Metabolic Status and Risk of Chronic Kidney Disease in French Overseas Populations With Morbid Obesity (OBECAMcohort).

I. SCIENTIFIC RATIONALE AND GENERAL DESCRIPTION OF THE RESEARCH

• Introduction The population of the Guadeloupe department consists of a majority (80%) of individuals of African descent. Overall, the prevalence of obesity is 23% (31% among women and 12% among men). French Polynesia is reported to have one of the highest obesity rates in the world, at approximately 50% (https://la1ere.francetvinfo.fr/polynesie/tahiti/polynesie-francaise/taux-d-obesite-la-polynesie-francaise-possede-l-un-des-taux-les-plus-eleves-au-monde-1469895.html.) This research project on morbid obesity will be conducted in the Guadeloupe department and the territory of French Polynesia. It aims to study the effect of metabolic status on the incidence of cardiovascular events, chronic kidney disease, and death among individuals with morbid obesity. This study will be carried out as a 5-year longitudinal follow-up.

Some obese individuals may not exhibit metabolic disorders and can be classified as having "metabolically healthy obesity"(Stefan N, 2008; Wildman RP, 2008).

Other obese individuals present with metabolic syndrome (MetS). This syndrome encompasses a wide range of cardiometabolic risk factors-typically including central obesity, insulin resistance, hypertension, and dyslipidemia-that significantly increase the risk of developing numerous chronic conditions (such as cardiovascular disease [CVD], diabetes, chronic kidney disease [CKD], and cancer) (Li C, 2024 ; O'Neill S, 2015).

Morbid obesity results from a variety of influences, combining environmental, behavioral, hormonal, genetic, and medical factors. Individuals with morbid obesity face an increased risk of cardiovascular and renal complications.

Regarding genetics, family history plays a key role; a genetic predisposition may cause some people to store fat more easily, thereby contributing to a high body mass index (BMI). (Li C, 2024) Metabolic status and genetic susceptibility can jointly impact cardiovascular events and all-cause mortality across various BMI categories (Li C, 2024) The discovery of genes involved in obesity has led to major advances in understanding the mechanisms of this metabolic disease-particularly in monogenic forms of obesity, where a single mutation is sufficient to trigger the condition.

The diagnosis of genetic forms of obesity has accelerated significantly thanks to the advent of next-generation sequencing (NGS). This technology is now readily accessible via a simple saliva sample, allowing for DNA extraction followed by sequence analysis.

Some of the genes involved in obesity may also play a role in the incidence of CKD.

Obesity is associated with the development and progression of chronic kidney disease (CKD)-mediated by conditions such as type 2 diabetes and hypertension, but also through direct effects on the kidneys (Friedman AN, 2021). Thus, obesity itself can increase the risk of CKD by raising metabolic demands on the kidneys, leading to higher glomerular capillary pressures and glomerular hypertrophy. The hyperinsulinemia frequently associated with obesity can also accelerate structural damage by interacting with angiotensin II and increasing collagen production and deposition (Kramer H., 2006) The association between MetS and an increased incidence of CKD appears to be well supported by empirical data (Kurella M, 2005; Thomas G, 2011) regardless of BMI (Zhang J, 2017).

Furthermore, findings from a review of studies indicated that MetS is a significant risk factor for renal dysfunction, necessitating close renal monitoring (Valizadeh A, 2024).

A cohort of subjects with morbid obesity from overseas territories will be established. This "OBECAM" cohort will make it possible to study the natural history of the condition and, specifically, to determine the incidence of complications based on the presence or absence of certain parameters of interest, including MetS.

CKD is defined as the presence of 1+ or greater proteinuria on routine urinalysis (urine dipstick) and/or an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m² (Kramer H, 2005; Takahashi K, 2024).

During follow-up, progression of CKD-in individuals who had CKD at baseline-is defined as a decrease in eGFR of at least 30% from the baseline value (Takahashi K, 2024).

• Hypotheses It is currently recognized that morbid obesity and MetS are associated with an increased risk of cardiometabolic complications and CKD. However, no study has yet evaluated this risk in these overseas regions.

We propose establishing a cohort of subjects with severe or morbid obesity across two overseas regions to study the occurrence of events in relation to various factors, notably the presence or absence of MetS.

We formulate the following hypotheses:

• Metabolic profiles and distribution of MetS components differ between the population groups.
• The 5-year incidence of events (cardiovascular events, kidney damage, death) is higher in morbidly obese subjects with MetS.
• The risk of developing or progressing to kidney damage is higher in obese subjects with MetS, and a difference in risk exists between the population groups (Caribbean and Polynesian).
• Differences in the distribution of gene variants associated with central adiposity or CKD are observed depending on metabolic status.
• Primary study objective. Study design.

Study outline:

This is a multicenter study to be conducted in Guadeloupe and French Polynesia involving individuals with morbid obesity; it comprises both a cross-sectional study and a longitudinal study.

-Descriptive and comparative cross-sectional study, to be conducted within the overall study population and in the Guadeloupe and French Polynesia subgroups.

Based on data obtained at inclusion (T0), this study will allow for: i) describing the natural history of the disease and the psychological and social consequences of the condition; ii) estimating the prevalence of risk factors and comorbidities; and iii) performing between-group comparisons based on various parameters (including ethnicity).

• Longitudinal study assessing the 5-year incidence of complications and deaths within the cohort. Longitudinal follow-up will enable the identification of factors that may contribute to the occurrence of these complications.
• At T0: Following the signing of informed consent, the physician will conduct an interview and clinical examination and perform biological assessments and additional tests. The Case Report Form (CRF) will be completed.
• At 1, 2, 3, 4, and 5 years:

Participants will be seen for follow-up consultations or day-hospital visits. Clinical examination findings and biological test results will be recorded. Obesity-related parameters and the occurrence of any events will be recorded.

• At 5 years: The incidence of cardiovascular complications, chronic kidney disease (CKD), and death will be calculated
• Project Outlook Morbid obesity is associated with a higher incidence of comorbidities. Taking multiple factors into account would enable the design of interventions that address the environmental, behavioral, medical, ethnic, and genetic aspects of morbid obesity.

It is becoming increasingly important to elucidate the underlying mechanisms of metabolic syndrome-associated CKD in individuals with morbid obesity, to develop strategies to prevent and slow the progression of kidney disease in the overseas territories.

Furthermore, identifying individuals at increased risk of CKD is a crucial task, given the high prevalence of the condition in these regions. This importance also stems from the impact that the progression of CKD to end-stage renal disease (ESRD) has on mortality, morbidity, quality of life, and healthcare resource utilization.

II - OBJECTIVES 2.1 Primary objective. To evaluate, at 5 years, the incidence (or progression) of CKD, based on the presence or absence of metabolic syndrome (MetS), in two overseas populations (Caribbean and Polynesian) with morbid obesity.

The definition of MetS according to the NCEP ATP III (Expert Panel on Detection and Treatment of High Blood Cholesterol), as modified by the American Heart Association will be used to identify patients with MetS based on the presence of at least 3 of the syndrome's components.

2.2 Secondary objective(s).

In both populations, the main secondary objectives are:

• To evaluate, at baseline (T0), the prevalence of metabolic syndrome and its components (abdominal obesity, dyslipidemia, dysglycemia, arterial hypertension, as defined above) and other comorbidities (heart failure, coronary artery disease, documented stroke).
• To identify factors associated with the presence of MetS at T0.
• To identify factors associated with the presence of CKD at T0.
• To estimate, at 5 years, the incidence of metabolic diseases (diabetes, dyslipidemias), cardiovascular diseases (coronary artery disease, stroke), and deaths within the cohort.
• To evaluate the association between gene variants linked to central adiposity and/or CKD and the occurrence of events, in association or interaction with other risk factors (social, occupational, environmental).
• To describe mathematical models integrating clinical and biological variables and events (complications). To verify the validity of these models using the collected data.

III - RESEARCH DESIGN 3.1 Events of interest Primary event of interest and outcome measure The primary outcome measure is the incidence or progression of CKD at 5 years. CKD incidence, in individuals who did not have CKD at cohort entry (T0), is defined as the presence of 1+ or greater proteinuria on routine urinalysis (dipstick) and/or an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m².

CKD progression, in individuals who had CKD at T0, is defined as a decrease in eGFR of at least 30% compared to baseline (T0).

Secondary events of interest and outcome measures:

• Baseline (T0) prevalence of the various parameters of interest: Cardiometabolic risk factors, cardiovascular complications (coronary artery disease, myocardial infarction, stroke, heart failure, atrial fibrillation/flutter), and all-cause mortality.

• Measures of association between MetS and CKD.
• For the 5-year longitudinal study:
• At 5 years:

Incidence of complications other than CKD: metabolic diseases (diabetes, dyslipidemia), cardiovascular diseases (coronary artery disease, stroke), and deaths within the cohort.

Patients will undergo identical follow-up, with regular visits. The occurrence of an event will be validated through additional tests and specialist consultations, regardless of the presence or absence of metabolic syndrome.

Appointment reminders (via telephone or mail) will be issued to minimize the number of patients lost to follow-up.

3.2 Risk factors studied

We will specifically consider metabolic syndrome (MetS) and its components. The MetS definition established by the NCEP ATP III (Expert Panel on Detection and Treatment of High Blood Cholesterol)-as modified by the American Heart Association -will be used to identify patients with MetS based on the presence of at least 3 of the following criteria:

• Waist circumference ≥ 102 cm in men and ≥ 88 cm in women
• Systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg
• HDL-cholesterol < 1.04 mmol/L (40 mg/dL) in men, < 1.29 mmol/L (50 mg/dL) in women
• Triglyceride level ≥ 1.69 mmol/L (150 mg/L)
• Fasting blood glucose ≥ 5.6 mmol/L (100 mg/dL) or treatment for these conditions (or criteria).

3.3 Research methodology

An observational longitudinal study based on a cohort of subjects with morbid obesity (BMI ≥ 40 kg/m² or > 35 kg/m² if at least one comorbidity is present).

This is a prospective cohort study including consecutive patients aged 18 to 76 years from two overseas regions.

Patients who have consented to inclusion in the cohort will be recruited in Guadeloupe-at the Basse-Terre Medico-Social Center (CMS), the Basse-Terre Hospital Center (CHBT), and the Nouvelles Eaux Marines (NEM) clinic-and in French Polynesia, at the Papeete SSRP Center (ORA ORA).

These facilities provide care for obese patients in outpatient and/or inpatient settings.

Schematic presentation. Visits and examinations All patients will be seen in the day hospital at least once a year for 5 years.

3.4 Measures taken to reduce and avoid bias

To minimize the amount of incomplete data, patients-and, if necessary, the physician responsible for the patient's care-will be contacted by telephone.

3.5 Study procedure 3.5.1 Procedure for a patient:

Selection:

• Individuals suffering from morbid obesity may be selected for the study at the outpatient or inpatient departments involved in the management of this metabolic disease.

Inclusion:

• Patients will be enrolled at four sites: i) The Obesity-Nutrition Day Hospital at the Basse-Terre CMS in Guadeloupe; ii) The Medical Department at the NEM Clinic in Guadeloupe; iii) The SSR (Post-acute and Rehabilitation Care) Department at Ora Ora in French Polynesia; iv) The Medicine C Department at the Basse-Terre Hospital Center (CHBT) in Guadeloupe.
• After the investigator verifies the inclusion and non-inclusion criteria, the study will be explained to the patient, and the information sheet will be provided. After a reflection period of at least three hours, the consent form will be signed by both the patient and the physician.

Follow-up:

• Patients will be seen once a year for 5 years at the departments where they were enrolled.

End of study:

The final visit will take place at the 5-year mark. Duration of patient participation in the study: 5 years. Participation in another study simultaneously or upon completion of this one: permitted.

3.6 Description of rules for permanent or temporary discontinuation If enrollment has not begun within two years of obtaining authorization from the CPP (Ethics Committee), the study will be terminated.

3.7. Description of discontinuation rules or "withdrawal criteria" for the subject, for a part of the trial, or for the trial as a whole.

In the event of subject discontinuation or withdrawal, patient data from T0 and the date of the visit preceding withdrawal will be included in the analysis.

IV - SELECTION AND EXCLUSION OF RESEARCH PARTICIPANTS

4.1 Inclusion criteria Patient enrollment will be conducted consecutively. Individuals with a BMI ≥ 40 kg/m² or > 35 kg/m² with at least one comorbidity (hypertension, diabetes, hypercholesterolemia, joint pain, obstructive sleep apnea syndrome, etc.) - With no history of bariatric surgery, or having undergone such a procedure more than 5 years ago

• Aged 18 years or older
• Of either gender
• Informed of the study objectives and constraints and having provided written consent; residents of Guadeloupe or French Polynesia

4.2 Non-inclusion criteria for research participants Refusal to participate Individuals with acute renal failure; those undergoing dialysis Those who have undergone bariatric surgery within the last 5 years Pregnant women, women in labor, and breastfeeding mothers Persons deprived of liberty by a judicial or administrative decision; persons subject to psychiatric care Minors Adults subject to legal protection measures or unable to provide consent

V - STATISTICAL ANALYSIS

5.1. Required sample size The study sample size was calculated using SYSTAT 13 software (utilities module).

Based on data from the Hypertension Detection and Follow-Up Program (HDFP), a 5-year incidence of CKD of 34% was reported for obese subjects (BMI ≥ 30 kg/m², including those with BMI > 35 kg/m²) (Kramer H, 2005).

For the present study, which focuses on two overseas populations:

• The 5-year incidence of CKD in individuals with morbid obesity (BMI ≥ 40 kg/m²) is unknown but is likely higher than that reported in the reference article (our hypothesis: approximately 37%).

• Assuming also that the incidence or progression of CKD in severely/morbidly obese individuals (BMI ≥ 35 kg/m²) with metabolic syndrome (MetS) is 1.6 times higher (i.e., 58%).

• Taking into account that approximately 30% of subjects with morbid obesity are estimated to have metabolically healthy obesity (29):

*For unequal group sizes (and an N2/N1 ratio of 2)

*For an α risk of 5% and a study power (1-β) of 80% It would be necessary to include 201 participants in each population group (i.e., approximately N2 = 134 and N1 = 67).

Accounting for potential "loss to follow-up" over 5 years (approximately 40 subjects in each population), the minimum number to be included would be:

• 240 individuals in Guadeloupe (100 at CMS, 70 at CHBT, and 70 at CNEM)

• 240 in French Polynesia. For the OBECAM cohort, a minimum of 480 consecutive volunteers aged 18 and older will be enrolled over a 12-month period and followed for 5 years.

Recruitment feasibility is high, as the number of patients with morbid obesity followed by these facilities exceeds 400 in each of the regions involved.

5.2. Description of statistical methods

• Description: Descriptive analysis will be performed for all parameters of interest and across all groups, reporting counts and percentages for qualitative variables, and means (±SD) and medians [IQR] for quantitative variables.

At the 5-year mark, the following will be evaluated:

i) Incidence of cardiovascular and metabolic complications, and CKD (Chronic Kidney Disease) ii) Incidence of death Incidence will be calculated for the overall population, for the two specific study populations, and for subjects with and without metabolic syndrome (MetS).

• Between-group comparisons:

ANCOVA will be used to compare mean values of the various quantitative variables of interest (including blood pressure, BMI, waist circumference, triglycerides, HDL-cholesterol, and fasting blood glucose).

• Logistic regression to:
• Measure the association between MetS and complications
• Measure the association between MetS and CKD.

Several logistic regression models will be tested for the overall population and for the two specific study populations.

Odds ratios (OR) and confidence intervals (CI) will be reported.

The relative risk (RR) of events will be calculated.

• Cox proportional hazards models to determine the risk of developing CKD and other complications, as well as the risk of mortality, while accounting for MetS, individual follow-up duration, and other parameters of interest.

Hazard ratios (HR) and confidence intervals (CI) will be reported. Data analysis location and software used

IBM SPSS Statistics and SYSTAT software will be used for statistical analysis.

5.3. Statistical significance level Results will be considered significant at p < 0.025 (for a one-tailed test) or p < 0.05 (for a two-tailed test).

Inclusion criteria

Patient enrollment will be conducted consecutively. Individuals with a BMI ≥ 40 kg/m² or > 35 kg/m² with at least one comorbidity (hypertension, diabetes, hypercholesterolemia, joint pain, obstructive sleep apnea syndrome, etc.)

• With no history of bariatric surgery, or having undergone such a procedure more than 5 years ago
• Aged 18 years or older
• Informed of the study objectives and constraints and having provided written consent; residents of Guadeloupe or French Polynesia

Exclusion criteria

• Refusal to participate Individuals with acute renal failure; those undergoing dialysis Those who have undergone bariatric surgery within the last 5 years Pregnant women, women in labor, and breastfeeding mothers Persons deprived of liberty by a judicial or administrative decision; persons subject to psychiatric care Minors Adults subject to legal protection measures or unable to provide consent