Infection is one of the most common complications in children with nephrotic syndrome (NS). The annual incidence of invasive bacterial infection based on retrospective case series was shown to be about 1-2%, and the cumulative risk for the 10-year susceptibility period was around 10–20% [
In China, the incidence of nosocomial infection has been reported to be as high as 34–79% in children with nephrosis [
There are several interpretations of this high risk of infection in NS, including urinary losses of factors B and D of the alternative complement pathway, impaired polymorph phagocytic function, edema, and secondary effects of corticosteroids and cytotoxic therapy [
The Chinese herbal medicine has been used to address infections for thousands of years. One representative medicine,
An 11-year-old boy was referred to Professor Huang Chunlin’s renal clinic because of repeated relapses of nephrotic syndrome. Nine years earlier, he had been diagnosed with primary nephrotic syndrome after the onset of limb edema. Prednisone at a dose of 60 mg/day was given and gradually withdrawn when complete remission was achieved after 1 month. However, he suffered his first relapse of nephrotic syndrome when he was on a prednisone dose of 15 mg/day due to an upper respiratory tract infection. Although the infection was controlled quickly, his nephrotic syndrome was not alleviated, forcing him to take the initial dose of prednisone (60 mg/day) again. Another complete remission was then achieved. In the subsequent 9 years, he experienced a total of eight relapses whenever the prednisone dose was reduced to lower than 20 mg/day. In particular in the last year, URTI occurred eight times, and NS relapsed three times, apparently triggered by URTI. Three months before this referral, he started taking prednisone at a dose of 60 mg/day for the same clinical situation described above, and it had been tapered gradually to 20 mg at the time of the visit. At that time, he presented with what appeared to be Cushing’s syndrome: flushed face, moon face, buffalo hump, and complaining of feeling fatigued and sweaty. Physical examination showed congestion of the throat with swelling of the bilateral tonsils and purple striae all over the body, but no edema of the lower limbs. Laboratory investigations showed the following: 24 h urinary protein was in the normal range, serum immunoglobulin (IgG) slightly low, serum albumin 38 g/L, and serum creatinine 45
His mother had heard about
The common clinical question was whether it would be effective to use
The PICO question was formulated as follows: in patients or a population with primary nephrotic syndrome, were
Thus, children with primary nephrotic syndrome, conventional treatment alone, upper respiratory infection rate.
All randomized controlled trials (RCTs) evaluating the use of
We designed a search filter restricted to articles relevant to the PICO question within PUBMED from (1966–2012.8), Embase.com (1980–2012.8), Cochrane Library (Issue 5, 2012), The Chinese Biomedicine Database (CBM from 1978–2012.8), WeiPu Chinese Scientific Magazine Database (VIP; 1989–2012.8), and China National Knowledge Infrastructure (CNKI; 1979–2012.8).
The search used a combination of search terms using relevant synonyms for the domain: “kidney diseases,” “glomerulonephritis,” “nephrosis,” “minimal change nephropathy,” “nephropathy,” “
The titles and abstracts of all published articles obtained from these search strategies were examined to determine whether they were applicable to the purpose of this study.
Titles and abstracts from the preliminary search results were checked independently by two authors (Chuan Zou and GuoBin Su) to identify clearly irrelevant studies that needed to be discarded. Full texts of the remaining studies were evaluated to judge whether the inclusion criteria were met. If information on key points was unclear, the relevant original authors of the articles were contacted by telephone for clarification.
Data extraction was conducted on full-text copies of all included trials using a data extraction form designed for the purpose. Data regarding the characteristics of the study, including the sample size, age, disease period, and clinical features of the children with NS, were gathered. The types and doses of different
The risk of bias in individual studies was assessed by the GRADE approach across five aspects: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other potential biases. The GRADE approach was used to evaluate the quality of evidence, and the results are presented in the Summary of Findings table. The quality rating for studies assessed using the GRADE approach has four levels: high, moderate, low, or very low.
Relative risk was calculated with the GRADEProfiler 3.2.2 (GRADE Working Group 2004–2007) and is shown in the GRADE Quality Assessments tables. A process was designed to combine data across studies to perform a meta-analysis when
Our search yielded 24 articles in PubMed, 120 in Embase.com, 37 in Cochrane Library, 30 in CBM, 301 in CNKI, and 25 in VIP (for search strategies, see Table
Search strategies.
Database | Searching strategies | Hits |
---|---|---|
PubMed (1966 |
P: (“Kidney diseases” |
P + I = 59 |
| ||
EMBASE (1974 |
P: #1 OR #2 OR #3 OR #4 OR #5 OR #6 |
P + I = 266 |
| ||
Cochrane Library (Issue 5, 2012) | Searching field: title, abstract, or keywords |
P: 37 |
| ||
CBM (1978 |
Subject or title or abstract: Nephritic syndrome AND respiratory infection | 30 |
| ||
CNKI (1979 |
Subject or title or abstract: Nephritic syndrome AND respiratory infection | 301 |
| ||
VIP (1989 |
Title or keyword: Nephritic syndrome AND respiratory infection | 25 |
*Refers to searching for all terms that begin with a word, enter the word followed by an asterisk (*).
Search process: flow diagram of included and excluded studies. A search for relevant studies was performed using the PubMed database, Embase, Cochrane library, CNKI, CBM, and VIP subsequently filtered out based on the inclusion/exclusion described.
Yuan et al. 2004 [
Xie and Peng 2010 [
We also identified two Cochrane reviews related to
We did not include J. Zhang and Y. Zhang (2008) [
We managed to get the URTI rate in the two remaining studies [
Characteristics of the included studies.
Study design | Population | Intervention | Comparison | Duration | Outcome | Followup | Adverse reaction | |
---|---|---|---|---|---|---|---|---|
Kang, 2005 [ |
Parallel RCT |
Age |
STD prednisone + Huangqi (Astragalus) granules |
Infection |
||||
STD prednisone | 3 to 6 months | URTI |
Not mentioned | NS | ||||
Relapse |
||||||||
| ||||||||
J. Chen and S. Q. Chen, 2008 [ |
Parallel RCT |
Age |
STD prednisone + Huangqi (Astragalus) granules (oral) |
Infection |
||||
STD prednisone | 3 months | URTI |
8 months | NS | ||||
Relapse |
STD prednisone: initial dose 1 mg/kg/d for 8–12 weeks. Every other day for 6 months. When urine protein is negative, decreased 5 mg/wk until reduced dose tapered gradually to 0.4 mg/kg/d over 6 months and maintained at this dose for 12–18 months. Finally, tapered gradually until withdrawal to 0.5 mg/kg/d, then 1 mg/kg every other day for 6 months.
STD prednisone + CTX: initial prednisone dose 1 mg/kg/d plus CTX 50 mg b.i.d.p.o. (total in 8 mg).
URTI: upper respiratory tubular infection; I: intervention; C: comparision.
Characteristics of the included Cochrane reviews.
Intervention | Comparision | Number of RCTs | Participants | |
---|---|---|---|---|
Wu et al., 2012 [ |
IVIG, thymosin, OTF, MPT, BCG, Lantigen B, TIAOJINING, Huangqi granules + baseline treatment | Baseline treatment | 12 | 762 |
| ||||
Yuan et al., 2008 [ |
Huangqi injection, Huangqi and red Chinese, Huangqi and Danggui + baseline treatment date | Baseline treatment | 3 | 128 |
IVIG: intravenous immunoglobulin; OTF: oral transfer factor; MPT: mannan peptide tablet; BCG: Bacillus Calmette-Guerin (BCG) vaccine injection; and baseline treatment: STD prednisone.
The quality of methods and reporting of results in the remaining five articles were appraised critically for quality of methodology, design, and data analysis using GRADE. The quality of these studies was low (Table
Quality assessment of the included studies.
Concealment of allocation | Randomization sequence generation | Blinding | Selective reporting | Intention-to-treat analysis | Level of evidence | |
---|---|---|---|---|---|---|
Kang, 2005 [ |
NS | Unclear1 | No | Not mentioned | Not mention | Unclear risk |
| ||||||
J. Chen and S. Q. Chen, 2008 [ |
NS | Quasi-randomization2 | No information | Not mentioned | Not mention | Unclear risk |
2The patients with nephrotic syndrome were allocated to the treatment and control groups according to the order of admission.
Grade assessment of studies. Question: should Huangqi versus conventional treatment be used for upper respiratory tract infection? Settings: parallel RCT.
Upper respiratory tract infection rate | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Quality assessment | No. of patients | Effect | Quality | Importance | ||||||||
No. of studies | Design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Huangqi | Conventional treatment | Relative (95% CI) | Absolute | ||
16/67 (23.9%) | 27/63 |
19 fewer per 100 (from 3 fewer to 29 fewer) | ||||||||||
2 | Randomised trials | Serious1 | No serious inconsistency | No serious indirectness | Serious2 | None | 10% | RR 0.56 (0.33 to 0.93) | 4 fewer per 100 (from 1 fewer to 7 fewer) |
|
Critical | |
40% | 18 fewer per 100 (from 3 fewer to 27 fewer) |
2Total number of events is less than 300, and a relative risk reduction (RRR) or relative risk increase (RRI) is greater than 25%.
According to the two studies included [
The patient was administered 2.25 g
Before 1940, mortality in children with nephrotic syndrome reached 40%, due, mainly, to infections [
Based on these findings,
According to the GRADE method of bias evaluation, there were potentially large biases in the included studies, which could have had an impact on the outcome. For example, there was no description of adequate sequence generation, allocation concealment, or blinding, which could have produced bias in selection, implementation, and measurement. All eligible studies were carried out in China and published in Chinese; thus, positive results were more likely to have been reported than negative results [
Although the level of evidence for using
Second, because each treatment has its own advantages and disadvantages, it is important for doctors to make clinical decisions by evaluating benefit, risk, and convenience from the patient’s point of view [
Finally, another key factor in clinical decision making is the cost. The possibility of a strong recommendation for a very good treatment can be reduced because of its high cost and unavailability. Thus, one of the crucial factors in recommendation strength is evidence regarding the conditions and demands of its practical use [
To summarize, we decided to administer Radix Astragali to the patient to prevent URTI, and the dose and course were referred to an expert for an opinion. According to Professor Huang’s experience of syndrome differentiation in Chinese medicine (CM), the outstanding symptoms of the boy were fatigue, hidrosis, and being prone to suffer from upper respiratory tract infection, indicating a lung Qi deficiency.
The authors declare that they have no conflict of interests and no relationship of interest with any drug manufacturer. There is no financial gain from using the drugs mentioned in this paper. The case presentation was approved by the patient and his parents.
C. Zou and G. Su contributed equally to the work and should be regarded as cofirst authors.
This work was supported by the Construction Project in 2011 from the Research Studio of Famous Old TCM Practitioners Experience Heritage, State Administration of Traditional Chinese Medicine (no. 2012KT1301), and Research Project for Practice Development of National TCM Clinical Research Bases.