How to cite this article: Alegría-Torres GA, Aguilar-Kitsu MA, Estrada-Loza MJ, Villasís-Keever MÁ. Cardiovascular risk factors in children with primary nephrotic syndrome. Rev Med Inst Mex Seguro Soc. 2015;53 Suppl 3:S284-93.
Received: August 14th 2014
Accepted: September 1st 2015
Gabriela Alejandra Alegría-Torres,a María Alejandra Aguilar-Kitsu,b María de Jesús Estrada-Loza,c Miguel Ángel Villasís-Keeverd
aServicio de Nefrología
bJefatura del Servicio de Nefrología
cServicio de Cardiología
dUnidad de Investigación en Epidemiología Clínica
Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Distrito Federal, México
Communication with: Miguel Ángel Villasís-Keever
Telephone: (55) 56 27 69 00, extensión 22501
Background: It has been suggested that patients with nephrotic syndrome (NS) have an increased frequency of cardiovascular risk factors. The aim of this study was to determine the frequency of cardiovascular risk factors in children with primary NS.
Methods: Cross-sectional, descriptive and prospective study. Fifty-five patients with primary NS were included. The presence of overweight/obesity, hypertension, dyslipidemias, hyperglycemia, elevated C-reactive protein and carotid intima-media thickness (IMT) was evaluated. The treatment time, the type of treatment and the number of relapses were analyzed. For statistical analysis chi-square and Spearman’s rho were used.
Results: The most frequent cardiovascular risk factor was increased carotid IMT (98.1 %), followed by hypertriglyceridemia (54.4 %) and total cholesterol (40 %). Patients with corticosensitive NS had fewer risk factors compared with patients with steroid-resistant NS. There was also a positive correlation of longer time of evolution and number of relapses with the increase in the number of factors.
Conclusions: Ninety-eight percent of children with primary NS had at least one cardiovascular risk factor. Certain clinical features, such as steroid-resistant NS, and the time of evolution and treatment, seem to be related to the presence of larger number of risk factors.
Keywords: Carotid intima-media thickness, Nephrotic syndrome, Obesity, Hypertension, Dyslipidemias.
Nephrotic syndrome (NS) is characterized by the presence of edema, proteinuria, hypoalbuminemia, and hyperlipidemia.1 In children, 90% of cases correspond to primary or idiopathic NS, i.e., when the syndrome is not part of any other causal disease such as systemic lupus erythematosus, syphilis, hepatitis B, HIV, or others.1,2 Primary NS annually presents two to seven new cases per 100,000 children under 18, with a prevalence of 12-16 per 100,000.1-4 About 90% are diagnosed between two and 10 years of age and it is more common in males, with a ratio of 2:1, although this male bias is lost in adolescence.5
The cardinal sign of NS is nephrotic proteinuria, defined by urinary protein/creatinine ratio values > 2 mg/dL in isolated urine samples, or by proteinuria > 40 mg/m2/24 h in 24-hour urine.3,4 Proteinuria is relatively selective for albumin, leading to hypoalbuminemia (albumin < 2.5 g/dL).5,6 A component of NS is hyperlipidemia, which in most patients is temporary and disappears with remission.1-4 However, Kisiazek et al. reported that up to 74% continue to have abnormal lipid levels despite achieving NS remission.7
The mainstay of idiopathic NS treatment is steroids. The usual pattern is the administration of oral prednisone 60 mg/m2/day for four to six weeks, followed by 40 mg/m2 every other day, with gradual decline in a range from 2-5 months. Under this scheme, taking into account the response to corticosteroids, NS is classified as cortisone-sensitive, cortisone-resistant, or cortisone-dependent.3,4 The frequency of steroid-sensitive NS is approximately 80%, while those steroid-resistant are about 20%.1-3 Within the steroid-sensitive group, 70 to 90% of patients develop one or more relapses and up to 60% may develop frequent relapses or steroid dependency.2-4 If remission is not achieved or in cases of steroid-dependent NS, second-line drugs are used such as cyclophosphamide, cyclosporine, mycophenolate, and chlorambucil.3,4
Furthermore, as in other diseases, it has been found that these patients may have increased cardiovascular risk. Thus, we have studied the presence of cardiovascular risk factors such as obesity, systemic arterial hypertension (SAH), dyslipidemia, and impaired glucose metabolism, which together constitute the so-called metabolic syndrome.8,9 There are also reports of the behavior of other factors in these patients, such as the determination of high-sensitivity C-reactive protein (CRP) (of which levels > 3 mg/L are considered a risk factor), or the measurement of carotid intima-media thickness (IMT) by B-mode ultrasound.10,11 All these factors form the basis of physiopathogenic cardiovascular diseases.8,9,12,13
There exist some studies on the prevalence of cardiovascular risk factors in the pediatric population with NS. Tkaczyk et al. studied markers of endothelial dysfunction (thrombomodulin, von Willebrand factor, and plasminogen activator inhibitor-1) in 132 children between 2 and 18 years old at different stages of the disease, and found that these biomarkers increased during relapse, and decreased at later stages, but always remained higher than in the group of healthy children.14 In 2005, Pelkowska and Sancewicz concluded that patients with steroid-dependent and steroid-resistant NS had endothelial dysfunction, after studying the degree of brachial artery dilation measured by flow in 41 subjects from nine to 20.3 years old, who were divided into two groups: the first had 24 patients in remission, listed as steroid-dependent or steroid-resistant; while the second had 17 patients in relapse. Brachial artery flow was below normal In both groups (63 and 52%, respectively).15 Subsequently in 2006, Ksiazek et al. studied the incidence of atherosclerosis in 50 children with idiopathic NS between 5.8 and 16.5 years of age, in whom the average time of disease progression was 7.8 years. IMT was measured in the common carotid and femoral artery; about 75% increase in IMT was found in the carotid.16
Furthermore, it has also been found that obesity and SAH are cardiovascular risk factors, but related to steroid use.5 For example, Nakamura et al. studied the body mass index (BMI) of 30 Japanese children with steroid-sensitive NS; they reported an obesity rate of 28.6 to 31% and observed a relationship of BMI with steroid dose and exposure time.17 Regarding SAH, it has been described that about 50% of patients with NS may present SAH, which can be associated with steroid use or also a state of hypervolemia.5
Existing information on the frequency of cardiovascular risk factors in children with primary NS is limited, so the aim of this study was to determine the prevalence of overweight/obesity, dyslipidemia, hypertension, elevated high-sensitivity C-reactive protein, and increased carotid intima-media thickness in children with primary nephrotic syndrome.
Observational, cross-sectional, descriptive, prolective study conducted at the Unidad Médica de Alta Especialidad Hospital de Pediatría of the Centro Médico Nacional Siglo XXI of the Instituto Mexicano del Seguro Social, in the Servicio de Nefrología Pediátrica, from September 2013 to January 2014. It included patients with primary NS, more than eight weeks of progression, from 1 to 16 years of age, of both sexes. We excluded patients with creatinine clearance < 60 mL/min/1.73 m2 sc, and patients with clinical evidence of infectious disease or edema. The selection of patients was non-probabilistic, with consecutive cases, in the order that they came to the nephrology department for evaluation and agreed to participate in the study.
Before the study, the research project was approved by the Local Ethics Committee on Health Research at the hospital. For participation, the patients' parents were asked to sign informed consent, while patients over eight signed a letter of informed consent as well.
The variables studied were: age, sex, nutritional status (according to BMI they were considered obese when at or above 95 percentile for sex and age, and overweight between 85 and 94 percentile), serum albumin, and proteinuria. NS was classified according to the definitions of Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group,3 into: steroid-sensitive (frequent or infrequent relapses), and steroid-dependent or steroid-resistant. Other variables were the time with NS (time from diagnosis to the time of the study period), current treatment, clinical status (remission or active disease), and number of relapses. For definitions of total hypercholesterolemia, LDL hypercholesterolemia, low HDL levels, and high triglycerides, the guidelines of the American Academy of Pediatrics were used.18 As such, it was considered hyperglycemia if the levels were > 100 mg/dL, increased levels of high-sensitivity CRP with values > 3 mg/L, and hypertension when BP was > 95th percentile for height and age.19
Once the study was approved, patients were identified with a diagnosis of primary NS who met the inclusion criteria. Patients who were accepted underwent measurement of weight, height, blood pressure by auscultation (after standardization), and sampling of fasting blood and urine to determine lipids, glucose, creatinine, high-sensitivity CRP, and albumin in blood, and determination of proteins in 24-hour urine. These tests were processed in the central laboratory. A single researcher performed carotid IMT measurement using Doppler USG in both common carotids based on the recommendations of the international consensus on radiology.20 Three measurements were made in each carotid and average measurements obtained. Phillips Sonos 5500 high-resolution ultrasound and a transducer > 7 MHz with gain optimization were used; carotid IMT was calculated into percentile and, based on data from Shroff et al.,21 IMT was considered increased when it was > 90th percentile for age. Prior to the measurement of carotid IMT in children with NS, measurement was standardized in 12 healthy children ages 1-13 years. All children underwent a conventional transthoracic echocardiography with 5 MHz transducer. Left ventricular hypertrophy (LVH) was considered ventricular mass > 110 grams.
For the statistical analysis, descriptive analysis was performed according to the scale of measurement of each of the variables, calculating measures of central tendency and dispersion. The variables with qualitative scale are presented in absolute numbers and percentages, while quantitative variables are presented with median as a measure of central tendency and measures of dispersion such as minimum and maximum values. Correlation of quantitative variables was performed with Spearman’s rho, while comparison of cardiovascular factors with patient characteristics was done with chi-squared. P values < 0.05 were considered statistically significant.
The study included 55 children with a diagnosis of primary NS, whose clinical and biochemical characteristics are described in Table I. Males predominated with 67.3% versus 32.7% of females, with a median age of eight years (range from one to 16). Of the 55 cases, the time of disease ranged from two to 156 months, with a median of 39 months. Of the patients, 14 were classified as steroid-sensitive (24.4%), 17 as steroid-dependent (30.9%), and 24 as steroid-resistant (43.6%). Forty-eight patients were in remission and seven patients had active disease without edema; the latter had steroid-resistant behavior. Regarding histological variety, 53 patients had renal biopsy at the time of study, of which 38.1% had minimal change, 36.3% mesangial proliferation, and 21% focal segmental glomerulosclerosis.
|Table I Clinical and histological characteristics of patients with nephrotic syndrome|
|Systolic blood pressure (mmHg)||100||80-134|
|Diastolic blood pressure (mmHg)||68||50-89|
|Type of nephrotic syndrome|
|Histological variety of nephrotic syndrome?|
|Minimal changes||21||38.1 *|
|Mesangial proliferation||20||36.3 *|
|Focal segmental glomerulosclerosis||12||21 *|
|Time of disease (months)||39||2-156|
|Time before first remission (weeks)||10.5||1-288|
|Number of relapses||3.5||0-15|
|Active disease||7||12.7 *|
|*Values expressed as absolute frequencies and percentages
?Five patients had no test
The biochemical and echocardiographic characteristics are described in Table II, which shows that median albumin, proteinuria, glucose, lipids, and CRP were within normal values.
|Table II Biochemical characteristics and carotid IMT of 55 children with primary nephrotic syndrome|
|Total cholesterol (mg/dL)||171.2||99-574.6|
|HDL cholesterol (mg/dL)||51.8||20.92-127.73|
|LDL cholesterol (mg/dL)||83.9||43.60-426.35|
|Carotid IMT (mm)||1.2||0.3-3|
|Carotid IMT = carotid intima-media thickness; HDL cholesterol = high-density lipoprotein; LDL cholesterol = low-density lipoprotein; PCR = C-reactive protein|
As for current treatment, 30 patients (54.5%) had treatment with calcineurin inhibitors (28 with cyclosporine and two with tacrolimus), 28 (50.9%) received steroids, 11 (20%) cyclophosphamide, seven (12%) were without drug treatment, two (3.6%) mycophenolate mofetil, and another two (3.6%) enalapril as an antiproteinuric. Of the 28 patients receiving steroids, 89% were taking another immunosuppressant.
Carotid IMT measurement and echocardiographic values
Carotid IMT was measured for the 55 patients, and they underwent an echocardiographic evaluation; after doing this we found that 98% had IMT above the 97th percentile for their age, with a median of 1.2 mm (minimum 0.3 mm and maximum 3 mm), and although it was not statistically significant (p = 0.15), a median of 1.0 mm was observed in those who were steroid-sensitive versus 1.2 mm in those steroid-resistant. The only case in which carotid IMT was within normal reference values was that of a patient with less than six months duration of NS, classified as steroid-sensitive without other cardiovascular risk factors. Furthermore, it was shown that 14 (25.4%) of the 55 patients had a ventricular mass greater than 110 g (with a variation in the 55 children from 28 to 191 grams), which translates to left ventricular hypertrophy.
Cardiovascular risk factors
It was reported that 98.1% of cases had carotid IMT in the 97th percentile for their age, 54.5% hypertriglyceridemia, 40% total hypercholesterolemia, 29% high LDL cholesterol, 23.6% obesity, 40% combined overweight/obesity, 16.3% CRP greater than 3 mg/L, 12.7% SAH, and 5.4% low HDL (Table III).
|Table III Cardiovascular risk factors in children with primary nephrotic syndrome|
|Risk factors||N = 55|
|Carotid IMT > 97 percentile||54||98.1|
|High LDL cholesterol||16||29.0|
|CRP > 3 mg/L||9||16.3|
|Low HDL cholesterol||3||5.4|
|Carotid IMT = carotid intima-media thickness;
high LDL cholesterol = elevated low-density lipoprotein; PCR = C-reactive protein;
low HDL cholesterol = low high-density lipoprotein
As shown in Figure 1, in the 54 patients for whom any risk factor (one to six factors) was detected, it was most common to have two factors (30%), followed by three factors (20%). The most frequent combination of factors was increased carotid IMT plus hypertriglyceridemia (47%).
Figure 1 Number of cardiovascular risk factors in children with primary nephrotic syndrome
When comparing the population by dividing by response to steroids (Table IV), we saw that steroid-sensitive patients had lower frequencies of obesity, hypertension, total hypercholesterolemia, low HDL cholesterol, and hypertriglyceridemia. However, only hypertriglyceridemia was statistically significant.
|Table IV Frequency of cardiovascular risk factors by response to steroids|
|Low HDL cholesterol||0||0||1||5.8||2||8.3||0.54|
|High LDL cholesterol||4||28.5||5||29.4||7||29.1||0.99|
|Carotid IMT > p97||13||92.8||17||100||24||100||0.15|
|CRP > 3 mg/L||1||7.1||5||29.4||3||12.5||0.61|
|Number of risk factors|
|* Chi-squared was used|
It was also observed that steroid-sensitive patients had fewer cardiovascular risk factors, and 70% had two or fewer risk factors unlike those steroid-resistant, of whom 62.4% of cases had three or more, although this was not statistically significant.
Considering whether the patients were in remission or not, hypertriglyceridemia, total hypercholesterolemia, and LDL cholesterol were more common in those with active disease, but only hypertriglyceridemia and LDL cholesterol were statistically significant.
We also found that although there is no relationship between carotid IMT and time of development of NS (rho = 0.021, p = 0.87), there a relationship between time of development and BMI (rho = 0.37, p = 0.005), DBP (rho = 0.30, p = 0.02), left ventricular mass (rho = 0.33, p = 0.13), and CRP (rho = 0.23, p = 0.08) (Figure 2). We also observed a trend that the greater the number of relapses, the more cardiovascular risk factors (rho = 0.27, p = 0.05).
Figure 2 Correlation between cardiovascular risk factors and time of progression of primary NS
In this study we explored the frequency of some traditional and some non-traditional cardiovascular risk factors, such as obesity, hypertension, dyslipidemia, and high-sensitivity CRP, as well as seeking the presence of subclinical atherosclerosis through determination of carotid IMT in patients with primary NS of pediatric age in the Mexican population, which so far had not been studied.
Primary NS patients receive treatment with steroids for a time ranging from 4 to 28 weeks,5 which may cause increase in body mass index and therefore the presence of obesity. In 2010, Nakamura et al. retrospectively studied 30 Japanese children with primary NS in order to assess changes in BMI after the end of steroid therapy, by dividing the population into those who remained obese (Group 1) and those who lost weight (Group 2); after 19 and 17 months of follow-up, respectively, these authors found an obesity frequency of 28.6% for Group 1 and 31% for Group 2; they concluded that the group with more weight retention had higher steroid doses and longer exposure time.17 In our study we documented an obesity rate of 23% and found a correlation between BMI and time of disease progression, data consistent with the aforementioned literature.
SAH is another complication of patients with NS. It is present in 13 to 51% of cases, and can be associated with hypervolemia and the adverse effects of steroids and cyclosporine;5 however, blood pressure figures are expected to improve with remission. The frequency of hypertension in our study was 12.7%. This frequency is similar to that reported by Candan et al. in 2014, who studied 37 children aged 7.9 to 18.8 years of age with primary steroid-resistant NS and compared them with a control group of 22 healthy children; they included children both in remission and relapse but with a GFR > 90 mL/min/1.73 m2 sc. Their main objective was the search for subclinical cardiovascular disease by determining left ventricular mass, increased IMT, pulse wave velocity, and ambulatory BP monitoring for 24 hours. They also obtained the last-year averages of proteinuria, total serum cholesterol, LDL, triglycerides, and albumin; measured hs-CRP, ferritin, and fibrinogen; and calculated the cumulative dose of steroids and cyclosporine. This group found a frequency of hypertension of 14%; however, these researchers measured BP by monitoring every half hour during the day and every hour at night for 24 hours, and unlike our study population, the majority of their cases were managed with ACEI or ARB. One finding that stands out from this study is that hypertension was predominantly at night and that there was a high prevalence of absence of the expected decline in BP during sleep.22 In our study, although we did not find such a high frequency of SAH, our patients were not in an edematous phase; however, the determination of BP was done at only one moment.
On the other hand, although measurement of left ventricular mass was not part of our objective, this was done to all children as part of the echocardiographic assessment, and we documented a 30% frequency of LVH. This finding is similar to that recently reported by Hooman et al. in 2013. The latter group studied carotid IMT and left ventricular mass in 51 children with primary NS who had at least one year of disease progression, GFR greater than 20 mL/min/1.73 m2 sc. The study included steroid-sensitive, steroid-dependent, and steroid-resistant children (and excluded children with edema) and compared them with a group of 75 healthy children; it was found that 41.7% of children with NS had LVH (p < 0.001), and there was a correlation between LVH and carotid stiffness (p = 0.005), proteinuria (p = < 0.001) and SAH (p = 0.019). Multivariate analysis revealed that ventricular mass index was mainly affected by SAH (p = 0.004). They moreover suggest that changes in carotid parameters occur early before LVH appears.23 In our study, out of the 14 patients with LVH, none were found hypertensive at the time of study; however, this hypertrophy could be explained by a state of hypertension at some point in their illness; on the other hand, we cannot say that SAH is the only reason for a patient with NS to have LVH, as this can also be explained by subclinical pulmonary microthrombosis, dyslipidemia, and obesity. The latter two conditions were found in our other patients because, out of the 14 cases with LVH, 43% were obese, 57% were overweight, 50% had hypertriglyceridemia, and 43% total hypercholesterolemia.
Dyslipidemia is a condition expected in children with NS and it is the most common lipid abnormality due to the high concentration of total cholesterol and LDL. These abnormalities are related to hypoalbuminemia, which determines reduction in plasma oncotic pressure and, in turn, increased hepatic synthesis of low-density lipoprotein (LDL), increased activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoAr), increased blood viscosity, and excessive purification of high density lipoprotein (HDL) and lecithin-cholesterol acetyltransferase (LCAT).1,2,4,12 However, this is expected to resolve with remission.1-5
Kziazek et al. published in 2009 a study of 50 patients with primary NS in remission, in which they looked for correlation between the persistence of lipid abnormalities during NS remission, and genetic polymorphism of the proteins involved in metabolism of lipoproteins, in which they included a total of 50 children with primary NS, of which 12 were steroid-resistant and 38 steroid-dependent, with a time of disease progression from 2.6 to 13.8 years. In 46 cases lipid profile was evaluated after eight weeks of remission, and in four cases of partial remission. The frequency of dyslipidemia was 74%.7 In the same study by Candan et al., the authors evaluated the presence of dyslipidemia and reported that 54% had total hypercholesterolemia > 200 mg/dL, 11% had HDL < 35 mg/dL, and 43% had LDL > 130 mg/dL, although it must be mentioned that 37% of the study population had hypoalbuminemia and proteinuria.22 The most common lipid abnormality in our study population was hypertriglyceridemia with 54.4%, followed by total hypercholesterolemia with 40%, and thirdly high LDL with 29%.
In 2008 Tkaczy et al. reported that most children with idiopathic NS had elevated levels of markers of endothelial lesion. These conclusions were obtained by studying 132 children with NS between ages 2 and 18, who were divided into four groups: one group in the acute phase of the disease, with proteinuria in the nephrotic range; another group during remission but still managed with steroids; another in steroid-free remission for five to ten months; and a fourth group in remission and steroid-free for over two years. All of them were measured for serum thrombomodulin, plasminogen activator inhibitor, and von Willebrand factor activity, all proposed as markers of endothelial lesion. These measurements were compared with a control group of 41 healthy children, and they found that the three markers studied were high, regardless of the phase of illness, although this increase was more pronounced in early relapse; however, both thrombomodulin and plasminogen activator inhibitor decrease as remission is achieved and with the passage of time, but never reach normal, unlike the von Willebrand factor, which remains high all the time. This condition may accelerate atherogenesis in patients with NS.14
Another biochemical marker proposed to detect endothelial lesion and subclinical atherosclerosis is the determination of high-sensitivity PCR. Currently its elevation is considered an independent risk factor for developing cardiovascular disease. The utility of measuring CRP in obese and hypercholesterolemic children has been suggested, and CRP concentration > 3 mg/L has been linked with higher systolic BP values in children and adolescents.24 It has also been proposed that in overweight or obese children, elevated CRP levels are associated with increased IMT. However, the results are not consistent; in Chile, Acevedo et al., studying 112 healthy children with a mean age of 11.3 years, measured ultra-sensitive CRP, dilation of the brachial artery, and carotid IMT using ultrasound, and reported a significant correlation between CRP levels and the degree of adiposity, but not with subclinical atherosclerosis parameters.25
In children with primary NS, Hooman et al. (study cited above) found no correlation between CRP and signs of cardiovascular disease, with mean serum concentration of hs-CRP of 0.4 mg/L.23 Our study also determined serum concentration of hs-CRP as a cardiovascular risk factor, and we found that 16% of the population had levels above 3 mg/L, with a median of 0.63 mg/L, a frequency that we might think would be higher when taking into account the proportions found of obesity, dyslipidemia, and increased carotid IMT; however, it should be mentioned that out of the nine patients with high PCR, two had obesity and two total hypercholesterolemia.
It is thought that idiopathic NS in adults can be a major risk factor for accelerated atherosclerosis; however, the role of this syndrome in the development of atherosclerosis in children is not clear: it is thought that periods of lipid abnormalities, steroid exposure, and time of disease progression may increase the risk of premature atherosclerosis.22
There are few studies designed to determine morbidity and mortality from cardiovascular events in adults who have had primary NS. Lechner et al. in 2004, on this topic, after studying a cohort of 40 out of 62 patients aged 25 to 53 years with a history of steroid-sensitive/steroid-dependent NS during childhood, in order to determine the frequency of cardiovascular events (CVE), found a frequency of CVE similar to the general population of the same age (8%); the cases with acute myocardial infarction (three) had other risk factors such as type 2 diabetes, hypertension, dyslipidemia, and one of them also consumed cocaine, and there were no deaths from any cause attributed to CVE.26
Furthermore, in addition to steroid exposure and dyslipidemia, NS patients often have additional risk factors such as SAH, obesity, inflammation, and longtime use of immunosuppressants such as cyclosporin A; Candan et al. found in their 2014 study that children with primary NS had significantly higher carotid IMT values, pulse wave velocity in the aorta and ventricular mass, compared with the control group (p < 0.001 for all). Average carotid IMT was 0.44 ± 0.22 mm vs. 0.30 ± 0.03 mm in the control group, p = 0.001; eight patients (22%) had an increase in IMT. Furthermore, they only found correlation between increased IMT and the presence of elevated proteinuria after multivariate regression analysis (R2 = 0.141, beta = 0.375, p = 0.022). An important point to note in this study is that 50% of cases took ACEI/ARB and 31% statins, which can impact results, the drugs being associated with a potentially protective effect for atherosclerosis.22
Hooman et al., in their 2013 publication, reported that average carotid IMT in children with NS was 0.42 mm (+ 0.14), whereas in controls it was 0.37 (+ 0.08). The factor that influenced IMT increase was duration of disease (p < 0.05), and no significant differences were found between those steroid-sensitive, steroid-dependent, or steroid-resistant in this study. As in Candan et al., the majority of children with NS were managed with ACEI or ARB, and 47% with statins.23 In our study we found that 98.1% of the population has increased carotid IMT, with an average well above the values considered normal in the pediatric population, and even the values obtained in the healthy children with whom IMT measurement was standardized in this study. We also found no correlation between IMT and response to steroids, nor with the time of progression as found by Hooman; a difference in our population compared to the patients studied by Candan et al. and Hooman et al. is that only 3.6% of our cases took ACEI and no patients used statins.
A limitation of this study, which should be considered in interpreting the results, is, on the one hand, the sample size, which could have affected the statistical analysis. Another limitation is that this is a cross-sectional study not designed to determine which factors are involved in causation; it also has unexplored confounding variables, such as family history of high cholesterol, family history of SAH, doses of immunosuppressives, cumulative steroid dose, dietary habits, and management and clinical and biochemical status prior to follow-up in this unit. Furthermore, the results cannot be generalized to all cases of NS, since our study population has the feature that most cases were referred to this unit for care due to non-response to treatment with steroids after a period of treatment in general hospitals. However, the strengths of this study are that it included patients with different clinical and biochemical behavior, cases with a long period of illness were included, and that only one person did the assessments of carotid IMT and echocardiography.
In this study, ~ 98% of children with primary NS have at least one cardiovascular risk factor due to increased carotid IMT, 50% have two or three cardiovascular risk factors, the most frequent combination of which is increased carotid IMT and dyslipidemia. The second and third most common risk factors were dyslipidemia (55%) and overweight/obesity (40%), respectively. Certain clinical features, such as steroid resistance and number of relapses, appear to be related to the presence of a greater number of cardiovascular risk factors.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.