Pediatric Nephrology (2018) 33:2299–2309

https://doi.org/10.1007/s00467-018-4036-x

ORIGINAL ARTICLE

Effect of atorvastatin on dyslipidemia and carotid intima-media

thickness in children with refractory nephrotic syndrome: a randomized
controlled trial
Pankaj Hari 1 & Priyanka Khandelwal 1 & Amit Satpathy 1 & Smriti Hari 1 & Ranjeet Thergaonkar 1 & R Lakshmy 2 &
Aditi Sinha 1 & Arvind Bagga 1

Received: 10 April 2018 / Revised: 18 July 2018 / Accepted: 25 July 2018 / Published online: 8 August 2018
# IPNA 2018

Abstract
Background Dyslipidemia is an important cardiovascular risk factor in steroid-resistant nephrotic syndrome (SRNS). Efficacy of
statins for treatment of hyperlipidemia in children with SRNS is unclear.
Methods This prospective, randomized, double-blind, placebo-controlled, parallel-group clinical trial enrolled 30 patients with
SRNS, aged 5–18 years, with serum low-density lipoprotein cholesterol (LDL-C) levels between 130 and 300 mg/dl, to receive a
fixed dose of atorvastatin (n = 15, 10 mg/d) or placebo (n = 15) by block randomization in a 1:1 ratio. Primary outcome was
change in serum LDL-C at 12 months. Change in levels of other lipid fractions, carotid intima-media thickness (cIMT), flow-
mediated dilation (FMD) of the brachial artery, and adverse events were also evaluated.
Results At the end of 12 months, atorvastatin was not superior to placebo in reducing plasma LDL-C levels, median percentage
reduction 15.8% and 9.5% respectively, in atorvastatin and placebo arms (n = 14 in each; P = 0.40). Apolipoprotein B levels
significantly declined with atorvastatin in modified intention-to-treat analysis (P = 0.01) but not in the per-protocol analysis.
There was no significant effect on other lipid fractions, cIMT and FMD. Adverse events were similar between groups. Change in
serum albumin was negatively associated with change in serum LDL-C, very low-density lipoprotein cholesterol, total choles-
terol, triglyceride, and apolipoprotein B (P < 0.001), irrespective of receiving atorvastatin, age, gender, body mass index, and
serum creatinine.
Conclusions Atorvastatin, administered at a fixed daily dose of 10 mg, was not beneficial in lowering lipid levels in children with
SRNS; rise in serum albumin was associated with improvement in dyslipidemia.

Keywords Hydroxymethylglutaryl-CoA reductase inhibitors . Hyperlipidemia . LDL cholesterol . Apolipoprotein B-100

Introduction Dyslipidemia is an important modifiable risk factor that may

also aggravate glomerulosclerosis and contribute to progres-
Nephrotic syndrome is a risk factor for accelerated atheroscle- sion of renal injury [5]. Nephrotic syndrome alters pathways
rosis [1]. Dyslipidemia, hypoalbuminemia, hypercoagulable involved in the synthesis, transport, remodeling, and catabo-
state, hypertension, and steroid-induced obesity contribute to lism of lipids leading to elevated total cholesterol, triglycer-
this risk [2]. While these abnormalities resolve with disease ides (TG), apolipoprotein B (apoB)-containing lipoproteins
remission in steroid responsive patients [3, 4], they persist in (very low-density lipoprotein [VLDL] and low-density lipo-
children with steroid-resistant nephrotic syndrome (SRNS). protein [LDL]), and lipoprotein(a) [6]. Statins inhibit hepatic
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. It
reduces cholesterol synthesis and upregulates LDL receptors
* Pankaj Hari
[email protected] causing clearance of atherogenic LDL cholesterol (LDL-C)
and apoB-containing lipoproteins from the circulation [6].
1
Statins have demonstrated long-term safety and efficacy to
Division of Nephrology, Department of Pediatrics, All India Institute
reduce LDL-C by 25–35% in children with familial hypercho-
of Medical Sciences, Ansari Nagar, New Delhi 110029, India
2
lesterolemia [7, 8]. Beneficial effect on endothelial dysfunc-
Department of Cardiac Biochemistry, All India Institute of Medical
tion, reflected by reduced progression of carotid intima-media
Sciences, Ansari Nagar, New Delhi 110029, India
2300 Pediatr Nephrol (2018) 33:2299–2309

thickness (cIMT) and improved flow-mediated dilation were excluded. Informed written consent was obtained from
(FMD) of the brachial artery, has been shown in patients with either parent before enrollment.
familial hypercholesterolemia [8] and nephrotic syndrome [9]
treated with statins. However, a Cochrane systematic review Randomization, allocation, and blinding
of randomized trials including 191 adults with idiopathic ne-
phrotic syndrome failed to demonstrate superiority of statins Allocation sequence was computer generated. Patients were
over placebo in reducing total and LDL cholesterol [10]. stratified based on degree of proteinuria (≤ 2+ and ≥ 3+ on
While, various guidelines recommend considering statins in dipstick) and randomly assigned in a 1:1 ratio, in permuted
childhood nephrotic syndrome with persistently high fasting blocks, to receive either 10 mg atorvastatin (Storvas; Ranbaxy
LDL-C [1, 11, 12], there is no clear consensus on its use Laboratories) or identical-appearing tablets as a single daily
because high-quality evidence from randomized trials is lack- dose on empty stomach. Treatment allocations were concealed
ing. We therefore proposed to examine, in a prospective ran- in opaque, sealed envelopes that were opened at randomization.
domized controlled trial, whether administration of statins was Medication, sufficient to last for 12 weeks, was packed in iden-
effective in improving dyslipidemia, cIMT and brachial artery tical containers and labeled with unique serial numbers based
FMD in children with SRNS. on the randomization list, ensuring allocation concealment.
Procedures for randomization, packing, and distribution of
medications were done by individuals who were not involved
in trial implementation. The investigators, patients, and out-
Methods
come assessors were blinded to the randomization schedule.
Trial design
Measurements
This prospective, randomized, placebo-controlled, parallel-
Patients’ weight and height were recorded; weight-for-age,
group clinical trial was designed to assess the efficacy of ator-
height-for-age, and body mass index-for-age standard devia-
vastatin (10 mg/day) to reduce serum LDL-C levels in patients
tion scores (SDS) were derived based on WHO growth refer-
with steroid-resistant nephrotic syndrome. This study was
ences [15]. Blood pressure was measured thrice and mean
conducted from July 2011 to February 2015 at a tertiary care
systolic and diastolic pressures were used to derive corre-
center following approval by the Institute ethics committee
sponding percentiles [16].
and Drug Controller General of India. The trial was registered
Serum total cholesterol, LDL-C, VLDL cholesterol (VLDL-
at the Clinical Trials Registry of India (http://ctri.nic.in; CTRI
C), high-density lipoprotein cholesterol (HDL-C), triglycerides,
2012/07/002761).
apolipoprotein A (apoA), and apolipoprotein B (apoB) were
estimated following a 12-h overnight fast. Total cholesterol
Participants and triglyceride levels were measured using enzymatic end-
point method [17]. HDL was estimated after precipitation of
Patients, aged 5–18 years, with SRNS were screened. LDL and VLDL using phosphotungstic acid and magnesium
Nephrotic syndrome was defined as the presence of [18]. LDL cholesterol (mg/dl) was calculated as follows [19]:
nephrotic-range proteinuria (3–4+ proteinuria by dipstick; LDL cholesterol = Total cholesterol − triglyceride/
spot urine protein to creatinine ≥ 2 mg/mg), hypoalbuminemia adjustable factor − HDL
(albumin < 2.5 g/dl), and edema. Steroid resistance was de- where the adjustable factor was established as the strata
fined as absence of remission despite treatment with prednis- specific median triglyceride: VLDL-C ratio [19] to adjust for
olone at a dose of 2 mg/kg/d for 4 weeks. Patients with LDL-C high triglyceride levels in patients with nephrotic syndrome.
levels between 130 and 350 mg/dl (detected on two occasions Apolipoproteins A, B, and high-sensitivity C-reactive pro-
1 week apart), who were receiving stable doses of immune- tein (hs-CRP) were estimated by nephelometry (Randox, UK)
suppressive medication for at least 6 months were eligible for and sandwich ELISA (BioCheck Inc., Foster City, CA),
randomization. Patients with nephrotic syndrome secondary respectively.
to systemic lupus or Henoch Schonlein purpura, estimated cIMT and brachial artery FMD were determined by the
glomerular filtration rate (eGFR) [13] less than 30 mL/min/ radiologist using high-resolution ultrasonography with multi-
1.73 m2, stage 2 hypertension, creatinine kinase (CK) levels frequency linear probe (5–12 MHz) and standard image set-
more than three times the upper limit of normal, history of tings [20]. Bilateral distal common carotid arteries, 1 cm prox-
jaundice or raised transaminases in the last 6 months, use of imal to the bifurcation, were imaged during end diastole, with
lipid-lowering drugs in the previous 3 months, and family the patient in supine position and the neck slightly extended.
history of premature cardiovascular disease (≤ 55 years in cIMT was defined as the distance between the leading edges
men or ≤ 65 years in female [14]) or residence > 250 km away of the lumen–intima interface and the media–adventitia
Pediatr Nephrol (2018) 33:2299–2309 2301

interface of the far wall of the carotid artery; mean of two Statistical analysis
recordings on both side was calculated. Assessment of brachi-
al artery FMD was done after 10-min rest in a temperature Continuous data were expressed as median (interquartile
controlled room, in fasting state [21]. A blood pressure cuff range) or mean ± SD. Data were analyzed by Pearson’s chi-
was applied to the widest part of the forearm below the square or Fisher’s exact test, as appropriate. Wilcoxon rank-
antecubital fossa, inflated to 50 mmHg above systolic BP sum test or Student’s t test were used for comparison.
and deflated after 4 min. Images were obtained at baseline, Generalized estimating equations (GEE) were used to analyze
following inflation, immediately after deflation and 90 s after predictors of serial values of lipids over 12 months. Linear
deflation; maximum dilatation was recorded. The change in regression on log-transformed variables was used to evaluate
the diameter of brachial artery from the baseline expressed as a association of change in cIMT and FMD with lipid levels and
percentage of the baseline diameter represented the FMD. All atorvastatin administration. Data was analyzed using Stata
studies were done by a single radiologist; the intra-observer version 14.0 (StataCorp 2015); P < 0.05 was considered
coefficient of variation of cIMT and brachial FMD at our significant.
center is 1.9% and 2.2%, respectively. For calculation of sample size, we assumed a reduction of
25% in the LDL-C in atorvastatin-treated group and 5% in
placebo group following NCEP step 1 diet. On the basis of a
Follow-up
previous study that showed the mean LDL-C level in children
with SRNS was 163 ± 20 mg/dl [22], 12 subjects were required
Patients were evaluated for blood pressure, evidence of infec-
in each group to detect a difference of 20% between the groups
tion, and adverse effects during follow-up at 1, 3, 6, 9, and
with an alpha error of 0.05 and power of 90%. Assuming a drop
12 months. Blood counts and levels of lipids, creatinine, albu-
out of 10%, sample size of 28 subjects was estimated (Stata
min, electrolytes, aspartate and alanine aminotransferase
version 11.0; StataCorp 2009). Since primary outcome was
(AST, ALT), alkaline phosphatase, CK, hs-CRP, and 24-h
change in levels of LDL-C from baseline, analyses were based
urine protein were measured at each visit. cIMT and brachial
on modified intention-to-treat approach that included all ran-
artery FMD were done at baseline, 6 months and 12 months.
domized participants who had at least one post-baseline mea-
Patients in both groups were instructed to take the
surement to calculate the primary outcome; last observation
National Cholesterol Education Program (NCEP) Step 1
was carried forward. We also report per-protocol analyses on
diet (less than 300 mg cholesterol and less than 30% of
patients who were followed up for 12 months.
total calories from fat, of which less than 10% was satu-
rated fat) throughout the trial period. Diet charts were
provided, and dietary intake was evaluated at each
Results
follow-up visit by dietary recall to ensure compliance.
Enalapril (0.2 to 0.5 mg/kg) or additional treatment with
Of 60 patients assessed, 30 were excluded (25 did not meet
amlodipine (0.1 to 0.3 mg/kg/d) was instituted to control
eligibility criteria, and 5 did not consent; Fig. 1). Of the 30
blood pressure. All patients received daily supplements of
randomized participants, 15 were assigned to receive treat-
calcium carbonate (250 to 500 mg) and vitamin D.
ment with atorvastatin and 15 with placebo. Four patients
were lost to follow-up (two in placebo, two in intervention
Outcomes group) and therapy discontinued in another three.
Discontinuation of therapy was due to lower respiratory tract
The primary outcome was the percent change in levels of infection in one patient in the placebo group and reduction of
LDL-C at 12 months. Secondary outcomes at 12 months eGFR < 30 ml/1.73m2/min in two patients in the intervention
were (i) percent change in levels of total cholesterol, tri- arm. Since two patients did not return after the randomization
glycerides VLDL-C, HDL-C, apoA, and apoB; (ii) percent visit, primary outcome data was analyzed in 28 patients using
change in brachial artery FMD and cIMT; and (iii) frequen- modified intention-to-treat analysis.
cy and type of adverse events. Safety assessments included
clinical and laboratory evaluation and monitoring for ad- Baseline characteristics
verse events, with reports to the ethics committee. Criteria
for withdrawal from study were LDL-C > 350 mg/dl (con- Children aged 11.6 ± 3.6 years, predominantly boys (70%),
firmed on two occasions 1 week apart), elevation of CK were randomized to receive 10 mg atorvastatin daily or place-
level more than 3 times or AST/ALT level more than twice bo. Baseline parameters were similar between the groups
the upper limit of normal persisting on two consecutive (Table 1). Twenty percent patients were younger than 10 years
measurements 2 weeks apart, and eGFR < 30 mL/min/ of age. The renal histology included minimal change disease
1.73 m2 or a serious adverse event. (MCD, 9), focal segmental glomerulosclerosis (FSGS, 9),
2302 Pediatr Nephrol (2018) 33:2299–2309

Fig. 1 Flow of patients through enrolment, randomization, treatment, and follow-up. Modified intention-to-treat analysis included all but one patient in
each group who did not return after randomization (N = 14 in each group). eGFR estimated glomerular filtration rate, LDL low-density lipoprotein

membranoproliferative glomerulonephritis (MPGN, 11), and gender, body mass index (BMI), and serum creatinine (GEE,
membranous nephropathy (1). Mean duration of disease was P > 0.1). At 12 months, the LDL-C levels were similar in the
50 ± 37 months. None were receiving calcineurin inhibitors two groups [mean difference 21.7 (95% CI − 57.9 to 101.4)
during study period; patients either discontinued calcineurin mg/dl]. The median percentage change in serum LDL-C be-
inhibitors at least 6 months prior to enrolment (N = 27) or tween baseline and 12 months was 15.8% and 9.5% in the
received only 0.2–0.3 mg/kg of alternate day oral predniso- intervention and placebo arms, respectively, on modified
lone for sub-nephrotic-range proteinuria (N = 3). All patients intention-to-treat analysis of 28 patients (P = 0.41, Table 3).
received enalapril for control of proteinuria; other ACE inhib- Similar change in LDL-C was also found on per-protocol anal-
itors or angiotensin receptor blockers were not used. ysis of 23 patients (16.2% versus 9.5% with atorvastatin and
placebo respectively, P = 0.30). Serum LDL-C was < 130 mg/
Lipid profile, cIMT, and FMD at 12-month follow-up dl at 12 months in five patients (35.7%) treated with atorvastat-
in compared to four patients (28.6%) in the placebo group (P =
Table 2 shows mean lipid levels during 12-month follow-up. 0.69). Median percentage change in total cholesterol, triglycer-
The use of atorvastatin compared to placebo did not significant- ide, VLDL-C, HDL-C, apoA, and hs-CRP was not significant-
ly change lipid levels over 12 months after adjusting for age, ly different in the two groups (Table 3, P > 0.5). There was
Pediatr Nephrol (2018) 33:2299–2309 2303

Table 1 Baseline characteristics

Atorvastatin, n = 15 Placebo, n = 15

Age (years) 12 (8.5, 15.3) 12 (10, 14)

Sex (male, %) 11 (73.3) 10 (66.7)
Height-for-age SDS − 1.9 (− 3.6, − 0.5) − 2.3 (− 3.0, − 0.9)
Weight-for-age SDS − 2.8 (− 4.0, − 1.1) − 1.4 (− 2.2, − 0.8)
Body mass index-for-age SDS − 1.7 (− 2.5, − 0.9) − 0.4 (− 1.3, 0.3)
Blood pressure SDS for height and age
Systolic 1. 2 (0.4, 1.7) 1.4 (0.6, 2.1)
Diastolic 1.4 (0.3, 1.6) 1.0 (0.6, 2.0)
Duration of disease, months 48 (24, 72) 36 (22, 60)
Serum creatinine, mg/dl 0.5 (0.4, 0.83) 0.5 (0.4, 0.7)
eGFR (ml/min/1.73 m2) 93.7 (71.8, 132.8) 102.5 (75.6, 144.9)
Total cholesterol (mg/dl) 302 (246, 337) 285 (256, 312)
Triglycerides (mg/dl) 177.5 (136.8, 218.3) 200 (145, 316)
Low-density lipoprotein cholesterol (mg/dl) 220.9 (159.3, 240.2) 201.9 (168.4, 234.8)
Very low-density lipoprotein cholesterol (mg/dl) 35.5 (27.4, 43.7) 40 (29, 63.2)
High-density lipoprotein cholesterol (mg/dl) 45 (39, 50) 51 (32, 55)
Apolipoprotein A (mg/dl) 171.5 (128.3, 198.3) 164 (125, 207)
Apolipoprotein B (mg/dl) 171 (127.5, 199) 149 (118, 183)
High-sensitivity C-reactive protein (mg/dl) 0.4 (0.1, 1.9) 1.1 (0.3, 5.1)
Creatinine phosphokinase (IU/l) 68.5 (45.5, 111.3) 63.0 (34.0, 76.0)
Serum albumin (mg/dl) 2.5 (1.7, 3.5) 2.8 (2.1, 3.1)
24-h urine protein (mg/day) 1310 (365, 2610) 1100 (440, 1600)
Brachial artery flow mediated dilation (%) 11.2 (5.8, 18.4) 11.4 (6.8, 20.0)
Mean carotid intima-media thickness (mm) 0.44 (0.40, 0.49) 0.47 (0.39, 0.50)

eGFR estimated glomerular filtration rate, SDS standard deviation score

Values are median (interquartile range) or number (%)

significant decline in apoB levels in patients treated with ator- significant association between cIMT or FMD and change in
vastatin compared to placebo (respective median change 19.9% lipid levels or per-kg dose of atorvastatin (data not shown).
versus 1.1%, P = 0.008). However, this decline was not statis-
tically significant in the per-protocol analysis (17.1% versus Predictors of serum lipid levels
3.9% respectively, P = 0.19).
Since a fixed dose of atorvastatin was used, we also ana- Following 12-month follow-up, median serum albumin and
lyzed the effect of weight-based dosing. Mean dose of atorva- 24-h urine protein levels in atorvastatin and placebo groups
statin was 0.39 ± 0.12 mg/kg (range 0.26 to 0.64 mg/kg). were 2.8 (1.9–3.4) g/dl, 2.9 (2–3.9) g/dl, 800 (70–1500) mg,
There was no significant correlation between change in lipid and 595 (165–1375) mg, respectively (P = 0.9 for both).
fractions and per-kg dose (P > 0.1). Change in lipid levels Change in BMI, systolic and diastolic blood pressure SDS,
were similar among children with the higher (> 0.39 mg/kg) and estimated GFR were similar between the intervention
versus lower doses (< 0.39 mg/kg; P > 0.1). and placebo groups over 12-month follow-up (P > 0.5). On
There was no significant difference in cIMT between pa- multivariate analysis, change in serum albumin was negative-
tients administered atorvastatin and placebo (P = 0.7 and 0.9 ly associated with change in levels of LDL-C, VLDL-C, total
at 6 months and 12 months, respectively; Table 2). Median cholesterol, triglyceride, and apoB irrespective of receiving
FMD at 12 months was 10.7 (9.2–16.2) % in patients receiv- atorvastatin and adjusting for age, gender, BMI, and serum
ing atorvastatin compared to 13.2 (8.3–15.8) % in those re- creatinine (GEE, P < 0.001); no significant association was
ceiving placebo (P = 1.0). Overall, mean cIMT showed a sta- obtained with HDL-C and apoA. Change in serum albumin
tistically insignificant decline from 0.456 ± 0.06 at baseline to did not vary by histopathological diagnosis (P = 0.32) and
0.437 ± 0.05 after 12 months in all patients (P = 0.11). association with change in eGFR was not seen (P = 0.60);
Similarly, median FMD at baseline was 11.3 (6.7–18.8) % albumin infusions were not used. Change in proteinuria was
and 12.2 (8.8–15.9) % at 12 months (P = 1.0). There was no not associated with blood lipid levels.
2304 Pediatr Nephrol (2018) 33:2299–2309

Table 2 Mean lipid levels, brachial artery flow-mediated dilation, and carotid intima-media thickness during 12-month follow-up

Baseline 3 months 6 months 12 months

Atorvastatin, n = 15 Atorvastatin, n = 14 Atorvastatin, n = 12 Atorvastatin, n = 11
Placebo, n = 15 Placebo, n = 13 Placebo, n = 12 Placebo, n = 12

Low-density lipoprotein cholesterol

Atorvastatin 209.5 ± 46.6 168.9 ± 70.6 157.4 ± 68.9 163.4 ± 103.0
Placebo 208.2 ± 47.6 187.4 ± 66.8 172.7 ± 65.7 194.2 ± 120.3
Total cholesterol
Atorvastatin 302.0 ± 67.0 255.7 ± 66.7 239.3 ± 70.2 243.3 ± 114.0
Placebo 294.4 ± 48.3 259.9 ± 71.0 257.1 ± 73.6 278.3 ± 125.3
Triglycerides
Atorvastatin 192.6 ± 84.1 223.3 ± 158.2 200.0 ± 87.4 178.8 ± 100.2
Placebo 216.4 ± 98.6 183.3 ± 85.6 199.4 ± 74.8 207.2 ± 102.6
Very low-density lipoprotein cholesterol
Atorvastatin 38.5 ± 16.8 44.6 ± 31.7 40.8 ± 17.5 35.8 ± 20.0
Placebo 43.3 ± 19.7 36.8 ± 17.0 39.9 ± 15.4 41.4 ± 20.5
High-density lipoprotein cholesterol
Atorvastatin 44.9 ± 10.0 47.8 ± 11.8 47.1 ± 8.0 48.6 ± 11.6
Placebo 46.5 ± 12.3 45.4 ± 14.3 49.1 ± 13.3 47.8 ± 10.7
Apolipoprotein A
Atorvastatin 170.1 ± 48.9 180.8 ± 47.6 178.3 ± 52.6 164.0 ± 39.5
Placebo 167.5 ± 44.8 173.4 ± 50.8 177.4 ± 48.0 174.5 ± 51.9
Apolipoprotein B
Atorvastatin 164.9 ± 47.9 133.7 ± 52.4 129.5 ± 52.2 115.8 ± 42
Placebo 153.9 ± 45.5 163.9 ± 43.7 145.2 ± 40.1 153.2 ± 42.4
Brachial artery flow-mediated dilation (%)
Atorvastatin 13.6 ± 12.8 11.6 ± 10.1 14.9 ± 12.9
Placebo 14.0 ± 8.3 16.6 ± 18.3 14.3 ± 8.4
Mean carotid intima-media thickness (mm)
Atorvastatin 0.44 ± 0.06 0.43 ± 0.08 0.44 ± 0.05
Placebo 0.46 ± 0.06 0.45 ± 0.06 0.45 ± 0.05

Adverse events patient in the placebo group had an episode of pneumonia

requiring hospitalization, hence was reported as a serious ad-
Most common adverse events were infections, comprising verse event and was withdrawn from the study at 3 months.
upper respiratory tract infection (27 episodes), acute gastroen- Median creatinine kinase at 12-month follow-up was 96 (58–
teritis (6 episodes), and pyoderma (2 episodes) (Table 4). One 160.5) IU/l and 108.3 (56.5–153.5) IU/l in the intervention

Table 3 Median percentage

change in biochemical and Atorvastatin, n = 14 Placebo, n = 14 P
radiological parameters after 12-
month therapy Low-density lipoprotein cholesterol 15.8 (− 0.9, 53.2) 9.5 (− 12.6, 39.8) 0.41
Total cholesterol 7.5 (− 1.0, 35.6) 3.7 (− 12.9, 35.0) 0.51
Triglycerides − 8.9 (− 41.3, 43.8) − 4.5 (− 65.6, 47.1) 0.90
Very low-density lipoprotein cholesterol 4.5 (− 47.1, 65.6) 8.9 (− 41.1, 43.8) 0.90
High-density lipoprotein cholesterol 10.4 (− 21.9, 29.1) 3.7 (− 18.7, 26.6) 0.57
Apolipoprotein A − 5.4 (− 18.3, 17.5) − 8.8 (− 21.1, 35.8) 0.90
Apolipoprotein B 19.9 (− 13.1, − 33.9) 1.1 (− 14.4, 41.4) 0.008
High-sensitivity C-reactive protein 100 (− 74.6, 341.7) 7.4 (− 117.0, 76.6) 0.95
Mean carotid intima-media thickness 0.1 (− 12.6, 5.9) − 5.7 (− 20.5, 6.7) 0.57
Brachial artery flow-mediated dilation − 7.9 (− 29.0, 88.8) − 9.6 (− 80.8, 61.8) 0.37
Pediatr Nephrol (2018) 33:2299–2309 2305

Table 4 Adverse events

Event Atorvastatin Placebo

Episodes of infection
Pneumonia 0 1a
Upper respiratory tract infection (episodes) 12 15
Acute gastroenteritis (episodes) 4 2
Pyoderma 2 0
Backache 3 3
Lower leg pain 2 2
Calf cramps 2 3
Knee pain 2 0
Headache 2 0
Abdominal pain 1 0
Poor appetite 1 0
Vomiting 0 1
Creatinine kinase (above upper limit of normal) 0 2
Aspartate aminotransferase > 70 IU/l (normal 10–35 IU/l) 0 0
Alanine aminotransferase > 80 IU/l (normal 10–40 IU/l) 1 0
a
Withdrawn from study

and placebo group respectively (normal 39–308 IU/l). Two There is limited data on the role of statins in treating dys-
patients in the placebo arm had transient asymptomatic eleva- lipidemia associated with refractory nephrotic syndrome
tion of serum CK (380 and 382 IU/l) that spontaneously re- (Table 5). Experience in pediatric age group is limited to only
solved within 2 weeks. None had CK more than 3-times the two prospective uncontrolled studies demonstrating decline in
upper limit of normal or symptoms suggestive of rhabdomy- triglycerides, LDL-C, and total cholesterol by 30–40% in 19
olysis. Cramps and pain in lower limbs and backache occurred patients over a period of 6–60 months [23, 24]. While we
in 9 and 8 patients in the atorvastatin and placebo group, observed that 36% patients had LDL-C levels below
respectively, that was associated with normal CK and resolved 130 mg/dl at 12 months, this was not significantly different
without discontinuation of study medication (Table 4). from placebo. In adults with nephrotic-range proteinuria, stud-
Median levels of aspartate and alanine aminotransferases at ies demonstrating beneficial effect of statins included clinical-
12 months were 21 (19–30) IU/l and 18 (12–24) IU/l respec- ly heterogeneous population comprising post-renal transplant
tively, in the atorvastatin group and 22.5 (19.3–35.3) IU/l and patients [26], lupus nephritis [26, 27], Alport syndrome [28],
17.5 (15–27.5) IU/l in the placebo group (normal 10–35 IU/l interstitial nephritis [28], and idiopathic membranous ne-
and 10–40 IU/l). One patient in the atorvastatin group had phropathy [29], limiting generalizability of these results to
asymptomatic elevation of alanine aminotransferase level children with nephrotic syndrome predominantly due to min-
more than twice the upper limit of normal (117 IU/l) that imal change disease or focal segmental glomerulosclerosis.
declined to normal within 2 weeks. Table 5 shows four randomized controlled trials conducted
in adults with nephrotic syndrome that were included in a
Cochrane systematic review [10, 30–33]. In this review, con-
Discussion cordant to our findings, no significant difference was found in
levels of serum LDL-C (mean difference − 5.1 mg/dL, 95%
This randomized controlled trial assessed the efficacy of a fixed CI − 68.3 to 58.2; n = 40), total cholesterol (mean difference −
dose of atorvastatin to decrease hypercholesterolemia in children 53.0 mg/dL, 95% CI − 159.5 to 53.5; n = 92), and triglyceride
with refractory nephrotic syndrome. At the end of 12 months, (mean difference − 38.9 mg/dL, 95% CI − 110.2 to 32.6; n =
atorvastatin administered at a dose of 10 mg/day was not supe- 40), between statins and control group after 3 months of ther-
rior to placebo in reducing plasma LDL-C levels. While atorva- apy. However, most results were based on single study data
statin significantly decreased serum apoB levels by 20% as and trials included were at high risk of reporting and selection
compared to 1% with placebo, this result lost statistical signifi- bias. Other studies in the review showing reduction in levels
cance in the per-protocol analysis. There was no beneficial effect of triglycerides, total, and LDL-C with statins reported out-
on other lipid fractions (total cholesterol, triglyceride, VLDL-C, comes as median/mean without standard deviation [30, 31] or
HDL-C, and apoA) on cIMT and brachial artery FMD. had methodological flaws [25], limiting their inclusion in the
 2306

Table 5 Studies describing role of statins in nephrotic syndrome

Study N; mean age (years) Patients, method Drug; dose Follow-up Result: effect on LDL cholesterol Result: effect on other lipid fractions,
(months) serum albumin, and proteinuria

Cohort studies in children

Coleman et al, 1996 [23] 7; 8 SRNS, cohort study Simvastatin; 5–40 mg/day 6–51 Not reported Decline in TC (41%) and TG
(44%) at 6 months
Sanjad et al, 1997 [24] 12; 4.8 SRNS, cohort study Lovastatin and simvastatin; 12–60 Decline by 44% Decline in TC (40%) and TG (33%)
up to 40 and 20 mg/day
Randomized control trials
Olbrich et al, 1999 [30]a 43; 44 NS, parallel Simvastatin; 24 Mean decline 47% Mean change − 39%, + 1%,
double-blind RCT 10–40 mg/day (LDL level in placebo and − 30% in TC, HDL, and TG
group not reported)
Toto et al, 2000 [25] 13; 43 NS, double-blind Pravastatin; 40 mg/day 2 Median decline 21.5% (P = 0.002) TC and TG decreased in
crossover RCT hypercholesterolemia (18% and
13%),
TC decreased (22%) in combined
hyperlipidemia
Gheith et al, 2002 [31]a 43; 23 SSNS and SRNS, Fluvastatin; 20 mg/day 12 Median decline 29 and 42% TC decreased by 35%, 38.3%, and 42%
open-label parallel from baseline after 6 and after 3, 6, and 12 months. Significant
RCT 12 months (no significant decline in proteinuria, increase in
reduction with placebo) serum albumin
Sharma et al, 2004 [32]a 40; 36 NS, placebo-controlled Lovastatin; 20 mg/day 3 Similar to placebo Increase in HDL and fall in TC; no
RCT change in TG; no change in
proteinuria
Gheith et al, 2009 [33]a 52; 18 SSNS and SRNS, Fluvastatin; 20 mg/day 12 Not reported TC similar as placebo at 3 months,
open-label parallel 6 months, and 1 year; significant
RCT rise in serum albumin at 1 year
Present study 30; 11.6 SRNS, double-blind Atorvastatin; 10 mg/day 12 Percentage decline similar to placebo Significant decline in apoB; no change
placebo-controlled, in TG, TC, HDL, apoA, cIMT,
parallel RCT brachial artery FMD

a
Included in Cochrane systematic review on lipid lowering therapies for nephrotic syndrome [10]
apoA apolipoprotein A, apoB apolipoprotein B, cIMT carotid intima media thickness, FMD flow mediated dilatation, HDL high-density lipoprotein, LDL low-density lipoprotein, NS nephrotic syndrome,
RCT randomized controlled trial, SRNS steroid-resistant nephrotic syndrome, SSNS steroid sensitive nephrotic syndrome, TC total cholesterol, TG triglyceride
Pediatr Nephrol (2018) 33:2299–2309
Pediatr Nephrol (2018) 33:2299–2309 2307

final meta-analysis [10]. We observed a mean difference of molecular link between proteinuria and hypertriglyceridemia
21.7 mg/dl in LDL-C levels between atorvastatin and placebo has been suggested to be podocyte injury triggered circulating
groups following 12-month therapy that was greater than re- factor angiopoietin-like-4 that inhibits clearance of triglycerides
ported in the Cochrane review; however, this was not statisti- by lipoprotein lipase [41]. Podocyte damage also upregulates
cally significant and confidence intervals were large. While serum proprotein convertase subtilisin kexin type 9 (PCSK9)
one study demonstrated significant rise in HDL-C with statins that degrades LDL receptors and results in hyperlipidemia [42].
(mean difference 5.4 mg/dL, 95% CI 2.3 to 8.5; n = 40) [32], This state of acquired LDL receptor deficiency may hamper the
other studies in the review did not show this effect, similar to action of statins, which act by upregulation of LDL receptors
the present study. We observed significant decline in apoB [43]. Statins therefore have no effect upon these complex path-
levels with atorvastatin similar to previous reports showing ophysiological mechanisms linking podocyte damage and hy-
increased clearance of apoB with statins [25]. We could not perlipidemia that may explain the inefficiency of statins to low-
explain the pathophysiological mechanism causing decline in er cholesterol levels in the present study. As evident from our
apoB levels in the absence of reduction in cholesterol levels. It findings, given the central role of proteinuria and hypoalbumin-
has been reported that apoB plays an important role in dys- emia in the pathogenesis of dyslipidemia, the target should be
function of vascular endothelium and is associated with coro- reversal or attenuation of proteinuria and therapeutic interven-
nary artery calcification [34]. Therefore, our finding of isolat- tion should aim at the renal–hepatic axis that regulates plasma
ed reduction in apoB with atorvastatin requires further evalu- cholesterol [6].
ation in a larger cohort. Atorvastatin at a dose of 10 mg/day was safe and well
Structural and functional abnormality on vascular imaging in tolerated in the present study. Myalgia or lower extremity
nephrotic syndrome, assessed respectively by ultrasonographic pain was complained by similar number of patients receiving
measurement of increased cIMT [22, 35] and reduced FMD of atorvastatin and placebo; this was not associated with CK
the brachial artery [36], represents one of the earliest stages of elevation. Prior studies have demonstrated long-term tolera-
atherogenesis. A previous open-label study showed improve- bility of statin in children older than 8 years with familial
ment in brachial artery FMD following atorvastatin in 8 out of hypercholesterolemia [44]. Higher doses of atorvastatin, ad-
10 adults with nephrotic syndrome that was significantly corre- ministered at 20 mg/day, were safe in children older than
lated to reduction of non-HDL-C [9]. Paucity of information 10 years [45]. While safety of statins has been extensively
exists on serial cIMT and FMD measurements in children with examined in adults, there is a concern that when initiated in
renal diseases especially nephrotic syndrome. In a series of 22 early childhood, it may adversely affect nervous system, im-
post-renal transplant patients, mean cIMT showed a declining mune function, hormonal milieu, and other systems. Since
trend from 0.46 to 0.43 mm with strict blood pressure control atorvastatin reduces LDL-C and triglycerides in a dose-
over 9-year follow-up [37]. Similarly, median decline in cIMT dependent manner, an escalating dosing schedule in non-
by 0.004 mm/year observed in the current study may have been responders could possibly have revealed a beneficial effect
due to dietary modifications and ACE inhibition. In children in the present trial. However, children younger than 10 years
with chronic kidney disease (CKD), FMD significantly im- of age constituted a fifth of the present cohort and limited
proved from 6.7 to 9.2% with high-dose vitamin D therapy over information on the long-term effect of statins on neurological
12 weeks [38]; patients in the present study had a higher FMD and pubertal development, especially in young children pre-
at baseline (11.3%). In another trial, 10 mg/day atorvastatin cluded incorporating dose escalation in the present trial de-
failed to change FMD (9.8 to 8%) in 8 children with CKD over sign. While we did not observe a significant effect of higher
8 weeks [39]. No significant improvement in brachial artery per-kilogram dosing, trend of declining lipid levels among
FMD in the present study may be explained by insignificant patients administered atorvastatin and the attrition of 23%
change in lipid levels with statins. suggests that the trial may have been under powered rather
Previous trials have shown a decline in serum lipid fractions than atorvastatin being clearly ineffective. Post hoc power
with statins paralleling rise in serum albumin in adults with was reduced to 68% with the current sample size and effect
nephrotic syndrome (Table 5). The impact of improvement of sizes, suggesting a type II error. It is also possible that treat-
albumin on subsequent lipid levels in adults with nephrotic ment effects might have been obscured by the introduction of
syndrome is well known [40]; this finding has not been ex- diet and ACE inhibition in both groups. Despite these limita-
plored in refractory nephrotic syndrome in pediatric patients. tions, this is the first prospective randomized controlled trial
We observed that rise in serum albumin was significantly asso- assessing the efficacy of a promising therapy for hyperlipid-
ciated with decline in serum LDL-C, triglyceride, and total emia in children with SRNS with a relatively long follow-up.
cholesterol levels irrespective of the allocated treatment, age, The results of this study are generalizable to children with
sex, BMI, and serum creatinine in post hoc analysis; rise in steroid resistance and major biopsy diagnoses of minimal
serum albumin was not associated with glomerular filtration change, focal segmental glomerulosclerosis, and
rate, histopathological diagnosis, or specific therapy. The membranoproliferative glomerulonephritis.
2308 Pediatr Nephrol (2018) 33:2299–2309

Conclusion 11. Nishi S, Ubara Y, Utsunomiya Y, Okada K, Obata Y, Kai H,

Kiyomoto H, Goto S, Konta T, Sasatomi Y, Sato Y, Nishino T,
Tsuruya K, Furuichi K, Hoshino J, Watanabe Y, Kimura K,
The findings from this study suggest that there is no clear Matsuo S (2016) Evidence-based clinical practice guidelines for
benefit of a fixed dose of atorvastatin on lowering lipid levels nephrotic syndrome 2014. Clin Exp Nephrol 20:342–370
in children with unremitting nephrotic syndrome; therapy to 12. Gipson DS, Massengill SF, Yao L, Nagaraj S, Smoyer WE, Mahan
raise serum albumin may instead be useful. While it seems JD, Wigfall D, Miles P, Powell L, Lin JJ, Trachtman H, Greenbaum
LA (2009) Management of childhood onset nephrotic syndrome.
logical to treat hyperlipidemia for prevention of accelerated Pediatrics 124:747–757
atherosclerosis, there is no proven benefit of statins on overall 13. Schwartz GJ, Gauthier B (1985) A simple estimate of glomerular
cardiovascular morbidity and mortality in children [10] and filtration rate in adolescent boys. J Pediatr 106:522–526
possible side effects are clear limitations for any therapeutic 14. Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (2001) Executive summary of the third report
enthusiasm. However, significant gaps in the evidence call for
of the National Cholesterol Education Program (NCEP) expert panel
adequately powered studies with longer follow-up and involv- on detection, evaluation, and treatment of high blood cholesterol in
ing higher doses of statins if necessary, to confirm our adults (adult treatment panel III). JAMA 285:2486–2497
findings. 15. de Onis M, Onyango AW, Borghi E, Siyam A, Nishida C,
Siekmann J (2007) Development of a WHO growth reference for
school-aged children and adolescents. Bull World Health Organ 85:
Funding This study was funded by Indian Council for Medical Research.
660–667
16. National High Blood Pressure Education Program Working Group
Compliance with ethical standards on High Blood Pressure in Children and Adolescents (2004) The
fourth report on the diagnosis, evaluation, and treatment of high
This study was conducted from July 2011 to February 2015 at a tertiary blood pressure in children and adolescents. Pediatrics 114:555–576
care center following approval by the Institute ethics committee and Drug 17. Wentz PW, Cross RE, Savory J (1976) An integrated approach to
Controller General of India. The trial was registered at the Clinical Trials lipid profiling: enzymatic determination of cholesterol and triglyc-
Registry of India (http://ctri.nic.in; CTRI 2012/07/002761). Informed erides with a centrifugal analyzer. Clin Chem 22:188–192
written consent was obtained from either parent before enrollment. 18. Steele BW, Koehler DF, Azar MM, Blaszkowski TP, Kuba K,
Dempsey ME (1976) Enzymatic determinations of cholesterol in
Conflict of interest The authors declare that they have no conflict of high-density-lipoprotein fractions prepared by a precipitation tech-
interest. nique. Clin Chem 22:98–101
19. Martin SS, Blaha MJ, Elshazly MB, Toth PP, Kwiterovich PO,
Blumenthal RS, Jones SR (2013) Comparison of a novel method vs
the Friedewald equation for estimating low-density lipoprotein cho-
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