The UK Chinese population with kidney failure: Clinical characteristics, management and access to kidney transplantation using 20 years of UK Renal Registry and NHS Blood and Transplant data.

BACKGROUND: Little is known about the clinical demographics of and access to transplantation for Chinese diaspora populations with kidney disease.
METHODS: The UK Renal Registry provided data on adults with ethnicity recorded as 'Chinese' or 'White' starting Kidney Replacement Therapy (KRT) 1/1/97-31/12/17. Baseline characteristics were compared between Chinese and White patients. Multivariable logistic regression models were used to investigate the relationships between Chinese ethnicity and i) being listed for deceased-donor transplantation at start of KRT, ii) being listed 2 years after start of KRT, iii) pre-emptive kidney transplantation, iv) kidney transplantation 3 years after start of KRT, and v) living-donor kidney transplantation (LDKT).
RESULTS: UK Chinese patients were younger at start of KRT (61.6 vs 65.6 years, p <0.001) and had more diabetic kidney disease (29% vs 20%, p<0.001) and glomerulonephritis (21% vs 13%, p<0.001) than White patients. We found evidence of interaction between ethnicity and sex. Compared to UK White men, UK Chinese men had lower odds of pre-emptive transplant (aOR 0.28, 95% CI [0.10-0.76]) and transplant within 3 years of KRT start (aOR 0.65, [95% CI 0.49-0.87], P = 0.004). UK White women and Chinese women had the same likelihood of pre-emptive transplant (aOR 0.78, 95% CI [0.38-1.61]), or transplant within 3 years of KRT start (aOR 0.94, 95% CI [0.60-1.46]). Both UK Chinese men and women had markedly lower odds of LDKT compared to Whites aOR 0.34 [95% CI 0.21-0.53].
CONCLUSIONS: UK Chinese are less likely to receive a LDKT. UK Chinese men have lower odds of accessing pre-emptive wait-listing and transplantation. Understanding whether these disparities reflect modifiable barriers will help ensure equitable access to transplantation.

Introduction

The China Kidney Disease Network (CK-NET) and Hong Kong Renal Registry have reported the main cause of chronic kidney disease in their populations is diabetes [1, 2], but the causes of kidney disease in the Chinese diaspora have not been well described.

Data from the United Kingdom (UK) Renal Registry (UKRR) has shown that 0.5% of people with kidney failure in the UK are of Chinese ethnicity [3]. 393,141 (0.7%) of the UK population are UK Chinese, a number that increased 59% between 2001 and 2011 [4, 5].

Ethnic differences in the cause of kidney disease [6], dialysis rates [7, 8] and access to kidney transplantation [9] have been investigated across the UK White, South Asian and Black populations, however these have not been investigated in the UK Chinese population. These previous analyses have provided evidence of ethnic inequity in access to living-donor kidney transplantation (LDKT): both UKRR analyses [10] and the Access to Transplantation and Transplant Outcome Measures (ATTOM) study have reported that patients from ethnic minority groups are less likely to access LDKT [11], even after adjustment for socioeconomic status (SES). However, these studies have either excluded UK Chinese patients, or combined the UK Chinese with other minority ethnic groups for analysis due to small numbers. Combining ethnic minority populations for analysis reduces granularity of the ethnicity data and potentially may mask heterogeneity between different ethnic minority groups as regards (i) differential incidences of kidney disease and (ii) disparities in access to dialysis and transplant treatments between individual ethnic minority populations. The UK renal research strategy has called for research to better understand ethnic inequity and differential rates of kidney disease among ethnic minority groups [12]. To this end, we aimed to investigate the clinical characteristics and access to transplantation in the UK Chinese population with kidney disease.

Materials and methods

Data on all incident adult (aged ≥18 years) patients starting kidney replacement therapy (KRT) was extracted for 20 years between 1/1/1997-31/12/2017 from centres submitting to the UKRR. Patients whose ethnicity was recorded as anything other than ‘Chinese’ or ‘White’, or with ethnicity data missing, were excluded. Patients who underwent kidney transplantation outside of the UK have been excluded. Data from centres that had poor completeness and quality of ethnicity data reporting were excluded. In keeping with UKRR reports, data from these centres were included in analysis from the year that they submitted ethnicity data for at least 70% of their patients. Patients were followed until death, censoring (recovery or lost to follow-up) or the end of the study period.

Exposure, outcomes and confounders

Our main exposure was Chinese ethnicity (binary variable UK Chinese = 1 UK White = 0). We had five outcome measures in relation to access to transplantation. These were; i) being listed on the deceased-donor kidney transplant waiting list at start of KRT ii) being listed on the deceased-donor waiting list 2 years after start of KRT iii) pre-emptive kidney transplantation (from deceased or living donor), iv) kidney transplantation at 3 years after start of KRT, and v) living-donor kidney transplantation at any time. For analyses relating to access to transplantation and wait-listing on the UK National Kidney Allocation Scheme, patients ≥75 years at the age of start of KRT were excluded because of the high prevalence of comorbidity which decreases the likelihood of transplantation and the very small proportion of patients receiving a kidney transplant in the UK in this age group. Data on co-morbidity were incomplete, but patients who were recorded as having known malignancy at start of KRT were excluded from analyses investigating transplant access.

We obtained data on the following variables: age; sex; socioeconomic status (SES); primary renal diagnosis (PRD); time from first seeing a nephrologist to start of KRT. PRD was grouped using pre-2012 ERA-EDTA coding, as updated ERA-EDTA codes were unavailable for a proportion of patients (See S1 Table). The UKRR does not collect individual-level SES data. Instead, Index of Multiple Deprivation scores were used as an area level measure of SES. The Index of Multiple Deprivation (IMD) is a measure of relative deprivation for small areas (neighbourhoods). Each country in the UK (England, Wales, Scotland and Northern Ireland) has an IMD. The IMD ranks all small areas within a country from most deprived to least deprived (1 = most deprived) using different domains, which can include: Income Deprivation, Employment Deprivation, Education, Skills and Training Deprivation, Health Deprivation and Disability, Crime, Barriers to Housing and Services, Living Environment Deprivation. The relative ranking of a small area is it’s IMD score (i.e. IMD score of 1 = most deprived) and these can be categorised into quintiles within each country (Quintile 1 = most deprived, Quintile 5 = least deprived). Each patient’s country-specific (English [13], Welsh [14], Scottish [15], Northern Irish [16]) IMD quintile was derived using their postcode (zipcode).

Statistical analyses

Means and standard deviations (SDs) were calculated for normally distributed continuous variables. Medians and interquartile ranges (IQRs) are presented for continuous variables whose distribution was not normal. Chi-square tests were used to compare categorical variables and Mann-Whitney U tests were used to compare medians. We identified missing data and investigated for any patterns of missingness. The proportion of missing data for categorical variables was compared for patients of UK Chinese and White ethnicities using Chi-Square tests, presented in S1 Table.

We performed and have presented complete case analyses. Specific variables (including Body Mass Index (BMI) and comorbidity data) had a high proportion of missing data (>50%) and so it was decided to exclude them from the analyses.

We used multivariable logistic regression models (Odds ratios (ORs), 95% Confidence Intervals (CIs) and p-values) to investigate the relationships between Chinese ethnicity (UK Chinese versus UK White) and i) being listed on the deceased-donor kidney transplant waiting list at start of KRT ii) being listed on the deceased-donor waiting list 2 years after start of KRT iii) pre-emptive kidney transplantation (from deceased or living donor), iv) kidney transplantation at 3 years after start of KRT, and v) living-donor kidney transplantation at any time. In addition for wait-listing at 2 years and transplant at 3 years we repeated the analysis using a competing-risks regression based on Fine and Gray’s proportional subhazards model [17, 18] to account for the competing risk of death prior to either being wait-listed or transplantation.

All models were run unadjusted and then adjusted for the following covariates, specified a priori, age group (18–25 years, 26–35 years, 36–45 years, 46–55 years, 56–65 years, 66–74 years), PRD, sex and SES. PRD was managed as a categorical variable (‘Diabetes’, ‘Glomerulonephritis’ and ‘Other’”).

We tested for a priori interactions between Chinese ethnicity and the covariates age, sex and SES. When we found evidence of interaction we performed analyses stratified by the covariate. ORs with 95% CIs were calculated using robust standard errors to account for clustering by kidney centre. All statistical analyses were completed using STATA 15 software [19].

On behalf of the Renal Association, the UK Renal Registry (UKRR) collects patient data without consent with approval under section 251 of the NHS Act (2006), granted by the Health Research Authority’s Confidentiality Advisory Group (ref 16/CAG/0064). Data are always pseudonymised prior to being analysed. The UKRR database has approval for research studies from the NHS North East Newcastle & North Tyneside 1 Research Ethics Committee (21/NE/0045). The UKRR is also permitted to share certain specified data items from its linked UKRR-NHSBT (NHS Blood and Transplant) dataset, including date of transplant and type of transplant received. The report was prepared with reference to the ‘REporting of studies Conducted using Observational Routinely-collected health Data (RECORD)’ Statement [20].

In the UK, all donation is overseen by NHS Blood and Transplant (NHSBT). For deceased donation, UK individuals can register as organ donors. In England, Wales, Scotland all adults are now considered to have ‘deemed consent’ or ‘deemed authorisation’ for organ donation: all adults are considered to have agreed to be an organ donor when they die unless they have a recorded decision not to donate, or are in an excluded group (those under the age of 18, people who lack the mental capacity to understand the new arrangements and take the necessary action, visitors to England, and those not living here voluntarily, people who have lived in England for less than 12 months before their death). In Northern Ireland unless individuals have registered as organ donors they are not considered to have agreed to donation. If an individual dies in circumstances in which organ donation is possible, an NHS specialist nurse will try to establish when a person is registered on the NHS Organ Donor Register. A patient’s family/close friends/next of kin will then be asked to support a decision for organ donation to go ahead, and clinicians will not proceed if there are family objections.

All living donors have to be assessed to have capacity to donate, and to be donating free from coercion or payment by an Independent Assessor from the Human Tissue Authority. Payment for organ donation or facilitating organ donation is illegal. In March 2015, the UK signed the Council of Europe Convention against Trafficking in Human Organs www.declarationofistanbul.org/resources/recommended-reading/the-councilof-europe-convention-against-trafficking-in-human-organs.

All living kidney donors are consented according to local transplant centre protocols during their work-up process, and consent confirmed at time of donation.

The clinical and research activities reported are consistent with the Principles of the Declaration of Istanbul as outlined in the ’Declaration of Istanbul on Organ Trafficking and Transplant Tourism’.

Results

Clinical characteristics

The dataset comprised of 92,689 incident KRT patients. 0.5% (n = 492) were of Chinese ethnicity, 76% (n = 70,560) were White. The remaining 23.5% of patients were of Asian ethnicity (10%), Black (6%) Other (2%), or had ethnicity data missing (5%).

For BMI and Comorbidity missing data was >60% and so these variables were excluded from the analyses. Otherwise the proportion of missing data for covariates was small (≤5%) (S1 Table).

The characteristics of the UK Chinese KRT population compared to the UK White KRT population are shown in Table 1. Chinese patients were younger at start of KRT (61.6 vs 65.6 years, p <0.001) than White patients. There were marked differences in the causes of kidney failure: UK Chinese patients had more diabetic kidney disease (29% vs 20%, risk difference 0.09, 95% CI 0.05–0.13, p<0.001) and glomerulonephritis than White patients (21% vs 13%, risk difference 0.08, 95% CI 0.04–0.11, p<0.001).

Table 1

Characteristics of UK Chinese and UK White KRT populations.

	Chinese n = 492	White n = 70,560	p value
Median age at start of KRT, years (IQR)	61.6 (47.7–72.1)	65.6 (51.8–75.2)	<0.001 **
Sex, n (%)			0.31 *
Male	399 (61)	44,442 (63)
Female	193 (39)	26,118 (37)
Missing	0 (0)	0 (0)
IMD quintile, n (%)			0.61 *
1 Most deprived	112 (23)	17, 585 (25)
2	119 (24)	15, 381 (22)
3	97 (20)	13,810 (20)
4	90 (18)	12,418 (18)
5 Least deprived	73 (15)	11,083 (16)
Missing	1 (0)	283 (0)
Cause of renal failure, n (%)			<0.001*
Diabetes	141 (29)	14,105 (20)
Glomerulonephritis	103 (21)	9,213 (13)
Hypertension	33 (7)	4,207 (6)
Polycystic kidney disease	27 (5)	5,434 (8)
Pyelonephritis	15 (3)	5,494 (8)
Renovascular disease	10 (2)	5,122 (7)
Uncertain	101 (21)	13,055 (19)
Other	43 (9)	11,691(17)
Missing	19 (4)	2,239 (3)
Treatment at start KRT, n (%)			0.02*
Haemodialysis	346 (70)	50,100 (71)
Peritoneal dialysis	128 (26)	15,964 (23)
Transplant	18 (4)	4,496 (6)
Missing	0 (0)	0 (0)
Median time from first seen by nephrologist to start of KRT, days (IQR)	784 (154, 1985)	826 (164, 2063)	0.60**a

*Chi2 test;

**Mann-Whitney U test

KRT = Kidney Replacement Therapy

a Completed case analysis.

Causes for glomerulonephritis in UK Chinese and White KRT patients are presented in Table 2.

Table 2

Causes of glomerulonephritis in the UK Chinese and White populations.

	Chinese n (%)	White n (%)	P value *
Glomerulonephritis- no histology	8 (8)	1266 (14)	0.005
Focal Segmental Glomerulosclerosis with nephrotic syndrome in children	0 (0)	101 (1)
Focal Segmental Glomerulosclerosis with nephrotic syndrome in adults	11 (11)	1037 (11)
IgA disease	55 (53)	3096 (34)
Dense deposit disease	0 (0)	85 (1)
Membranous nephropathy	9 (9)	918 (10)
Membranoproliferative glomerulonephritis	7 (7)	504 (5)
Crescentic glomerulonephritis	1 (1)	504 (5)
Glomerulonephritis with biopsy in adults	12 (12)	1706 (19)
Total	103	9213

*Fisher’s exact test.

Management

There was moderate evidence that more Chinese patients started KRT on peritoneal dialysis that White patients (26% vs 23%, p = 0.02). There was no evidence of difference between the UK Chinese KRT population and the White KRT population in median days from first seen by nephrologist to start of KRT KRT (784 vs 826, p = 0.60).

Access to transplantation

The findings of the multivariable logistic regression analyses are presented in Table 3.

Table 3

Results of multivariable logistic regression analyses investigating Chinese ethnicity and access to wait-listing and transplantation.

	Unadjusted analysis	Adjusted analysis*
	Chinese vs White	Chinese vs White
	OR, (95% CI),	OR, (95% CI),
	P-value	P-value
Waitlisted at KRT start	0.78 (0.59–1.02), P = 0.07	0.74 (0.56–0.98), P = 0.03
Waitlisted at 2 years	1.29 (1.06–1.58), p = 0.01	1.26 (1.0–1.6), p = 0.06
Pre-emptive transplant	0.52 (0.32–0.84), P = 0.007	0.49 (0.30–0.81), P = 0.005
Transplanted within 3 years of KRT start	0.74 (0.58–0.93), P = 0.01	0.65 (0.49–0.87), P = 0.004
Living donor kidney transplant	0.34 (0.22–0.52), P<0.001	0.34 (0.21–0.53), P<0.001

*Adjusted for age, sex, primary renal disease, and socioeconomic status.

Even after adjustment for potential confounders, UK Chinese patients had lower odds of being waitlisted at the start of KRT (adjusted OR (aOR) 0.74, [95% CI 0.56–0.98], P = 0.03) but were as likely to be waitlisted at 2 years (aOR 1.26, [95% CI 1.00–1.60], P = 0.06) compared to White patients. The results from the competing risk model were almost identical (subdistribution hazard ratio (SHR) 1.19 [1.00–1.41] P = 0.05). UK Chinese individuals were also less likely to receive a pre-emptive kidney transplant (aOR 0.49, [95% CI 0.30–0.81], P = 0.005) and less likely to be transplanted within 3 years of starting KRT (aOR 0.65, [95% CI 0.49–0.87], P = 0.004) compared to White patients. Chinese patients were 66% less likely to receive a LDKT than White patients (aOR 0.34, 95% CI [0.21–0.53], P<0.001). Adjusted competing risk analyses and cause-specific proportional hazard ratios are presented in S2 Table and were very similar to the results from the logistic models.

There was evidence of statistical interaction between Chinese ethnicity and sex for the outcome variables of access to pre-emptive transplant (likelihood ratio test = 0.05), and access to transplant at 3 years (likelihood ratio test p = 0.04): Chinese men were less likely than White men to have a pre-emptive transplant (aOR 0.28, 95% CI [0.10–0.76]), or be transplanted within 3 years of KRT start (aOR 0.50, 95%CI [0.34–0.73]). However Chinese women appeared to be as likely as White women to have a pre-emptive transplant (aOR 0.78, 95% CI [0.38–1.61]), or to be transplanted within 3 years (aOR 0.94, 95% CI [0.60–1.46]).

Discussion

To our knowledge, this study is the first to describe renal disease and access to transplantation in the UK Chinese population, and one of the first to describe renal disease in the Chinese diaspora. We found a greater burden of diabetes in the UK Chinese KRT population compared to the White KRT population: this may reflect a high prevalence of diabetes in the UK Chinese, or a greater pre-disposition to diabetic nephropathy in Chinese individuals with diabetes as compared to Whites and requires further investigation. The prevalence of diabetes in the UK Chinese was reported as 3.8% in men and 3.3% in women [21] in 2004, but may have increased subsequently, as has been reported in China [22, 23] and Hong Kong [24], where prevalence of diabetes has risen and is reported as 11% and 10% respectively. Specific variations in RAGE [25], ELMO1 [26] and TGF-β1 [27] genes, and their gene-environment interactions, have been found to be associated with diabetic nephropathy in the Han Chinese population, but have not been investigated in the Chinese diaspora, where environmental exposures may be different. The Chinese Kidney Disease Network (CK-NET) has reported a 15.1% prevalence of glomerulonephritis in their CKD population, 10.6% of which were diagnosed with IgA nephropathy, a number which had fallen from 19% in 2010 [1], which is lower than the 54% prevalence of IgA nephropathy in patients with glomerulonephritis in this UK study. The reasons behind this require further investigation.

The slightly increased rates of PD in UK Chinese patients may be associated with relatively lower average BMIs in the Chinese population [28]. The quantity of missing BMI data in the UKRR dataset prevented investigation of this association in this study. Hong Kong have had a successful “PD first” policy for more than 30 years, with 72.9% of their dialysis population being treated with PD [29]. It may be that familiarity with this mode of kidney replacement therapy has led to increased uptake of PD in the UK Chinese KRT population. Additionally, studies from Hong Kong have suggested that high transporter status is less common [30] and lower dialysis volumes [31] are required in their cohort. It would be beneficial to elucidate whether this is also the case in the UK Chinese KRT population, and if so, peritoneal dialysis encouraged.

Our findings suggest that UK Chinese men are less likely to receive a pre-emptive kidney transplant, or to receive a transplant 3 years after start of KRT than UK White men; UK Chinese women are no less likely to receive a pre-emptive transplant, or to receive a transplant 3 years after start of KRT than UK White women. However, both UK Chinese men and women are less likely to receive a LDKT.

Whether these disparities reflect modifiable barriers at health system, clinician or patient level requires further investigation. We found no evidence that the UK Chinese population (both men and women) with kidney failure are presenting late to nephrology services and thus precluding timely transplant work-up, with no significant difference in time from first seen by nephrologist to start of KRT between UK Chinese and White patients. Our finding of no difference in the subdistribution hazard of wait-listing at 2 years, after accounting for the competing risk of death before wait-listing, for UK Chinese patients (both men and women) compared to White patients suggests that fitness for transplantation is not a significant barrier; however the UK Chinese may require more time to be assessed as suitable. Multicentre cross-sectional studies have demonstrated that estimated glomerular filtration rate (eGFR) calculations [32, 33], in particular the Modification of Diet in Renal Disease study (MDRD) equation can overestimate GFR when compared to cystatin C based GFR measurements in a Chinese cohort. However another Chinese cohort study found that eGFR calculations underestimated GFR compared to gold standard iohexol measurements, especially in diabetic patients [34]. Therefore, inaccuracy of standard eGFR calculations, validated in White and Black patients, may also be hindering accurate assessment of kidney function in the UK Chinese.

Sex disparity in access to kidney transplantation (lower in women than men on KRT) has previously been observed in the UK and worldwide [35-37], due in part to pregnancy induced HLA sensitisation. It has been suggested that ethnic minority women are particularly affected due to being more likely to be multiparous [38, 39]. A questionnaire based study examining sex disparity in an African-American haemodialysis cohort further found that women were less likely to have discussions around and be evaluated for a kidney transplant than men [40]. However, our findings suggest that UK Chinese women are no less likely to be pre-emptively listed or receive a kidney transplant at 3 years after starting KRT than White women; whether UK Chinese women are less sensitized, have a cultural advantage (e.g. increased care-giver support) or differences in attitude towards kidney transplantation requires further investigation. A population based retrospective cohort study found lower mortality from breast and cervical cancer in Ontarian Canadian Chinese immigrant women compared to the general population [41], even when removing the “healthy immigrant” effect. A potential reason suggested was that Chinese women were more likely to pursue aggressive anti-neoplastic treatments due to cultural differences in treatment philosophy. Our findings highlight that barriers to kidney transplantation may be individual to certain ethnic minority groups; research combining ethnic minority populations together for analysis may fail to appreciate this heterogeneity.

The reasons why the UK Chinese KRT population, both men and women, are less likely than White patients to receive a LDKT are not well understood. A qualitative study examining the views of Chinese immigrants to Canada [42] towards both deceased and living organ donation reported the importance of “filial piety” in this cohort- the concept of respect for parents and elders. Whilst this study described a potential conflict between the desire to return the body whole in death to parents and ancestors as an act of respect and living or deceased organ donation, it also suggested a willingness to consider living donation amongst interviewees, especially from parent to child. A survey in a Malaysian Chinese cohort similarly reported concerns around the sanctity of the body in death [43]. However, this has not been investigated in other Chinese diaspora, and previous studies have shown that attitudes towards organ donation can change depending on host country [44].

Strengths and limitations

This study utilised national UK registry and NHSBT data to investigate a previously unstudied group: the UK Chinese population with renal failure. The UKRR is one of few renal registries internationally to collect individual level ethnicity data [45], which enabled us to describe the clinical demographics and access to transplantation in this more specific ethnic group, which may not have been possible elsewhere. However, this study has a number of limitations: i) The data regarding ethnicity were physician entered, and may not match how the ethnic group with which the patient identifies ii) Data on patient BMI and co-morbidity were incomplete and prevented the use of these variables in our analysis. In particular we were unable to ascertain the prevalence of co-morbidities which may have precluded transplantation in the study cohort. (iii) The number of UK Chinese people in the study was relatively small.

The reasons for the observed disparity in wait-listing and access to deceased donor transplantation between UK Chinese men and women requires further investigation. Future research should use qualitative methods with the UK Chinese population to elucidate whether there are cultural or information barriers to kidney donation within this population, or attitudes which may favour kidney transplantation, in particular focused on understanding whether there are differences between UK Chinese men and women.

Whether the differential rates of kidney disease seen in the UK Chinese in our study is also the case in other Chinese diaspora patient groups also requires further study.

In summary, our study has found evidence that the UK Chinese KRT population differs from the White KRT population. Although the number of UK Chinese with kidney failure is small, we have found evidence that these individuals, in particular UK Chinese men, are disadvantaged in access to wait-listing and transplantation. Early identification and support of this population may therefore be beneficial.

Missing data analysis.

(DOCX)

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Competing risk analyses.

(DOCX)

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Results of multivariable logistic regression analyses investigating Chinese ethnicity and access to wait-listing and transplantation, stratified by sex.

(DOCX)

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(PDF)

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12 Jul 2021

PONE-D-21-05646

The UK Chinese population with kidney failure: Clinical characteristics, management and access to kidney transplantation using 20 years of UK Renal Registry and NHS Blood and Transplant Data

PLOS ONE

Dear Dr. Wong,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The Editor reviewed the manuscript and recommends several changes and corrections. Please read specific comments.

Reviewer # 1:

The paper by Wong et al goes over the differences in causes of renal failure, access to transplantation and other characteristics in UK White and UK Chinese patient populations. The paper appears well written and the study was methodologically sound. It is surprising that statistically significant differences were found when the Chinese cohort was only about 500 patients in size and adjustment by regression confounders was applied. There is certainly no reason to question the presented results, though I speculate that applying more conservative testing with verification of logistic regression’s assumptions (which almost everyone seems to skip nowadays) would lead to problems related to sample size. Good points were made regarding higher rates of diabetes and possible need for a special method for GFR calculation in Chinese patients

Reviewer # 2:

Please address the following points:

The analysis is a comparison of Chinese and White populations listed in the UK registry system. Please provide details of exclusions (percentages) for Chinese and White populations.

Please explain more precisely the category as “being listed on the deceased donor waiting list for 2 years” and “kidney transplantation at 3 years after start of KRT”. Does the first category mean to be listed at least 2 years and more? Does the kidney transplantation category mean kidney transplantation within 3 years? Please clarify these terms. Also, pre-emptive transplantation is from deceased or live donor?

What mean “data on co-morbidity were incomplete”.

Please explain “The UKRR does not collect individual-level SES data. Index of Multiple Deprivation (IMD) scores were used as an area level measure of SES” as this statement is not clear. The authors collect and use SES data but then say that such data are not collected. Please clarify and explain better SES data collection.

Please explain Index of Multiple Deprivation (IMD) scores as an average reader is not familiar with this system. It is also not clear what is most deprived vs. least deprived and differences among coutries. Please explain.  How the authors calculated IMD for missing data? The statement is that IMD for England was used. Please explain.

The statistical analysis is not clear for missing data “We identified missing data and investigated for any patterns of missingness.”

The statement “Intervals (CIs) and p-values) to investigate the relationships between Chinese ethnicity (UK Chinese versus UK White) and the five outcomes listed above” is not clear. Where is listed above?

Please confirm the statement “The UK Renal Registry has been granted a section 251 exemption by the Health Research Authority, allowing the sharing and processing of identifiable patient information from kidney units without individual patient consent.”

The Results section provide that “. 0.5% (n=501) were of Chinese ethnicity, 76% (n=70,575) were White”. What is the remaining percentage? Please clarify.

Please explain how in Table 3, the analysis was adjusted for SES for cases that have missing data? The Materials and Methods state that there are many missing data.

Please provide more attention for the results showing differences between males and females. What is the reason for the difference in Chinese males to be so significantly different than Chinese females? Please confirm or refute the assumption that all differences revealed in this manuscript are refer exclusively to the Chinese males. Please try to explain this unique observation by possible different variables.

The Discussion section has conclusions about the entire Chinese population (males and females) whereas the results showed to be concentrated in Chinese males. Please clarify and make additional analyses to make sure what conclusions refer to the entire Chinese population (males and females with the same rates in reported observations) vs. conclusions exclusively found in Chinese male population. Please make very clear what observations are in which Chinese groups.

The limitation section should be more specific as well as the conclusion section needs to reflect the documented observations regarding gender disparities.

The authors need to confirm the entire analysis in Chinese male vs. Chinese female population. The differences at different levels of analyses need to be clearly indicated. The Results and Discussion sections need to be adjusted.

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Additional Editor Comments (if provided):

The Editor reviewed the manuscript and recommends several changes and corrections. Please read specific comments.

Reviewer # 1:

The paper by Wong et al goes over the differences in causes of renal failure, access to transplantation and other characteristics in UK White and UK Chinese patient populations. The paper appears well written and the study was methodologically sound. It is surprising that statistically significant differences were found when the Chinese cohort was only about 500 patients in size and adjustment by regression confounders was applied. There is certainly no reason to question the presented results, though I speculate that applying more conservative testing with verification of logistic regression’s assumptions (which almost everyone seems to skip nowadays) would lead to problems related to sample size. Good points were made regarding higher rates of diabetes and possible need for a special method for GFR calculation in Chinese patients

Reviewer # 2:

Please address the following points:

The analysis is a comparison of Chinese and White populations listed in the UK registry system. Please provide details of exclusions (percentages) for Chinese and White populations.

Please explain more precisely the category as “being listed on the deceased donor waiting list for 2 years” and “kidney transplantation at 3 years after start of KRT”. Does the first category mean to be listed at least 2 years and more? Does the kidney transplantation category mean kidney transplantation within 3 years? Please clarify these terms. Also, pre-emptive transplantation is from deceased or live donor?

What mean “data on co-morbidity were incomplete”.

Please explain “The UKRR does not collect individual-level SES data. Index of Multiple Deprivation (IMD) scores were used as an area level measure of SES” as this statement is not clear. The authors collect and use SES data but then say that such data are not collected. Please clarify and explain better SES data collection.

Please explain Index of Multiple Deprivation (IMD) scores as an average reader is not familiar with this system. It is also not clear what is most deprived vs. least deprived and differences among coutries. Please explain. How the authors calculated IMD for missing data? The statement is that IMD for England was used. Please explain.

The statistical analysis is not clear for missing data “We identified missing data and investigated for any patterns of missingness.”

The statement “Intervals (CIs) and p-values) to investigate the relationships between Chinese ethnicity (UK Chinese versus UK White) and the five outcomes listed above” is not clear. Where is listed above?

Please confirm the statement “The UK Renal Registry has been granted a section 251 exemption by the Health Research Authority, allowing the sharing and processing of identifiable patient information from kidney units without individual patient consent.”

The Results section provide that “. 0.5% (n=501) were of Chinese ethnicity, 76% (n=70,575) were White”. What is the remaining percentage? Please clarify.

Please explain how in Table 3, the analysis was adjusted for SES for cases that have missing data? The Materials and Methods state that there are many missing data.

Please provide more attention for the results showing differences between males and females. What is the reason for the difference in Chinese males to be so significantly different than Chinese females? Please confirm or refute the assumption that all differences revealed in this manuscript are refer exclusively to the Chinese males. Please try to explain this unique observation by possible different variables.

The Discussion section has conclusions about the entire Chinese population (males and females) whereas the results showed to be concentrated in Chinese males. Please clarify and make additional analyses to make sure what conclusions refer to the entire Chinese population (males and females with the same rates in reported observations) vs. conclusions exclusively found in Chinese male population. Please make very clear what observations are in which Chinese groups.

The limitation section should be more specific as well as the conclusion section needs to reflect the documented observations regarding gender disparities.

The authors need to confirm the entire analysis in Chinese male vs. Chinese female population. The differences at different levels of analyses need to be clearly indicated. The Results and Discussion sections need to be adjusted

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a. Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that  reviewed and approved the UK Renal Registry research programme. Please include relevant approval numbers.

In addition, please provide additional information about the patient records/samples used in your retrospective study, including whether all data were fully anonymized before you accessed them, and also state whether the ethics committee that approved the research programme waived the need for written informed consent.

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-https://www.era-edta.org/VirtualCongress2020/Accepted_Abstracts_ERAEDTA_2020.pdf

-https://academic.oup.com/ndt/article/35/Supplement_3/gfaa142.P0772/5853027

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: The paper by Wong et al goes over the differences in causes of renal failure, access to transplantation and other characteristics in UK White and UK Chinese patient populations. The paper appears well written and the study was methodologically sound. It is surprising that statistically significant differences were found when the Chinese cohort was only about 500 patients in size and adjustment by regression confounders was applied. There is certainly no reason to question the presented results, though I speculate that applying more conservative testing with verification of logistic regression’s assumptions (which almost everyone seems to skip nowadays) would lead to problems related to sample size. Good points were made regarding higher rates of diabetes and possible need for a special method for GFR calculation in Chinese patients.

Reviewer #2: Please address the following points:

The analysis is a comparison of Chinese and White populations listed in the UK registry system. Please provide details of exclusions (percentages) for Chinese and White populations.

Please explain more precisely the category as “being listed on the deceased donor waiting list for 2 years” and “kidney transplantation at 3 years after start of KRT”. Does the first category mean to be listed at least 2 years and more? Does the kidney transplantation category mean kidney transplantation within 3 years? Please clarify these terms. Also, pre-emptive transplantation is from deceased or live donor?

What mean “data on co-morbidity were incomplete”.

Please explain “The UKRR does not collect individual-level SES data. Index of Multiple Deprivation (IMD) scores were used as an area level measure of SES” as this statement is not clear. The authors collect and use SES data but then say that such data are not collected. Please clarify and explain better SES data collection.

Please explain Index of Multiple Deprivation (IMD) scores as an average reader is not familiar with this system. It is also not clear what is most deprived vs. least deprived and differences among coutries. Please explain. How the authors calculated IMD for missing data? The statement is that IMD for England was used. Please explain.

The statistical analysis is not clear for missing data “We identified missing data and investigated for any patterns of missingness.”

The statement “Intervals (CIs) and p-values) to investigate the relationships between Chinese ethnicity (UK Chinese versus UK White) and the five outcomes listed above” is not clear. Where is listed above?

Please confirm the statement “The UK Renal Registry has been granted a section 251 exemption by the Health Research Authority, allowing the sharing and processing of identifiable patient information from kidney units without individual patient consent.”

The Results section provide that “. 0.5% (n=501) were of Chinese ethnicity, 76% (n=70,575) were White”. What is the remaining percentage? Please clarify.

Please explain how in Table 3, the analysis was adjusted for SES for cases that have missing data? The Materials and Methods state that there are many missing data.

Please provide more attention for the results showing differences between males and females. What is the reason for the difference in Chinese males to be so significantly different than Chinese females? Please confirm or refute the assumption that all differences revealed in this manuscript are refer exclusively to the Chinese males. Please try to explain this unique observation by possible different variables.

The Discussion section has conclusions about the entire Chinese population (males and females) whereas the results showed to be concentrated in Chinese males. Please clarify and make additional analyses to make sure what conclusions refer to the entire Chinese population (males and females with the same rates in reported observations) vs. conclusions exclusively found in Chinese male population. Please make very clear what observations are in which Chinese groups.

The limitation section should be more specific as well as the conclusion section needs to reflect the documented observations regarding gender disparities.

The authors need to confirm the entire analysis in Chinese male vs. Chinese female population. The differences at different levels of analyses need to be clearly indicated. The Results and Discussion sections need to be adjusted.

**********

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Reviewer #1: Yes: Dulat Bekbolsynov

Reviewer #2: No

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25 Nov 2021

Please also find the below response in the uploaded file "Response to Reviewers"

Dear Editors,

Many thanks for your review of our manuscript “The UK Chinese population with kidney failure: Clinical characteristics, management and access to kidney transplantation using 20 years of UK Renal Registry and NHS Blood and Transplant Data”, and the opportunity to respond to reviewer’s comments and improve our manuscript.

Please find our responses to points raised below, with reviewer comments in bold:

Reviewer 1:

The paper by Wong et al goes over the differences in causes of renal failure, access to transplantation and other characteristics in UK White and UK Chinese patient populations. The paper appears well written and the study was methodologically sound. It is surprising that statistically significant differences were found when the Chinese cohort was only about 500 patients in size and adjustment by regression confounders was applied. There is certainly no reason to question the presented results, though I speculate that applying more conservative testing with verification of logistic regression’s assumptions (which almost everyone seems to skip nowadays) would lead to problems related to sample size. Good points were made regarding higher rates of diabetes and possible need for a special method for GFR calculation in Chinese patients

We thank the reviewer for their time reviewing this manuscript, and for their positive comments regarding the discussion.

Reviewer 2:

Thank you for taking the time to review our paper, and for your detailed response. Please find answers to individual points below.

1) The analysis is a comparison of Chinese and White populations listed in the UK registry system. Please provide details of exclusions (percentages) for Chinese and White populations.

All patients whose ethnicity was recorded by the UK Renal Registry as ‘Chinese’ or ‘White’ were included.

2) Please explain more precisely the category as “being listed on the deceased donor waiting list for 2 years” and “kidney transplantation at 3 years after start of KRT”. Does the first category mean to be listed at least 2 years and more? Does the kidney transplantation category mean kidney transplantation within 3 years? Please clarify these terms. Also, pre-emptive transplantation is from deceased or live donor?

“Being listed on the deceased-donor kidney transplant waiting list 2 years after start of KRT”

This outcome category includes all individuals with a date of being listed on the deceased-donor kidney transplant waiting list within 2 years, or ≤730 days, of their date of start of Kidney Replacement Therapy (KRT).

“Kidney transplantation at 3 years after start of KRT”

This outcome category includes all individuals with a date of kidney transplantation within 3 years, or ≤1095 days, of their date of start of KRT.

“Pre-emptive transplantation”

Many thanks for bringing this to our attention. This outcome category includes all individuals who received a kidney transplant prior to starting another form of KRT, and includes individuals receiving deceased and living donor kidney transplant. Additional information has been added in the Exposures, outcomes and confounders section of the Methods to clarify: “iii) pre-emptive kidney transplantation (from deceased or living donor)” page 5, line 16.

3) What mean “data on co-morbidity were incomplete”.

The UK Renal Registry collects data on an individual’s co-morbidities, including ischaemic heart disease and malignancy. However, these data were incomplete: as stated in the results section under “Clinical Characteristics”, missing data was >60%.

4) Please explain “The UKRR does not collect individual-level SES data. Index of Multiple Deprivation (IMD) scores were used as an area level measure of SES” as this statement is not clear. The authors collect and use SES data but then say that such data are not collected. Please clarify and explain better SES data collection.

Please explain Index of Multiple Deprivation (IMD) scores as an average reader is not familiar with this system. It is also not clear what is most deprived vs. least deprived and differences among coutries. Please explain.  How the authors calculated IMD for missing data? The statement is that IMD for England was used. Please explain.

Many thanks for highlighting the need for further clarity in this section. It has now been amended in the manuscript to:

“The UKRR does not collect individual-level SES data. Instead, Index of Multiple Deprivation scores were used as an area level measure of SES. The Index of Multiple Deprivation (IMD) is a measure of relative deprivation for small areas (neighbourhoods). Each country in the UK (England, Wales, Scotland and Northern Ireland) has an IMD. The IMD ranks all small areas within a country from most deprived to least deprived (1=most deprived) using different domains, which can include: Income Deprivation, Employment Deprivation, Education, Skills and Training Deprivation, Health Deprivation and Disability, Crime, Barriers to Housing and Services, Living Environment Deprivation. The relative ranking of a small area is it’s IMD score (i.e. IMD score of 1= most deprived) and these can be categorised into quintiles within each country.(Quintile 1= most deprived, Quintile 5= least deprived).

Each patient’s country-specific (English(13), Welsh(14), Scottish(15), Northern Irish(16)) IMD quintile was derived using their postcode (zipcode).” Page 6, lines 4-16.

Data were analysed assuming that any patient with IMD score data but missing country of residence data, lived in England. However, on review, no patient in the dataset had an IMD score without also having country of residence data. The sentence “For patients missing data on country of residence, the patient’s IMD quintile was calculated using the IMD quintile parameters for England, as the majority of patients were from this nation” has therefore been deleted for clarity.

5) The statistical analysis is not clear for missing data “We identified missing data and investigated for any patterns of missingness.”

Thank you for bringing this to our attention.

This has now been amended to “We identified missing data and investigated for any patterns of missingness. The proportion of missing data for categorical variables was compared for patients of UK Chinese and White ethnicities using Chi-Square tests, presented in S1 Tables of Supplementary Materials.” (Page 6, lines 22-25)

6) The statement “Intervals (CIs) and p-values) to investigate the relationships between Chinese ethnicity (UK Chinese versus UK White) and the five outcomes listed above” is not clear. Where is listed above?

The five outcomes investigated are listed in the section Exposure, outcomes and confounders: “We had five outcome measures in relation to access to transplantation. These were; i) being listed on the deceased-donor kidney transplant waiting list at start of KRT ii) being listed on the deceased-donor waiting list 2 years after start of KRT iii) pre-emptive kidney transplantation (from deceased or living donor), iv) kidney transplantation at 3 years after start of KRT, and v) living-donor kidney transplantation at any time”.

For clarity, these five outcomes have now been listed again in the Statistical Analyses section (page 7, lines 6-10).

7) Please confirm the statement “The UK Renal Registry has been granted a section 251 exemption by the Health Research Authority, allowing the sharing and processing of identifiable patient information from kidney units without individual patient consent.”

This statement has been clarified following request from the journal editors. It now reads: “On behalf of the Renal Association, the UK Renal Registry (UKRR) collects patient data without consent with approval under section 251 of the NHS Act (2006), granted by the Health Research Authority’s Confidentiality Advisory Group (ref 16/CAG/0064). Data are always pseudonymised prior to being analysed. The UKRR database has approval for research studies from the NHS North East Newcastle & North Tyneside 1 Research Ethics Committee (21/NE/0045)”. (Page 7 Lines 23-34 and Page 8 Lines 1-6)

8) The Results section provide that “. 0.5% (n=501) were of Chinese ethnicity, 76% (n=70,575) were White”. What is the remaining percentage? Please clarify.

The results section has now been amended to: “0.5% (n=501) were of Chinese ethnicity, 76% (n=70,575) were White. The remaining 23.5% of patients were of Asian ethnicity (10%), Black (6%) Other (2%), or had ethnicity data missing (5%) (Page 10, Lines 4-5).

Please explain how in Table 3, the analysis was adjusted for SES for cases that have missing data? The Materials and Methods state that there are many missing data.

The Materials and Methods does not refer to many missing data for this particular variable. The number of patients missing SES/IMD data, as presented in Table 1, for UK Chinese (n=1) and UK White (n=283) patients was small (<1% for both groups). For patients with IMD missing data, completed case analysis was undertaken.

9) Please provide more attention for the results showing differences between males and females. What is the reason for the difference in Chinese males to be so significantly different than Chinese females? Please confirm or refute the assumption that all differences revealed in this manuscript are refer exclusively to the Chinese males. Please try to explain this unique observation by possible different variables.

The Discussion section has conclusions about the entire Chinese population (males and females) whereas the results showed to be concentrated in Chinese males. Please clarify and make additional analyses to make sure what conclusions refer to the entire Chinese population (males and females with the same rates in reported observations) vs. conclusions exclusively found in Chinese male population. Please make very clear what observations are in which Chinese groups.

The limitation section should be more specific as well as the conclusion section needs to reflect the documented observations regarding gender disparities.The authors need to confirm the entire analysis in Chinese male vs. Chinese female population. The differences at different levels of analyses need to be clearly indicated. The Results and Discussion sections need to be adjusted.

Thank you for highlighting this interesting finding.

Statistical interactions between Chinese ethnicity and Sex were found for the outcome variables of (i) Pre-emptive transplant, and (ii) Transplantation within 3 years of KRT start, such that only UK Chinese men were less likely to receive a pre-emptive transplant, or a transplant within 3 years of KRT start compared to UK White men.

No evidence of a statistical interaction between Chinese ethnicity and Sex was found for the associations with outcome variables Waitlisting at KRT start, Waitlisting at 2 years, or Living donor kidney transplantation.

An additional table presenting results of multivariable logistic regression analyses investigating Chinese ethnicity and access to wait-listing and transplantation, stratified by Sex, has been added in S3 Tables in Supplementary Materials for clarity. Existing S2 Tables in supplementary materials presents competing risks models investigating the association between access to wait-listing and transplantation at 3 years, competing risk of death before wait-listing or transplantation, stratified by Sex.

These findings have also been made more explicit in the Discussion section which now reads:

“Our findings suggest that UK Chinese men are less likely to receive a pre-emptive kidney transplant, or to receive a transplant 3 years after start of KRT than UK White men; UK Chinese women are no less likely to receive a pre-emptive transplant, or to receive a transplant 3 years after start of KRT than UK White women. However, both UK Chinese men and women are less likely to receive a LDKT. (Page 15, Lines 18-22)” Where results discussed include both UK Chinese men and women, the Discussion has been amended to include “(both men and women)” (Page 16, lines 1 and 5, Page 17 line 9).

The reasons for this disparity between UK Chinese men and women is currently unclear and requires further investigation. Alongside this UK renal registry analysis, I am also undertaking qualitative interviews examining the views of the UK Chinese towards kidney transplantation from both deceased and living donor which aims to gain a deeper understanding of these results, for instance to understand whether UK Chinese men encounter additional cultural, social or medical barriers to pre-emptive transplantation or transplantation within 3 years of starting KRT.

I have amended the Strengths and Limitations to reflect this:

“The reasons for the observed disparity in wait-listing and access to deceased donor transplantation between UK Chinese men and women requires further investigation. Future research should use qualitative methods with the UK Chinese population to elucidate whether there are cultural or information barriers to kidney donation within this population, or attitudes which may favour kidney transplantation, in particular focused on understanding whether there are differences between UK Chinese men and women. (Page 18, lines 8-15)”.

Journal Requirements:

Many thanks for taking the time to review this paper.

1) Please ensure that your manuscript meets PLOS ONE's style requirement

The manuscript has now been amended to meet PLOS ONE’s style requirements.

2) Thank you for including your ethics statement:  "The UK Renal Registry has been granted a section 251 exemption by the Health Research Authority, allowing the sharing and processing of identifiable patient information from kidney units without individual patient consent".

a. Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that reviewed and approved the UK Renal Registry research programme. Please include relevant approval numbers.

In addition, please provide additional information about the patient records/samples used in your retrospective study, including whether all data were fully anonymized before you accessed them, and also state whether the ethics committee that approved the research programme waived the need for written informed consent.

b. Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

Ethics statement has been amended in both the manuscript and online submission to:

“On behalf of the Renal Association, the UK Renal Registry (UKRR) collects patient data without consent with approval under section 251 of the NHS Act (2006), granted by the Health Research Authority’s Confidentiality Advisory Group (ref 16/CAG/0064). Data are always pseudonymised prior to being analysed. The UKRR database has approval for research studies from the NHS North East Newcastle & North Tyneside 1 Research Ethics Committee (21/NE/0045)” (Page 7, lines 23-24 and Page 8, lines 1-6).

3. We note that your study involved tissue/organ transplantation. Please provide the following information regarding tissue/organ donors for transplantation cases analyzed in your study.

a. Please provide the source(s) of the transplanted tissue/organs used in the study, including the institution name and a non-identifying description of the donor(s).

b. Please state in your response letter and ethics statement whether the transplant cases for this study involved any vulnerable populations; for example, tissue/organs from prisoners, subjects with reduced mental capacity due to illness or age, or minors.

c. In the Methods, please provide detailed information about the procedure by which informed consent was obtained from organ/tissue donors or their next of kin. In addition, please provide a blank example of the form used to obtain consent from donors, and an English translation if the original is in a different language.

d. Please indicate whether the donors were previously registered as organ donors. If tissues/organs were obtained from deceased donors or cadavers, please provide details as to the donors’ cause(s) of death.

e. Please provide the participant recruitment dates and the period during which transplant procedures were done (as month and year).

f. Please discuss whether medical costs were covered or other cash payments were provided to the family of the donor. If so, please specify the value of this support (in local currency and equivalent to U.S. dollars).

a. Please provide the source(s) of the transplanted tissue/organs used in the study, including the institution name and a non-identifying description of the donor(s).

This study was undertaken using retrospective data from the UK Renal Registry (UKRR) and NHS Blood and Transplant. Data from the UKRR is provided for research fully pseudonymised as per its section 251 approval granted by the Health Research Authority’s Confidentiality Advisory Group.  It is therefore not possible to identify the donors for individual patients in this cohort.

However, the great majority of kidney transplants reported in this registry study were undertaken in the UK. Of 501 UK Chinese patients who received a kidney transplant between 1/1/97-31/12/17, only 9 patients (5.2% of total) received kidney transplants abroad: 7 patients within 3 years of KRT start, 2 patients after 3 years of KRT start. Of 70,575 UK White patients who received a kidney transplant in this time period, only 15 patients (0.1% of total) received kidney transplants abroad: 12 patients within 3 years of KRT start, 3 patients after 3 years of KRT start.

In the UK, all donation is overseen by NHS Blood and Transplant (NHSBT). All living donors have to be assessed to have capacity to donate, and to be donating free from coercion or payment by an Independent Assessor from the Human Tissue Authority. Payment for organ donation or facilitating organ donation is illegal. In March 2015, the UK signed the Council of Europe Convention against Trafficking in Human Organs www.declarationofistanbul.org/resources/recommended-reading/the-councilof-europe-convention-against-trafficking-in-human-organs. Therefore all transplant activity in the UK as reported in this paper adheres to the Declaration of Istanbul.

The manuscript has now been amended such that the small number of patients transplanted outside of the UK have been excluded in analyses as the UKRR holds no information as to the providence of the organs transplanted.

This has been updated in the methods section to read: “Patients who underwent kidney transplantation outside of the UK have been excluded from analyses” (Page 5, Line 5)

b. Please state in your response letter and ethics statement whether the transplant cases for this study involved any vulnerable populations; for example, tissue/organs from prisoners, subjects with reduced mental capacity due to illness or age, or minors.

The ethics statement has now been amended to read:

“In the UK, all donation is overseen by NHS Blood and Transplant (NHSBT). All living donors have to be assessed to have capacity to donate, and to be donating free from coercion or payment by an Independent Assessor from the Human Tissue Authority. Payment for organ donation or facilitating organ donation is illegal. In March 2015, the UK signed the Council of Europe Convention against Trafficking in Human Organs www.declarationofistanbul.org/resources/recommended-reading/the-councilof-europe-convention-against-trafficking-in-human-organs. Therefore all transplant activity in the UK as reported in this paper adheres to the Declaration of Istanbul. All living donors in England, Wales and Northern Ireland must be more that 18 years old at time of donation, in Scotland the legal lower age limit is 16 years old.”

c. In the Methods, please provide detailed information about the procedure by which informed consent was obtained from organ/tissue donors or their next of kin. In addition, please provide a blank example of the form used to obtain consent from donors, and an English translation if the original is in a different language.

This study was undertaken using retrospective UKRR and NHSBT data. The UKRR collates data received from UK renal centres. We as the authors and the UK Renal Registry were therefore not directly involved with identifying or obtaining informed consent from donors or recipients.

However in the UK, consent for donation of organs in overseen by NHSBT. The following statement has been added to the Methods section:

“In the UK, all donation is overseen by NHS Blood and Transplant (NHSBT). For deceased donation, UK individuals can register as organ donors. In England, Wales, Scotland all adults are now considered to have ‘deemed consent’ or ‘deemed authorisation’ for organ donation: all adults are considered to have agreed to be an organ donor when they die unless they have a recorded decision not to donate, or are in an excluded group (those under the age of 18, people who lack the mental capacity to understand the new arrangements and take the necessary action, visitors to England, and those not living here voluntarily, people who have lived in England for less than 12 months before their death). In Northern Ireland unless individuals have registered as organ donors they are not considered to have agreed to donation. If an individual dies in circumstances in which organ donation is possible, an NHS specialist nurse will try to establish when a person is registered on the NHS Organ Donor Register. A patient’s family/close friends/next of kin will then be asked to support a decision for organ donation to go ahead, and clinicians will not proceed if there are family objections.

All living donors have to be assessed to have capacity to donate, and to be donating free from coercion or payment by an Independent Assessor from the Human Tissue Authority. Payment for organ donation or facilitating organ donation is illegal. In March 2015, the UK signed the Council of Europe Convention against Trafficking in Human Organs www.declarationofistanbul.org/resources/recommended-reading/the-councilof-europe-convention-against-trafficking-in-human-organs.

All living kidney donors are consented according to local transplant centre protocols during their work-up process, and consent confirmed at time of donation”. (Page 8, Lines 9-25 and Page 9, Lines 1-8)

A blank example of a consent form used has been uploaded.

d. Please indicate whether the donors were previously registered as organ donors. If tissues/organs were obtained from deceased donors or cadavers, please provide details as to the donors’ cause(s) of death.

In the UK, organs can be donated after death even if an individual has not been registered as an organ donor. In practice, this is only undertaken with consent from a potential donor’s family and next of kin.

Donor cause of death was not relevant to the analyses undertaken in this study.

Individuals receiving organs from donors outside of the UK, where protocols for donor consent cannot been verified, have now been removed (please see response 3a).

e. Please provide the participant recruitment dates and the period during which transplant procedures were done (as month and year).

Patients included in this study were transplanted between 1/1/97-31/12/17.

f. Please discuss whether medical costs were covered or other cash payments were provided to the family of the donor. If so, please specify the value of this support (in local currency and equivalent to U.S. dollars).

These data are not collected by the UKRR.

The NHS in the UK is a publicly funded healthcare system that is free to users at the point of access. Kidney donation incurs no direct medical costs to the donor. However, NHS England commissioning policy for reimbursement of living donors aims to ensure that the financial impact on living donors is cost neutral: it is founded on the premise that there should be no financial incentive or disincentive in becoming a living donor. It specifies that travel expenses will be reimbursed by the NHS for all living donors (from UK or overseas), with additional loss of earnings, child care, employment costs and accommodation reimbursement considered on an individual basis (https://www.england.nhs.uk/wp-content/uploads/2018/08/Policy-Reimbursement-of-Expenses-for-Living-Donors-Updated-August-2018.pdf).

4. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

5. Please include your amended funding statements within your cover letter; we will change the online submission form on your behalf.

The amended funding statement is included in a cover letter and in this response to reviewers, as below:

“This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund, grant number 204813/Z/16/Z.”

6. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical.

This has now been amended.

7. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 2 in your text; if accepted, production will need this reference to link the reader to the Table.

Thank you for highlighting this, Table 2 has now been referenced in the main text (Page 10, Lines 15-16).

8. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly.

Captions have now been included for Supporting Information files.

9.  We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

1) https://www.journaltocs.ac.uk/index.php?action=tocs&journalISSN=1460-2385

2) https://www.era-edta.org/VirtualCongress2020/Accepted_Abstracts_ERAEDTA_2020.pdf

3) https://academic.oup.com/ndt/article/35/Supplement_3/gfaa142.P0772/5853027

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

The first (1) publication referred to is a website (journaltocs.ac.uk) which updates with new journal articles regularly, with this link being for articles from Nephrology Dialysis and Transplantation. I do not recognise any of these papers and the site updates articles regularly- would it be possible get some further clarification as to which paper the overlap refers to?

The last 2 links, (2) and (3) are two links to the abstract for an earlier draft of this work, which was submitted to the ERA-EDTA conference and accepted for poster presentation. Poster abstracts were published in an NDT supplement. It may have been that (1) refers to the same abstract publications prior to the website updating. Please let me know if this abstract needs referencing in the main manuscript.

Submitted filename: PLOS One Response to Reviewers V3.docx

Click here for additional data file.

9 Feb 2022

The UK Chinese population with kidney failure: Clinical characteristics, management and access to kidney transplantation using 20 years of UK Renal Registry and NHS Blood and Transplant Data

PONE-D-21-05646R1

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15 Feb 2022

PONE-D-21-05646R1

The UK Chinese population with kidney failure: Clinical characteristics, management and access to kidney transplantation using 20 years of UK Renal Registry and NHS Blood and Transplant Data

Dear Dr. Wong:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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