World Journal Of Pediatrics-articles

Author Affiliations: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China (Li JG, Ding J, Wang F, Zhang HW)

Corresponding Author: Jie Ding, MD, PhD, Department of Pediatrics, Peking University First Hospital, No. 1, Xianmen Dajie, Beijing 100034, China (Tel: 8610 66551122 ext 3236; Fax: 8610 66134261; Email: djnc_5855@126.com).

Background: Proteinuria is one of the risk factors for the progression of renal diseases including Alport syndrome (AS), a hereditary glomerular renal disease. This study aimed to evaluate the efficacy of angiotensin converting enzyme inhibitors (ACEIs) and/or tripterygium, a Chinese herbal medicine widely used in Chinese patients with hematuria and proteinuria, on proteinuria in patients with AS.

Methods: Twenty-nine children were enrolled into this retrospective study. Patients were divided into 3 therapy groups: ACEI group, tripterygium group, and ACEI plus tripterygium group.

Results: In the 29 children, 23 were male and 6 female. In the ACEI group and the tripterygium group, the effective rate was 87.5% and 25.0%, respectively and in the ACEI plus tripterygium group was 42.9%.

Conclusions: ACEI is effective in controlling proteinuria of AS patients. Tripterygium should be carefully administered in controlling proteinuria of AS patients.

Key words: Alport syndrome; angiotensin converting enzyme inhibitor; herbal medicine; tripterygium

Alport syndrome (AS) is a hereditary nephritis manifested by hematuria, sensorineural hearing loss, ocular lesions and progressive renal failure.[1] Almost all male patients with X-linked AS (XLAS) and all patients with autosomal recessive AS (ARAS) present proteinuria during the progression of the disease.^[1] Studies have shown that the degree of proteinuria is related to the progression of renal function.^[2] Thus efforts have been made to control proteinuria for a slow progression of AS, such as the application of ACEI/ARB, cyclosporine, or mineralocorticoid receptor antagonist spironolactone (SP) in patients or animal models of AS.^[3-10] Tripterygium, a cheap Chinese herbal medicine, is also effective to decrease proteinuria in some renal diseases. The present retrospective study aimed to evaluate the effects of ACEI and tripterygium on proteinuria of children with AS.

The diagnosis of AS was based on the clinical manifestations and laboratory investigation, including sensorineural hearing loss, eye abnormality, positive family history of chronic renal failure, the characteristic ultrastructural changes of the glomerular basement membrane shown by an electron microscope, abnormal staining of α chains of type IV collagen in epidermal basement membrane or in glomerular basement membrane, and COL4A5 mutations.

From June 1998 to December 2007, 29 children who met these criteria were enrolled in the study. These children were divided into three groups according to the administration of different drugs: ACEI group, tripterygium group, and ACEI plus tripterygium group.

Effectiveness of treatment was defined as proteinuria decreased after treatment for more than 4 months.

This group included 12 children who received ACEI treatment. Their mean age at diagnosis and initial therapy was 6.7 years and 9.8 years, respectively. The average dose of captopril was 15 mg to 75 mg per day according to the body weight (0.3-0.5 mg/kg, every 8 hours). The dose of monopril was 5 mg or 10 mg per day. After 4 to 6 month treatment, proteinuria increased in 1 child, but decreased in 6 children. After 9 to 12 month treatment, proteinuria decreased in 6 children. The average reduction of proteinuria ranged from 14.0% to 78.0% (Fig. 1). The abnormal renal function was detected in 1 child after 1 year of ACEI treatment. Unfortunately, there were no data on renal function before the treatment.

This group consisted of 9 children treated with tripterygium. Their mean age at the detection of proteinuria and beginning of the therapy was 9.4 years and 13.1 years, respectively. The average dose of tripterygium was 20 mg to 60 mg per day according to the body weight of the children (1-2 mg/kg per day). After 4-6 month treatment, proteinuria decreased in 2 children but increased in 6. After 9-12 month treatment, proteinuria increased in 4 children (Fig. 2). The renal function of the 2 children was abnormal before and after the treatment. No children showed renal dysfunction during the follow-up.

This group comprised 8 children who received ACEI plus tripterygium treatment. Their mean age at detection of proteinuria and initial treatment was 8.3 years and 11.6 years, respectively. The dose of tripterygium ranged from 15 mg to 60 mg per day. The dose of ACEI ranged from 5 mg to 37.5 mg per day. After 4-6 month treatment and 9-12 month treatment, proteinuria increased in 4 children but decreased in 3 (Fig. 3). Only 1 of the 8 children was detected with renal dysfunction after the treatment for 18 months. Unfortunately, there were no data on the renal function before the treatment.

ACEI related side-effects including cough and renal function deterioration were not observed in the ACEI group. In the tripterygium group, some children presented with irregular menstruation and reduced white blood cell count. Only one girl had to withdraw the treatment with tripterygium because of irregular menstruation.

Alport syndrome is a hereditary progressive nephritis.^[1] Once proteinuria appeared, the progression of renal function would accelerate.^[11] Several drugs have been applied in patients or animal models of AS,^[3-6,7-9,12] but their effects on AS are controversial. Cyclosporine is beneficial in slowing the progression of renal function in patients or animal models of AS, whereas the nephrotoxicity caused by cyclosporine would limit the long-term application.^[8,13] In other studies, ACEI (0.05-0.5 mg/kg per day) was used to control proteinuria in AS patients. But the effect of ACEI was not consistent in the studies.^[3-5,10,14]

Before the therapy in our study, there was no significant difference in demographic data of patients in the three groups. In the ACEI group, the percentage of proteinuria reduction in 4-6 months and 9-12 months was 85.7% and 100.0% respectively. A study^[15] found that routine treatment with ACEI was unnecessary in the early stage of AS patients with sub-nephrotic range proteinuria. Another study,^[5] however, showed that ACEI was effective in controlling proteinuria when lower than 50 mg/kg per day, but was not effective to nephrotic-range proteinuria. We found that ACEI was effective in controlling proteinuria regardless of the level of proteinuria, the nephrotic range, and the lower level of pretienuria. We suggest that AS patients with proteinuria should be given ACEI as early as possible. Our data showed that the longer ACEI was administered, the better the effect of controlling proteinuria exhibited. Thus we suggest a long-time ACEI treatment for AS patients with proteinuria.

There was no satisfactory therapy for AS. Tripterygium, a Chinese herbal medicine, showed effects in decreasing proteinuria or/and hematuria in patients with renal diseases. The mechanism of tripterygium in the treatment of glomerular diseases was regarded as suppressing immuno-effects, inhibiting glomerular mesangial proliferation and extracellular matrix accumulation, delaying glomerular sclerosis, and ameliorating the podocyte injury.^[16-19] In addition, tripterygium is relatively cheap and will increase the compliance of patients. However, our study did not show any significant effects as we expected in controlling the proteinuria of AS patients. Most of the patients showed increase of proteinuria after treatment. Only one girl with AS treated with tripterygium showed good effect except for abnormal menstruation (data not shown). She presented with obvious proteinuria after withdrawal of the tripterygium treatment because of abnormal menstruation, but her proteinuria decreased again when tripterygium was continued. Therefore, the effects of tripterygium need a further study.

In the ACEI group, no side-effects were observed. In the tripterygium group, neutropenia or abnormal menstruation was noticed.

There are some limitations in our study. First, the present study is a retrospective study and did not enroll cases with placebo as controls, because such study design is difficult to be approved by the ethical committee. Second, it will be better if the effect of the therapy was assessed by the change of renal function. Unfortunately the glomerular filtration rate was not regularly detected in the follow up. In addition, the suitable age for starting drug therapies and the proper dosage of drugs are still undecided.

In conclusion, ACEI was an effective and safe drug in controlling proteinuria of AS patients, but tripterygium did not show any significant effects in our study. Tripterygium should be carefully administered in controlling proteinuria of AS patients. A multicenter and prospective trial is needed to evaluate the efficacy of drugs in AS patients.

We are grateful to physicians who have referred patients to our department. We also thank all physicians and nurses in the Division of Pediatric Nephrology, Peking University First Hospital including Liu JC, Chen Y, Yao Y, Xiao HJ, Huang JP, Zhong XH and Yang JY.

Funding: This work was supported by grants from the National Natural Science Foundation of China (30170992, 30672259), National 10th Five-Year Project (2003BA712A11-23) and National 11th Five-Year Scientific and Technical Supporting Programs (2006BAI05A07).

Ethical approval: The study was approved by the Ethics Committee of Peking University First Hospital, China (2006023).

Contributors: Li JG wrote the main body of the article under the supervision of Ding J. Wang F and Zhang HW provided gene diagnosis of Alport syndrome. Ding J is the guarantor.

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