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Ren Fail
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Renal Failure
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10.1080/0886022X.2024.2404486
2404486
Version of Record
Research Article
Clinical Study
Clinical analysis of sirolimus therapy in children with refractory nephrotic syndrome
N. Zhang et al.
Renal Failure
Zhang Nan a
Jiang Le b
Li Sanni a
Zheng Yingying c
Dong Lei a
Zhao Yile a
a Department of Pharmacy, Children's Hospital of Hebei Province Affiliated with Hebei Medical University, Shijiazhuang, China
b Office of Academic Research, The Second Hospital of Hebei Medical University, Shijiazhuang, China
c Department of Pharmacy, The Third Hospital of Hebei Medical University, Shijiazhuang, China
CONTACT Yile Zhao childrenhealth@yeah.net No. 133, Jianhua South Street, Shijiazhuang, Hebei Province, China.
17 9 2024
2024
17 9 2024
46 2 240448616 5 2024
9 9 2024
10 9 2024
KnowledgeWorks Global Ltd.17 9 2024
published online in a building issue17 9 2024
© 2024 Children’s Hospital of Hebei Province Affiliated with Hebei Medical University. Published by Informa UK Limited, trading as Taylor & Francis Group
2024
Children’s Hospital of Hebei Province Affiliated with Hebei Medical University
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

To investigate the clinical efficacy of sirolimus in treating children with refractory nephrotic syndrome, the clinical data for 22 children from the Children's Hospital of Hebei Province were analyzed retrospectively. There were 16 boys and six girls, and the treatment period was from September 2015 to April 2021. There were two patients with steroid-dependent nephrotic syndrome (SDNS), six patients with frequently relapsing nephrotic syndrome (FRNS), and 14 patients with steroid-resistant nephrotic syndrome (SRNS). All patients were defined as having refractory nephrotic syndrome. There were 12 patients (including nine SRNS patients and three FRNS patients) with minimal change disease (MCD), three patients (three SRNS patients) with focal segmental glomerular sclerosis (FSGS), one FRNS patient with mesangial proliferative glomerulonephritis (MsPGN), and six patients without a kidney biopsy. Compared with levels before sirolimus treatment, 24-hour urine protein (24-h UP), low-density lipoprotein cholesterol (LDL-C), urea (Ur) and serum creatinine (SCr) levels were significantly lower (all p < 0.05). Moreover, albumin (Alb) was significantly increased (p < 0.05), and there were no significant differences in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), immunoglobulin A (IgA), immunoglobulin G (IgG) or immunoglobulin M (IgM) (all p > 0.05) at the first follow-up. Sirolimus is effective as the first treatment of some children with refractory nephrotic syndrome, but its long-term efficacy and adverse reactions still require follow-up.

Keywords

Sirolimus
child
refractory nephrotic syndrome
treatment
Medical Science Research Project Program of Hebei Province 20220773 This work was financially supported by Medical Science Research Project Program of Hebei Province (Grant No. 20220773).
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pmcIntroduction

Primary nephrotic syndrome (PNS) is a group of primary glomerular clinical syndromes characterized by massive proteinuria, hypoalbuminemia, and generalized edema (with or without hyperlipidemia). PNS can be divided into frequently relapsing nephrotic syndrome (FRNS), steroid-dependent nephrotic syndrome (SDNS) and steroid-resistant nephrotic syndrome (SRNS), which are collectively known as refractory nephrotic syndrome (RNS), due to the sensitivity to glucocorticoid therapy and urinary protein conversion. RNS in children has been a serious disease in recent years, and its incidence is increasing. Because of its complex etiology and difficulty in treating, it can progress to chronic kidney failure. Therefore, it is necessary to actively explore effective treatment methods.

Because the therapeutic dosage of glucocorticoids often exceeds the physiological dosage, children may suffer adverse reactions while achieving remission of the disease. In addition, glucocorticoids alone are not effective and must be combined with other immunosuppressants. Common steroid toxicities during the treatment of RNS in children include new or worsening obesity and/or overweight status, sustained hypertension, hyperglycemia, behavioral/psychiatric disorders, sleep disruption, cushingoid features, striae rubrae/distensae, glaucoma, ocular cataracts, bone pain, avascular necrosis, and impaired statural growth (height velocity < 25th percentile and/or height < 3rd percentile) in a child with normal growth before the start of steroid treatment. Anemia, acute diarrhea, oral ulcers, and hepatic impairment may occur after sirolimus treatment, all of which can be resolved with symptomatic management.

Sirolimus has anti-tissue proliferation and anti-fibrosis effects and can inhibit the proliferation of vascular smooth muscle and endothelial cells by inhibiting a variety of cytokines, such as platelet-derived growth factor, fibroblast growth factor, and endothelial cell growth factor, thus reducing interstitial fibrosis. Fibrosis plays an important role in the pathogenesis of nephrotic syndrome. Therefore, we used a sirolimus treatment protocol. Children are in an important stage of growth and development, so various organ functions are not yet fully developed and mature. As a result, their tolerance to drugs and compliance are poor, and serious adverse reactions are likely to occur. Therefore, in the selection of immunosuppressants, determining how to weigh and balance the efficacy and adverse reactions to drug treatment has become a common goal for pediatricians and sick families.

Various immunosuppressant drugs have advantages and disadvantages, including toxicity and side effects [1]. Individualized and comprehensive treatment options are needed because of the intricate etiology of RNS and the prolonged course of the disease [2]. How to select the best immunosuppressant treatment is an urgent clinical issue waiting to be addressed. In this study, we investigated the clinical efficacy, improvement in clinical biochemical parameters, and occurrence of adverse reactions to sirolimus in the treatment of RNS in children to provide more evidence-based medical evidence for the treatment of RNS in children.

Methods

The clinical data of 22 children from the Children's Hospital of Hebei Province with RNS admitted from September 2015 to April 2021 who received sirolimus therapy were analyzed retrospectively. Data for retrospective analysis were obtained from medical records. The inclusion criteria were as follows: children were younger than 16 years, and the disease was characterized by FRNS, SDNS, or SRNS. The exclusion criteria were as follows: other kidney diseases, allergies to sirolimus, and incomplete clinical data. FRNS was defined as ≥ two recurrences within six months or ≥ four recurrences within one year. SDNS are defined as those who are sensitive to steroids but relapse within two weeks of two consecutive dose reductions or discontinuation. SRNS were defined as those who remained positive for urine protein for > four weeks on adequate treatment with prednisone. The sex, age, type of nephrotic syndrome, pathological type, immunosuppressant history, laboratory results and adverse reactions during sirolimus treatment were recorded. The laboratory results included 24-h urine protein quantification (24-h UP), serum albumin (Alb), blood lipids (total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG)), humoral immunity (immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM)), and kidney function (urea (Ur) and serum creatinine (SCr)). Kidney biopsies were subjected to HE staining and immunofluorescence, and other laboratory results were obtained via a fully automated biochemistry analyzer and a fully automated coagulation analyzer. The children with RNS in this study were treated with a treatment regimen of steroids combined with oral sirolimus capsules. The dose of sirolimus was 0.03 mg/(kg·d), and the treatment lasted for three months. This study was approved by the ethical committee of the hospital. All patients signed the consent form.

SPSS 26.0 software was used for statistical analyses in this study. Age and laboratory results are presented as the means ± standard deviations or medians (interquartile ranges) according to their distributions. The triglyceride levels of 22 children with RNS before sirolimus treatment and at the first follow-up were analyzed via the paired rank sum test, and other laboratory results were analyzed via the paired t test. A P value less than 0.05 was considered statistically significant.

Results

There were 16 boys and six girls comprising the 22 patients, of whom the age of onset was 28.50 (18.00, 40.50) months (8 ∼ 84 months), the age at the first application of sirolimus was 41.00 (26.25, 81.00) months (16 ∼ 181 months), and the duration of disease before sirolimus treatment was 6.50 (3.75, 40.50) months (1 ∼ 97 months).

There were two patients with SDNS, six patients with FRNS, and 14 patients with SRNS. There were 12 patients with minimal change disease (MCD), three patients with focal segmental glomerular sclerosis (FSGS), one patient with mesangial proliferative glomerulonephritis (MsPGN), and six patients without a kidney biopsy.

Table 1 shows the immunosuppressants used before sirolimus treatment. In addition to the use of glucocorticoids, 10 children did not use other immunosuppressants, five children used one immunosuppressant, four children used two immunosuppressants successively, and three children used three immunosuppressants successively before sirolimus treatment. One patient received mizoribine, one patient received mycophenolate mofetil, four patients received cyclosporine A, seven patients received tacrolimus, and nine patients received cyclophosphamide.

Table 1. Immunosuppressant used before sirolimus treatment.

Patients number	IS used before sirolimus treatment	
10	P	
3	P、CYC	
1	P、CyA	
1	P、Tac	
1	P、CYC、CyA	
2	P、Tac、CYC	
1	P、MMF、Tac	
2	P、CYC、CyA、Tac	
1	P、Tac、CYC、Miz	
IS, immunosuppressant; P, prednisone; CYC, cyclophosphamide; CyA, cyclosporine A; Tac, tacrolimus; MMF, mycophenolate mofetil; Miz, mizoribine.

The follow-up time for the first treatment evaluation was three months. In this series, nine patients achieved partial remission of nephrotic syndrome during the first treatment, and 13 did not. Table 2 shows the effectiveness of sirolimus for different steroid responses. These partial-remission children included four patients with FRNS, one patient with SDNS, and four patients with SRNS. The pathological types of these partial-remission children included four patients with MCD, one patient with FSGS, one patient with MsPGN, and the other pathological types were unknown.

Table 2. Sirolimus effectiveness for different steroid responses.

Variables	FRNS (n = 6)	SDNS (n = 2)	SRNS (n = 14)	
Partial remission	4 (66.7%)	1 (50.0%)	4 (28.6%)	
Absent remission	2 (33.3%)	1 (50.0%)	10 (71.4%)	
Partial remission, positive morning urine protein [≤ (++)] and/or disappearance of edema and serum albumin > 25 g/L; Absent remission, morning urine protein ≥ (+++); FRNS, frequently relapsing nephritic syndrome; SDNS, steroid dependent nephrotic syndrome; SRNS, steroid resistant nephrotic syndrome.

No sirolimus-related adverse reactions were identified through the end of the first treatment. Table 3 shows a comparison of the laboratory results of 22 children with RNS before sirolimus treatment and at the first follow-up. The results revealed that after sirolimus treatment, the 24-h UP, LDL-C, Ur and SCr levels significantly decreased (all p < 0.05), the Alb level significantly increased (p < 0.05), and there were no significant differences in the TC, HDL-C, TG, IgA, IgG and IgM levels (all p > 0.05) at the first follow-up.

Table 3. Comparison of laboratory results of 22 children with RNS before sirolimus treatment and the first treatment follow-up.

Parameters	Before Sirolimus Treatment	First Treatment Follow-Up	95%CI	variations	t/Z	P-value	
24-h UP (g/24h)	4.38 ± 2.32	0.40 (0.11, 2.37)	0.5349–1.9006	(–)	5.150	<0.001*	
Alb (g/L)	18.40 (14.45, 29.50)	26.25 ± 8.29	22.5784–29.9307	(+)	−2.331	0.030*	
TC (mmol/L)	10.97 ± 4.86	9.73 (7.17, 13.70)	8.7277–12.4314	(–)	0.465	0.647	
HDL-C (mmol/L)	2.12 ± 0.73	2.00 ± 0.72	1.6756–2.3171	(–)	0.638	0.531	
LDL-C (mmol/L)	7.97 ± 4.21	6.23 ± 3.41	4.7151–7.7394	(–)	2.087	0.049*	
TG (mmol/L)	2.62 (2.03, 3.93)	2.48 (1.73, 4.20)	2.2278–5.4203	(–)	−0.065	0.948	
Ur (mmol/L)	4.53 ± 2.12	3.15 ± 1.06	2.6842–3.6213	(–)	3.376	0.003*	
SCr (umol/L)	28.68 ± 10.61	21.86 ± 7.81	18.4013–25.3260	(–)	5.250	<0.001*	
IgA (g/L)	0.88 ± 0.51	0.81 ± 0.45	0.6067–1.0069	(–)	1.537	0.139	
IgG (g/L)	2.79 (1.64, 4.60)	2.79 (2.10, 4.20)	2.3179–4.8239	(–)	−0.651	0.522	
IgM (g/L)	1.34 ± 0.54	1.20 ± 0.39	1.0255–1.3718	(–)	1.787	0.088	
24-h UP, 24-h urine protein quantification; Alb, Albumin; TC, Total cholesterol; HDL-C, High density lipoprotein cholesterol; LDL-C, Low density lipoprotein cholesterol; TG, Triglyceride; Ur, Urea; SCr, Serum creatinine; IgA, Immunoglobulin A; IgG, Immunoglobulin G; IgM, Immunoglobulin M; 95%CI, 95% Confidence Interval for first treatment follow-up; (+) Higher outcomes after sirolimus than before treatment; (-) Lower outcome after sirolimus than before treatment; P-value, the difference between before sirolimus treatment and first treatment follow-up; *means p < 0.05.

Discussion

Massive proteinuria resulting from glomerular filtration barrier lesions is the main pathological link of nephrotic syndrome, so reducing urinary protein is the core of treatment [3,4]. Glucocorticoids are not only the choice of drugs for anti-inflammatory and immunosuppressive therapy in nephrotic syndrome patients but also the most effective drugs for inducing urinary protein loss. Although glucocorticoids are the first-line drugs for treatment of RNS, the disease condition is often not effectively controlled with hormone drugs alone. Moreover, when children with RNS are treated with glucocorticoids for a long time, the incidence of adverse drug reactions, such as Cushing's syndrome, ophthalmic diseases, decreased bone mineral density, and growth restrictions, is high [5–7]. Several retrospective studies have shown that long-term glucocorticoid use is a significant independent predictor of multiple adverse effects and that this risk is related to dose and time [8]. At present, there is no uniform treatment for RNS [9], and the difficulties of drug treatment focus mainly on how to achieve lasting and effective remission in children and minimize diseases and treatment-related side effects.

Sirolimus, formerly known as rapamycin, is a macrolide immunosuppressant. Sirolimus can inhibit the activation and proliferation of T lymphocytes and the synthesis of immunoglobulin in B lymphocytes in vivo, thereby exerting immunosuppressive effects [10]. Sirolimus does not inhibit calcineurin after binding to cytoplasmic proteins and thus does not appear to cause nephrotoxicity resulting from calcineurin inhibitors. In this study, sirolimus showed therapeutic advantages in humoral immunity and kidney function, but the determination of early monitoring indicators during treatment and the control of adverse events remains to be further studied. Clinical experience with sirolimus for the treatment of RNS in children is immature, and we need to actively explore the timing of administration and effective dosage. On the basis of currently available clinical data, sirolimus has advantages over other immunosuppressants in terms of adverse effects.

Despite significant decreases in 24-h UP and increases in Alb during the first treatment, the response to sirolimus is not optimal, which may be related to individual variability in the drug used in different pathological types [11]. In this study, the dose of sirolimus was 0.03 mg/(kg·d), and the dose of prednisone combined with sirolimus was 1.5 ∼ 2 mg/(kg·d). There are few studies on using sirolimus in the treatment of nephrotic syndrome in children. The therapeutic drug monitoring of sirolimus is not routinely carried out in our hospital, and the effective dose of sirolimus needs to be further explored and standardized.

Children with nephrotic syndrome have abnormal lipid metabolism, and hyperlipidemia is associated with decreased plasma colloid osmotic pressure, while the severity of hyperlipidemia is closely negatively correlated with decreased osmotic pressure [12,13]. Hypercholesterolemia in children with nephrotic syndrome is associated with increased hepatic synthesis of lipoproteins and decreased catabolism, where the main cause of hypertriglyceridemia is impaired lipid metabolism [14]. Compared with levels before sirolimus treatment, LDL-C levels remained high despite significant reductions, whereas TC, HDL-C, and TG did not improve significantly. Abnormalities in lipid metabolism induced by nephrotic syndrome can be reversed with remission of the disease [15], and it is clear that sirolimus does not play a satisfactory role in improving hyperlipidemia.

RNS treatment in children is not effective, as hypoproteinemia, lipids and other metabolic disorders seriously affect the growth and development of children and their quality of life. Persistent proteinuria can stimulate glomerular mesangial cell proliferation, glomerulosclerosis, tubular epithelial cell damage, and tubulointerstitial fibrosis, ultimately leading to irreversible damage to the kidney and even the development of chronic kidney failure [16,17]. We need to select immunosuppressants in combination with clinical manifestations and complications, kidney pathological changes, drug treatment reactions, drug toxic side effects, individual differences in children and their economic status, etc. [18,19]. Medication should be taken under the premise of following standardized treatments of evidence-based medicine and seeking a balance between eliminating urine protein and reducing adverse drug reactions as much as possible to maximize clinical benefits while minimizing risks [20,21].

In a study on pediatric SRNS in China, nephrologists concluded that the combination regimen of steroids, tacrolimus and sirolimus was safer and more effective than the combination regimen of steroids and tacrolimus. The former combination regimen improved biochemical indices, such as cholesterol, blood creatinine, glomerular filtration rate, albumin, and 24-h UP. Moreover, it reduced the rate of disease recurrence and the incidence of adverse effects. However, our study participants were children with RNS, and the treatment regimen was steroids combined with sirolimus. We hope that more clinical data will support the standardized application of sirolimus in the future. Sirolimus is a new attempt to treat RNS in children and can maintain disease remission in some children. In this study, some patients were transferred to another hospital, and some patients were switched to other immunosuppressants; thus, the sample size was small, and the follow-up period was short. The therapeutic effect of sirolimus on different pathological types and whether long-term sirolimus treatment is needed require multicenter, large-sample, prospective studies to explore the effective dose and course of sirolimus.

Acknowledgement

The authors would like to appreciate all participating physicians and children who participated in this study and their families.

Ethical statement

This study was approved by the ethical committee of the hospital in December 2021.

Report number of 202136. All patients signed the consent form.

Author contributions

Nan Zhang and Yile Zhao were responsible for drafting and revising the article. Sanni Li, Yingying Zheng and Lei Dong were involved in data collection. Le Jiang performed statistical analysis. All authors provided final manuscript approval.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

Data are available within the article.
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