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. 2023 Apr 13;18(4):e0284154. doi: 10.1371/journal.pone.0284154

Risk factors associated with the discordance in kidney function decline rate in identical twins

Jeong Ah Hwang 1,#, Jaeun Shin 1,#, Eunjung Cho 1, Shin Young Ahn 1,2, Gang-Jee Ko 1,2, Young Joo Kwon 1,2, Ji Eun Kim 1,2,*
Editor: Muzamil Olamide Hassan3
PMCID: PMC10101412  PMID: 37053150

Abstract

Background

The rate of kidney function decline is different for each individual regardless of any difference in the medical histories. This study set out to identify the risk factors for high discordance in kidney function decline in an identical twin cohort.

Methods

This study included 333 identical twins from the Korean Genome and Epidemiology Study who were categorized into two groups according to the estimated glomerular filtration rate (eGFR) decline: the slow and rapid progressor groups. The mean differences of variables were compared between the two groups. We calculated the difference in the annual eGFR change between twins and analyzed the risk factors associated with high discordance in twins who had > 5 mL/min/1.73 m2 /yr of the intra-twin difference in the annual eGFR decline. Identical twins with diabetes and baseline eGFR < 60 mL/min/1.73 m2 were excluded.

Results

The high discordance twins showed significant differences in body mass index; waist-to-hip ratio; total body fat percentage; and levels of blood hemoglobin, serum fasting glucose, albumin, triglyceride, and uric acid; however, there were no differences in low discordance twins. Multivariable logistic regression showed that blood hemoglobin level is the only significant factor associated with high discordance of eGFR decline in twins.

Conclusions

Blood hemoglobin level may play a role in the individual differences in kidney function decline.

Introduction

Chronic kidney disease (CKD), which is defined as a kidney dysfunction of over 3 months, is an important public health issue [1, 2]. CKD is a complex disease with heterogeneous and ambiguous clinical presentations. There are various clinical diseases related to the development of CKD, such as diabetes, hypertension, and ischemic cardiovascular diseases, however, some patients with CKD have an elusive etiology [3].

CKD is quite common in the general population worldwide, with an estimated global prevalence of 11% to 13% [2]. The annual estimated glomerular filtration rate (eGFR) decline has been heterogeneously reported in previous studies but generally declines at a rate of 1 mL/min/year [4]. However, the rate of kidney function decline is different per individual, and the reason for the difference remains unclear [5].

Recently, novel methods and tools for genetic testing have evolved, and the effort to find the genetic etiology in CKD using these tools is increasing [6]. Nevertheless, the mendelian etiology of kidney disease and the novel findings in genetic mutations related to kidney dysfunction only account for a part of CKD cases [3, 7–10], and a large proportion of CKD etiologies remain unelucidated.

In this study, we aimed to evaluate the possible non-genetic factors associated with annual kidney function decline in the general population besides natural aging using an identical twin cohort.

Materials and methods

Study setting and study cohort

This observational analysis included a prospective cohort of twins from the Korean Genome and Epidemiology Study (KoGES). The KoGES twin and family cohort consisted of 3,399 individuals who were twins or other family members related to twins. In this cohort, health screenings and surveys were conducted at baseline (2005–2013) and follow-up (2008–2014). The general characteristics of the KoGES twin and family cohort have been published elsewhere [11].

The inclusion criteria were monozygotic twins with both baseline and follow-up laboratory measurement data. The exclusion criteria were fraternal twins, one or both of the twins having diabetes or baseline kidney dysfunction and those who had error in datasets. The definition of kidney dysfunction in exclusion criteria was eGFR < 60mL/min/1.73m2, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation at baseline [12]. Diabetes is a major factor associated with kidney dysfunction; thus, we excluded the participants who had diabetes. Diabetes was defined as a self-report of diabetes or baseline serum fasting glucose of ≥126 mg/dL. The flow diagrams for the inclusion and exclusion criteria are shown in Fig 1.

Fig 1. Flow diagram for participant selection.

Fig 1

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This study was exempted from a review from the institutional review board of Korea University Guro Hospital (IRB No. 2021GR0532) and informed consent was waived due to the use of public cohort data that could not identify the participants.

Data collection

Demographic and social characteristics were retrieved, such as age, sex, body mass index (BMI), waist-to-hip ratio (WHR), alcohol consumption status, smoking status, and medical histories, including hypertension, dyslipidemia, cerebral infarction, and myocardial infarction. Baseline serum and urine laboratory tests were retrieved, including hemoglobin, glucose, albumin, total cholesterol, LDL cholesterol, triglyceride, and uric acids. Daily nutrient intake was calculated and processed using a food frequency questionnaire. The validity and reproducibility of this food frequency questionnaire are provided in a previous study [13]. Each nutrient intake was normalized by dividing the participant’s raw data by body weight.

The annual eGFR decline rate was calculated using the formula: (eGFR at follow-up—eGFR at baseline)/follow-up duration (year). The intra-twin difference in eGFR decline rate was calculated by subtracting eGFR decline rate of the slow progressor twin from the eGFR decline rate of the other twin (who is the rapid progressor). Intra-twin difference of other baseline clinical characteristics were also calculated using the formula: (value in ’Slow progressor’—value in ’Rapid progressor’).

Study group classification

All twins were assigned to either the rapid or slow eGFR change groups based on their annual eGFR decline rate. For example, when twins have an eGFR decline rate of 1 and 3 mL/min/1.73 m2/yr, then one of the twins with an eGFR decline rate of 3 mL/min/1.73 m2/yr is included in the rapid eGFR change group and the other twin with an eGFR decline rate of 1 mL/min/1.73 m2/yr was included in the slow eGFR change group. For pair of twins with the same annual eGFR decline rate, we randomly included each twin in each group, rather than manually selecting those with slow or rapid eGFR progression based on the aforementioned criteria.

After classifying rapid or slow eGFR changes in all twins, we defined high-discordant twins as the intra-twin difference of eGFR decline rate > 5 mL/min/1.73 m2/yr. Likewise, low-discordant twins were defined as twins with an intra-twin difference in eGFR reduction of 5 mL/min/1.73 m2/yr or less. These classification criteria for twins with high or low discordance are based on the definition of rapid progression in the 2012 KDIGO Chronic Kidney Disease Guidelines [14]. These differences in eGFR decline rate within twins were classified regardless of their respective absolute eGFR decline rate.

The method for the study group classification is briefly outlined in Fig 2.

Fig 2. Schematic flow for study group classification and analysis.

Fig 2

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Study outcome

This study aimed to determine the non-genetic risk factor which predicts the rapid progression of kidney function. Therefore, the main outcome of this study is the risk for high discordance twins who have a disparity of eGFR decline rate of >5 mL/min/1.73m2 /yr. The association between outcome (high discordance group) and various clinical and demographic characteristics was assessed.”

Statistical analysis

Continuous variables are shown as means with standard deviations or medians with interquartile ranges. Categorical variables are presented as numbers and percentages. The missing rates of variables were 0–3.0%. The method used for handling missing data was complete case analysis, disregarding cases with partially missing data. A pairwise comparison between twins was performed using the paired t-test. Univariate and multivariable logistic regression analyses were conducted to find risk factors for high discordance twins. Age, sex, and significant variables (p < 0.1) in the univariate analysis were adjusted for multivariable analysis. For logistic regression analyses, all baseline characteristics except for age and sex were included as covariates in the form of intra-twin differences [(value in slow progressor)-(value in rapid progressor)]. Statistical significance was set at p < 0.05. All statistical analyses were performed using Stata version 15.0 (StataCorp LLC, TX, US), and the graph was drawn using GraphPad Prism version 9.0.0 (GraphPad Software, Inc., CA, US).

Results

Baseline characteristics and annual eGFR change in twins

This study included 332 monozygotic twins (male, 107 twins; mean age, 38.1±7.3 years) in the KoGES twin and family cohort after applying the inclusion and exclusion criteria. The mean annual eGFR change in the slow and rapid progressor groups were -0.62 [-2.5–1.28] mL/min/1.73 m2 and -2.79 [-5.54 –-0.88] mL/min/1.73 m2, respectively. The minimum and maximum intra-twin differences in annual eGFR change were 0 mL/min/1.73 m2 and 33.0 mL/min/1.73 m2, respectively. A total of 8 pairs (2.4%) of twins showed exactly the same eGFR change rates (0 mL/min/1.73 m2 in the intra-twin difference of annual eGFR change).

Baseline characteristics of the low and high discordance twins stratified by the rate of annual kidney function decline as either a slow progressor or rapid progressor

There were 51 twins (15.4%) in the high discordance group. The baseline characteristics of twins in the high and low discordance groups were listed in Table 1. In the low discordance group, all baseline characteristics, including comorbidities, laboratory findings, and nutritional consumption status, showed no intra-twin differences except baseline eGFR. Meanwhile, in the high discordance group, the slow progressor participants showed a higher BMI, waist-hip ratio, body fat percentage, lower eGFR, and higher levels of blood hemoglobin, serum fasting glucose, albumin, total cholesterol, triglyceride, and uric acid than those in the rapid progressor group. Hypertension was more frequent in the slow progressor group than in the rapid progressor group, while systolic and diastolic blood pressures were not different in both groups.

Table 1. Comparison of baseline characteristics between slow and rapid eGFR progressor in twins stratified by high or low discordance of eGFR decline rate.

Low discordance twins (Intra-twin difference of annual eGFR decline < 5%) High discordance twins (Intra-twin difference of annual eGFR decline ≥ 5%)
Slow progressor n = 281 Rapid progressor n = 281 Paired t-test p-value Slow progressor n = 51 Rapid progressor n = 51 Paired t-test p-value
Annual eGFR change, % -0.7 [-2.5–0.7] -2.2 [-4.5 - -0.7] <0.001 1.2 [-2.4–4.6] -7.6 [-9.1 - -2.9] <0.001
Demographics and Baseline Clinical Characteristics
Age, year 38.1±7.3 38.1±7.3 37.8±7.4 37.8±7.4
Male sex, n (%) 94 (33.5) 94 (33.5) 13 (25.5) 13 (25.5)
Body mass index, kg/m 2 22.9±3.0 22.9±3.1 0.717 23.3±2.9 22.5±2.4 0.013
Waist-to-hip ratio, cm/cm 0.83±0.06 0.83±0.08 0.866 0.83±0.06 0.83±0.06 0.261
Body fat percentage, % 28.1±7.5 28.4±7.6 0.238 30.8±7.9 29.3±9.0 0.111
Smoking status, n (%) 0.665 0.811
    Never 189 (67.3) 190 (67.9) 38 (74.5) 40 (78.4)
    Ex 30 (10.7) 33 (11.8) 6 (11.8) 3 (5.9)
    Current 62 (22.1) 57 (20.4) 7 (13.7) 8 (15.7)
Alcohol consumption, n (%) 0.103 0.159
    Never 65 (23.2) 81 (29.0) 14 (27.5) 8 (15.7)
    Ex 24 (8.6) 16 (5.7) 3 (5.9) 5 (9.8)
    Current 191 (68.2) 182 (65.2) 34 (66.7) 38 (74.5)
Systolic blood pressure, mmHg 111.0±13.8 111.2±14.5 0.917 113.5±13.4 112.9±12.3 0.708
Diastolic blood pressure, mmHg 71.3±10.2 71.1±10.1 0.585 70.5±9.1 70.8±9.2 0.826
Clinical Histories
Myocardial infarction, n (%) 0 (0) 3 (1.1) 0.083 1 (2.0) 0 (0) 0.322
cerebral infarction, n (%) 0 (0) 1 (0.4) 0.318 1 (2.0) 0 (0) 0.322
Hypertension, n (%) 13 (4.6) 17 (6.1) 0.347 7 (13.7) 3 (5.9) 0.044
Dyslipidemia, n (%) 11 (3.9) 19 (6.8) 0.099 3 (5.9) 0 (0) 0.083
Laboratory Findings
Baseline eGFR, mL/min/1.73 m 2 93.4±13.1 96.2±12.8 <0.001 92.9±14.1 103.3±12.3 <0.001
Hemoglobin, g/dL 13.9±1.6 13.8±1.7 0.505 13.8±1.9 13.3±1.9 0.004
Glucose, mg/dL 88 [84–93] 88 [83–93] 0.605 88 [84–95] 86 [82–90] <0.001
Albumin, g/dL 4.6±0.3 4.6±0.3 0.1 4.6±0.2 4.6±0.3 0.02
Total cholesterol, mg/dL 185.5±36.4 184.6±36.8 0.624 192.3±32.7 183.4±32.0 0.016
LDL cholesterol, mg/dL 114.1±34.8 113.5±33.1 0.71 114.2±32.3 112.3±29.6 0.546
Triglyceride, mg/dL 100.5±73.5 97.8±56.3 0.556 118.0±94.0 83.4±52.7 0.007
Uric acid, mg/dL 4.7±1.3 4.7±1.4 0.981 4.8±1.7 4.3±1.7 <0.001
Nutrition intake (body weight adjusted)
Total calorie intake, kcal 32.8±14.5 33.5±15.2 0.723 32.2±11.8 31.9±14.7 0.719
Protein, g 1.1±0.7 1.2±0.6 0.664 1.1±0.5 1.2±0.7 0.787
Fat, g 0.6±0.5 0.6±0.4 0.666 0.6±0.4 0.6±0.4 0.773
Sugar, g 5.6±2.3 5.7±2.6 0.796 5.5±2.0 5.4±2.3 0.646
Ca, mg 8.9±8.0 8.7±7.6 0.812 7.7±3.9 9.0±6.8 0.254
P, mg 17.1±10.4 17.5±10.0 0.715 16.3±6.6 17.3±10.3 0.711
Fe, mg 0.2±0.2 0.2±0.1 0.986 0.2±0.1 0.2±0.1 0.613
K, mg 44.3±34.1 46.0±30.8 0.551 40.0±19.1 45.8±30.7 0.303
Na, mg 48.7±29.1 50.1±32.6 0.529 44.5±23.0 48.5±32.8 0.576
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Abbreviations: eGFR, estimated glomerular filtration rate; LDL, low density lipoprotein.

Risk analysis for high discordance in eGFR decline in twins

In univariable logistic regression analysis, the high intra-twin differences in BMI, total body fat, HTN and levels of baseline eGFR, hemoglobin, fasting glucose, triglyceride, and uric acid were significantly associated with high discordance of eGFR decline. In multivariable logistic regression, a higher difference in baseline eGFR, blood fasting glucose, and hemoglobin levels was the significant factor associated with the high discordance group. For every 1 ml/min/1.73 m2 increase in baseline eGFR, the risk of the high discordance group was reduced by 11%. For every 1 mg/dL increase in blood glucose difference (higher glucose level in the slow progressor group than in the rapid progressor group), the risk for the high discordance in eGFR decline increased by 1.07 times (p = 0.013). In a similar way, the increased difference of hemoglobin level by 1 g/dL was associated with 1.45 times risk for high discordance group (p = 0.027) (Table 2). Fig 3 shows intra-twin differences in blood glucose and blood hemoglobin levels in the high and low discordance groups.

Table 2. Logistic regressions for high discordance twins in eGFR decline rate according to intra-twin difference in each clinical variable.

Univariable logistic Multivariable logistic
OR (95% CI) p-value OR (95% CI) p-value
Age 0.99 (0.95–1.04) 0.774 0.99 (0.94–1.03) 0.573
Sex 1.47 (0.75–2.89) 0.41 1.67 (0.74–3.76) 0.216
Intra-twin difference of values (value in ’Slow progressor’—value in ’Rapid progressor’)
Anthropometric factors
    Waist-hip ratio 9.27 (0.03–2593.89) 0.439
    Body mass index 1.22 (1.05–1.42) 0.008 1.02 (0.83–1.25) 0.886
    Body fat percentage 1.08 (1.01–1.15) 0.019 1.00 (0.93–1.08) 0.937
    Systolic blood pressure 1.00 (0.98–1.03) 0.71
    Diastolic blood pressure 0.99 (0.96–1.03) 0.683
Hypertension 3.91 (1.26–12.15) 0.018 1.97 (0.50–7.77) 0.335
Laboratory findings
    eGFR 0.89 (0.85–0.93) <0.001 0.89 (0.85–0.94) <0.001
    Hemoglobin 1.46 (1.11–1.91) 0.006 1.45 (1.04–2.03) 0.027
    Albumin 2.56 (0.79–8.30) 0.118
    Total cholesterol 1.01 (1.00–1.02) 0.082
    Glucose 1.09 (1.05–1.14) <0.001 1.07 (1.01–1.13) 0.013
    Triglyceride 1.01 (1.00–1.01) 0.008 1.00 (1.00–1.01) 0.14
    LDL cholesterol 1.00 (0.99–1.01) 0.761
    Uric acid 2.18 (1.47–3.25) <0.001 1.07 (0.65–1.78) 0.783
Nutritional intake per body weight
    Total calorie intake 1.00 (0.99–1.02) 0.667
    Protein 0.99 (0.70–1.42) 0.977
    Fat 1.10 (0.69–1.77) 0.689
    Sugar 1.02 (0.92–1.14) 0.642
    Ca 0.99 (0.95–1.02) 0.409
    P 1.00 (0.97–1.02) 0.898
    Fe 0.74 (0.13–4.40) 0.743
    K 1.00 (0.99–1.01) 0.669
    Na 1.00 (0.99–1.01) 0.877
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* Adjusted for age, sex and variables which shown p<0.01 in univariable logistic analysis.

Abbreviations: OR, odds ratio; CI, confidence interval; LDL, low density lipoprotein.

Fig 3. Blood glucose and hemoglobin levels according to the difference in eGFR decline in twins.

Fig 3

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With the dotted line as the center, the plot on the left and right represent (A) glucose and (B) hemoglobin levels in the low and high discordance groups, respectively. Circular dots indicate the slow progressor among the twins, whereas the triangular dots indicate the rapid progressor. The lines connecting the circle and triangle dots represent each pair of twins.

Discussion

This prospective Korean cohort study on twins provides intra-twin differences in annual eGFR changes. There were several possible risk factors associated with the high discordance of eGFR decline (> 5 mL/min/1.73 m2 /yr) in twins, including BMI, WHR, total body fat, and levels of hemoglobin, triglyceride, and uric acid. Low blood glucose and hemoglobin levels in the rapid progressor group were significantly associated with the increased risk for high intra-twin eGFR decline rate discordance compared to the slow progressor group even after multivariable adjustment.

Monozygotic twins arise from the same single cell and share most of their genetic variants. However, monozygotic twins show phenotypic discordance for many traits from birth weight to complex diseases [15]. This discordance in an isogenic individual can be caused by somatic mutation, which shows different genotypes by different organs [15, 16] and epigenetic changes, such as DNA methylation and multiple environmental factors [17]. The classic approach to define the contribution of genetic and environmental factors to complex human diseases is to compare the clinical phenotypes in monozygotic twins. Because twins have the most similar genetic factors related to diseases, although epigenetic factors cannot be ignored, the present study with a twin cohort may represent possible environmental factors affecting the phenotype of kidney function decline without previously known renal insufficiency or diabetes.

In comparing baseline characteristics between groups, we found that several factors related to malnutrition, such as BMI, waist-hip ratio, body fat percentage, hemoglobin, fasting glucose, and triglyceride, showed significant differences in the high discordance group. In previous studies, body composition metrics, such as BMI, WHR, and total body fat percentage, were significantly correlated with individual nutritional status. In previous studies, body composition metrics, such as BMI, WHR, and total body fat percentage, were significantly correlated with individual nutritional status [18, 19]. Moreover, these metrics seem to be important mediators for the eGFR decline rate in the present study, whose results are consistent with those of previous studies. Several studies have shown that any gain in body weight is associated with better survival in CKD, and that fat-free lean body mass is essentially representative of muscle mass and confers a survival advantage [20]. In a national cohort of US veterans with an eGFR of >60 mL/min/1.73 m2, the lowest risk for loss of kidney function was noted in patients with BMI levels between 25 and 30 kg/m2, whereas a consistent U-shaped association between BMI and a rapid loss of kidney function was noted for BMI levels of <25 and >30 kg/m2 [20]. Additionally, a U-shaped association between BMI and kidney function was noted in another US veteran cohort [21]. A study with Korean nationwide population showed a higher risk for end-stage renal disease in underweight patients with diabetes [22]. Low blood hemoglobin, fasting glucose, triglyceride, and uric acid levels also suggest nutritional impairment according to previous studies [23–26]. Although twins report similar daily nutritional consumption status, nutritional markers found in their blood were significantly decreased, especially in individuals included in the rapid progressor group. This finding suggests that differences in intestinal absorption status between the twins may affect the rate of kidney function decline. Moreover, several studies on the gut-kidney axis associated with gut microbiota affecting nutrient absorption have been reported [27–29]. Further evaluation of the interplay between kidney function and nutritional assessment and intestinal absorption status is warranted.

In addition, we found that blood glucose and hemoglobin levels were associated with eGFR decline rates even after adjusting for several nutritional markers and body composition metrics. Low blood glucose is known to be associated with increased mortality, CVD and ESRD in diabetes patients as well as the increased risk for the development of new-onset diabetes [30]. In a large nationwide T2DM cohort study, clinically significant hypoglycemia was associated with a 1.8 and 1.5-fold greater risk of developing incident CKD and all-cause mortality [31, 32], and post hoc analysis of Action in Diabetes and Vascular disease: PreterAx and DiamicroN Controlled Evaluation (ADVANCE) study showed that hypoglycemia was associated with increased risks of micro- and macro-vascular events [33]. However, hypoglycemia has not been well studied in the general population without diabetes. Even after patients with diabetes were excluded from this study cohort, low blood glucose was associated with a rapid eGFR decline. Although, the exact mechanism between low blood glucose and renal dysfunction is not well understood, some potential relationships may be proposed based on previous studies [34–38]. For example, a preclinical study has demonstrated that hypoglycemia can cause elevated nonesterified fatty acid in adipose tissue, which is subsequently associated with kidney damage [34]. Hypoglycemia could induce sympathetic surges, altering renal hemodynamics, which may be responsible for the progression of kidney dysfunction [35]. Furthermore, low blood glucose might indicate subclinical damage to kidney. The role of the kidney is critical to maintaining glucose homeostasis. The kidney has gluconeogenesis capability and contributes to 20% glycogen production [36]. In the proximal segment of the tubular nephron, SGLT1 and SGLT2 provide highly efficient glucose reabsorption [36–38]. In this context, hypoglycemia may be an early sign of kidney dysfunction. Anemia is a well-known risk factor for the progression of CKD. A prospective observational case-control study reported a greater annual decline in calculated creatinine clearance in patients with diabetes and a hemoglobin level of < 12 g/dL than in those with a hemoglobin level of ≥ 12 g/dL [39]. A randomized clinical trial for early and deferred treatment of anemia in CKD showed that early treatment may delay the progression of kidney function decline [40]. However, there is only limited number of studies on the association between anemia and kidney function decline in the general population without prior kidney disease. Recently, one Chinese population study showed that anemia and hemoglobin were independently associated with the rapid decline in kidney function after adjusting for potential confounding factors [41]. The mechanisms underlying the association between anemia and CKD progression are unclear. However, it has been hypothesized that anemia causes tissue hypoxia and consequently leads to alterations in gene expression patterns, triggering adaptive pathways related to hypoxia-inducing factors in parallel with the induction of noxious mediators involved in the progression of renal injury. The present study not only supports the previous findings but highlights the role of hypoglycemia and anemia as an environmental phenotype rather than a genetic variation affecting kidney function in the general population.

Although it remains unclear which pathophysiologic mechanism of kidney function is affected by anemia, some hypotheses might be suggested. Kidney is somehow sensitive to changes in oxygen delivery [42]. Anemia impairs oxygen delivery to tissues and thus affects organ function, including cardiac function. A triad of worsening anemia, CKD, and cardiac function induces a vicious cycle referred to as the cardiorenal anemia syndrome [43]. Anemia in kidney disease may accelerate the decline in renal function by inducing tubulointerstitial hypoxia [42]. Additionally, anemia may be associated with chronic inflammation [44]; although we do not know the clear reason for this association, we hypothesized that hemoglobin is an early detector of a rapid decline in eGFR and should be considered important when managing the nutritional and environmental status of individuals to maintain kidney function.

To the best of our knowledge, this is the first study to find the environmental factors associated with kidney function decline in the general population using a twin cohort. However, this study has several limitations. First, the genetic information of the twins was not available. As we previously mentioned, somatic mutations or epigenetic differences in twins might have affected the results of this study. Second, the reason for the differences in the hemoglobin levels could not be ascertained due to the lack of data, such as iron profiles, folic acid, vitamin B12, and peripheral blood smears. Though we assessed the food consumption data in this cohort, other nutritional factors, including gut microbiota and their metabolic function which may be related to the environmental difference in twins, need further evaluation.” Third, the cause of kidney dysfunction is not known because the cohort only has two time- point measurements (baseline and follow up) and lacks urinalysis. Furthermore, some of the comorbidities related to kidney dysfunction, such as heart failure and glomerulonephritis, were unavailable. Finally, although our study evaluated a prospective cohort with a follow-up dataset, the causal relationship between hemoglobin levels and kidney function decline cannot be suggested due to the retrospective study design.

Conclusions

In this identical twin cohort with little genetic difference, some of the twins showed high discordance of progression rate of kidney dysfunction. Environmental and nutritional differences affecting fasting glucose and hemoglobin levels may be important clues for this discordance between twins. Therefore, further analysis of the pathophysiology of glucose and hemoglobin metabolism in terms of environmental changes affecting kidney damage is warranted.

Data Availability

The data supporting the findings of this study are available in clinical database from Korean Ge-nome and Epidemiology Study and are accessible after permission from http://is.kdca.go.kr (accessed on Sep 2022).

Funding Statement

This study was supported by a grant from the KOREAN NEPHROLOGY RESEARCH FOUNDATION (Young Investigator Research Grant, 2022). The funders played no role in the conduct of the study, and the study was performed independently by the authors.

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Decision Letter 0

Muzamil Olamide Hassan

4 Jul 2022

PONE-D-22-15736Risk factors associated with the discordance in kidney function decline rate in identical twinsPLOS ONE

Dear Dr. Kim

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. Your submission has been reviewed by two external peer reviewers and myself. The reviewers raises a number of very detailed points particularly concerning methodology and statistical analysis, some of which may require considerable work in returning to the data, if the requested data even exists:

  • State how participants with chronic kidney disease, heart failure and glomerulonephritis were excluded

  • State how acute deterioration of kidney function in study participants was excluded

  • Define progression according to 2012 KDIGO Clinical Practice Guideline

  • State the baseline eGFR for the cohort

  • Provide data on urinary protein excretion rate

  • State how sample size/power was calculated

  • Re-analysis of multivariate logistic regression model based on the comments provided by the reviewers

Please submit your revised manuscript by Aug 18 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Muzamil Olamide Hassan

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PLOS ONE

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Additional Editor Comments:

Ji Eun Kim and colleagues conducted a retrospective identical twins cohort study to assess the risk factors associated with the discordance in kidney function decline rate in identical twins. They found that blood hemoglobin level may play a role in the individual differences in kidney function decline. However, the authors should take into account the following in order to improve the quality of the manuscript.

Major comments:

1. There are concerns about the absence of details in the methodology adopted and in the lack of clarity of some definitions. It is very important for the authors to confirm if participants with background CKD were excluded or not? It is not clear why the authors did not assess for urinary protein excretion rate (proteinuria)? I suggest that the result of estimation of urinary protein excretion rate should be provided. Also, it is important for the authors to define slow progressors and rapid progressors using the 2012 KDIGO Clinical Practice guideline.

2. Exclusion criteria – How many of this cohort had heart failure and glomerulonephritis? Were these clinical entity excluded?

3. How was acute deterioration of kidney function excluded in the study participants?

4. The sentence “We calculated the intra-twin difference in the annual eGFR change by calculating the eGFR chang in the slow progressor group minus that in the fast progressor group.” (line 122 – 123) should be moved to section on methodology.

5. The authors should state the baseline eGFR for the study cohort.

6. How was hypertension defined in this cohort? I wonder if the rate of CKD progression is related to hypertension, so would be interested in how many slow progressor vs rapid progressor had hypertension. The percentage of slow progressors vs rapid progressors with hypertension should be included in table 1.

7. It is not very clear how the authors arrived at the choice and numbers of independent variables used in the multivariate logistic regression model. I suggest that the regression model should be re-analysed with the inclusion of established risk factors for CKD progression (e.g hypertension and proteinuria). Also the method (backward or forward or stepwise) of inclusion of independent variables in the model should be stated.

8. What were the rates of missing data? If data are complete for all participants, this should be stated.

9. Line 136-138 “in the high discordance group, the slow progressor group showed a higher …………..serum fasting glucose ……..than those of the rapid progressor group” It will be nice to see median (interquartile range) value for serum fasting glucose.

10. Table 1 – The mean±SD values stated for albumin and iron for slow progressor group and rapid progressor group in both low and high discordance twins were exactly the same but the p-values for the 2 pairs were different. I suggest that the authors should double check their data and statistics.

11. Inability to assess the relationship between gut microbiota dysbiosis, nutrient absorption and decline in eGFR should be discussed as part of the limitation.

12. The conclusion did not reflect the exact finding of this study – nutritional related factors were not established as predictors of high discordance of eGFR decline. I suggest a revision to the concluding statement.

Minor comments:

1. No page numbers

2. There are typos that require correction.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for inviting me to review this manuscript “Risk factors associated with the discordance in kidney function decline rate in identical twins.” The authors aimed to analyze the effect of environmental factors on kidney dysfunction in an identical twin cohort.

I have the following concerns with the study.

1. Assessment of kidney function decline takes into account absolute rate of loss of kidney function (Al-Aly Z, Zeringue A, Fu J et al. Rate of kidney function decline associates with mortality. J Am Soc Nephrol 2010; 21: 1961–1969) or percentage change in the kidney function (Cheng TY, Wen SF, Astor BC et al. Mortality risks for all causes and cardiovascular diseases and reduced GFR in a middle-aged working population in Taiwan. Am J Kidney Dis 2008; 52: 1051–1060).

2. The authors categorised participants into high discordant and low discordant and then into rapid progressors and slow progressors in each group based on ≥5% annual eGFR changes. The KDIGO 2012 clinical practice guideline defined progression as a “certain drop” in eGFR defined as a drop in GFR grade associated with a ≥25% decline in eGFR from baseline and “Rapid Progression” as sustained decline in eGFR of more than 5ml/min/1.73m2/yr. I suggest that authors should use clear guidelines in defining technical terms such as rapid progressors.

3. Authors should kindly provide detailed information on the number of times samples were taken to assess renal function during the 3 years period. This is important because studies have shown that the more the frequency of samples collection, the better the confidence and precision in assessing progression of kidney function. Furthermore, do the rapid progressors have a sustained annual eGFR decline of at least 5ml/min/1.73m2/yr

4. Urine albumin excretion estimation such as Urine Albumin-creatinine ratio (ACR) is a recognized predictor of progression of kidney disease. Since this or any other data showing evidence of proteinuria was not included in this study, I suggest it should be included as a limitation.

5. Other predictors of kidney function decline should be included in the multiple logistic regression model with the exception of diabetes since its an exclusion factor. I suggest that in addition to Age and gender, recognized predictors of decline in kidney function must be chosen apriori based on previous literature.

6. I have a strong concern about how the independent variables in the multivariable logistic regression model were derived (i.e difference between slow progressors and rapid progressors). This may have resulted in loss of valuable information during the regression analysis. Also, authors need to demonstrate how they checked for Multicollinearity and other assumptions of Multiple logistic regression model especially for variables like body mass index and body fat percentage. I suggest the authors should use Variance inflation factor. Kindly show the overall statistical details of your Multiple Logistic regression model.

7. Kindly demonstrate evidence of adequacy of sample size.

8. I suggest that Hypoxia inducible factors (HIF) including oxygen-dependent and oxygen-independent HIF-regulators should be discussed in relation to haemoglobin level which is the only independent predictor.

9. Figure 1 should be expanded to provide clarity in the study design. This should show clearly the number of patients in High discordant group and low discordant group. Also,it should clearly show the number of participants in slow progressor and rapid progressor.

Reviewer #2: Major Revision:

Jeong Ah Hwang et al in this study assessed for the risk factors associated with high discordance in annual kidney function decline

in a cohort of identical twins. Though, this is the first study to look at factors associated with discordance in kidney function decline in a cohort of identical twins, this article is very difficult to comprehend. In addition, there are lot of issues with the Materials and method section of this article.

- Authors only excluded diabetic and those who had error in data sets. One is not sure if the cohort they studied have some individuals with background chronic kidney disease. I there are, they need to be excluded from the study. It will add value, if in the result section, the mean(±SD) baseline eGFR of the cohort could be displayed in Table 1.

- The authors did not clearly state what their study outcomes were under the Study outcome section.

- Authors did not clearly define the terms “Rapid progressors and Slow progressors”. Definition of slow/rapid progressors for this study is not clear.

Minor Revision

Abstract,

Background

Line 26:

Line 27 and 28: “We aim to analyze the effect of environmental factors on kidney dysfunction in an identical twin”- This is not the aim of this study. I suggest it is replaced with “This study set out to identify the risk factors for high discordance in kidney function decline in an identical twin cohort.

Methods:

lines 29-31: According to this manuscript, the 333 identical twins were categorized into two groups according to the inter-twin difference in the annual eGFR decline: High discordance twins and low discordance twins, and individual twin were further classified as either a slow progressor or a rapid progressor.

Line 30 : “ eGFR” should be written in full as “estimated glomerular filtration rate (eGFR)”. It can be abbreviated subsequently

Lines Please kindly remove the sentence “identical twins with diabetes were excluded”. This sentence should have come before “The mean difference in the annual …………. who had >5%.........annual eGFR decline.”

Introduction:

Line 1-2:

Lines 48-49 : consider changing the phrase “ but most patients with CKD have an elusive etiology.” to “ however, some patients with CKD have an elusive etiology.”

Line 51

Line 59-61: Please consider changing the phrase “non genetic factors affecting kidney dysfunction besides natural aging in the general population using an identical twin cohort to exclude genetic contribution” to “non genetic factors associated with annual kidney function decline in the general population besides natural aging using an identical twin cohort.”

Materials and Methods:

Study Cohort:

Line 69: Please consider changing “can be found elsewhere “to “have been published elsewhere”

Line 71: twins with background kidney disease should also be excluded from the cohort.

Study Outcome

The study outcomes are not clearly stated in this paragraph. The authors should let us know what their study outcomes are.

Data Collection:

This section should come immediately after Study cohort (Before study outcome.)

Lines 96 and 99 : I suggest the authors replace the word ‘collected’ with “retrieved”

Lines 96/97: Pls kindly remove the sentence “ Body fat percentage was measured by dual X ray absorptiometry”

Statistical Analysis:

Lines 109 and 110: Please remove phrase “to determine whether the mean difference between pairs of measurement was zero or not”.

Lines 111-112: If level of significance was set at 0.05, why were significant variables with (p<0.1) in univariate analysis adjusted for in multivariate analysis ? If level of significance for this study was set at 0.05, please kindly stick to it in your analysis.

Results

Baseline characteristics and annual eGFR change in twins

Line 122 &123: The sentence “We calculated the intra-twin differences in the annual eGFR change in the slow progressor group minus that in the fast progressor group.” Should come under Methods section.

Line 128&129: the subtitle “Difference of clinical characteristics of renal function between the twins in slow or rapid progressor groups- should be changed to “ Baseline Characteristics of the Low and high discordance twins stratified by the rate of annual kidney function decline as either a low progressor or rapid progressor).

Line 130-132: The sentence “To find the factors affecting the intra twin difference in eGFR decline rates, the twins were classified as high discordance and low discordance twins who had >5% and <5% of intra twin difference in annual eGFR change respectively” should have been mentioned under “ study outcome in Materials and Methods”

Line 144: It should be “Risk analysis for high discordance in eGFR decline in twins ”

Line 145-146. The sentences” To find the risk factors associated with high discordance ………….were conducted” and “ Except for age and sex, all baseline characteristics were included as covariates in the form of intra twin differences.” Should be under “S tudy Outcome in Materials and Methods”. These sentences should not be under the “Result section”

Lines 156-160: Fig 2. Blood hemoglobin levels according to the difference in eGFR decline in Identical Twins- should be the title for Fig. 2 while “With dotted line as the center, the plot

on the left ………………low and high groups respectively. Circular dots indicate the slow progressor……. whereas the triangular dots indicate the rapid progressor. The lines connecting the circular and triangular dots represent each pair of twins” should be the legends to Fig 2.

Discussion:

Lines 183-186: The authors stated that they (their study) found that chronic illness and nutritional insufficiency might play a significant role in rapid kidney function decline in the general population.

This study did not demonstrate the above findings. Authors may need to re phrase this sentence.

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Reviewer #1: No

Reviewer #2: No

**********

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: Abstract.docx

Click here for additional data file. (52.1KB, docx)

Decision Letter 1

Muzamil Olamide Hassan

8 Nov 2022

PONE-D-22-15736R1Risk factors associated with the discordance in kidney function decline rate in identical twinsPLOS ONE

Dear Dr Ji Eun Kim,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but but yet to 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. Reviewer #2 has requested for additional clarifications regarding how the twins were stratified in situations when the annual rate of eGFR decline in both twins are the same. Could you kindly provide this information?  Kindly refer to the comments by Reviewer #2 for other typos requiring revision.

Please submit your revised manuscript by Dec 23 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muzamil Olamide Hassan

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for inviting me to review the revised manuscript “Risk factors associated with the discordance in kidney function decline rate in identical twins.”

The authors have made requested corrections in the revised manuscript.

Reviewer #2: Minor Revision:

1. Data Collection: Authors should include how of intra twin difference in annual eGFR decline and other variables (Demographic and clinical variables) were defined for this study.

2. Study group Stratification: Line 95-99. Definition of slow and Rapid progressors and the example given by the authors was noted. However it will be nice for the author to let us know how the twins will be stratified in situations when the annual rate of eGFR decline in both twins are the same. For example, If the rate of eGFR decline in both twins is 1ml/min/1.73m2/yr OR rate of eGFR decline in both twins is 4ml/min/1.73m2/yr. In the 2 scenarios mentioned, how did the authors stratified into rapid / slow progressor when the annual rate of eGFR decline in both twins are the same.

3. Result, Line 156: Please remove the phrase " which was similar to results in the paired t test.

4. Table 1: Please change "Demographic characteristics" to " Demographics and Baseline Clinical Characteristics"

5. Discussion, line 225- 226. Please add reference to the sentence " Although, the exact mechanism...................based on previous studies". There should be a "comma" after the word "Although"

6. Line 267: Better written as " Third, the cause of kidney dysfunction is not known because the cohort only has two time- point measurements (baseline and follow up) and lacks urinalysis.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Decision Letter 2

Muzamil Olamide Hassan

4 Jan 2023

PONE-D-22-15736R2Risk factors associated with the discordance in kidney function decline rate in identical twinsPLOS ONE

Dear Dr. Kim,

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.

There is still an outstanding query that the authors are yet to address in the latest revision. The reviewer is asking how will you stratify the twins in situations where the annual rate of eGFR decline in both twins are the same. Taking for example, If the rate of annual eGFR decline in each of the twin is 2ml/min/1.73m2/yr, how will you decide who will be the slow progressor/ rapid progressor group? If none of the participants in the comparison group did not have the same annual eGFR decline, kindly state this clearly in your methodology. Should there be any pair that fit the senario described by the reviewer, kindly provided an explanation how the pair(s) were stratified in the methodology section. Please submit your revised manuscript by Feb 18 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muzamil Olamide Hassan

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Minor:

Authors are yet to answer one of my questions in the last review. The Authors' response to the question was for intra twin difference in eGFR decline and did not address my concern.

1. Study group Stratification: Definition of slow and Rapid progressors and the example given by the authors were noted i.e. when twins have an eGFR decline rate of 1 and 3 mL/min/1.73 m2 98 /yr, then one of the twins with an eGFR decline rate of 3 mL/min/1.73 m2 99 /yr is included in the rapid eGFR change group and the other twin with an eGFR decline rate of 1 mL/min/1.73 m2 100 /yr was included in the slow eGFR group.

My Question: How did the authors stratify the twins in situations where the annual rate of eGFR decline in both twins are the same. For example, If the rate of annual eGFR decline in each of the twin is 2ml/min/1.73m2/yr, how will you decide who will be the slow progressor/ rapid progressor group.

2. lines 92-94 should be written as "The annual eGFR decline rate was calculated using the formula: (eGFR at follow-up - eGFR at baseline)/follow-up duration (year). The intra-twin difference in eGFR decline rate was calculated by subtracting eGFR decline rate of the slow progressor twin from the eGFR decline rate of the other twin (who is the rapid progressor). Intra-twin difference of other baseline clinical characteristics were also calculated using the formula: (value in 'Slow progressor' - value in 'Rapid progressor')

Line 145: Slow progressor " not low progressor"

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Bolanle Aderonke Omotoso

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Decision Letter 3

Muzamil Olamide Hassan

6 Mar 2023

PONE-D-22-15736R3Risk factors associated with the discordance in kidney function decline rate in identical twinsPLOS ONE

Dear Dr. Kim,

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.

Kindly revise the methodology section in line with reviewer's comments highlighted in yellow below.Thank you

Please submit your revised manuscript by Apr 20 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muzamil Olamide Hassan

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Thank you for addressing the concerns on study group classification. However the authors are yet to include this in the method section of this manuscript. Please, I suggest you kindly make amends.

STUDY GROUP CLASSIFICATION Page 6:

1. Line 98-99: I suggest you re write the first sentence as

"All twins were assigned to either the rapid or slow eGFR change groups based on their annual eGFR decline rate"

2. I suggest that the sentence " For pair of twins with the same annual eGFR decline rate, we randomly included each twin in each group, rather than manually selecting those with slow or rapid eGFR progression based on the aforementioned criteria." should come after the sentence "All twins were included in the relatively rapid or slow...............................in slow eGFR change" (lines 100-104)

3. Delete the sentence "That is, even if both have a high eGFR decline rate (e.g. 7 ml/min/1.73m2/yr for both twins) or both have a low eGFR decline rate (e.g. 1 ml/min/1.73m2/yr for both twins), they were classified as the same group if the intra-twin difference of eGFR decline rate in each pair was the same. (lines 1111-113)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Bolanle Aderonke Omotoso

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Decision Letter 4

Muzamil Olamide Hassan

27 Mar 2023

Risk factors associated with the discordance in kidney function decline rate in identical twins

PONE-D-22-15736R4

Dear Dr. Kim,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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.

Kind regards,

Muzamil Olamide Hassan

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Muzamil Olamide Hassan

4 Apr 2023

PONE-D-22-15736R4

Risk factors associated with the discordance in kidney function decline rate in identical twins

Dear Dr. Kim:

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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Muzamil Olamide Hassan

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

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    Data Availability Statement

    The data supporting the findings of this study are available in clinical database from Korean Ge-nome and Epidemiology Study and are accessible after permission from http://is.kdca.go.kr (accessed on Sep 2022).

    Articles from PLOS ONE are provided here courtesy of PLOS

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