Journal of Clinical Medicine Article Exploring Renal Changes after Bariatric Surgery in Patients with Severe Obesity Anna Oliveras 1,2,3,4, * , Susana Vázquez 1,2 , María José Soler 5 , Isabel Galceran 1,2 , Xavier Duran 2 , Albert Goday 2,6,7 , David Benaiges 2,6,7 , Marta Crespo 1,2,3,4 , Julio Pascual 1,2 and Marta Riera 2,4 1 Nephrology Department, Hospital Universitari del Mar, 08003 Barcelona, Spain; svazquez@hospitaldelmar.cat (S.V.); igalceran@hospitaldelmar.cat (I.G.); mcrespo@hospitaldelmar.cat (M.C.); julpascual@gmail.com (J.P.) 2 IMIM, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain; xduran@imim.es (X.D.); agoday@hospitaldelmar.cat (A.G.); dbenaiges@hospitaldelmar.cat (D.B.); mriera1@imim.es (M.R.) 3 Department of Experimental and Health Sciences, Area of Medicine, Universitat Pompeu Fabra, 08002 Barcelona, Spain 4 Red de Investigación Renal (REDINREN), Instituto Carlos III-FEDER, 28029 Madrid, Spain 5 Nephrology Research Group, Vall d’Hebron Research Institute (VHIR), Nephrology Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; mjsoler01@gmail.com 6 Endocrinology Department, Hospital Universitari del Mar, 08003 Barcelona, Spain 7 Medicine Department, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain * Correspondence: aoliveras@hospitaldelmar.cat; Tel.: +34-932-483-483 Abstract: Obesity-related hyperfiltration leads to an increased glomerular filtration rate (GFR) and hyperalbuminuria. These changes are reversible after bariatric surgery (BS). We aimed to explore obesity-related renal changes post-BS and to seek potential mechanisms. Sixty-two individuals  with severe obesity were prospectively examined before and 3, 6 and 12 months post-BS. Anthro-  pometric and laboratory data, 24 h-blood pressure, renin-angiotensin-aldosterone system (RAS) Citation: Oliveras, A.; Vázquez, S.; components, adipokines and inflammatory markers were determined. Both estimated GFR (eGFR) Soler, M.J.; Galceran, I.; Duran, X.; Goday, A.; Benaiges, D.; Crespo, M.; and albuminuria decreased from the baseline at all follow-up times (p-for-trend <0.001 for both). Pascual, J.; Riera, M. Exploring Renal There was a median (IQR) of 30.5% (26.2–34.4) reduction in body weight. Plasma glucose, glycosy- Changes after Bariatric Surgery in lated hemoglobin, fasting insulin and HOMA-index decreased at 3, 6 and 12 months of follow-up Patients with Severe Obesity. J. Clin. (p-for-trend <0.001 for all). The plasma aldosterone concentration (median (IQR)) also decreased Med. 2022, 11, 728. https://doi.org/ at 12 months (from 87.8 ng/dL (56.8; 154) to 65.4 (56.8; 84.6), p = 0.003). Both leptin and hs-CRP 10.3390/jcm11030728 decreased (p < 0.001) and adiponectine levels increased at 12 months post-BS (p = 0.017). Linear Academic Editor: Franco Bassetto mixed-models showed that body weight (coef. 0.62, 95% CI: 0.32 to 0.93, p < 0.001) and plasma aldos- terone (coef. −0.07, 95% CI: −0.13 to −0.02, p = 0.005) were the independent variables for changes Received: 29 December 2021 in eGFR. Conversely, glycosylated hemoglobin was the only independent variable for changes in Accepted: 27 January 2022 albuminuria (coef. 0.24, 95% CI: 0.06 to 0.42, p = 0.009). In conclusion, body weight and aldosterone Published: 29 January 2022 are the main factors that mediate eGFR changes in obesity and BS, while albuminuria is associated Publisher’s Note: MDPI stays neutral with glucose homeostasis. with regard to jurisdictional claims in published maps and institutional affil- Keywords: bariatric surgery; hyperfiltration; albuminuria; renin-angiotensin axis; aldosterone; iations. glucose metabolism Copyright: © 2022 by the authors. 1. Introduction Licensee MDPI, Basel, Switzerland. This article is an open access article Worldwide obesity has nearly tripled since 1975 [1]. Obesity is associated with an in- distributed under the terms and crease in morbidity and mortality, mainly from cardiovascular disease and diabetes, among conditions of the Creative Commons others [2]. In addition, obesity is also a major risk factor for the development of chronic Attribution (CC BY) license (https:// kidney disease [3]. Obesity is usually characterized by an abnormally high glomerular creativecommons.org/licenses/by/ filtration rate (GFR) and long-lasting hyperfiltration may cause renal lesions similar to 4.0/). secondary focal segmental glomerulosclerosis, the so-called obesity-related glomerulopathy, J. Clin. Med. 2022, 11, 728. https://doi.org/10.3390/jcm11030728 https://www.mdpi.com/journal/jcm J. Clin. Med. 2022, 11, 728 2 of 12 leading to a decrease in GFR and hyperalbuminuria [4]. In patients with severe obesity, both hyperfiltration and albuminuria are a consequence of increased intraglomerular pressure and glomerular surface area. Although the prevalence of microalbuminuria or proteinuria is higher in obese patients who have diabetes, albuminuria is still higher in non-diabetic obese patients than in the general population [5]. Finally, increased body mass index (BMI) has been linked to a loss of renal function, as well as a higher risk of end-stage renal disease [5]. In severely obese patients, lifestyle changes often fail to significantly reduce body weight. Fortunately, bariatric surgery (BS), a surgical approach that can be performed through different technical procedures, promotes weight loss so that it achieves much better results. Beyond weight loss, BS leads to the improvement of various obesity-related diseases such as hypertension, disorders of glucose and lipid metabolism, obstructive sleep apnea or non-alcoholic steatohepatitis, among others. More importantly, a recent meta-analysis [6] showed a reduction in major adverse cardiovascular events in patients with obesity and cardiovascular disease who underwent BS compared with those who did not have surgery. Recently, obesity-induced hyperfiltration and albuminuria have been shown to be reversible after bariatric surgery [4,7]. Altered renal haemodynamics as well as a deleterious adipocytokine pattern favored by obesity appear to be at the root of both obesity-related renal impairment and its improvement after BS, at least in diabetics [4,8,9]. Here we sought to assess changes in renal function at different follow-up times in patients with severe obesity undergoing BS. In addition, we explored the possible role of the renin-angiotensin aldosterone system (RAS), changes in glucose metabolism, and in- flammation as potential mechanisms mediating these changes. 2. Materials and Methods 2.1. Methods 2.1.1. Study Design and Patients The BARIHTA study is a prospective observational trial in a cohort of consecutively enrolled patients with severe obesity scheduled to undergo BS (clinicaltrials.gov identifier: NCT03115502). Details about BARIHTA trials have been previously published [10]. Thus, the BARIHTA study prospectively recruited outpatients with severe obesity who went to consultations at the Hospital del Mar (Barcelona, Catalonia, Spain) seeking surgical treat- ment. All individuals (both sexes, aged 18–60 years) with a medical indication for surgical intervention and who agreed to undergo the treatment with BS were invited to participate. Indications for BS included those patients with a body mass index (BMI) > 40 kg/m2 or grade II obesity (BMI > 35 kg/m2 ) plus associated comorbidities (i.e., type 2 diabetes melli- tus, obesity-associated hypoventilation disorders, high blood pressure, or dyslipidemia). Patients with any endocrine disease causing obesity or severe psychiatric diseases were excluded. Detailed information on the trial was provided by qualified professionals of the Hypertension and Vascular Risk Unit (Nephrology Department, Hospital del Mar). The exclusion criteria comprised the ruling out of the BS program for any reason or the refusal to give consent. The trial was approved by the local institutional Ethic Committee in accordance with the Declaration of Helsinki, and written informed consent was obtained from all participants. Here we evaluate and report the effects of BS on renal function and explore its possible mechanisms by analyzing its relationship with various components of the renin-angiotensin- aldosterone system (RAS), along with inflammatory markers and adipokines, as previously specified per protocol. Demographic, anthropometric and clinical data were recorded from all participants as a baseline. Anthropometric characteristics, pharmacological treatment, office- and 24 h-ambulatory-blood pressure (BP) recordings, routine laboratory tests, including renal function as assessed by the estimated glomerular filtration rate (eGFR) and by determining albuminuria, and determinations of components of the RAS, adipokines and inflammatory markers, were obtained at baseline and 1, 3, 6 and 12 months after surgery. Changes at follow-ups are evaluated from three months on to avoid the major hemodynamic instability J. Clin. Med. 2022, 11, 728 3 of 12 one month after BS. Hypertension was considered if previously diagnosed and/or if the baseline 24 h-BP was ≥130/80 mmHg. Diabetes mellitus (DM) was considered if the patient received antidiabetic treatment or had ≥2 fasting plasma glucose determinations ≥126 mg/dL or if glycosylated haemoglobin A1c was >6.5%. About one-third of the study population was under treatment with at least one drug that interfered with the RAS. Given that these drugs could introduce a bias by interfering with renal function parameters, the main analyzes were performed separately in both the entire cohort and in the untreated patients. 2.1.2. Procedures Blood Pressure Measurements Brachial-BP measurements and calculation of central-BP and other arterial parameters through the oscillometric method (ARCSolver algorithm) were obtained from a Mobil-O- Graph® NG-ambulatory blood pressure (NG-ABPM) device by IEM, Stolberg, Germany. The monitor was placed on a working day between 08:00–10:00 h A.M., and after a 5 min rest, BP was consecutively determined four times at 1-min intervals. The mean was es- tablished as office BP. Brachial artery waveforms were then automatically recorded at 20-min intervals. Suitably sized cuffs were used according to the arm circumference mea- sured in each study visit. All patients had recordings of good technical quality (≥70% valid readings). If not, a new ambulatory-BP-monitoring (ABPM) was repeated within 1 week. Laboratory Analyses Urinary Albumin Excretion Urinary albumin excretion (measured by turbidimetry; lower detection limit: 0.3 mg/dl; intra-assay and inter-assay variation coefficients: 1.3% and 4.3%, respectively) was deter- mined before BS and at the determined follow-up time-points and measured as the average of urinary albumin/creatinine ratio (ACR) from 2 fresh first-morning-void urine samples obtained on separate days. Microalbuminuria was defined as an ACR ≥ 30 mg/g. Serum Creatinine and eGFR Serum creatinine (SCr) was measured by an enzymatic modified Jaffe reaction (CREA; Roche Diagnostics) using the Hitachi Modular System Analyzer (Roche Diagnostics), consistent with the current National Kidney Disease Education Program recommendations for standardizing SCr measurement [11]. The intra-assay coefficient of variation was 2.3%. There is no current agreement as to the best method to estimate the GFR in individuals with severe obesity. However, in a recently reported study [12], the modified Cockcroft- Gault (CG) equation performed best in both the overall population and the obese subgroup in terms of strength of correlation, mean bias and accuracy, as compared to both the IDMS (isotope dilution mass spectrometry) traceable simplified Modification of Diet in Renal Disease [13] and the Chronic Kidney Disease-Epidemiology Collaborative equations [14]. We obtained equivalent results to that report. Therefore, although we initially performed the analyzes by obtaining the eGFR using the three formulas separately, in the final analysis we only report data on eGFR according to the CG equation, with adjustments for body surface area. Renin-Angiotensin-Aldosterone System (RAAS) Components Plasma renin activity (PRA) and plasma aldosterone concentration, as well as angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme-2 (ACE2) activ- ities, were measured by validated laboratory methods [15]. Details on assay performance are reported in Appendix A. Adipokines and Inflammatory Parameters Leptin, adiponectin, and other cytokines and inflammatory markers, e.g., resistin, angiopoietin-2, MCP-1 and high-sensitivity C-reactive protein (hs-CRP), were also deter- mined. See Appendix B. J. Clin. Med. 2022, 11, 728 4 of 12 Surgical Techniques Either laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrec- tomy (LSG) were performed, and any of these two were chosen for each patient based on clinical criteria and the consensus of the Bariatric Surgery Unit. In this line, LSG was preferred in younger patients, in those with a BMI ranging from 35–40 kg/m2 , as a first-step treatment in cases with a body mass index (BMI) > 50 kg/m2 and when drug malabsorp- tion was to be avoided [16]. The LRYGB technique involved a 150-cm antecolic Roux limb with 25-mm circular pouch–jejunostomy and exclusion of 50 cm of the proximal jejunum. In LSG, the longitudinal resection of the stomach from the angle of His to approximately 5 cm proximal to the pylorus was performed using a 36-French bougie inserted along the lesser curvature. 2.1.3. Statistical Analyses Elementary statistical methods were applied with statistical package SPSS for Win- dows version 25.0 (Cary, NC, USA). The normality assumption for continuous variables was tested through the Kolmogorov–Smirnov test. Variables fulfilling this normality as- sumption were summarized as the mean ± S.D. or the median (interquartile range, IQR) otherwise. Categorical data were presented as frequencies and percentages. Comparisons of analyzed variables between two observed periods were carried out by paired t tests or Wilcoxon signed rank tests. Pearson or Spearman correlation coefficients were used for testing bivariate correlations as appropriate. Separate linear mixed-models were built for both the variation of eGFR-CG and the variation of albuminuria. All variables which deviate from the normal distribution were log-transformed (ln) before being introduced into the model. In these models, data were expressed as regression coefficient, 95% confi- dence interval (95% CI) and p-value. A change was considered significant if the two-side alpha level was ≤0.05. We used the statistical package SPSS for Windows version 25.0 (Cary, NC, USA), and STATA package version 15 (STATA Corp., College Station, TX, USA), for statistical analysis. About one-third of the study population received treatment with one or more drugs that interfered with RAS. Given that these drugs could introduce a bias by interfering with renal function parameters, the main analyses were performed separately in both the entire cohort and in the untreated patients. 3. Results Sixty-two patients completed the BARIHTA study, and information on renal changes was available for all of them at the baseline and follow-ups. A flowchart is supplied (Figure S1). Baseline characteristics are shown in Table 1. Fifty-five patients (89%) had hyperfiltration, i.e., eGFR > 120 mL/min/1.73 m2 , before BS. None of the patients had chronic kidney disease based on the estimated glomerular filtration rate, nor did any of them die at follow-up. 3.1. Changes in Renal Function Parameters The estimated GFR decreased from 155.9 ± 36.3 to 127.7 ± 27.4 mL/min/1.73 m2 (p < 0.001), reflecting the hyperfiltration that characterizes patients with severe obesity. In addition, the albuminuria, as measured by the log-transformed albumin-creatinine ratio (lnACR), decreased from 1.85 ± 1.08 to 1.56 ± 0.73 (p = 0.056). Both the estimated GFR (Figure 1A) and the albuminuria (Figure 1B) experienced a progressive decrease from baseline to the final observation 12 months after BS at all follow-up times (p for trend <0.001 for both). 3.2. Changes in Body Weight, Body Mass Index, and Waist Circumference Overall, there was a median (IQR) 30.5% (26.2–34.4) reduction in body weight 12 months after BS. Body mass index was 42.7 ± 5.6 kg/m2 at baseline and 29.7 ± 4.8 kg/m2 one year after BS (p < 0.001). Figure S2 (Supplemental Material) shows the mean (error bars Age, Year (Mean ± S.D.) 42.1 ± 9.3 Sex, women, n (%) 48 (77.4) Body weight, kg (mean ± S.D.) 117.4 ± 18.9 J. Clin. Med. 2022, 11, 728 Waist circumference, cm (mean ± S.D.) 132.3 ± 11.55 of 12 Body mass index, Kg/m (mean ± S.D.) 2 42.6 ± 5.5 Race, n (%) - 95% CI) body weight at each Caucasian 56 (90.3) follow-up point. Waist circumference was 132.5 ± 12.0 cm - African 1 (1.6) A waist and 105.5 ± 13.3 cm, at baseline and 12 months after BS, respectively (p < 0.001). - circumference (cm) decrease Hispano-American 5 (8.1) was confirmed in both men (140.2 ± 14.3 vs. 111.4 ± 16.3) and women (129.8 ± 10.1Current ± 11.7), (p vs. 103.4smokers, n (%) < 0.001 for both comparisons). 17 (27.4) Surgical procedure, n (%): - characteristics. Table 1. The baseline clinical Sleeve gastrectomy 27 (43.5) - Roux-en-Y gastric bypass 35 (56.5) Age, Year (Mean ± S.D.) 42.1 ± 9.3 Sex, women, n (%) Hypertension, n (%) 48 (77.4) 24 (38.7) Body weight, kg (mean ± S.D.) Type 2-Diabetes 117.4 ± 18.9 Mellitus, n (%) 7 (11.3) Waist circumference, cm (mean ± S.D.) Chronic kidney disease *, n (%) 132.3 ± 11.5 0 (0) Body mass index, Kg/m2 (mean ± S.D.) 42.6 ± 5.5 Race, n (%) Previous major vascular event, n (%) 3 (4.8) * estimated -Caucasianglomerular filtration rate <60 mL/min/1.73 m2. 56 (90.3) -African 1 (1.6) 3.1.-Hispano-American Changes in Renal Function Parameters 5 (8.1) Current smokers, n (%) 17 (27.4) The estimated GFR decreased from 155.9 ± 36.3 to 127.7 ± 27.4 mL/min/1.73 m2 (p < Surgical procedure, n (%): 0.001), reflecting -Sleeve gastrectomythe hyperfiltration that characterizes 27 (43.5) patients with severe obesity. In addition, the albuminuria, -Roux-en-Y gastric bypass as measured by the35log-transformed (56.5) albumin-creatinine ratio Hypertension, n (%) 24 (38.7) (lnACR), decreased from 1.85 ± 1.08 to 1.56 ± 0.73 (p = 0.056). Both the estimated GFR Type 2-Diabetes (Figure 1A) and Mellitus, n (%) the albuminuria (Figure 1B) 7experienced (11.3) a progressive decrease from Chronic kidney disease *, n (%) 0 (0) baseline to the final observation 12 months after BS at all follow-up times (p for trend Previous major vascular event, n (%) 3 (4.8) <0.001 for both). * estimated glomerular filtration rate <60 mL/min/1.73 m2 . Figure 1. The changes in eGFR (1A) and albuminuria (1B) from baseline (before BS) to 12 months Figure 1. The changes in eGFR (1A) and albuminuria (1B) from baseline (before BS) to 12 months post-BS, with mid-points at 3 and 6 months. eGFR-CG = estimated glomerular filtration rate by the post-BS, with mid-points at 3 and 6 months. eGFR-CG = estimated glomerular filtration rate by the Cockcroft-Gault equation; lnACR = neperian logarithm of albumin-creatinine ratio. Values of both Cockcroft-Gault equation; lnACR = neperian logarithm of albumin-creatinine ratio. Values of both eGFR-CG and lnACR are given as mean ± SD. eGFR-CG and lnACR are given as mean ± SD. 3.3. Variation of Blood Pressure As previously reported [10], office systolic and diastolic BP, both central and peripheral, significantly decreased at 12 months, even though more than 60% of the cohort were normotensives. In addition, central 24-h SBP decreased at 12 months, with a mean of (95% confidence interval) −3.1 mmHg (−5.5 to −0.7), p = 0.01 after adjustment for age and sex. There was a statistically significant correlation between the variation at 12 months of peripheral 24-h systolic blood pressure (SBP) and the variation of both body weight (rho = 0.453, p = 0.001) and waist circumference (rho = 0.316, p = 0.030). of (95% confidence interval) −3.1 mmHg (−5.5 to −0.7), p = 0.01 after adjustment for age and sex. There was a statistically significant correlation between the variation at 12 months of peripheral 24-h systolic blood pressure (SBP) and the variation of both body weight (rho J. Clin. Med. 2022, 11, 728 6 of 12 = 0.453, p = 0.001) and waist circumference (rho = 0.316, p = 0.030). 3.4. Changes in Glucose Metabolism Parameters and in RAS Components 3.4. Changes in Glucose Metabolism Parameters and in RAS Components Figure 2 shows the overall mean (95% CI) of fasting glucose before BS (0 months) Figure 2 shows the overall mean (95% CI) of fasting glucose before BS (0 months) and and at 3, 6 and 12 months of follow-up. As noted, there is an initial decrease at 3 months at 3, 6 and 12 months of follow-up. As noted, there is an initial decrease at 3 months that is that is maintained maintained throughout throughout the firstthe yearfirst year of follow-up of follow-up (p for trend(p