Ethnic differences in kidney function in childhood: the Born in Bradford Cohort Renal Study

Background: Endstage kidney failure rates are higher in South Asians than in White Europeans. Low birth weight is associated with adult chronic kidney disease and is more common in South Asians. Foetal kidney size was smaller in South Asians in the Born in Bradford (BiB) birth cohort. As part of BiB follow up, we aimed to investigate if there were ethnic differences in kidney function and blood pressure in early childhood and whether this was different by foetal kidney size. Methods: Serum creatinine, cystatin C, urea, and urinary albumin to creatinine ratio (ACR), protein to creatinine ratio (PCR) and retinol binding protein (RBP) were analysed in blood and urine samples from those who participated in the BiB follow-up at 7–11 years. Ethnicity was categorised by parental self-report as White European and South Asian. Estimated glomerular filtration rate (eGFR) was calculated using Schwartz, and cystatin C Zappitelli and Filler equations. Linear regression was used to examine the association between ethnicity and eGFR, PCR and blood pressure. Results: 1591 children provided blood (n=1403) or urine (n=625) samples. Mean eGFR was 92 ml/min/1.73m 2 (standard deviation (SD) 9) using Schwartz (n=1156) and 94 (SD 11) using Zappitelli (n=1257). CKD prevalence was rare (1 with eGFR <60 ml/min/1.73m 2, 14 (2.4%) had raised ACR (>2.5 mg/mmol in boys/3.5 mg/mmol in girls). Diastolic blood pressure was higher in South Asian children (difference 2.04 mmHg, 95% CI 0.99 to 3.10) but was not significant in adjusted analysis. There was no evidence of association in adjusted models between ethnicity and any eGFR or urinary measure at this age. Conclusions: There was no evidence of significant ethnic differences in kidney function at pre-pubertal age despite differences in kidney volume at birth. Longitudinal follow-up is required to track ethnic patterns in kidney function and blood pressure as children develop through puberty.


Introduction
The incidence of end stage kidney failure (ESKF) is higher and occurs at a younger age in adults of South Asian heritage compared to White Europeans 1,2 .The reasons are not fully understood but Type 2 diabetes and diagnosed hypertension are more common in South Asian adults 3,4 and blood pressure (BP) is higher at similar levels of obesity [3][4][5] .Whilst two primary care studies in the UK reported decreased stage 3 chronic kidney disease (CKD) prevalence in South Asians, the prevalence was higher in South Asians at more advanced stages 3,4 .Albuminuria is more common in South Asians 6 .Data on differences in CKD progression to ESKF in South Asians and competing risk of mortality are limited 7 .
The excess incidence of advanced CKD has major implications for disease burden internationally, as the South Asian diaspora increases and ages, and globally with over 1 billion people on the Indian subcontinent.CKD is an independent factor for cardiovascular disease, and understanding causation is key to prevention of CKD and its complications in such populations.
Kidney development is one area of focus as low birth weight (LBW) is more common in South Asians 8,9 and is associated with adult chronic diseases such as hypertension and Type 2 diabetes that are associated with CKD [10][11][12] .A systematic review and a subsequent study found an association between LBW and CKD though there were no specific data on South Asians 13,14 .One hypothesis to explain such CKD risk is that intra-uterine growth retardation (IUGR), especially in the third trimester when foetal kidney development occurs, leads to reduction in nephron number 15,16 and lower kidney size at birth 17,18 .As nephron number is fixed at birth 15 , compensatory glomerular hypertrophy, hyperfiltration and hypertension, could lead to further reduction in nephrons, and susceptibility to kidney damage 19,20 .IUGR has been found to be associated with albuminuria in infancy 21,22 , with similar estimated Glomerular Filtration Rate (eGFR) at age 2 despite smaller kidney size, suggesting hyperfiltration 22 , and with diastolic blood pressure (dBP) at age 6 23 .
The Born in Bradford (BiB) birth cohort is a prospective longitudinal multi-ethnic birth cohort study that aims to examine the impact of environmental, psychological and genetic factors on health and wellbeing in a deprived population.The full BiB cohort recruited 12453 women involving 13776 pregnancies (13858 births) between 2007 and 2010 24 .ln a renal subset of BiB (n= 1587), we showed that mean foetal kidney volume at 34 weeks gestation was 16% lower in South Asian babies 25 .In the Generation R cohort in the Netherlands, lower foetal kidney volume was independently associated with reduced eGFR and kidney volume at age 6 26 .In the BiB cohort, dBP was higher in Pakistani children at age 4/5 years 27,28 .
The BiB cohort is an ideal context in which to explore the origins of ethnic differences in CKD.This study aimed to investigate whether there were ethnic differences in kidney function and damage and BP in childhood (age 7-11 years) and whether this was different by foetal kidney size.

Baseline recruitment in pregnancy
Women were recruited to the BiB cohort study while attending for their glucose tolerance test (OGTT), offered to all pregnant women registered at Bradford Royal Infirmary at 24-28 weeks of gestation.
BiB children aged 7-11 years and their families were followed up using a multi-method approach between 2017 and 2020 (BiB Growing Up Study) 29 .Detailed parent and child questionnaires, BP, anthropometry and blood samples were collected.Written informed consent was collected for the follow-up and for continued routine data linkage.

Renal ultrasound sub-study recruitment in pregnancy
A renal sub-study was nested within the full BiB cohort at baseline.Women who were attending for the OGTT at 26-28 weeks of gestation, had consented for the main BiB study and completed the baseline questionnaire, were invited to undertake a further foetal ultrasound scan (USS) at 34 weeks for standard anthropometrics and foetal renal dimension measurement.Data on renal ultrasound was available for 1802 women, details of recruitment and ultrasonography were published previously 25 .

Follow-up population
Recruitment for the renal US sub-study follow-up commenced in January 2018 and was initially limited to children whose mothers had participated in the baseline renal sub-study and had a foetal ultrasound, termed the BiB renal ultrasound followup.This was expanded to the broader cohort due to lower than expected uptake and children who had blood sampling as part of their BiB Growing-Up follow-up were included.From January 2019, all participants who agreed to blood sampling were also asked to provide a urine sample.We called this the BiB extended renal follow-up.Study recruitment ended in March 2020.
For this analysis we only included those with a White European or South Asian ethnicity, who were born at term and who provided blood or urine measures.Figure 1 shows the pattern of recruitment.
Participants' height and weight were measured without shoes and in light clothing.BP measurements were taken at the brachial artery preferably on the left arm, twice with skinfold measurements in between the first and second measurement, using an Omron electronic monitor 705-CPII.The appropriate cuff size was used.Children were seated for two minutes prior to the BP measurement.One BP measurement was recorded per child consistent with other studies undertaken within a school setting 30,31 .Non-fasting blood samples were taken.First morning

Amendments from Version 1
Text was revised in response to peer reviewer comments to add more detail on the blood pressure measurement, study limitations and conclusion.
Any further responses from the reviewers can be found at the end of the article urine samples were taken at home and transported to the Bradford Royal Infirmary laboratory.Data collection was undertaken by trained staff in schools, clinics or at the participant's home using standard operating procedures.

Laboratory methods
Blood samples were analysed for creatinine, urea and cystatin C. Creatinine and urea were analysed on Beckman AU650.The creatinine calibrator is traceable to the Isotope Dilution Mass Spectrometry (IDMS) reference method used by the National Institute of Standards and Technology Standard Reference Material 967.The coefficient of variation (CV) for serum creatinine was 5.7%.Cystatin C was measured using particle enhanced immunoturbidimetric assay on Roche/Hitachi cobas c systems.The assay is standardised against the ERM-DA471/IFCC certified reference material for cystatin C. CVs were 1.6-2.6% in the range assayed.
Urine samples were analysed for protein, albumin, creatinine and retinol binding protein (RBP).The urine protein method was based on Pyrogallol red, urine albumin using a turbidometric assay and urine creatinine was an enzymatic assay, all measured on Beckman AU680.The limit of detection for urine albumin was 3mg/L.CVs were 2.6% for creatinine, 8% for albumin and 7.5% for protein.RBP was measured using the immunonephelometry method on a Siemens Atellica630 Neph Nephelometer.The reference range is <15mg/L, the limit of detection is 3mg/L and CV was 5.3%.

Renal and BP outcomes
Outcomes included eGFR, urinary albumin to creatinine ratio (ACR), urinary protein to creatinine ratio (PCR), RBP and systolic blood pressure (sBP) and dBP.Each outcome was considered separately and all (except RBP) were assessed as continuous variables.eGFR was calculated using four published equations as follows: • Schwartz creatinine only = 41.3*(height(m)/ S cr ) 32 BSA was calculated using the Du Bois formula 36 (BSA = weight (kg) 0.425 x height (cm) 0.725 x 0.007184).BP was not identified as a covariate to adjust for from the directed acyclic graph (DAG) but as the direction of this relationship is not known, we included BP as a covariate (Figure 2).
The selection of covariates into the multivariable models were guided by a DAG constructed using DAGitty v3.0 38 .We adjusted for foetal renal volume in the sub-sample that had renal ultrasound scans in pregnancy.A statistical significance level of 0.01 with 95% confidence interval (CI) was used.
Data on covariates such as marital status, employment status and housing tenure collected through baseline questionnaires were missing in women who did not complete the questionnaire (n=1057 of 12453 women from the BiB baseline sample).Some of these women completed an additional questionnaire at follow-up which reduced the missing data on ethnicity and educational attainment but not on other covariates.It was not possible to impute missing data as data were missing on all variables collected using the baseline questionnaire.
We undertook sensitivity analysis to explore the impact of differences in timing of height measurement and blood sampling for the Schwartz eGFR formulae by comparing estimates using standardised height, height as measured without accounting for timing between sampling and measurement, and sample restricted to those with height measurement and blood sample at the same.We also undertook sensitivity analysis replacing BSA with BMI in eGFR, ACR and PCR models.

Ethical approval
Ethical approval was granted by the Bradford Research Ethics Committee (ref.07/H1302/112 for original cohort and 16/YH/0320 (IRAS 207543) for Growing Up).

Results
In total, 1591 children were available for this analysis, 1403 provided a blood sample and 625 a urine sample (Figure 1).Overall, 605 from the baseline BiB renal ultrasound sub-study were eligible and provided either a blood and/or urine sample, a response rate of 34% (Figure 1, Table 1).
In total, 986 provided samples (largely blood) in the BiB extended follow-up group, and for response were compared to those who participated in the follow-up but did not provide blood samples.The response rate in both groups was higher in South Asians and in boys, but there was no difference in birthweight or renal volume between responders and non-responders (Table 1).
Of the 1591 participants, 69.1% were South Asian and 40.1% had further and higher maternal education (Table 2).Mean maternal age was 28.0 years (standard deviation (SD) 5.5) and mean maternal BMI at antenatal booking was 26.3 kg/m 2 (SD 5.7).10% of mothers smoked during pregnancy and 11% reported consuming alcohol.Compared to White European mothers, South Asian mothers were more likely to: be older; be married; to own their own home, be of lower educational attainment and higher parity, and less likely to work, smoke or drink alcohol during pregnancy.A higher percentage had gestational diabetes.Renal volume, birthweight and renal volume adjusting for birthweight were significantly lower in South Asian babies.
Mean eGFR was 92 ml/min/1.73m 2 (SD 9) using Schwartz combined and 94 ml/min/1.73m 2 (SD 11) using Zappitelli (Table 2).CKD prevalence was rare (1 with eGFR <60 ml/min/1.73m 2 , 14 (2.4%) with ACR ≥2.5 mg/mmol in boys/3.5 mg/mmol in girls).RBP results were within the normal range for the whole sample.Mean eGFR was slightly higher in South Asian children when using creatinine formulae, but no difference was seen in Cystatin C or Cystatin C based eGFR.Mean ACR and PCR were similar in both ethnic groups.sBP was similar in both ethnic groups but mean dBP was slightly higher in South Asians (72 mmHg, SD 10) than in White Europeans (70 mmHg, SD 9) and the difference was significant (p<0.001).sBP had a small negative correlation with cystatin C eGFR (-0.12) but all other correlation estimates of BP and eGFR/ACR/PCR were <0.1.
Whilst South Asian children had higher eGFR than White European children using creatinine-based formulae and a higher dBP, these findings were only significant in the unadjusted models and the socio-demographic model for dBP (Table 3).There were no other significant associations between ethnicity and Cystatin C eGFR, ACR, PCR and sBP at 7-11 years in any model.eGFR estimates were similar when child BMI was adjusted for instead of BSA (Extended data, Supplementary Table 1 39 ).
Adjusting for renal volume in the BiB renal ultrasound follow-up subsample did not affect the estimates (Table 4).
There was little difference when measured height was used regardless of timing between blood sample and height measurement or when the sample was restricted to the subset with blood sample and height measurement at the same time (Extended data, Supplementary Table 3 39 ).8.9 ± 0.9 8.8 ± 0.9 -9.7 ± 1.0 9.7 ± 1.0 9.7 ± 0.9 -*Non-response for the BiB renal ultrasound cohort were those who had a foetal renal ultrasound at baseline but did not provide blood or urine sample for follow-up.Nonresponse for the BiB extended renal follow-up were those who had no renal ultrasound at baseline, participated in the Growing up follow-up but did not provide either blood or urine samples for renal analysis.

Discussion
South Asian adults are at high risk of premature severe CKD.Prevention of adult CKD may be informed by better understanding of the early origins and lifecourse determinants.Using BiB data, we have previously shown that South Asian infants have smaller kidneys compared with white European infants 25 .
In this study whilst unadjusted models found higher dBP and higher creatinine-based eGFR in South Asian children, there were no significant ethnic differences in adjusted models on renal function or BP at 7-11 years.These results suggest that any impact of reduced foetal renal volume was not biologically significant on kidney function by this age or alternatively that there was compensation for the presumed reduced nephron number at birth by hyperfiltration 19 .It is therefore possible that changes may manifest later in development, hence the need for further follow-up.
Published data on ethnic differences in childhood kidney function are very limited.Ethnic differences in kidney volume and function in various ethnic groups (which did not include those from the Indian subcontinent) were found in the Generation R cohort in the Netherlands.Compared to Dutch children, Moroccan and Turkish children aged 6 had a higher eGFR whereas Dutch Antillean and Surinamese-Creole children had a lower eGFR 40 .Surinamese Hindustani children had lower kidney volume.The authors concluded that whilst these differences were not clinically significant (i.e.requiring nephrology referral), they may track and alter adult CKD risk.
The BP findings extends BiB findings of higher dBP in South Asian Pakistani children aged 4-5 years, which was not related to socioeconomic factors 27,28 .Ethnic differences in BP were found in the Generation R cohort with Cape Verdean and Turkish children having higher sBP and dBP compared to Dutch children 40 .In a review, higher dBP in Pakistani children was found in the 1999 Health Survey for England (5-15 years) though not in three other studies where ethnicity was combined as South Asian; but was also found in a crosssectional study in England at 9-10 years and in a longitudinal school-based cohort in London at 14-16 years (though not at 11-13 years) [41][42][43] .
Our study strengths include a large predominantly bi-ethnic population from the same city, availability of baseline foetal and maternal data on covariates, a subsample with detailed ultrasonography with high reliability in pregnancy for renal measures and first morning urine sample taken to measure albuminuria and proteinuria.We measured both creatinine and cystatin C so could compare the findings using the different formulae, all have been validated in paediatric populations.eGFR calculated using the Schwartz creatinine only formula was higher than that using the Zappitelli cystatin C, similar to other studies 44,45 .eGFR calculated using the Filler formula was the highest which has been observed previously 44 .Cystatin C formulae may be more sensitive than creatinine formulae for evaluating kidney function which has been suggested previously given it is freely filtered by glomeruli, fully catabolised by renal tubules and not excreted by non-renal routes 46 .As in adults there is no correction for ethnicity in eGFR formulae.
There were limitations to the study.Uptake to follow-up was lower than expected in the renal ultrasound sub-study, and we had to supplement with recruitment opportunistically from those providing a blood sample.This limited our power to study renal volume effects and led to the inclusion of a sample with higher levels of missing baseline data as a proportion of mothers had not filled out the baseline questionnaire.We did not attempt to impute missing values as we had limited data on such individuals.The lower than expected uptake highlights the challenge of undertaking follow-up in a population with ethnic diversity with high levels of socio-economic disadvantage, especially with invasive testing.There was a difference in timing between anthropometric measurements and blood sampling in some children which might have affected the creatinine based eGFR measurement though we used growth centile charts to take this into account, and sensitivity analysis showed no difference.However, we had a slightly higher proportion of South Asian children (54%) than White children (40%) with a difference in timing between the blood sample and height measurement.The growth centile charts are for the UK general population and may overestimate eGFR in South Asian children.Our assessment of kidney function and BP were based on a single measure as in other studies and any variation is likely to reduce the strength of any associations.We had no valid measures of kidney volume in childhood as this was not practically feasible.
We found lower levels of microalbuminuria (2.5%) than in the Generation R cohort (7.1%) in children followed up at median age of 5.9 years (95% range, 5.7 to 6.6) using the same cut-offs to define microalbuminuria 47 .The prevalence of albuminuria in children aged 5-18 years from the Australian Health Survey 2011-2013 was 12.8% and higher in girls (15.5%) than in boys (10.2%) 48.A population-based cross-sectional study in Australia (2015-16) reported a higher prevalence of albuminuria (15.1% overall, 20.8% in girls and 10.1% in boys) in children aged 11-12 years 49 .The cut-off used to define albuminuria in both Australian studies was different (ACR >3.4 mg/mmol ACR).All three studies used a random urine sample whereas we used the first morning urine sample.The lower prevalence in our study is unexplained.
In conclusion, there was no evidence of significant ethnic differences in kidney function at pre-pubertal age despite the lower kidney volume at birth in South Asian babies in those with foetal renal ultrasound scans.However South Asian children may be at higher long-term CKD risk through reduced foetal kidney volume with compensatory hyperfiltration, higher BP, and greater propensity to adverse metabolic patterns.Promoting kidney development through childhood and adolescence, for example by aiming for normal weight trajectory and obesity avoidance would be relevant for all children but especially those with higher adult CKD risk such as South Asians.Further longitudinal follow-up is required in the BiB cohort through adolescence when any propensity to metabolic risk becomes more apparent, measuring kidney function and ideally size, to see how kidney function and BP measures track, and to determine if there are emerging differences by ethnicity.This would inform population strategies and risk stratification to prevent adult CKD.

Data availability
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Extended data
Open Science Framework: Supplementary tables for: Ethnic differences in kidney function in childhood: the Born in Bradford Cohort Renal Study.https://doi.org/10.17605/OSF.IO/ MZHAK 39 .

Midori Awazu
Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan The manuscript is basically unchanged.My previous comments regarding the calculation of eGFR in South Asian children and the use of BP index have not been addressed.The authors have not described the limitations of the study on these points either.
For example I previously pointed out the presence of the paper on eGFR formulae in South Asian adults, yet the authors have kept the following description; "As in adults there is no correction for ethnicity in eGFR formulae." They have described the method of BP measurement, but what is the rationale for the following?
"One BP measurement was recorded per child consistent with other studies undertaken within a school setting." Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Developmental origins of health and disease, pediatric nephrology, development, blood pressure I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.The authors report on a longitudinal data of mixed ethnicity (South Asians Vs White British) birth cohort in England, concentrating on kidney volume at 34 weeks gestation (absolute and corrected for birth weight) and kidney function as assessed during school age, including serum creatinine, cystatin C and urine albumin.The authors report that even though birth weight corrected kidney volume was lower in children of South Asian ancestry.kidney function was not significantly different The overall rate of detection of permanent kidney damage in this study was low ( only 1 with eGFR <60 ml/min/1.73m2,14 (2.4%) with ACR ≥2.5 mg/mmol in boys/3.5 mg/mmol in girls).
The study reflects a huge effort, and its results are worth a indexing.My concern remains on the methodology, regarding mostly: Selection bias: only < 2000 out of 13000 pregnancies have been originally followed since pregnancy. 1.
The accuracy of a fetal US (which may be unable to pick the kidneys at their maximal longitudinal diameter) to assess true kidney volume.

Specific critiques:
Page 5 :"Child height required to calculate eGFR... was measured at the same visit as the blood sample in 52.0%, the height measurement was standardised to time of sample using centile charts if not measured at the same visit."Please comment on the possible bias of this analytical decision, specially.related to: Are there different normal growth charts for White British and South Asians? 1.
Could there be more South Asians than White British with missing heights? 2.
Did the authors consider using the new height independent child eGFR equations developed by Pottel et al. ?

3.
Minor critiques: Page 3 : "Women who were attending for the OGTT at 26-28 weeks of gestation... etc".Please clarify this abbreviation when first used: is it "oral glucose tolerance test"?

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate?I cannot comment.A qualified statistician is required.

Are the conclusions drawn adequately supported by the results? Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Clinical pediatric nephrology, epidemiology of childhood CKD, genetic renal diseases I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.>6000 of the original cohort were followed up at 7-11 years.The renal study was undertaken in a sub-sample and the sample size of 1591 are the participants that provided a blood or urine sample for renal analysis.We assessed difference in sample characteristics at follow-up using selected descriptive variables at baseline (presented in Table 1).There was no obvious major response bias but limited our statistical power as uptake to the follow-up component was lower than expected.The low uptake highlights the challenge of undertaking follow-up in a population with high levels of socio-economic disadvantage and ethnic diversity, especially with invasive testing.We have stated this as a limitation.

1.
The fetal ultrasounds were performed by experienced sonographers and intraobserver reliability was high.We are unaware what study the reviewer is referring to regarding the accuracy of the fetal ultrasound and would appreciate if the reviewer could direct us to this.

Specific critiques:
No, the growth chart used is for the UK general population and used in clinical practice.However, this could overestimate eGFR and we have added this as a limitation. 1.
All children had a recorded height measurement.There was a slightly higher proportion of South Asian children (54%) than White children (40%) with a difference in timing between the blood sample and height measurement which may have introduced bias due to the greater use of growth charts in south Asian.

2.
Thank you for the suggestion of height independent eGFR equations.This equation requires a population median serum creatinine which we do not have.We have taken a similar approach and used equations used in other literature that we have cited.

3.
Minor critiques: Thank you, we have clarified the abbreviation at first use in the first paragraph under the methods section.
Competing Interests: No competing interests were disclosed.

Midori Awazu
Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan The study aimed to investigate ethnic differences in kidney function and blood pressure (BP) in early childhood, specifically comparing South Asian and White European children.In 1591 children aged 7-11 years, estimated glomerular filtration rate (eGFR), urine albumin to creatinine ratio, and BP were assessed.The results showed no significant ethnic differences in kidney function at prepubertal age, despite previous findings of smaller fetal kidney size in South Asian children.Diastolic BP was slightly higher in South Asian children.
The aim of the study is important and the methods are appropriate except for the following two points.
In adult South Asians, eGFRCr was reported to overestimate measured GFR, and the modified equation has been created (Jessani, Am J Kidney Dis, 2014) Overshooting by compensation (higher eGFR than White European children), however, is unlikely.

1.
Regarding BP measurement, the authors do not state which measurement value (before or after the skinfold measurement or the average of the two) was used.The arm width is expected to be variable with the age of the study subjects (7-11 years).Was the right cuff size selected?Also, as the authors stated, the BP was measured on one occasion only.The difference of diastolic pressure between South Asian and White European children is subtle and could result from small variations during BP measurements.

2.
One more important point is that in children BP is assessed according to reference values by gender, age, and height.Therefore BP index (BP divided by 95th percentile BP for each patient) not raw values should be used for comparison.
Could you show in supplementary data the kidney function and BP in the subgroup of patients with actual small volume kidney (for example kidney volume or length < -2 SDS) irrespective of ethnicity?

5.
Could the authors comment on the public health message to take up in this study in addition to tracking kidney function and BP in the BiB cohort? 6.

Is the work clearly and accurately presented and does it cite the current literature? Yes
Is the study design appropriate and is the work technically sound?Yes

Are sufficient details of methods and analysis provided to allow replication by others? Yes
If applicable, is the statistical analysis and its interpretation appropriate?Yes Are all the source data underlying the results available to ensure full reproducibility?Yes

Are the conclusions drawn adequately supported by the results? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Pediatrics, Kidney disease, epidemiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
(socio-demographic, maternal/pregnancy factors and child factors) with model 3 being the fully adjusted model including all the covariates from the DAG.
476 children with eGFR of 60-89 ml/min/1.73.We haven't presented the BP >95th centile as not sure what the benefit would be.

4.
Thank you for this suggestion.We have looked into this and unfortunately the numbers are too small for us to be able to present this.

5.
Our findings did not identify any ethnic specific action per se but we have added the following sentence to the conclusion paragraph: promoting kidney development through childhood and adolescence, for example by aiming for normal weight trajectory and obesity avoidance would be relevant for all children but especially those with higher adult CKD risk such as south Asians. 6.

Figure 1 .
Figure 1.CONSORT flow chart of recruitment from the BiB Growing Up study.

Figure 2 .
Figure 2. Directed acyclic graph illustrating the relationship between ethnicity and childhood kidney function.BMI=body mass index.

Reviewer Report 16
May 2023 https://doi.org/10.21956/wellcomeopenres.19697.r56927© 2023 Awazu M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Child height required to calculate eGFR using both Schwartz equations was measured at the same visit as the blood sample in 52.0%, the height measurement was standardised to time of sample using centile charts if not measured at the same visit.Birth weight, gender and gestational age at birth; age and measured weight and height at follow-up.Measured weight and height were used to calculate BMI and body surface area (BSA).BMI was converted to age-and sex-adjusted z-scores according to the UK 1990 growth reference charts. Child:

Table 3 . Summary table of differences in kidney function, kidney damage and blood pressure by ethnicity: univariable and multivariable.
*estimated Glomerular Filtration Rate (eGFR) Socio-demographic model is adjusted for maternal age, maternal educational attainment, housing tenure, employment status and marital status, all at pregnancy and child age at kidney function measurement Maternal/pregnancy model is socio-demographic model plus maternal BMI, parity, alcohol consumption in pregnancy, maternal smoking in pregnancy, and gestational diabetes Fully adjusted model is maternal/pregnancy model plus birthweight, child body surface area (for kidney outcomes) or body mass index (for blood pressure) and child gender (all outcomes), and systolic and diastolic blood pressure (for eGFR, cystatin C, ACR and PCR only).Complete results of the Fully adjusted models is shown in Extended data, Supplementary

Table 2 39 . Table 4 . Summary table of differences in kidney function, kidney damage and blood pressure by ethnicity in the subset with renal ultrasound scans at 34 weeks gestation: univariable and multivariable adjusting for renal volume.
eGFR = estimated Glomerular Filtration Rate Fully adjusted model is adjusted for maternal age, maternal educational attainment, housing tenure, employment status and marital status, all at pregnancy; maternal BMI, parity, alcohol consumption in pregnancy, maternal smoking in pregnancy, gestational diabetes, birthweight, child body surface area (for kidney outcomes) or body mass index (for blood pressure), child gender, and renal volume (measured using ultrasound scans at 34 weeks of gestation) (all outcomes) and additionally for systolic and diastolic blood pressure (for eGFR, cystatin C, ACR and PCR only). * 1. eGFRcys, on the other hand, underestimates measured GFR (Wang Y, Kidney Int Rep, 2021).In view of these facts, the use of Schwarz or Zappitelli formulae in South Asian children cannot be justified.The modified formulae to estimate eGFR in South Asian children is needed.Page 13, right first line; "As in adults there is no correction for ethnicity in eGFR formulae."Thisstatement is erroneous.It is currently not available in children but is needed.The higher creatinine-based eGFR in South Asian children than White European children is in fact contrary to what is expected.The authors speculate this to be due to compensation.