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Nephrology 19 (2014) 426–431
Original Article
Renal histological features of school-age children with asymptomatic haematuria and/or proteinuria: A multicenter study YIHUI ZHAI,1 HONG XU,1 QIAN SHEN,1 QI CAO,1 GUANGHUA ZHU,2 MINJIANG WEI,3 LI SUN,1 HAIMEI LIU,1 JIA RAO,1 XIAOYAN FANG,1 JING CHEN1 and WEI GUO1 1 Department of Nephrology and Rheumatology, Children’s Hospital of Fudan University, 2Departent of Nephrology, Children’s Hospital of Shanghai Jiaotong University, and 3Renal Division, Department of Pediatrics, Xinhua Hospital of Shanghai Jiaotong University, Shanghai, China
KEY WORDS: glomerulonephritis, haematuria, proteinuria, renal biopsy, urinalysis. Correspondence: Professor Hong Xu, Department of Nephrology and Rheumatology, Children’s Hospital of Fudan University. No. 399 Wanyuan Rd., Shanghai 201102, China. Email: [email protected] Accepted for publication 4 April 2014. Accepted manuscript online 10 April 2014. doi:10.1111/nep.12260
SUMMARY AT A GLANCE This paper describes examines renal disease in children with asymptomatic urinary abnormalities. Children with isolated microscopic haematuria did not often have significant renal disease on biopsy. The incidence of significant renal disease was higher in those with proteinuria.
ABSTRACT: Aim: The risk of asymptomatic haematuria and/or proteinuria development into chronic progressive glomerulonephritis (CPG) is unclear. The indications for renal biopsy and follow-up on these asymptomatic children remain controversial. Methods: A multicenter, retrospective study was performed to investigate the renal histological features of school-age children with asymptomatic urine abnormalities. Results: A total of 112 asymptomatic children’s renal biopsy data were studied. Most of the children (71%) received a renal biopsy because of isolated microscopic haematuria (IH), and these children were predominantly (60%) proven to have only mild lesions in the glomeruli. Approximately 30% of the children were biopsied because of asymptomatic proteinuria with or without microscopic haematuria (HP or isolated asymptomatic proteinuria (IP)), and these children were mostly (44–83%) indicated to have CPG, such as IgA nephropathy, focal segmental glomerulosclerosis, and Alport syndrome. The junior high school students had a greater percentage of HP than the primary school children. IgA nephropathy was the most common diagnosis in children who received renal biopsy because of HP. Conclusions: Our findings indicate that IP and especially HP may have a high risk of development into CPG. IH, however, has a relatively low risk of severe histological lesions. Thus, IH per se might not be suggested as an indication for early renal biopsy. Long-term follow-up is necessary for these asymptomatic children.
Glomerulonephritis is one of the major causes of end stage renal disease (ESRD) worldwide, especially in Asian countries, including China.1 It may develop without obvious symptoms at a young age, but just with abnormal urinalysis, such as isolated microscopic haematuria and/or asymptomatic proteinuria. Glomerulonephritis may further progress insidiously, and even develop to ESRD. Therefore, regular population-based urinary screenings of the paediatric population have been performed in Japan, Taiwan, and Korea.2–4 With urinalysis, asymptomatic children with chronic progressive glomerulonephritis, such as IgA nephropathy5 or membranoproliferative glomerulonephritis (MPGN)6,7 have a chance to be detected early, diagnosed and treated, and better prognosis has been demonstrated by evidence from a large population.8 426
In Shanghai, China, we have performed a preliminary school urinary screening study since 2003, and over 114 000 primary and junior ‘healthy’ school students have undergone urinalysis. During these screenings, approximately 1% of children were found to have asymptomatic haematuria and/or proteinuria, and some of them were proven to have chronic progressive glomerulonephritis such as IgA nephropathy.9 One problem we encountered is how to follow-up the asymptomatic children with urine abnormalities. Therefore, in the present study, we collected renal biopsy data of 112 asymptomatic school-age children from three paediatric renal centres in Shanghai, China and retrospectively analyzed the renal histological features of these children, to assess the risk of asymptomatic haematuria and/or proteinuria development into chronic progressive © 2014 Asian Pacific Society of Nephrology
Renal biopsy results of asymptomatic children
glomerulonephritis, explore the indications for renal biopsy and follow-up in these asymptomatic children. This study may also help to assess the importance of school urinary screening in asymptomatic ‘healthy’ children in Shanghai, China, and guide us following-up such children in a costeffective manner.
METHODS Subjects This was a multicenter, retrospective study, which had approval from the local ethics committee and was performed in accordance with the Declaration of Helsinki. Potential subjects were primary and junior high school students from 7 to 14 years old, who had a renal biopsy from 2003 to 2010 because of persistent asymptomatic proteinuria and/or microscopic haematuria in three paediatric renal centres in Shanghai, China. The asymptomatic school-age children included in the study were defined as children without specific symptoms of kidney diseases, such as macroscopic haematuria or oedema, but with urine abnormalities such as asymptomatic haematuria (isolated microscopic haematuria) and/or mild-moderate asymptomatic proteinuria without oedema. Children with urinary symptoms such as frequent micturition or odynuria were excluded. Those with non-urinary specific symptoms such as cough, vomit, diarrhoea, or simply fever were included. Causes such as hypercalciuria, urinary tract infection, renal anatomic abnormalities, trauma, thrombosis, acute poststreptococcal glomerular nephritis, nutcracker phenomenon and orthostatic proteinuria were routinely ruled out before renal biopsy. Questionnaires were delivered to three centres. A total of 112 subjects (7–14 years) from three renal centres (centre A: 40 cases, centre B: 47 cases, centre C: 25 cases) were included. Medical history (including family histories of haematuria/ proteinuria/glomerulopathies) and renal biopsy data were reviewed and collected by paediatric nephrologists from each of the renal centres. Data were then stored in an electronic database, and analyzed by paediatric nephrologists from centre A. In all subjects, isolated microscopic haematuria was confirmed by microscopy. In addition, the amount of proteinuria was measured by urine dipsticks, confirmed by sulfosalicylic acid test or measured by spot urine protein-to-creatinine ratio, and in most cases by 24-h urine protein excretion. Renal biopsy specimens were examined by senior paediatric renal pathologists from each of the three centres using light microscopy, indirect immunofluorescence, and electron microscopy. The pathologic diagnosis was conducted according to World Health Organization (WHO) criteria for renal disease classification.10
Statistical analysis The continuous variables were described using the mean ± standard deviation (SD). Data were compared using the χ2 test (Fisher’s exact test). Unconditional multivariate logistic analysis was applied to assess the effects of independent determinants on histological diagnosis. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for categorical variables. A P-value of less than 0.05 was considered significant. All statistics were performed using SPSS version 19.0 (IBM Corporation, New York, NY, USA). © 2014 Asian Pacific Society of Nephrology
Table 1 General information of children with urine abnormalities
Median age (years) Gender Male Female Urinalysis Average urine RBC 50/hp Median 24 h Upro (g) (range) Elevated blood pressure Reduced eGFR How urine abnormalities detected School urine screening Health examination During diagnosis of other diseases
IH
IP
HP
9
11
12
34 46
4 5
16 7
32 38 10
0 0
0.80 (0.16–1.72) 1 0
37 12 31
2 1 6
3 15 5 0.43 (0.18–2.7) 1 2 3 2 18
eGFR, estimated glomerular filtration rate; HP, microhaematuria with asymptomatic proteinuria; IH, isolated microhaematuria; IP, isolated asymptomatic proteinuria; Upro, urine protein excretion.
RESULTS Urine results of asymptomatic school age children Of the 112 asymptomatic school age children (7–14 years), the indication for a renal biopsy in the majority (71%) of cases was isolated microscopic haematuria (IH) (male 43%), whereas 8% had a renal biopsy for isolated asymptomatic proteinuria (IP) (male 44%), and 21% for combination of both (HP) (male 67%). As for the different reasons for detecting asymptomatic proteinuria and/or microscopic haematuria in these children, 38% were identified by the school urine screening study conducted in Shanghai since 2003, whereas others were identified by self-requested health examination (13%) or during diagnosis of non-renal diseases such as respiratory infection, gastroenteritis and diarrhoea (49%) (Table 1). Among all of the asymptomatic children, males comprised 48%. The median age of the first detection of urine abnormalities was 9 years old (range from 7–14 years). Among these cases, the median age of the first detection of IH was 9 years old (range from 7–14 years), and for IP was 11 years old (range from 7–13 years). The median age for first detection of HP was the oldest, 12 years old (range from 7–14 years) (Fig. 1A). The constituent ratio of urine abnormalities of each age group indicated that in primary school children aged 7–11 years, most children had IH, whereas in older junior high school children aged 12–14 years, many more had HP. The differences between the primary and junior high groups were significant (P < 0.0001) (Fig. 1B). The average time period between first detection of urine abnormalities and kidney biopsy was 10 months, and was different among the three types of urine abnormalities. Children with IH had 427
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Fig. 1 Age distribution of urine abnormalities. (A) The median age of the first detection of isolated microscopic haematuria (IH) was 9 years, isolated asymptomatic proteinuria (IP) was 11 years and microhaematuria with asymptomatic proteinuria (HP) was 12 years. (B) The primary school children had more IH, , IH; , while junior high school children had more HP (P < 0.0001). , HP. IP;
the longest average period, 12 months; IP, 8 months; and HP the shortest average period, 7 months. Most children (98%) had normal blood pressure at the time of renal biopsy, except two children who were subsequently diagnosed with IgA nephropathy had elevated blood pressure. Most children (98%) had normal renal function at the time of renal biopsy, except two children who were subsequently diagnosed with Alport syndrome and IgA nephropathy, respectively, who had an eGFR approximately 80 mL/min per 1.73 m2 (Table 1). Thirteen percent of children had family histories of haematuria, proteinuria or glomerulopathies. Among them, most (93%) presented with isolated microscopic haematuria during the period of this study. Family history details were very limited, so its correlation with the eventual diagnosis was uncertain.
Renal biopsy results of asymptomatic children Renal biopsy results indicated that most of the children (47%) had minor glomerular abnormality (MGA), 14% had thin basement membrane nephropathy (TBMN), which was thought to have a benign outcome, but still nearly 40% of children might have progressive glomerulonephritis, such as IgA nephropathy, focal segmental glomerulosclerosis (FSGS), or Alport syndrome (Fig. 2). Among them, children with IH were mainly proven to have MGA (56%) and TBMN (19%) after renal biopsy, IP mainly to be MGA (56%) and IgA nephropathy (33%), and those with HP had the worst results, mainly IgA nephropathy (79%) (P < 0.0001) (Table 2). Half of the children with IgA nephropathy had 428
Fig. 2 Renal biopsy results of asymptomatic children. In total 112 cases, 53 (47%) were minor glomerular abnormality (MGA), 16 (14%) were thin basement membrane nephropathy (TBMN), 29 (26%) were IgA nephropathy, four (3%) were focal segmental glomerulosclerosis (FSGS), six (5%) were focal glomerulonephritis, two (2%) were Alport syndrome, one (1%) was mesangial proliferative glomerulonephritis (MsPGN), and one (1%) was sclerosing glomerulonephritis (SGN). , MGA; , TBMN; , IgA nephropathy; , FSGS; , Focal glomerulonephritis; , Alport syndrome; , MsPGN; , SGN.
Table 2 Urine abnormalities related to renal biopsy results n (%)
Urinalysis IH IP HP
MGA
TBMN
IgAN
Others
45 (56) 5 (56) 3 (13)
15 (19) 0 (0) 1 (4)
8 (10) 3 (33)) 18 (79)
12 (15) 1 (11) 1 (4)
Fisher
P-value
39.432
0.8 g was significantly related to progressive glomerulonephritis (P < 0.05). Among the IH group, the number of urinary erythrocyte was not significantly related to histological severity (P > 0.05).
Comparison of renal biopsy data among three renal centres When comparing data among the three centres, we found that IgA nephropathy was the most common diagnosis in © 2014 Asian Pacific Society of Nephrology
Renal biopsy results of asymptomatic children
Table 3 Comparison of renal biopsy data among three centres n (%)
Centres A B C
MGA
TBMN
IgAN
Others
15 (38) 25 (53) 13 (52)
4 (10) 12 (26) 0 (0)
16 (40) 6 (13) 7 (28)
5 (12) 4 (8) 5 (20)
Fisher
P-value
17.748
0.005
Others included FSGS, focal glomerulonephritis, Alport syndrome, MsPGN or SGN. Fisher: Fisher’s exact test. FSGS, focal segmental glomerulosclerosis; MGA, minor glomerular abnormalities; MsPGN, mesangial proliferative glomerulonephritis; SGN, sclerosing glomerulonephritis; TBMN, thin basement membranous nephropathy.
centre A (40%), while MGA was the most common diagnosis in centre B (53%) and C (52%). The difference among the three centres was significant (P < 0.01) (Table 3). Possible reasons for these differences were that centre A had the lowest percent of patients with IH who received a renal biopsy compared with those from centre B and C (47% vs 89% and 76%, respectively). However, centre A had the most percentage of patients with IP and HP who received a renal biopsy compared to those in centre B and C (IP: 89% vs 2%, 9%; HP: 76% vs 8%, 16%, respectively), which was consistent with our finding that HP was mainly related to IgA nephropathy. Variation among the three centres were significant (P < 0.01), and might be due to different indications for renal biopsy.
DISCUSSION Glomerulonephritis in children may develop insidiously,11,12 progress slowly, and a few cases may even reach ESRD. Different types of glomerulonephritis may have similar urine presentation in the early asymptomatic stage. In the present study, we analyzed renal biopsy data of school-age children with asymptomatic haematuria and/or proteinuria, and found that chronic progressive glomerulonephritis such as IgA nephropathy, FSGS, and Alport syndrome represent approximately 40% of cases. This relatively high proportion of chronic progressive glomerulonephritis suggests that asymptomatic haematuria and/or proteinuria in school-age children should receive increased attention. Importantly, 26% of the biopsied population had a diagnosis of IgA nephropathy, which is the most common variety of primary glomerulonephritis in the world today. Long-term follow-up studies have revealed that the disease progresses to renal failure in 20 to 50% of adult patients over 20 years13 and 11% of paediatric patients over 15 years.14 Many studies have reported that early treatment of this condition may reduce the progression of renal damage.15–17 Therefore, early detection and diagnosis of IgA nephropathy by urine screening in children is of great significance in improving the longterm outcome of IgA nephropathy. © 2014 Asian Pacific Society of Nephrology
Our data indicated that asymptomatic children with different patterns of urine abnormalities, IH, IP or HP, had different severities of renal pathological lesions. Therefore, we recommend treating them in different ways. As shown in our data, 75% of the patients with IH were diagnosed as MGA or TBMN by renal biopsy. The major urinary presentation of MGA or TBMN was IH, as 85% of patients with MGA and over 90% of patients with TBMN presented as IH. In addition, the number of urinary erythrocytes was not related to severity of renal pathological lesions among children with IH. Therefore, in terms of indication for renal biopsy, we recommend that IH per se might not be enough as a sufficient indication for early renal biopsy in asymptomatic children. However, proteinuria was the independent factor for severe renal pathological lesions. The asymptomatic proteinuria and/or with haematuria were highly related to IgA nephropathy as shown by our data that 33% of IP and 79% of HP were diagnosed as IgA nephropathy. These results are consistent with the other study that found a high prevalence of IgA nephropathy among proteinuric patients by mass screening.18 Therefore, we suggest that urine abnormalities such as HP might be involved in more severe pathological change, and require more medical care with early renal biopsy. Isolated microscopic haematuria has traditionally been regarded as benign. However, more extensive information, including the long-term follow-up of patients who present initially with microscopic haematuria, has begun to challenge this view. For example, an adjusted hazard ratio of 18.5 for the development of ESRD in people with isolated haematuria was observed over a period of 22 years in a study of over 1 million young Israeli adults.19 Many of the familial causes of microscopic haematuria, of which some may be progressive with up to 14–50% progression in late adulthood in some populations.20 Therefore, we recommend long-term follow-up of the children with isolated microscopic haematuria. During the long-term follow-up, we should seek the risk factors responsible for disease progression. For example, genetic testing can be performed among the children with family histories of haematuria and/or proteinuria or ESRD for the early diagnosis of hereditary renal diseases such as Alport syndrome.20,21 Moreover, some biochemistry data, for instance, increased urinary excretion of microalbumin may help in differentiating progressive glomerulonephritis in children with IH, as manifested by a higher frequency of IgA nephropathy diagnosed than that of TBMN with elevated level of urinary excretion of microalbumin as reported in our previous study,22 and it may also predict the progression of the renal diseases, especially IgA nephropathy as Assadi reported.23 During follow-up the children with IP/HP, 24 h urinary protein excretion may act as an important clinical indicator for renal biopsy criterion in children with asymptomatic constant isolated proteinuria, as our data indicated that Upro >0.8 g was significantly related to progressive glomerulonephritis, such as IgA nephropathy. In addition, the spot urine 429
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protein-to-creatinine ratio (uP/Cr) may also act as an convenient clinical indicator as reported by Hama, who showed that uP/Cr ≥0.5 g/g might be an adequate criterion, as manifested by more cases of FSGS diagnosed than that of glomerular minor lesion.24 Moreover, new methodology such as urinary proteomics25 might be worthwhile to be considered for exploring new biomarkers in the urine26,27 in addition to gene analysis to assist in the differentiation of potential progressive cases requiring a renal biopsy for confirmation. From the comparison data of three centres in Shanghai, we noticed that indication for renal biopsy and follow-up of asymptomatic children were not quite uniform. We believe there are complicated reasons for this, including the patient parents’ concern and desires. However, based on our data, we recommend treating asymptomatic children differently according to the patterns of urine abnormalities and other relevant lab results as we mentioned above. Based on our data, we believe that children with asymptomatic glomerular microscopic haematuria and/or persistent proteinuria may have chronic progressive glomerulonephritis. Thus, we see the importance of school urinary screening in early detection of asymptomatic urine abnormalities. In the present study, we found that 9 to 12 years old was the common age ranges for first-time detection of urine abnormalities. Especially for those children with HP, 12 years old was the peak age. Children with IgA nephropathy had a median age of first detection of urine abnormalities of 11 years old. In our previous study on urine screening in Shanghai school children, we reported that junior high school children had more urine abnormalities (1.61%) than that of primary school children (0.70%), and there was a peak at 12 years of age.9 Data from Taipei also indicated that children 12 or 13 years old had the highest positive rate of heavy proteinuria.28 Therefore, we suggest that if one wants to choose a starting urine screening age in Shanghai, China, with costeffectiveness considerations, 12 years old might be the best choice. The limitation of our study is that it was just a retrospective study from three selected centres and lacks follow-up data. As these patients were all asymptomatic school-age children, long-term follow-up is required to fully evaluate the significance of early detection of asymptomatic haematuria and/or proteinuria in children for delaying the progression of chronic glomerulonephritis. However, experience from other countries has provided strong support for the significance of early detection of urine abnormalities in early diagnosing of chronic progressive glomerulonephritis (i.e. 70–80% of mesangial proliferative glomerulonephritis and 65–80% of membranous proliferative glomerulonephritis (MPGN) were diagnosed early because of the detection of urine abnormalities during school urine screening in Japan2), slowing down of disease progression, improving clinical outcome (i.e. fewer cases of severe renal pathological lesions, fewer cases of hypertension, no case of renal func430
tion insufficiency in patients with MPGN who were detected early due to urine screening6,29), decreasing incidence of dialysis and delaying the age of ESRD for approximately 10 years.30 Therefore, we believe early detection of urine abnormalities by urine screening in asymptomatic children is of great significance in early detection of chronic progressive glomerulonephritis, and provides an opportunity for early treatment and better outcome.
CONCLUSION Considerable numbers of school-age children with asymptomatic haematuria and/or proteinuria may have chronic progressive glomerulonephritis. They should be managed in different ways. IH per se might not be an appropriate indication for early renal biopsy of children, whereas children with IP or HP may have higher risks for IgA nephropathy. Therefore, they may require relatively early renal biopsy. School urinary screening is a good method for early detection of children with asymptomatic haematuria and/or proteinuria, and 12 years old might be the most appropriate age for initiation of school urinary screening in Shanghai, China in terms of cost-effectiveness. Long-term follow-up is necessary for asymptomatic children.
ACKNOWLEDGEMENTS All phases of this study were supported by a Project ‘Application of the Practical Technique to Children’s health Care and common diseases in the Rural Areas’, supported by the Ministry of Health in China, 2010–2013 no. 201002006.
REFERENCES 1. Zhang L, Wang F, Wang L et al. Prevalence of chronic kidney disease in China: A cross-sectional survey. Lancet 2012; 379: 815–22. 2. Murakami M, Yamamoto H, Ueda Y, Murakami K, Yamauchi K. Urinary screening of elementary and junior high-school children over a 13-year period in Tokyo. Pediatr. Nephrol. 1991; 5: 50–3. 3. Cho BS, Kim SD, Choi YM, Kang HH. School urinalysis screening in Korea: Prevalence of chronic renal disease. Pediatr. Nephrol. 2001; 16: 1126–8. 4. Lin CY, Sheng CC, Lin CC, Chen CH, Chou P. Mass urinary screening and follow-up for school children in Taiwan Province. Acta Paediatr. Taiwan 2001; 42: 134–40. 5. Ieiri N, Hotta O, Taguma Y. Impact of annual urine health check-up system to obtain clinical remission in patients with IgA nephropathy. Contrib. Nephrol. 2007; 157: 104–8. 6. Iitaka K, Moriya S, Nakamura S, Tomonaga K, Sakai T. Long-term follow-up of type III membranoproliferative glomerulonephritis in children. Pediatr. Nephrol. 2002; 17: 373–8. 7. Kawasaki Y, Suzuki J, Nozawa R, Suzuki H. Efficacy of school urinary screening for membranoproliferative glomerulonephritis type 1. Arch. Dis. Child. 2002; 86: 21–5. 8. Yamagata K, Iseki K, Nitta K et al. Chronic kidney disease perspectives in Japan and the importance of urinalysis screening. Clin. Exp. Nephrol. 2008; 12: 1–8. © 2014 Asian Pacific Society of Nephrology
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9. Zhai YH, Xu H, Zhu GH et al. Efficacy of urine screening at school: Experience in Shanghai, China. Pediatr. Nephrol. 2007; 22: 2073–9. 10. Churg J, Bernstein J, Glassock RJ. Renal Disease: Classification and Atlas of Glomerular Diseases, 2nd edn. New York: Igaku-Shoin Medical Publishers Inc, 1995. 11. Liu JC, Xiao HJ, Yang JY, Yao Y, Huang JP, Wang SX. Clinicopathological study of 212 children with primary focal segmental glomerular sclerosis. Zhonghua Er Ke Za Zhi 2010; 48: 928–33. 12. Paik KH, Lee BH, Cho HY et al. Primary focal segmental glomerular sclerosis in children: Clinical course and prognosis. Pediatr. Nephrol. 2007; 22: 389–95. 13. Appel GB, Waldman M. The IgA nephropathy treatment dilemma. Kidney Int. 2006; 69: 1939–44. 14. Yoshikawa N, Tanaka R, Iijima K. Pathophysiology and treatment of IgA nephropathy in children. Pediatr. Nephrol. 2001; 16: 446–57. 15. Coppo R, Peruzzi L, Amore A et al. IgACE: A placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. J. Am. Soc. Nephrol. 2007; 18: 1880–88. 16. Harmankaya O, Ozturk Y, Basturk T, Obek A, Kilicarslan I. Efficacy of immunosuppressive therapy in IgA nephropathy presenting with isolated hematuria. Int. Urol. Nephrol. 2002; 33: 167–71. 17. Kamei K, Nakanishi K, Ito S et al. Long-term results of a randomized controlled trial in childhood IgA nephropathy. Clin. J. Am. Soc. Nephrol. 2011; 6: 1301–7. 18. Yamagata K, Takahashi H, Tomida C, Yamagata Y, Koyama A. Prognosis of asymptomatic hematuria and/or proteinuria in men. High prevalence of IgA nephropathy among proteinuric patients found in mass screening. Nephron 2002; 91: 34–42. 19. Vivante A, Afek A, Frenkel-Nir Y et al. Persistent asymptomatic isolated microscopic hematuria in Israeli adolescents and young adults and risk for end-stage renal disease. JAMA 2011; 306: 729–36.
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20. Gale DP. How benign is hematuria? Using genetics to predict prognosis. Pediatr. Nephrol. 2013; 28: 1183–93. 21. Deltas C, Pierides A, Voskarides K. The role of molecular genetics in diagnosing familial hematuria(s). Pediatr. Nephrol. 2012; 27: 1221–31. 22. Zheng Y, Xu H, Zhou L et al. Clinicopathological features of paediatric renal biopsies in Shanghai over a 31 year period. Nephrology (Carlton) 2012; 17: 274–7. 23. Assadi FK. Value of urinary excretion of microalbumin in predicting glomerular lesions in children with isolated microscopic hematuria. Pediatr. Nephrol. 2005; 20: 1131–5. 24. Hama T, Nakanishi K, Shima Y et al. Renal biopsy criterion in children with asymptomatic constant isolated proteinuria. Nephrol. Dial. Transplant. 2012; doi: 10.1093/ndt/gfr750. 25. Mischak H, Delles C, Klein J, Schanstra JP. Urinary proteomics based on capillary electrophoresis-coupled mass spectrometry in kidney disease: Discovery and validation of biomarkers, and clinical application. Adv. Chronic Kidney Dis. 2010; 17: 493–506. 26. Thongboonkerd V. Proteomic analysis of renal diseases: Unraveling the pathophysiology and biomarker discovery. Expert Rev. Proteomics 2005; 2: 349–66. 27. Moon PG, Lee JE, You S et al. Proteomic analysis of urinary exosomes from patients of early IgA nephropathy and thin basement membrane nephropathy. Proteomics 2011; 11: 2459–75. 28. Lin CY, Sheng CC, Chen CH, Lin CC, Chou P. The prevalence of heavy proteinuria and progression risk factors in children undergoing urinary screening. Pediatr. Nephrol. 2000; 14: 953–9. 29. Yanagihara T, Hayakawa M, Yoshida J et al. Long-term follow-up of diffuse membranoproliferative glomerulonephritis type I. Pediatr. Nephrol. 2005; 20: 585–90. 30. Yamagata K, Takahashi H, Suzuki S et al. Age distribution and yearly changes in the incidence of ESRD in Japan. Am. J. Kidney Dis. 2004; 43: 433–43.
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Nephrology 19 (2014) 426–431
Original Article
Renal histological features of school-age children with asymptomatic haematuria and/or proteinuria: A multicenter study YIHUI ZHAI,1 HONG XU,1 QIAN SHEN,1 QI CAO,1 GUANGHUA ZHU,2 MINJIANG WEI,3 LI SUN,1 HAIMEI LIU,1 JIA RAO,1 XIAOYAN FANG,1 JING CHEN1 and WEI GUO1 1 Department of Nephrology and Rheumatology, Children’s Hospital of Fudan University, 2Departent of Nephrology, Children’s Hospital of Shanghai Jiaotong University, and 3Renal Division, Department of Pediatrics, Xinhua Hospital of Shanghai Jiaotong University, Shanghai, China
KEY WORDS: glomerulonephritis, haematuria, proteinuria, renal biopsy, urinalysis. Correspondence: Professor Hong Xu, Department of Nephrology and Rheumatology, Children’s Hospital of Fudan University. No. 399 Wanyuan Rd., Shanghai 201102, China. Email: [email protected] Accepted for publication 4 April 2014. Accepted manuscript online 10 April 2014. doi:10.1111/nep.12260
SUMMARY AT A GLANCE This paper describes examines renal disease in children with asymptomatic urinary abnormalities. Children with isolated microscopic haematuria did not often have significant renal disease on biopsy. The incidence of significant renal disease was higher in those with proteinuria.
ABSTRACT: Aim: The risk of asymptomatic haematuria and/or proteinuria development into chronic progressive glomerulonephritis (CPG) is unclear. The indications for renal biopsy and follow-up on these asymptomatic children remain controversial. Methods: A multicenter, retrospective study was performed to investigate the renal histological features of school-age children with asymptomatic urine abnormalities. Results: A total of 112 asymptomatic children’s renal biopsy data were studied. Most of the children (71%) received a renal biopsy because of isolated microscopic haematuria (IH), and these children were predominantly (60%) proven to have only mild lesions in the glomeruli. Approximately 30% of the children were biopsied because of asymptomatic proteinuria with or without microscopic haematuria (HP or isolated asymptomatic proteinuria (IP)), and these children were mostly (44–83%) indicated to have CPG, such as IgA nephropathy, focal segmental glomerulosclerosis, and Alport syndrome. The junior high school students had a greater percentage of HP than the primary school children. IgA nephropathy was the most common diagnosis in children who received renal biopsy because of HP. Conclusions: Our findings indicate that IP and especially HP may have a high risk of development into CPG. IH, however, has a relatively low risk of severe histological lesions. Thus, IH per se might not be suggested as an indication for early renal biopsy. Long-term follow-up is necessary for these asymptomatic children.
Glomerulonephritis is one of the major causes of end stage renal disease (ESRD) worldwide, especially in Asian countries, including China.1 It may develop without obvious symptoms at a young age, but just with abnormal urinalysis, such as isolated microscopic haematuria and/or asymptomatic proteinuria. Glomerulonephritis may further progress insidiously, and even develop to ESRD. Therefore, regular population-based urinary screenings of the paediatric population have been performed in Japan, Taiwan, and Korea.2–4 With urinalysis, asymptomatic children with chronic progressive glomerulonephritis, such as IgA nephropathy5 or membranoproliferative glomerulonephritis (MPGN)6,7 have a chance to be detected early, diagnosed and treated, and better prognosis has been demonstrated by evidence from a large population.8 426
In Shanghai, China, we have performed a preliminary school urinary screening study since 2003, and over 114 000 primary and junior ‘healthy’ school students have undergone urinalysis. During these screenings, approximately 1% of children were found to have asymptomatic haematuria and/or proteinuria, and some of them were proven to have chronic progressive glomerulonephritis such as IgA nephropathy.9 One problem we encountered is how to follow-up the asymptomatic children with urine abnormalities. Therefore, in the present study, we collected renal biopsy data of 112 asymptomatic school-age children from three paediatric renal centres in Shanghai, China and retrospectively analyzed the renal histological features of these children, to assess the risk of asymptomatic haematuria and/or proteinuria development into chronic progressive © 2014 Asian Pacific Society of Nephrology
Renal biopsy results of asymptomatic children
glomerulonephritis, explore the indications for renal biopsy and follow-up in these asymptomatic children. This study may also help to assess the importance of school urinary screening in asymptomatic ‘healthy’ children in Shanghai, China, and guide us following-up such children in a costeffective manner.
METHODS Subjects This was a multicenter, retrospective study, which had approval from the local ethics committee and was performed in accordance with the Declaration of Helsinki. Potential subjects were primary and junior high school students from 7 to 14 years old, who had a renal biopsy from 2003 to 2010 because of persistent asymptomatic proteinuria and/or microscopic haematuria in three paediatric renal centres in Shanghai, China. The asymptomatic school-age children included in the study were defined as children without specific symptoms of kidney diseases, such as macroscopic haematuria or oedema, but with urine abnormalities such as asymptomatic haematuria (isolated microscopic haematuria) and/or mild-moderate asymptomatic proteinuria without oedema. Children with urinary symptoms such as frequent micturition or odynuria were excluded. Those with non-urinary specific symptoms such as cough, vomit, diarrhoea, or simply fever were included. Causes such as hypercalciuria, urinary tract infection, renal anatomic abnormalities, trauma, thrombosis, acute poststreptococcal glomerular nephritis, nutcracker phenomenon and orthostatic proteinuria were routinely ruled out before renal biopsy. Questionnaires were delivered to three centres. A total of 112 subjects (7–14 years) from three renal centres (centre A: 40 cases, centre B: 47 cases, centre C: 25 cases) were included. Medical history (including family histories of haematuria/ proteinuria/glomerulopathies) and renal biopsy data were reviewed and collected by paediatric nephrologists from each of the renal centres. Data were then stored in an electronic database, and analyzed by paediatric nephrologists from centre A. In all subjects, isolated microscopic haematuria was confirmed by microscopy. In addition, the amount of proteinuria was measured by urine dipsticks, confirmed by sulfosalicylic acid test or measured by spot urine protein-to-creatinine ratio, and in most cases by 24-h urine protein excretion. Renal biopsy specimens were examined by senior paediatric renal pathologists from each of the three centres using light microscopy, indirect immunofluorescence, and electron microscopy. The pathologic diagnosis was conducted according to World Health Organization (WHO) criteria for renal disease classification.10
Statistical analysis The continuous variables were described using the mean ± standard deviation (SD). Data were compared using the χ2 test (Fisher’s exact test). Unconditional multivariate logistic analysis was applied to assess the effects of independent determinants on histological diagnosis. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for categorical variables. A P-value of less than 0.05 was considered significant. All statistics were performed using SPSS version 19.0 (IBM Corporation, New York, NY, USA). © 2014 Asian Pacific Society of Nephrology
Table 1 General information of children with urine abnormalities
Median age (years) Gender Male Female Urinalysis Average urine RBC 50/hp Median 24 h Upro (g) (range) Elevated blood pressure Reduced eGFR How urine abnormalities detected School urine screening Health examination During diagnosis of other diseases
IH
IP
HP
9
11
12
34 46
4 5
16 7
32 38 10
0 0
0.80 (0.16–1.72) 1 0
37 12 31
2 1 6
3 15 5 0.43 (0.18–2.7) 1 2 3 2 18
eGFR, estimated glomerular filtration rate; HP, microhaematuria with asymptomatic proteinuria; IH, isolated microhaematuria; IP, isolated asymptomatic proteinuria; Upro, urine protein excretion.
RESULTS Urine results of asymptomatic school age children Of the 112 asymptomatic school age children (7–14 years), the indication for a renal biopsy in the majority (71%) of cases was isolated microscopic haematuria (IH) (male 43%), whereas 8% had a renal biopsy for isolated asymptomatic proteinuria (IP) (male 44%), and 21% for combination of both (HP) (male 67%). As for the different reasons for detecting asymptomatic proteinuria and/or microscopic haematuria in these children, 38% were identified by the school urine screening study conducted in Shanghai since 2003, whereas others were identified by self-requested health examination (13%) or during diagnosis of non-renal diseases such as respiratory infection, gastroenteritis and diarrhoea (49%) (Table 1). Among all of the asymptomatic children, males comprised 48%. The median age of the first detection of urine abnormalities was 9 years old (range from 7–14 years). Among these cases, the median age of the first detection of IH was 9 years old (range from 7–14 years), and for IP was 11 years old (range from 7–13 years). The median age for first detection of HP was the oldest, 12 years old (range from 7–14 years) (Fig. 1A). The constituent ratio of urine abnormalities of each age group indicated that in primary school children aged 7–11 years, most children had IH, whereas in older junior high school children aged 12–14 years, many more had HP. The differences between the primary and junior high groups were significant (P < 0.0001) (Fig. 1B). The average time period between first detection of urine abnormalities and kidney biopsy was 10 months, and was different among the three types of urine abnormalities. Children with IH had 427
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Fig. 1 Age distribution of urine abnormalities. (A) The median age of the first detection of isolated microscopic haematuria (IH) was 9 years, isolated asymptomatic proteinuria (IP) was 11 years and microhaematuria with asymptomatic proteinuria (HP) was 12 years. (B) The primary school children had more IH, , IH; , while junior high school children had more HP (P < 0.0001). , HP. IP;
the longest average period, 12 months; IP, 8 months; and HP the shortest average period, 7 months. Most children (98%) had normal blood pressure at the time of renal biopsy, except two children who were subsequently diagnosed with IgA nephropathy had elevated blood pressure. Most children (98%) had normal renal function at the time of renal biopsy, except two children who were subsequently diagnosed with Alport syndrome and IgA nephropathy, respectively, who had an eGFR approximately 80 mL/min per 1.73 m2 (Table 1). Thirteen percent of children had family histories of haematuria, proteinuria or glomerulopathies. Among them, most (93%) presented with isolated microscopic haematuria during the period of this study. Family history details were very limited, so its correlation with the eventual diagnosis was uncertain.
Renal biopsy results of asymptomatic children Renal biopsy results indicated that most of the children (47%) had minor glomerular abnormality (MGA), 14% had thin basement membrane nephropathy (TBMN), which was thought to have a benign outcome, but still nearly 40% of children might have progressive glomerulonephritis, such as IgA nephropathy, focal segmental glomerulosclerosis (FSGS), or Alport syndrome (Fig. 2). Among them, children with IH were mainly proven to have MGA (56%) and TBMN (19%) after renal biopsy, IP mainly to be MGA (56%) and IgA nephropathy (33%), and those with HP had the worst results, mainly IgA nephropathy (79%) (P < 0.0001) (Table 2). Half of the children with IgA nephropathy had 428
Fig. 2 Renal biopsy results of asymptomatic children. In total 112 cases, 53 (47%) were minor glomerular abnormality (MGA), 16 (14%) were thin basement membrane nephropathy (TBMN), 29 (26%) were IgA nephropathy, four (3%) were focal segmental glomerulosclerosis (FSGS), six (5%) were focal glomerulonephritis, two (2%) were Alport syndrome, one (1%) was mesangial proliferative glomerulonephritis (MsPGN), and one (1%) was sclerosing glomerulonephritis (SGN). , MGA; , TBMN; , IgA nephropathy; , FSGS; , Focal glomerulonephritis; , Alport syndrome; , MsPGN; , SGN.
Table 2 Urine abnormalities related to renal biopsy results n (%)
Urinalysis IH IP HP
MGA
TBMN
IgAN
Others
45 (56) 5 (56) 3 (13)
15 (19) 0 (0) 1 (4)
8 (10) 3 (33)) 18 (79)
12 (15) 1 (11) 1 (4)
Fisher
P-value
39.432
0.8 g was significantly related to progressive glomerulonephritis (P < 0.05). Among the IH group, the number of urinary erythrocyte was not significantly related to histological severity (P > 0.05).
Comparison of renal biopsy data among three renal centres When comparing data among the three centres, we found that IgA nephropathy was the most common diagnosis in © 2014 Asian Pacific Society of Nephrology
Renal biopsy results of asymptomatic children
Table 3 Comparison of renal biopsy data among three centres n (%)
Centres A B C
MGA
TBMN
IgAN
Others
15 (38) 25 (53) 13 (52)
4 (10) 12 (26) 0 (0)
16 (40) 6 (13) 7 (28)
5 (12) 4 (8) 5 (20)
Fisher
P-value
17.748
0.005
Others included FSGS, focal glomerulonephritis, Alport syndrome, MsPGN or SGN. Fisher: Fisher’s exact test. FSGS, focal segmental glomerulosclerosis; MGA, minor glomerular abnormalities; MsPGN, mesangial proliferative glomerulonephritis; SGN, sclerosing glomerulonephritis; TBMN, thin basement membranous nephropathy.
centre A (40%), while MGA was the most common diagnosis in centre B (53%) and C (52%). The difference among the three centres was significant (P < 0.01) (Table 3). Possible reasons for these differences were that centre A had the lowest percent of patients with IH who received a renal biopsy compared with those from centre B and C (47% vs 89% and 76%, respectively). However, centre A had the most percentage of patients with IP and HP who received a renal biopsy compared to those in centre B and C (IP: 89% vs 2%, 9%; HP: 76% vs 8%, 16%, respectively), which was consistent with our finding that HP was mainly related to IgA nephropathy. Variation among the three centres were significant (P < 0.01), and might be due to different indications for renal biopsy.
DISCUSSION Glomerulonephritis in children may develop insidiously,11,12 progress slowly, and a few cases may even reach ESRD. Different types of glomerulonephritis may have similar urine presentation in the early asymptomatic stage. In the present study, we analyzed renal biopsy data of school-age children with asymptomatic haematuria and/or proteinuria, and found that chronic progressive glomerulonephritis such as IgA nephropathy, FSGS, and Alport syndrome represent approximately 40% of cases. This relatively high proportion of chronic progressive glomerulonephritis suggests that asymptomatic haematuria and/or proteinuria in school-age children should receive increased attention. Importantly, 26% of the biopsied population had a diagnosis of IgA nephropathy, which is the most common variety of primary glomerulonephritis in the world today. Long-term follow-up studies have revealed that the disease progresses to renal failure in 20 to 50% of adult patients over 20 years13 and 11% of paediatric patients over 15 years.14 Many studies have reported that early treatment of this condition may reduce the progression of renal damage.15–17 Therefore, early detection and diagnosis of IgA nephropathy by urine screening in children is of great significance in improving the longterm outcome of IgA nephropathy. © 2014 Asian Pacific Society of Nephrology
Our data indicated that asymptomatic children with different patterns of urine abnormalities, IH, IP or HP, had different severities of renal pathological lesions. Therefore, we recommend treating them in different ways. As shown in our data, 75% of the patients with IH were diagnosed as MGA or TBMN by renal biopsy. The major urinary presentation of MGA or TBMN was IH, as 85% of patients with MGA and over 90% of patients with TBMN presented as IH. In addition, the number of urinary erythrocytes was not related to severity of renal pathological lesions among children with IH. Therefore, in terms of indication for renal biopsy, we recommend that IH per se might not be enough as a sufficient indication for early renal biopsy in asymptomatic children. However, proteinuria was the independent factor for severe renal pathological lesions. The asymptomatic proteinuria and/or with haematuria were highly related to IgA nephropathy as shown by our data that 33% of IP and 79% of HP were diagnosed as IgA nephropathy. These results are consistent with the other study that found a high prevalence of IgA nephropathy among proteinuric patients by mass screening.18 Therefore, we suggest that urine abnormalities such as HP might be involved in more severe pathological change, and require more medical care with early renal biopsy. Isolated microscopic haematuria has traditionally been regarded as benign. However, more extensive information, including the long-term follow-up of patients who present initially with microscopic haematuria, has begun to challenge this view. For example, an adjusted hazard ratio of 18.5 for the development of ESRD in people with isolated haematuria was observed over a period of 22 years in a study of over 1 million young Israeli adults.19 Many of the familial causes of microscopic haematuria, of which some may be progressive with up to 14–50% progression in late adulthood in some populations.20 Therefore, we recommend long-term follow-up of the children with isolated microscopic haematuria. During the long-term follow-up, we should seek the risk factors responsible for disease progression. For example, genetic testing can be performed among the children with family histories of haematuria and/or proteinuria or ESRD for the early diagnosis of hereditary renal diseases such as Alport syndrome.20,21 Moreover, some biochemistry data, for instance, increased urinary excretion of microalbumin may help in differentiating progressive glomerulonephritis in children with IH, as manifested by a higher frequency of IgA nephropathy diagnosed than that of TBMN with elevated level of urinary excretion of microalbumin as reported in our previous study,22 and it may also predict the progression of the renal diseases, especially IgA nephropathy as Assadi reported.23 During follow-up the children with IP/HP, 24 h urinary protein excretion may act as an important clinical indicator for renal biopsy criterion in children with asymptomatic constant isolated proteinuria, as our data indicated that Upro >0.8 g was significantly related to progressive glomerulonephritis, such as IgA nephropathy. In addition, the spot urine 429
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protein-to-creatinine ratio (uP/Cr) may also act as an convenient clinical indicator as reported by Hama, who showed that uP/Cr ≥0.5 g/g might be an adequate criterion, as manifested by more cases of FSGS diagnosed than that of glomerular minor lesion.24 Moreover, new methodology such as urinary proteomics25 might be worthwhile to be considered for exploring new biomarkers in the urine26,27 in addition to gene analysis to assist in the differentiation of potential progressive cases requiring a renal biopsy for confirmation. From the comparison data of three centres in Shanghai, we noticed that indication for renal biopsy and follow-up of asymptomatic children were not quite uniform. We believe there are complicated reasons for this, including the patient parents’ concern and desires. However, based on our data, we recommend treating asymptomatic children differently according to the patterns of urine abnormalities and other relevant lab results as we mentioned above. Based on our data, we believe that children with asymptomatic glomerular microscopic haematuria and/or persistent proteinuria may have chronic progressive glomerulonephritis. Thus, we see the importance of school urinary screening in early detection of asymptomatic urine abnormalities. In the present study, we found that 9 to 12 years old was the common age ranges for first-time detection of urine abnormalities. Especially for those children with HP, 12 years old was the peak age. Children with IgA nephropathy had a median age of first detection of urine abnormalities of 11 years old. In our previous study on urine screening in Shanghai school children, we reported that junior high school children had more urine abnormalities (1.61%) than that of primary school children (0.70%), and there was a peak at 12 years of age.9 Data from Taipei also indicated that children 12 or 13 years old had the highest positive rate of heavy proteinuria.28 Therefore, we suggest that if one wants to choose a starting urine screening age in Shanghai, China, with costeffectiveness considerations, 12 years old might be the best choice. The limitation of our study is that it was just a retrospective study from three selected centres and lacks follow-up data. As these patients were all asymptomatic school-age children, long-term follow-up is required to fully evaluate the significance of early detection of asymptomatic haematuria and/or proteinuria in children for delaying the progression of chronic glomerulonephritis. However, experience from other countries has provided strong support for the significance of early detection of urine abnormalities in early diagnosing of chronic progressive glomerulonephritis (i.e. 70–80% of mesangial proliferative glomerulonephritis and 65–80% of membranous proliferative glomerulonephritis (MPGN) were diagnosed early because of the detection of urine abnormalities during school urine screening in Japan2), slowing down of disease progression, improving clinical outcome (i.e. fewer cases of severe renal pathological lesions, fewer cases of hypertension, no case of renal func430
tion insufficiency in patients with MPGN who were detected early due to urine screening6,29), decreasing incidence of dialysis and delaying the age of ESRD for approximately 10 years.30 Therefore, we believe early detection of urine abnormalities by urine screening in asymptomatic children is of great significance in early detection of chronic progressive glomerulonephritis, and provides an opportunity for early treatment and better outcome.
CONCLUSION Considerable numbers of school-age children with asymptomatic haematuria and/or proteinuria may have chronic progressive glomerulonephritis. They should be managed in different ways. IH per se might not be an appropriate indication for early renal biopsy of children, whereas children with IP or HP may have higher risks for IgA nephropathy. Therefore, they may require relatively early renal biopsy. School urinary screening is a good method for early detection of children with asymptomatic haematuria and/or proteinuria, and 12 years old might be the most appropriate age for initiation of school urinary screening in Shanghai, China in terms of cost-effectiveness. Long-term follow-up is necessary for asymptomatic children.
ACKNOWLEDGEMENTS All phases of this study were supported by a Project ‘Application of the Practical Technique to Children’s health Care and common diseases in the Rural Areas’, supported by the Ministry of Health in China, 2010–2013 no. 201002006.
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