event group than the no TE event group, but this difference between the two groups as regards the level of proteinuria was not statistically significant ().
Table 6. Comparison between the two studied groups according to the urinary protein/creatinine ratio.
In the TE event group, 4 patients (36.4%) were steroid resistant and 7 patients (63.7%) were steroid sensitive, also the percentage of steroid resistant NS (SRNS) was 36.4% in the TE event group vs 25.2% in the no TE event group, but this difference was not statistically significant. During the study period, 4 patients (1.8%) died, one of them was from the TE event group (out of 11 patients with a percentage of 9.1%), this patient had a huge intra atrial thrombus ().
Table 7. Comparison between the two studied groups according to response to steroids.
4. Discussion
Nephrotic syndrome (NS) is one of the most common childhood kidney diseases, characterized by nephrotic range proteinuria, hypoalbuminemia, generalized edema, and hyperlipidemia. TE is one of the major and serious complications of childhood NS [Citation1,Citation2,Citation18].
Studies about the frequency TE events in NS are few and varied, and most have been done on adult patients [Citation6,Citation8–15]. The present work was designed to study the frequency of TE events in childhood INS.
In the current study, the percentage of patients with TE events was 4.9%. This percentage is close to published data (4–5%) [Citation11,Citation21,Citation22]. Some studies reported a lower incidence of 1.8–3% [Citation9,Citation23,Citation24]. Kerlin et al. reported a higher percentage reaching 9.2% which was explained by inclusion of patients with secondary NS, with a much higher percentage reaching 28.1% reported by Zhang et al. where he underwent screening computed tomographic pulmonary angiography and computed tomographic renal angiography [Citation10,Citation12].
The mean age of onset of NS in patients with TE events was 5.05 ± 2.87 years, slightly higher than that of the no TE event group, but this difference was not statistically significant. This shows that the age of onset of NS does not affect the frequency of the TE events in pediatric patients with idiopathic NS in our study. Similar results were mentioned by Nijad et al. [Citation19] in their study on 43 INS pediatric patients (8 patients with TE events and 35 patients with no TE events) where the age of onset of NS did not affect the frequency of occurrence of TE events.
The male-to-female ratio was 2.3:1. Specific data on sex influence on the prevalence of TE in pediatric patients with NS are limited. Our results showed male predominance in the TE event group which was consistent with reports from Boussetta et al. [Citation25] and Yan-Li et al. [Citation26] On the contrary, Nejad et al. [Citation19] Reported a more prevalence of TE among girls with NS with a female-to-male ratio of 3:1. Branchford et al. reported a ratio of 1:1 [Citation27].
The duration from the onset of NS till the occurrence of the first TE event ranged from 1 month to 48 months, most of the TE events (63.6%) occurred during the 1st 6 months of NS diagnosis and 81.8% occurred during the first year of diagnosis, either with the first presentation or with subsequent relapses. Andrew et al. [Citation8]and Kerlin et al.[Citation10] reported similar findings where most of the TEs developed within 3 months of NS diagnosis.
All the patients had one TE event, except 4 patients (36.4%) who had 2 TE events each. In a Midwest Pediatric Nephrology Consortium (MWPNC) study[Citation10] , a comprehensive chart review identified 326 children with NS, TE events occurred in 30 of them, out of which 7 (23%) had more than one TE event. In a Brazilian study, 2 of the 9 NS patients with thrombosis (22%) had two episodes at different times [Citation29].
As regard the sites of thrombosis, cerebral venous sinuses were the most common site (54.5%) followed by DVT and PE (27.3% each). In concordance with our study, cerebral venous sinuses were the most common site for thrombosis in a Tunisian study by Boussetta et al. [Citation28] and an Indian study by Suri et al. [Citation11]. Some studies reported that DVT was the most common site of thrombosis [Citation10,Citation19]. RVT was the most common site of thrombosis followed by PE as described in a Chinese retrospective study [Citation26]. Lilova et al. reported no CSVT in their study and the cerebral event was middle cerebral artery thrombosis[Citation23].
The lipid profile showed that triglycerides and total cholesterol level were elevated in most of the patients during proteinuria (some at the onset and some at relapses of NS). All patients with TE events showed elevated TG and cholesterol levels, the mean TG level was higher in the TE event group (392.7 ± 128.9) than the no TE event group (321.9 ± 174.2) and this difference was statistically significant. Thus, TG level may be a factor that increases the risk of TE. Al-Bahrani in 2017 showed that TG and cholesterol levels were significantly increased in NS patients and showed that dyslipidemia can lead to TE complications and cardiovascular risks[Citation30]. Similar results were reported in other pediatric and adult studies[Citation29,Citation31].
Serum albumin was low in all patients during proteinuria (some at the onset and some at relapses of NS), with no statistically significant difference in the albumin levels between the 2 groups. Similar results were reported by Kerlin et al. where serum albumin nadir (1.8 g/dl) was not predictive of TE. On the contrary, Nejad et al. [Citation19] reported that serum albumin level in the 8 NS patients with TE was significantly lower than the 35 NS patients with no TE events. Studies showing a significantly lower serum albumin level in patients with NS and TE events were described in adult studies [Citation13,Citation32,Citation33].
In the current study, all TE events occurred during the proteinuric state, similar results were reported in the literature [Citation23,Citation34]. Other studies showed that some of the TE events occurred during remission of NS [Citation9,Citation11,Citation29]. The effect of the degree of proteinuria on the occurrence of TE is a matter of controversy. In the current study the median protein/creatinine ratio was 9.0 mg/mg, and there was no statistically significant difference as regards the degree of proteinuria between the two groups, suggesting that the degree of proteinuria does not significantly increase the likelihood of developing TE in children with INS. Kerlin et al. reported that heavy proteinuria was independently a predictive risk for TE in pediatric NS [Citation10].
The pattern of NS (response to steroid therapy) showed that most patients were steroid sensitive (complete resolution, steroid dependent NS (SDNS), frequent and infrequent relapser NS), and only 24% were steroid resistant. In the TE event group, the percentage of SRNS was 36.4% vs 25.2% in the no TE event group, but this difference was not statistically significant. Boussetta et al. [Citation25] reported a close percentage (36.8%) of SRNS, Candelaria et al. reported a 22% of SRNS [Citation29], while Lilova et al. [Citation23] reported a 44.4% among their cohorts. Some studies reported that SRNS was the prevailing pattern in nephrotic patients with TE events [Citation26,Citation34].
The outcome of TE was favorable with complete resolution of thrombosis and no subsequent sequelae in 10 patients (91%), while one patient (9.1%) died from obstructive shocked caused by the huge intracardiac thrombus. Tavil et al. reported that 70.5% of the patients resolved without sequelae, 17.6% had sequelae and 11.7% died (deaths were due to other causes than thrombosis, e.g. sepsis, multiorgan failure, … etc.) [Citation34]. Andrew et al. [Citation35] reported that 7% of the patients died while Lv et al. [Citation26] reported no deaths in their study.
5. Conclusion
In conclusion, this study showed that the frequency of TE events is not uncommon among INS children and most of the events occurred early during the course of the disease. The most common site of thrombosis was the cerebral vessels. There was no significant relationship between the degree of proteinuria, serum albumin level, and the occurrence of TE events, while the level of triglycerides was significantly higher in patients who developed TE events.
Abbreviations
| NS | = | nephrotic syndrome |
| INS | = | idiopathic nephrotic syndrome |
| TE | = | thromboembolism |
| VTE | = | venous thromboembolism |
| DVT | = | deep vein thrombosis |
| RVT | = | renal vein thrombosis |
| PE | = | pulmonary embolism |
| CSVT | = | cerebral sino-venous thrombosis |
| ICA | = | internal carotid artery |
| TG | = | triglycerides |
| SRNS | = | steroid resistant nephrotic syndrome |
| MWPNC | = | Midwest Pediatric Nephrology Consortium |
| SDNS | = | steroid dependant nephrotic syndrome |
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Notes on contributors
Moustafa Mahmoud Mohamed Marei
Moustafa Mahmoud Mohamed Marei Assistant lecturer of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Email: [email protected]
Mahmoud Mohiel-Din El-Kersh
Dr. Mahmoud Mohiel-Din El-Kersh Professor of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Email: [email protected]
Mohamed alaa-Eldin Hassan Thabet
Dr. Mohamed alaa-Eldin Hassan Thabet Professor of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Email: [email protected]
Dalia abdel moaty ibrahim Elneily
Dr. Dalia abdel moaty ibrahim Elneily professor of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Email: [email protected]
Nancy abdel-salam Kamel
Dr. Nancy abdel-salam Kamel Lecturer of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Email: [email protected]
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