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The Spectrum of Children's Kidney Diseases—2403 Renal Biopsy-proven Cases from a Single Centre in China between 1999 and 2019


 Background: This study aimed to investigate the clinical and pathological characteristics and the profile of and temporal changes in glomerular diseases in 2403 paediatric renal biopsies from 1999 to 2019.Methods: Renal biopsies performed on children aged ≤18 years between 1999 and 2019 were analysed at our centre. We analysed the clinical and histological characteristics, distribution of paediatric renal diseases with various clinical presentations, and changes in the pattern of kidney disease during the study period.Results: The most common primary glomerular disease was IgA nephropathy (IgAN) (24.3%), followed by minimal change disease (MCD) (15.3%) and membranous glomerulonephritis (MN) (13.1%). Henoch-Schonlein purpura nephritis (HSPN) (18.1%) and lupus nephritis (LN) (7.2%) were the most frequently recorded secondary glomerular diseases. Alport syndrome and thin basement membrane nephropathy (TBMN) were the most common inherited glomerular diseases, accounting for 1.2% and 0.6% of the total glomerular diseases in children, respectively. The number of boys with IgAN, MCD and IgM nephropathy (IgMN) was significantly higher than that of girls, while the number of girls with MN and LN was significantly higher than that of boys. The frequencies of MCD, MN, IgMN and endocapillary proliferative glomerulonephritis (EnPGN) in the 13-18-year-old group were significantly higher than those in the 0-12-year-old group, while the frequencies of IgAN, mesangial proliferative glomerulonephritis (MsPGN) and focal proliferative glomerulonephritis (FPGN) were lower than those in the 0-12-year-old group. The ratio of Alport syndrome and TBMN in the 0-12-year-old group was significantly higher than that in the 13-18-year-old group. The proportion of patients with MCD and MN in 2010-2019 was significantly higher than that in 1999-2009, while the ratio of IgAN, MsPGN, IgMN, EnPGN, membranoproliferative glomerulonephritis (MPGN), HSPN and HBV-associated glomerulonephritis (HBV-GN) decreased. MCD (28.5%) was the most common cause of nephrotic syndrome (NS). In children with haematuria and proteinuria, HSPN (38.8%) and IgAN (36.9%) were more common than other glomerular diseases. IgAN (39.4%) was the most common cause of AKI. Sclerosing glomerulonephritis (SGN) (21.1%) was the main cause of progressive chronic kidney disease (CKD).Conclusions: Glomerular diseases in children were related to sex and age. From 1999 to 2019, the spectrum of children's kidney disease in our centre changed significantly.

Conclusions: Glomerular diseases in children were related to sex and age. From 1999 to 2019, the spectrum of children's kidney disease in our centre changed signi cantly.

Background
Chronic kidney disease (CKD) has become one of the major diseases threatening global public health [1,2]. It is a major chronic disease that causes a high medical burden and seriously affects quality of life. If CKD is not diagnosed and treated in time, the mortality of CKD will be signi cantly increased once it develops into end-stage renal disease (ESRD) [3]. Therefore, how to detect and treat CKD early in children is a clinical problem to be solved.

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The aetiology of CKD varies in different regions and ethnic groups. Congenital anomalies of the kidney and urinary tract (CAKUT) are the main causes of CKD in children in developed countries [1,4,5], while glomerular diseases are the main causes in developing countries [6][7][8][9]. Glomerular disease is still the main cause of CKD in children in China [6]. The diagnosis and treatment of glomerular diseases mainly depend on renal biopsy. Renal biopsy is an invasive procedure with the risk of haemorrhage and arteriovenous stula. Therefore, it is very important to study the spectrum of glomerular diseases; the relationship between renal pathology and clinical manifestations; and the relationship between glomerular diseases and age, sex and years. This will correctly diagnose glomerular disease in children without renal biopsy. In China, there are few centres that study glomerular diseases in children.
This study retrospectively analysed the clinical and pathological data of 2403 renal biopsies of children in a single centre; clari ed the constitution, changes and distribution of kidney diseases; and analysed them according to the patient's sex and age.

Inclusion and exclusion criteria
From 1999 to 2019, we selected 2453 children with kidney disease under the age of 18 who underwent renal biopsy. The exclusion criteria were pathological results of renal biopsy with less than 5 glomeruli under a light microscope, incomplete clinical data, or tubulointerstitial disease or renal vascular disease without glomerular lesions. Finally, 50 cases were excluded, and 2403 cases were included in this analysis. The patients and/or parents signed the consent form before renal biopsy. The research was in compliance of the declaration of Helsinki and approved by the ethics committee of the Second Hospital of Hebei Medical University. Before enrollment, written informed consent was provided by patients or their guardians.

Clinical classi cation
According to the clinical classi cation standard of children's glomerular disease formulated by the Chinese Medical Association in 2000, we divided 2403 children into six clinical types: nephrotic syndrome (NS), acute kidney injury (AKI), progressive CKD (de ned as eGFR < 60 mL/min/1.73 m 2 ), proteinuria, haematuria, and proteinuria with haematuria. The glomerular ltration rate was calculated by the swatch formula. NS was de ned as proteinuria greater than 50 mg/kg·d or greater than 3.5 g/kg and serum albumin less than 30 g/L. Proteinuria that does not meet the criteria for NS is de ned as proteinuria.

Indications and contraindications for percutaneous renal biopsy
The indications for percutaneous renal biopsy include steroid-resistant NS, a part of steroid-dependent and frequently recurrent NS; NS with glomerular haematuria or renal insu ciency or hypertension or low complement; unexplained persistent haematuria and/or proteinuria; unknown AKI or unexplained progressive CKD; nephrotic proteinuria or NS or gross haematuria or AKI caused by Henoch-Schonlein purpura nephritis (HSPN); and other secondary glomerulonephritides. The contraindications for renal puncture include an isolated kidney, displaced kidney, abnormal renal structure, coagulation disorder, ESRD and renal infection.

Pathological examination
All pathological tissues were examined by light microscopy and immuno uorescence, and approximately 50% of them were further examined by electron microscopy.

Grouping
According to age, they were divided into two groups: 0-12 years old and 13-18 years old. According to the time of renal puncture, they were divided into two groups: 1999-2009 and 2010-2019. According to sex, they were divided into male and female groups. According to the clinical classi cation of children's kidney disease, they were divided into 6 groups: NS, AKI, progressive CKD, proteinuria, haematuria and proteinuria with haematuria. The constituent ratios of renal pathology in different sexes, ages and years were compared. The constituent ratio of renal pathology corresponding to different clinical types was compared.

Statistical analysis
Data were expressed as the mean ± SD. The chi-square test was used to analyse the constituent ratio. SPSS 23.0 software was used for statistical analysis. A P value of ≤ 0.05 was considered to be statistically signi cant.

General information
A total of 2403 renal biopsy specimens were analysed from 1999 to 2019, including 1411 males and 992 females, with a male to female ratio of 1.4:1. The average age at renal biopsy was 13.5 ± 3.4 years old. The youngest was 1 month, 708 cases (29.5%) were 0-12 years old, and 1695 cases (70.5%) were 13-18 years old. From 1999 to 2009, 1055 patients (43.9%) underwent renal biopsy, and 1348 patients (56.1%) underwent renal biopsy from 2010 to 2019. The most common clinical syndrome was NS (50.1%), followed by haematuria and proteinuria (38.3%) ( Table 1). diseases. Alport syndrome and thin basement membrane nephropathy (TBMN) were the most common inherited glomerular diseases, accounting for 1.2% and 0.6% of the total glomerular diseases in children, respectively ( Figure 1).
The relationship between glomerular diseases and sex As described in Table 2, the number of boys with IgAN, MCD and IgM nephropathy (IgMN) was signi cantly higher than that of girls, while the number of girls with MN was signi cantly higher than that of boys. In secondary glomerular diseases, the number of girls with LN was signi cantly higher than that of boys, and there was no signi cant difference in the proportion of HSPN between the two groups. There was also no signi cant difference in the proportions of Alport syndrome and TBMN between the two groups. The relationship between glomerular diseases and age As shown in Table 3, in primary glomerular diseases, the frequencies of MCD, MN, IgMN and endocapillary proliferative glomerulonephritis (EnPGN) in the 13-18-year-old group were signi cantly higher than those in the 0-12-year-old group, while the frequencies of IgAN, mesangial proliferative glomerulonephritis (MsPGN) and focal proliferative glomerulonephritis (FPGN) were lower than those in the 0-12-year-old group. There was no signi cant difference between the two age groups in secondary glomerulonephritis. The ratio of Alport syndrome and TBMN in the 0-12-year-old group was signi cantly higher than that in the 13-18-year-old group.

Changes of spectrum in glomerulonephritis
As shown in Table 4  Clinicopathologic correlation of paediatric glomerular diseases As shown in Table 5, the constituent ratio of renal pathology corresponding to different clinical types was different. MCD (28.5%) was the most common cause of NS, followed by MN (23.7%), IgAN (14.8%) and LN (9.6%). In children with haematuria and proteinuria, HSPN (38.8%) and IgAN (36.9%) were more frequent than other glomerular diseases. The common causes of proteinuria were glomerular minor   decreasing year by year [20]. Idiopathic membranous nephropathy is one of the most common causes of adult NS. In China, MN (43.3%) has become the most common primary glomerular disease, as opposed to IgAN. The prevalence of idiopathic MN in China has increased signi cantly, especially in young patients in the early stage [22]. Some studies have found that the frequency of MN is associated with long-term exposure to high levels of PM2.5 in the air [23]. The highest proportion of MN in our study may be because our region has the highest level of PM2.5 in the air. In the past 10 years, the incidence of HBV-GN and EnPGN has decreased signi cantly, which may be due to the widespread use of hepatitis B vaccines in China and timely antibiotic treatment for pharyngitis.
Our study found that boys were more likely to suffer from MCD and IgAN, while girls were more likely to suffer from LN, which was consistent with previous reports [12,20]. This sex difference may be due to differences in chromosome and sex hormone levels [24]. For example, many genes carried on the X chromosome, such as those encoding FoxP3 and the Toll-like receptors TLR7 and TLR8, are associated with the pathogenesis of autoimmune diseases [26], which may play a very important role in the pathogenesis of systemic lupus erythematosus (SLE).
MCD (28.5%) was the most common cause of NS. The common cause of haematuria was GML (50.0%), followed by IgAN (15.9%). In children with haematuria and proteinuria, HSPN (38.8%) and IgAN (36.9%) were more common than other glomerular diseases. Patients with simple microscopic haematuria can be followed up. If there is proteinuria or gross haematuria, renal biopsy is recommended.

Conclusions
Glomerular diseases in children were related to sex and age. From 1999 to 2019, the spectrum of children's kidney disease in our centre changed signi cantly. This study described the prevalence of renal biopsy in children in central China and provided a reference for a better understanding and prevention of kidney diseases.

Declarations
Ethics approval and consent to participate The research was in compliance of the declaration of Helsinki and approved by the ethics committee of the Second Hospital of Hebei Medical University. Before enrollment, written informed consent was provided by patients or their guardians.

Consent for publication
Not applicable.