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Urinary sodium excretion after gastric bypass surgery
Surgery for Obesity and Related Diseases ] (2017) 00–00
Original article
Urinary sodium excretion after gastric bypass surgery Neil G. Docherty, B.Sc., Ph.D.a,b,*, Lars Fändriks, M.D., Ph.D.a, Carel W. le Roux, M.B.Ch.B., M.Sc., F.R.C.P., F.R.C.Path., Ph.D.a,b,c, Peter Hallersund, M.D., Ph.D.a, Malin Werling, M.D., Ph.D.a a
Department of Gastrosurgical Research & Education, Institute of Clinical Sciences Sahlgrenska Academy at University of Gothenburg Sahlgrenska University Hospital, Gothenburg, Sweden b Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland c Investigative Science, Imperial College London, London, UK Received January 24, 2017; revised March 9, 2017; accepted April 3, 2017
Abstract
Background: Gut–kidney signaling is implicated in sodium homeostasis and thus blood pressure regulation. Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity confers a pronounced and long-lasting blood pressure lowering effect in addition to significant weight loss. Objectives: We set out to establish whether RYGB is associated with an intrinsic change in urinary sodium excretion that may contribute to the reported blood pressure lowering effects of the procedure. Setting: University hospital Methods: Five female patients (age range: 28–50 yr) without metabolic or hypertensive co-morbidities were included in a study involving four 24-hour residential visits: once before surgery and 10 days, 3 months, and 20 months after surgery. Creatinine and sodium were measured in fasting plasma samples and 24-hour urine samples and creatinine clearance, estimated glomerular filtration rate, and indices of urinary sodium excretion were calculated. Fasting and 60-minute postprandial blood samples from each study day were assayed for pro-B-type natriuretic peptide (NT-proBNP). Results: Increases in weight-normalized urinary sodium excretion of up to 2.3-fold in magnitude occurred at 20 months after surgery. Median fractional excretion of sodium at 20 months was double that seen before surgery. Fasting NT-proBNP levels were stable or increased (1.5- to 5-fold). Moreover, a small postprandial increase in NT-proBNP was observed after surgery. Conclusions: Renal fractional excretion of sodium is increased after RYGB. A shift toward increased postoperative basal and meal associated levels of NT-proBNP coincides with increased urinary sodium excretion. The data support a working hypothesis that an enhanced natriuretic gut– kidney signal after RYGB may be of mechanistic importance in the blood pressure lowering effects of this procedure. (Surg Obes Relat Dis 2017;]:00–00.) r 2017 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Gastric bypass; Sodium; Urine; Natriuresis; Weight loss
*
Correspondence: Neil G. Docherty, B.Sc., Ph.D., Department of Gastrosurgical Research & Education, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE41345 Gothenburg, Sweden. E-mail: [email protected]
The well-described mortality benefits of bariatric surgery are accounted for in part by reductions in cardiovascular disease [1,2]. The combination of improvements in lipid profile and systolic blood pressure after surgery likely explain much of the risk reduction vis-à-vis myocardial
http://dx.doi.org/10.1016/j.soard.2017.04.002 1550-7289/r 2017 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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N. G. Docherty et al. / Surgery for Obesity and Related Diseases ] (2017) 00–00
infarction and stroke [3,4]. Roux-en-Y gastric bypass (RYGB) is superior in achieving blood pressure targets versus several intensified lifestyle modification approaches [5–7]. Reductions in blood pressure precede weight loss after RYGB and occur as early as the first postoperative week [8]. The Longitudinal Assessment of Bariatric Surgery consortium reports a dissociation in 3-year rates of remission of hypertension between RYGB (38.2%) and gastric banding (17.4%). We recently reported that in the Swedish Obese Subjects (SOS) study, a relative reduction in blood pressure (3.6 mmHg systolic and 3.5 mmHg diastolic) is sustained at 10 years after surgery in patients who underwent RYGB but not in those who underwent gastric banding or vertical banded gastroplasty [4,9]. These data suggest that an intrinsic blood pressure lowering pathway is activated by the particulars of the RYGB anatomic reconfiguration [10]. Oral sodium chloride administration increases urinary sodium excretion to a greater extent than iso-osmolar intravenous infusion [11]. This raises the possibility that a natriuretic gut–kidney axis is operative in normal physiology as part of the homeostatic control of plasma sodium, serving to buffer against potential pressor effects of dietary salt loading. Enteroendocrine hormones including glucagon-like peptide 1 (GLP-1), vasointestinal polypeptide, gastrin/cholecystokinin, peptide YY, and uroguanylin have been reported to provoke a natriuretic response, and one or more of these may be particularly important during the postprandial period (e.g., GLP-1) [12]. When controlling for weight, the blood pressure lowering effects of RYGB observed in SOS were associated with a 20 mmol delta increase in 24-hour urinary sodium excretion versus baseline [9]. In a series of 33 RYGB patients followed prospectively for 22 months, reductions in body weight and 6 and 7 mmHg decreases in systolic and diastolic pressure, respectively, were associated with urinary sodium loss [13]. Obesity is associated with hypervolemia but is paradoxically associated with reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and this may contribute to essential hypertension [14]. Fasting NT-proBNP levels are increased within normal range after Roux-en Y gastric bypass (RYGB) [15] leading, to the suggestion that BNP may be a mediator or sentinel of a primary natriuretic effect of RYGB. Demonstration of a blood pressure lowering shift in the tone and responsivity of the intrinsic gut–kidney natriuretic axis after RYGB is suggested by existing data. That said, the phenomenon has not been reported in a setting that controls for confounders such as variations in dietary sodium intake. The data from the SOS study indicated that, while in the free-living context increases in natriuresis do occur after RYGB, these coincided with reports of increased dietary sodium intake [4,9]. Whether increases in sodium intake arose as a cause or consequence of changes in
urinary sodium excretion could not be disambiguated in analysis of the data. We therefore sought to build on the existing data by conducting a controlled longitudinal study. We hypothesized that the fractional excretion of sodium (FE-Na) would increase in individuals after RYGB, thus proffering an explanation for increases in urinary sodium excretion. This hypothesis could be directly addressed in the controlled setting of the present study given its longitudinal, pre- and postsurgery, repeated-measure design and the fact that dietary sodium intake was standardised during 24-hour urine collections. Moreover, we sought to ascertain whether there were temporal and meal-associated changes in NT-proBNP levels after RYGB, which may be of mechanistic importance as an intermediate in the gut–kidney axis. Materials and methods The study was performed at the Department of Gastrosurgical Research & Education, Sahlgrenska University Hospital, Gothenburg, Sweden in accordance with the Declaration of Helsinki and under ethical approval from the regional ethical review board in Sweden (no: 740-10). Participants were fully briefed on the study protocol and provided written consent. Participants were recruited from clinic at the Sahlgrenska University Hospital, Gothenburg, Sweden. To be included in the study, participants needed to have a body mass index (BMI) that met the eligibility criteria for surgical intervention (participant BMI range: 39.1–44.8 kg/m2). Furthermore, recruitment was restricted to those who were nonsmokers, were not currently on any medications, with stable weight during the 3 months preceding study initiation, and not diagnosed with any obesity-related co-morbidities, including diabetes and hypertension. After enrollment, participants were prescribed multivitamin and mineral supplements but were not required to follow any presurgical weight loss regimen. Study visits were scheduled to allow for synchronization of participants with regard to phase of menstrual cycle. RYGB was performed laparoscopically and involved fashioning a gastric pouch (10–20 mL) connected to the jejunum in an antecolic–antegastric Roux-en-Y construction. Roux-limb length was 75 cm, and the entero–entero anastomosis was created 30 cm distal from the ligament of Treitz. Study visits Participants attended four 24-hour study visits; preoperatively (weight stable phase: visit 1), 10 days and 3 months after surgery (weight loss phase: visits 2 and 3), and 20 months after surgery (weight stable phase 2: visit 4). The residential setting was a 3 3 3 m hotel style room equipped to permit indirect calorimetry recordings from exhausted air leaving the room. This “metabolic chamber”
Gastric Bypass Increases Urinary Sodium Excretion / Surgery for Obesity and Related Diseases ] (2017) 00–00
design was used to assess energy expenditure, the results of which have previously been reported [16]. The evening before visits 1 and 4, participants consumed a standardized meal of mashed potatoes and meatballs between 19:00 and 20:00. The evening before visits 2 and 3, participants consumed a semiliquid meal containing 200 kcal and 300 kcal, respectively. Participants arrived at the study site at 07:30 on the morning of study visits after having fasted (11 hours) and had height, weight, and body composition determined by DEXA scanning (LUNAR radiation, Madison WI, USA). A standardized 400 kcal breakfast was then consumed outside of the chamber, and serial fasting and postprandial blood samples were collected. In the metabolic chamber, participants received a fixed lunch at 13:30, a fixed dinner at 18:00, a snack at 21:00, and a fixed breakfast the following morning at 08:40. Portion size and caloric content were reduced at visits 2 and 3 relative to visits 1 and 4 for a total calorie intake of 1000 kcal at visit 2 and 1250 kcal at visit 3 versus 1920 kcal at visits 1 and 4. Dietary intake including sodium content was thus equivalent for all participants at each visit (Table 1).
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ELISA module on the Cobas 8000 autoanalyzer (Roche Diagnostics, Hoffmann-La Roche, Basel, Switzerland). Calculation of urinary sodium excretion rate and FE-Na Urinary sodium excretion rate was determined in mEq/24 hr/kg of weight. To calculate FE-Na, the following formula was used: (Urine Na / Serum Na) / (Urine Cr / Serum Cr) 100. Calculation of creatinine clearance and estimated glomerular filtration rate Creatinine clearance was calculated using the formula (urinary creatinine/serum creatinine) (24-hour diuresis / 1440) and normalized by bodyweight to generate mL/min/kg values. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula [17], which has been validated for use in patients with obesity [18]. Statistical analyses
Determination of sodium and creatinine in urine and plasma Fasting plasma samples and aliquots of 24-hour urine collections were analyzed for sodium and creatinine by routine biochemistry on an auto-analyzer platform at the Department of Clinical Biochemistry, St Vincent’s University Hospital, Dublin, Ireland. NT-proBNP electrochemiluminescence NT-proBNP is the N-terminal cleavage product of proBNP and has a plasma half-life of 120 minutes, 6 times that of the active peptide BNP hormone, thus making its measurement a more suitable index of BNP release. NT-proBNP was measured by electrochemiluminescent
1 2 3 4 5
Results Weight loss, urinary flow rate, and urinary sodium excretion after RYGB
Table 1 Study visit protocol Participant
For inferential statistics, the sample size precluded the use of normality tests, and the data are summarized using the median and interquartile range, the latter being bracketed in the text. Time-dependent changes in the profiles of each parameter studied are presented graphically and were assessed by nonparametric repeated measures analysis of variance. Statistical comparisons between preoperative and 20-month postoperative weight stability were made by paired analyses (Wilcoxon signed-rank test) and unpaired group comparison (Mann–Whitney U test). In all cases, a value of P o .05 was considered statistically significant. All analyses were conducted using GraphPad PRISM Version 6.
Weight (kg)
BMI (kg/m2)
% BMI loss
0m
20 m
0m
20 m
0–20 m
124.1 115.6 122.2 117.8 111.4
63.0 82.5 83.1 76.2 77.9
44.8 41.4 41.3 39.1 41.9
22.3 30.3 28.1 25.5 29.5
50.1 26.8 32.0 34.9 29.6
BMI ¼ body mass index. Participants were studied for approximately 36 hours in total, including a 24-hour residential period in a metabolic chamber. Dietary intake was identical between participants at each visit.
At 20-month follow-up, the average percentage reduction in BMI was 34.7 ⫾ 9.1% (Table 2). Median urinary output at visit 1 was 1800 (1055) mL/24 hr. This fell significantly at 1 week after surgery and stabilized at 20 months after surgery at visit 4 at 1300 (1018) mL/24 hr or 20.6 (9) mL/kg/24 hr when controlled for weight (Fig. 1). Urinary sodium excretion was significantly decreased 1 week after surgery at visit 2 versus values obtained at visit 1. A significant increase versus visit 2 was observed at visit 4. When controlled for weight and compared across weight stable phases (visit 1 versus visit 4), a significant 2.3-fold
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eGFR, creatinine clearance, and FE-Na at weight stability before and after RYGB
Table 2 Weight loss after RYGB Time
Activity
Location
evening before visit 19:00 07:30 08:15 08:30 411:00
Standardized evening meal Fasting blood sampling DEXA Standardized breakfast Postprandial blood sampling Standardized lunch Standardized dinner Standardized snack Basal metabolic rate recording Standardized breakfast
Home
13:30 18:00 21:00 07:30 08:40
Research facility (outside metabolic chamber)
Research facility (Inside metabolic chamber þ24 hr urine)
RYGB ¼ Roux-en-Y gastric bypass; DEXA ¼ dual-energy X-ray absorptiometry. All patients reported marked reductions in total weight loss with attendant body mass index (BMI) reduction. The average percentage reduction in BMI was 34.7 ⫾ 9.1% (n ¼ 5).
increase in median urinary sodium excretion was evident by visit 4 1.9 (1.7) mEq/kg/24 hr versus .9(0.2) mEq/kg/24 hr (Fig. 2).
We used the Chronic Kidney Disease Epidemiology Collaboration equation to calculate eGFR. Although we used creatinine rather than cystatin C in the equation, percentage changes in serum creatinine at the fourth visit 20 months after surgery were minor (mean 6.7%, min 0 and max 10%) and no significant difference in creatinine clearance was found (1.07 [0.38] mL/min/kg versus 1.29 [0.81] mL/min/kg; Fig. 3A). Calculated eGFR was not significantly different between determinations made at visit 1 and visit 4 (95 [24.5] mL/min/1.73 m2 versus 104 [16.5] mL/min/1.73 m2; Fig. 3B). Median FE-Na values significantly increased versus baseline values from visit 1 to 20 months after surgery, doubling from .3 (.1) to .6 (.3) (Fig. 3). Relationship between NT-proBNP levels and changes in FE-Na after RYGB By visit 4 at 20 months after surgery, 4 out of 5 participants reported fasting levels of NT-proBNP that were equivalent to or elevated (1.5- to 5-fold) versus baseline at
Fig. 1. Changes in urine output after Roux-en-Y gastric bypass. (A) A 24-hour urine collection was made at each study visit, and flow rates were determined. Urinary output over 24 hours was compared at weight stability between visits 1 and visit 4 either without controlling for weight (B) or normalizing for weight (C). *P o .05 versus preoperative baseline (visit 1). #P o .05 at baseline (visit 1) versus 20-month postoperative (visit 4) (n ¼ 5).
Gastric Bypass Increases Urinary Sodium Excretion / Surgery for Obesity and Related Diseases ] (2017) 00–00
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Fig. 2. Changes in urinary sodium excretion after Roux-en-Y gastric bypass. (A) Urinary sodium concentration was calculated in 24-hour urine collections from each study visit and excretion rates determined using concentration values and flow rates. Urinary sodium excretion was compared at weight stability between visits 1 and visit 4 either without controlling for weight (B) or normalizing for weight (C). *P o .05 versus preoperative (visit 1). #P o .05 1-week postoperative (visit 2) versus 20-month postoperative (visit 4). &P o .05 at preoperative baseline (visit 1) versus 20 months’ postoperative (visit 4) (n ¼ 5).
visit 1. All patients reported a characteristic profile of shifting from either no change or a minor reduction (up to 10%) in NT-proBNP levels at 60 minutes after the preoperative test meal to values up to 10% higher than baseline 60 minutes after test meal administration 20 months after surgery. Notably, one patient reported a 50% decrease in baseline fasting NT-proBNP levels at 20 months after surgery and was the only participant not to show a marked increase in FE-Na at that time point (Fig. 4). Discussion We previously stated that long-term improvements in blood pressure in the SOS study are more marked in recipients of RYGB and when controlled for weight loss and are accompanied by small but durable increases in diuresis and urinary sodium excretion not seen with other bariatric procedures [9]. The present study sought to further investigate this phenomenon in the setting of a controlled study in which evidence of differences in renal sodium handling and NT-pro-BNP could be monitored from the preoperative period to the period of stable maximal weight
loss. The study was conducted with participants without evidence of hypertension as we hypothesised that an intrinsic physiologic shift in renal sodium handling characterized by increased FE-Na occurs after RYGB and should be best observed under controlled conditions in nonhypertensives. In summary, we report that under conditions of 24-hour residential dietary control, a cohort of 5 nonhypertensive females with obesity had significantly increased weightnormalized measures of diuresis and urinary sodium excretion. Moreover, we show that this may be dependent on altered renal tubular sodium handling because increases in FE-Na are observed in the absence of alterations in eGFR or creatinine clearance rates. We also measured fasting and postprandial NT-proBNP and confirmed previous studies that reported modest increases within the normal reference range in humans after RYGB [15]. Notably, when data are examined without adjusting for altered weight after surgery, urine volume is decreased and changes in urinary sodium excretion do not reach statistical significance. It may be argued that by factoring in BMI, an artefact is introduced that creates an apparent diuresis after weight loss. This is countered by our previous observations
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Fig. 3. Fractional excretion of sodium after Roux-en-Y gastric bypass. (A) Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate. (B) Creatinine clearance and (C) fractional excretion of sodium were assessed and compared between visits 1 and 4. *P o .05 at preoperative baseline (visit 1) versus 20-month postoperative (visit 4) (n ¼ 5).
in the SOS study showing that delta increase in diuresis at 2 years after RYGB was 200% that seen after gastric banding procedures, despite intergroup differences in BMI
Fig. 4. Fasting and postprandial N-terminal pro-brain natriuretic peptide (NT-proBNP) after Roux-en-Y gastric bypass. (A) NT-proBNP levels were measured in plasma at fasting and 60 minutes after initiation of a 400 kcal standardized breakfast at visit 1 (preoperative baseline) and visit 4 (20 months postoperative). (B) Paired comparison of percentage change in NTproBNP levels from 0 to 60 minutes during a fixed meal test at visit 1 and visit 4.
reduction being only in the region of 20%. It could be suggested that reductions in lean muscle mass after RYGB could interfere with the calculation of FE-Na by reducing serum creatinine levels. However, serum creatinine levels were not significantly decreased in this study after RYGB. How, then, are the changes in sodium excretion that occur after RYGB elicited? Plasma sodium is freely filtered at the glomerulus at a rate proportional to the glomerular filtration fraction, which under normal circumstances is approximately 20% of renal plasma flow. Approximately 99.5% of the filtered sodium load is reclaimed from the nascent urine during its journey through the renal tubule. The majority (90%) of reabsorption occurrs in the renal proximal tubule and thick ascending limb of the loop of Henle. Fine-tuning of variations in the excreted load are determined at the distal tubule, connecting tubule, and collecting duct through the actions of peptide and steroid hormones, and these regulated pathways influence circulatory volume. Under normal physiologic conditions, FE-Na, as it pertains to cardiovascular control, is usually modulated within a narrow range that oscillates around a value of .5. The balance of activity between 2 principal opposing neurohormonal systems (the renin angiotensin aldosterone system and the cardiac natriuretic peptide system) plays a critical role in determining the balance of fine-tuning of
Gastric Bypass Increases Urinary Sodium Excretion / Surgery for Obesity and Related Diseases ] (2017) 00–00
sodium excretion [19]. Regulation of the functioning of these systems is multi-layered, with weight and fat distribution playing an important modulatory role in the balance. Alleviation of obesity after RYGB can, via numerous mechanisms, foster reductions in blood pressure through effects on the opposing pressor and natriuretic pathways, which modulate renal sodium handling in favor of natriuresis [20]. Reductions in intra-abdominal pressure [21] and retroperitoneal and renal sinus fat [22] associated with obesity after RYGB could alleviate intrarenal pressure and oppose slow-tubular flow rate–based augmentation of sodium reabsorption and reduce renal renin release. Moreover, attenuation of renal renin release could also be affected via decreases in circulating leptin concentrations, which would serve to reverse obesity-associated increases in renal efferent sympathetic nerve activity [23]. A potential role for reductions in circulating angiotensinogen due to reduced adipose tissue could also be implicated [24]. RYGB-induced weight loss could also redress pathogenic enhancement of renal mineralocorticoid receptor activation, which is described as increasing distal tubular sodium reabsorption in obesity [25]. On the other side of the equation, RYGB-induced weight loss may reverse obesity-associated reductions in basal and volume loading–primed release of natriuretic peptides [26] and reduce obesity-associated increases in circulating neprilysin, the major peptidase involved in the degradation of natriuretic peptides [27]. Thus, although RYGB may affect blood pressure control through purely weight loss–driven pathways, the presence of an enhanced gut–kidney natriuretic axis after RYGB is a conceptually interesting proposition and may be the additional factor that explains the differential effects of restrictive versus intestinal bypass–based bariatric procedures in relation to blood pressure lowering. The potential for exaggerated activity of a gut–kidney natriuretic axis after RYGB also draws a parallel to the effect of RYGB on enteroinsular signaling, which is characterized by pronounced augmentation of the gut–pancreas insulin secretory “incretin” signal secondary to the actions of hormones such GLP-1. GLP-1 may be implicated in enhanced sodium excretion after RYGB. GLP-1 is increased after RYGB but not after purely restrictive bariatric procedures [16,28]. Infusion of GLP-1 over 3 hours doubles urinary sodium excretion [29] and is associated with a reduction in urinary Hþ excretion, implying a role for the inhibition of the proximal tubular sodium–hydrogen antiporter 3 (NHE3) in this effect. Ex vivo tubular micropuncture and gene expression/activity studies in rats support this hypothesis [30]. This response is sustained in a mouse model of obesity and diabetes in response to exendin-4 administration [31]. Oral sodium loading in rats increases both GLP-1 and natriuresis, and administration of the GLP-1 receptor agonist Exendin-4 in rats increases the FE-Na [32].
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Comparing RYGB with best medical care plus or minus exenatide (GLP-1 receptor agonist) shows a significant reduction from 2.8 to .5 in the mean number of blood pressure lowering medications required after 12 months [33]. Notably, an intermediate effect was observed when exenatide was added to usual care, implying that exaggerated postprandial gut hormone responses after RYGB (e.g., GLP-1) may be implicated in cardiovascular improvements. This is coherent with the emerging data demonstrating that at medium-term follow-up, cardiovascular mortality of patients with type 2 diabetes treated with liraglutide is reduced by 22% [34]. A gut–heart–kidney natriuretic axis involving GLP-1 stimulation of natriuretic peptide release and subsequent cyclic GMP–dependent induction of natriuresis has recently been elucidated in mice [35]. This may be mediated via inhibition of the epithelial sodium channel in the distal nephron. Thus, the existence of such an axis should be further investigated after RYGB in humans. Such studies may extend knowledge of the multifunctional nature of the altered enteroendocrine signals generated in the gut after RYGB. Although the results of the present study are interesting and appear to support and extend previous findings, questions remain as to whether the changes seen in urinary sodium excretion are sufficient to contribute to the improvements in hypertension seen after RYGB. Better understanding of this and the mechanisms involved could hold potential for guiding the development of new pharmacologic or dietary approaches to promoting natriuresis. A pertinent question in the context of diabetes is whether discontinuation of exogenous insulin or reduction in endogenous hyperinsulinemia after surgery serve to enhance or unmask the natriuretic effects of RYGB in diabetics. Exogenous insulin drives renal sodium reclamation through direct effects on renal sodium transporter expression and activity (e.g., NHE3) [36]. On the flip side, relapse of diabetes with hyperinsulinemia or reinstatement of insulin therapy may have the potential to reduce endogenous natriuretic pathway activation post-RYGB. Despite its small sample size, strengths of the present study include the controlled dietary setting, the controlled collection of the 24-hour urine sample and fasting and postprandial blood samples, and the coverage of weight stable and dynamic weight loss phases before and after surgery. The cohort data and sample bank that allowed us to address the specific research question posed here was established with the primary intention of generating data for a focused study on energy expenditure. Therefore, certain gaps in the data collection exist that limit the scope of interpretations. For example, ad libitum water intake was not measured in the study, the specific sodium content of the diet was not quantified, and blood pressure measurements were not taken during the study visits. That said, the
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critical factor was to ensure that equivalent sodium loading occurred in nonhypertensives, and this was achieved with the study design. Furthermore, the lack of a control group achieving similar weight loss does limit our ability to estimate the relative contribution of bypass-specific phenomena to the overall improvements in sodium excretion occurring with weight loss. Such a comparison may be best approached through comparative experimental animal studies in which weight matching can be robustly achieved with lower variance. Calculation of eGFR, clearance, and FE-Na using cystatin C may also be preferable in studies involving significant weight loss, although in the present study the lack of significant differences in serum creatinine allows the data to be interpreted with confidence. Future studies in animal models should focus on profiling what specific changes in gene expression and protein function underpin the natriuretic effect of RYGB to narrow the list of candidate effectors to profile in the blood. Complementary clinical research studies involving direct intestinal installation of sodium chloride plus or minus different macronutrient stimuli coupled to blood sampling for gut hormones and assessment of urinary sodium excretion could follow to help pinpoint mechanisms and mediators in humans. In this context, the inclusion of peptide hormone receptor antagonists could be incorporated in crossover studies to profile the specific involvement of particular enteroendocrine hormones (e.g., use of Exendin 9–39 to block the effect of GLP-1). Conclusion The present manuscript provides evidence that FE-Na is enhanced after RYGB and may be of mechanistic importance in the better blood pressure lowering effects of this procedure versus other bariatric interventions. A credible working hypothesis for interrogation in future studies is that this phenomenon relies on enhancement of natriuretic gut– kidney signaling after intestinal bypass. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. Acknowledgments Financial support came from a Swedish Research Council award to L.F.(K2010-55 X-21432-01-2), The Gothenburg Medical Association (M.W.), The Sahlgreska University Hospital (L.F.), and a Science Foundation Ireland award to C.l.R. (12/YI/B2480). References [1] Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med 2007;357(8):753–61.
[2] Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357 (8):741–52. [3] Docherty NG, le Roux CW. Improvements in the metabolic milieu following Roux-en-Y gastric bypass and the arrest of diabetic kidney disease. Exp Physiol 2014;99(9):1146–53. [4] Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351(26):2683–93. [5] Hofso D, Nordstrand N, Johnson LK, et al. Obesity-related cardiovascular risk factors after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention. Eur J Endocrinol 2010;163(5):735–45. [6] Martins C, Strommen M, Stavne OA, Nossum R, Marvik R, Kulseng B. Bariatric surgery versus lifestyle interventions for morbid obesity–changes in body weight, risk factors and comorbidities at 1 year. Obes Surg 2011;21(7):841–9. [7] Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA 2013;309(21):2240–9. [8] Ahmed AR, Rickards G, Coniglio D, et al. Laparoscopic Roux-en-Y gastric bypass and its early effect on blood pressure. Obes Surg 2009;19(7):845–9. [9] Hallersund P, Sjostrom L, Olbers T, et al. Gastric bypass surgery is followed by lowered blood pressure and increased diuresis - long term results from the Swedish Obese Subjects (SOS) study. PloS One. 2012;7(11):e49696. [10] Courcoulas AP, Christian NJ, Belle SH, et al. Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity. JAMA 2013;310(22):2416–25. [11] Lennane RJ, Carey RM, Goodwin TJ, Peart WS. A comparison of natriuresis after oral and intravenous sodium loading in sodiumdepleted man: evidence for a gastrointestinal or portal monitor of sodium intake. Clin Sci Mol Med 1975;49(5):437–40. [12] Michell AR, Debnam ES, Unwin RJ. Regulation of renal function by the gastrointestinal tract: potential role of gut-derived peptides and hormones. Annu Rev Physiol 2008;70:379–403. [13] Celik F, Ahdi M, Meesters EW, van de Laar A, Brandjes DP, Gerdes VE. The longer-term effects of Roux-en-Y gastric bypass surgery on sodium excretion. Obes Surg 2013;23(3):358–64. [14] Taylor JA, Christenson RH, Rao K, Jorge M, Gottlieb SS. B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide are depressed in obesity despite higher left ventricular end diastolic pressures. Am Heart J 2006;152(6):1071–6. [15] Abrahamsson N, Engstrom BE, Sundbom M, Karlsson FA. Gastric bypass surgery elevates NT-ProBNP levels. Obes Surg 2013;23 (9):1421–6. [16] Werling M, Fandriks L, Olbers T, et al. Roux-en-Y gastric bypass surgery increases respiratory quotient and energy expenditure during food intake. PloS One. 2015;10(6):e0129784. [17] Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604–12. [18] Lemoine S, Guebre-Egziabher F, Sens F, et al. Accuracy of GFR estimation in obese patients. Clin J Am Soc Nephrol 2014;9 (4):720–7. [19] Rojas-Vega L, Gamba G. Mini-review: regulation of the renal NaCl cotransporter by hormones. Am J Physiol Renal Physiol 2016;310 (1):F10–4. [20] Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesityinduced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res 2015;116(6):991–1006. [21] Sugerman H, Windsor A, Bessos M, Wolfe L. Intra-abdominal pressure, sagittal abdominal diameter and obesity comorbidity. J Intern Med 1997;241(1):71–9.
Gastric Bypass Increases Urinary Sodium Excretion / Surgery for Obesity and Related Diseases ] (2017) 00–00 [22] Foster MC, Hwang SJ, Porter SA, Massaro JM, Hoffmann U, Fox CS. Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study. Hypertension 2011;58(5):784–90. [23] Carlyle M, Jones OB, Kuo JJ, Hall JE. Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension 2002;39(2 Pt 2):496–501. [24] Marcus Y, Shefer G, Stern N. Adipose tissue renin-angiotensinaldosterone system (RAAS) and progression of insulin resistance. Mol Cell Endocrinol 2013;378(1-2):1–14. [25] Nagase M, Fujita T. Role of Rac1-mineralocorticoid-receptor signalling in renal and cardiac disease. Nat Rev Nephrol 2013;9(2):86–98. [26] Savoia C, Volpe M, Alonzo A, Rossi C, Rubattu S. Natriuretic peptides and cardiovascular damage in the metabolic syndrome: molecular mechanisms and clinical implications. Clin Sci 2009;118 (4):231–40. [27] Standeven KF, Hess K, Carter AM, et al. Neprilysin, obesity and the metabolic syndrome. Int J Obes 2011;35(8):1031–40. [28] le Roux CW, Welbourn R, Werling M, et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann Surg 2007;246(5):780–5. [29] Gutzwiller JP, Tschopp S, Bock A, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab 2004;89(6):3055–61.
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[30] Crajoinas RO, Oricchio FT, Pessoa TD, et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagonlike peptide-1. Am J Physiol Renal Physiol 2011;301(2):F355–63. [31] Rieg T, Gerasimova M, Murray F, et al. Natriuretic effect by exendin4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. Am J Physiol Renal Physiol 2012;303(7):F963–71. [32] Kutina AV, Golosova DV, Marina AS, Shakhmatova EI, Natochin YV. Role of vasopressin in the regulation of renal sodium excretion: interaction with glucagon-like peptide-1. J Neuroendocrinol 2016;28(4). [33] Liang Z, Wu Q, Chen B, Yu P, Zhao H, Ouyang X. Effect of laparoscopic Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus with hypertension: A randomized controlled trial. Diabetes Res Clin Pract 2013;101(1):50–6. [34] Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Eng J Med 2016;375 (4):311–22. [35] Kim M, Platt MJ, Shibasaki T, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med 2013;19(5):567–75. [36] Klisic J, Hu MC, Nief V, et al. Insulin activates Na(þ)/H(þ) exchanger 3: biphasic response and glucocorticoid dependence. Am J Physiol Renal Physiol 2002;283(3):F532–9.
Original article
Urinary sodium excretion after gastric bypass surgery Neil G. Docherty, B.Sc., Ph.D.a,b,*, Lars Fändriks, M.D., Ph.D.a, Carel W. le Roux, M.B.Ch.B., M.Sc., F.R.C.P., F.R.C.Path., Ph.D.a,b,c, Peter Hallersund, M.D., Ph.D.a, Malin Werling, M.D., Ph.D.a a
Department of Gastrosurgical Research & Education, Institute of Clinical Sciences Sahlgrenska Academy at University of Gothenburg Sahlgrenska University Hospital, Gothenburg, Sweden b Diabetes Complications Research Centre, Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland c Investigative Science, Imperial College London, London, UK Received January 24, 2017; revised March 9, 2017; accepted April 3, 2017
Abstract
Background: Gut–kidney signaling is implicated in sodium homeostasis and thus blood pressure regulation. Roux-en-Y gastric bypass (RYGB) surgery for morbid obesity confers a pronounced and long-lasting blood pressure lowering effect in addition to significant weight loss. Objectives: We set out to establish whether RYGB is associated with an intrinsic change in urinary sodium excretion that may contribute to the reported blood pressure lowering effects of the procedure. Setting: University hospital Methods: Five female patients (age range: 28–50 yr) without metabolic or hypertensive co-morbidities were included in a study involving four 24-hour residential visits: once before surgery and 10 days, 3 months, and 20 months after surgery. Creatinine and sodium were measured in fasting plasma samples and 24-hour urine samples and creatinine clearance, estimated glomerular filtration rate, and indices of urinary sodium excretion were calculated. Fasting and 60-minute postprandial blood samples from each study day were assayed for pro-B-type natriuretic peptide (NT-proBNP). Results: Increases in weight-normalized urinary sodium excretion of up to 2.3-fold in magnitude occurred at 20 months after surgery. Median fractional excretion of sodium at 20 months was double that seen before surgery. Fasting NT-proBNP levels were stable or increased (1.5- to 5-fold). Moreover, a small postprandial increase in NT-proBNP was observed after surgery. Conclusions: Renal fractional excretion of sodium is increased after RYGB. A shift toward increased postoperative basal and meal associated levels of NT-proBNP coincides with increased urinary sodium excretion. The data support a working hypothesis that an enhanced natriuretic gut– kidney signal after RYGB may be of mechanistic importance in the blood pressure lowering effects of this procedure. (Surg Obes Relat Dis 2017;]:00–00.) r 2017 American Society for Metabolic and Bariatric Surgery. All rights reserved.
Keywords:
Gastric bypass; Sodium; Urine; Natriuresis; Weight loss
*
Correspondence: Neil G. Docherty, B.Sc., Ph.D., Department of Gastrosurgical Research & Education, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, SE41345 Gothenburg, Sweden. E-mail: [email protected]
The well-described mortality benefits of bariatric surgery are accounted for in part by reductions in cardiovascular disease [1,2]. The combination of improvements in lipid profile and systolic blood pressure after surgery likely explain much of the risk reduction vis-à-vis myocardial
http://dx.doi.org/10.1016/j.soard.2017.04.002 1550-7289/r 2017 American Society for Metabolic and Bariatric Surgery. All rights reserved.
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N. G. Docherty et al. / Surgery for Obesity and Related Diseases ] (2017) 00–00
infarction and stroke [3,4]. Roux-en-Y gastric bypass (RYGB) is superior in achieving blood pressure targets versus several intensified lifestyle modification approaches [5–7]. Reductions in blood pressure precede weight loss after RYGB and occur as early as the first postoperative week [8]. The Longitudinal Assessment of Bariatric Surgery consortium reports a dissociation in 3-year rates of remission of hypertension between RYGB (38.2%) and gastric banding (17.4%). We recently reported that in the Swedish Obese Subjects (SOS) study, a relative reduction in blood pressure (3.6 mmHg systolic and 3.5 mmHg diastolic) is sustained at 10 years after surgery in patients who underwent RYGB but not in those who underwent gastric banding or vertical banded gastroplasty [4,9]. These data suggest that an intrinsic blood pressure lowering pathway is activated by the particulars of the RYGB anatomic reconfiguration [10]. Oral sodium chloride administration increases urinary sodium excretion to a greater extent than iso-osmolar intravenous infusion [11]. This raises the possibility that a natriuretic gut–kidney axis is operative in normal physiology as part of the homeostatic control of plasma sodium, serving to buffer against potential pressor effects of dietary salt loading. Enteroendocrine hormones including glucagon-like peptide 1 (GLP-1), vasointestinal polypeptide, gastrin/cholecystokinin, peptide YY, and uroguanylin have been reported to provoke a natriuretic response, and one or more of these may be particularly important during the postprandial period (e.g., GLP-1) [12]. When controlling for weight, the blood pressure lowering effects of RYGB observed in SOS were associated with a 20 mmol delta increase in 24-hour urinary sodium excretion versus baseline [9]. In a series of 33 RYGB patients followed prospectively for 22 months, reductions in body weight and 6 and 7 mmHg decreases in systolic and diastolic pressure, respectively, were associated with urinary sodium loss [13]. Obesity is associated with hypervolemia but is paradoxically associated with reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and this may contribute to essential hypertension [14]. Fasting NT-proBNP levels are increased within normal range after Roux-en Y gastric bypass (RYGB) [15] leading, to the suggestion that BNP may be a mediator or sentinel of a primary natriuretic effect of RYGB. Demonstration of a blood pressure lowering shift in the tone and responsivity of the intrinsic gut–kidney natriuretic axis after RYGB is suggested by existing data. That said, the phenomenon has not been reported in a setting that controls for confounders such as variations in dietary sodium intake. The data from the SOS study indicated that, while in the free-living context increases in natriuresis do occur after RYGB, these coincided with reports of increased dietary sodium intake [4,9]. Whether increases in sodium intake arose as a cause or consequence of changes in
urinary sodium excretion could not be disambiguated in analysis of the data. We therefore sought to build on the existing data by conducting a controlled longitudinal study. We hypothesized that the fractional excretion of sodium (FE-Na) would increase in individuals after RYGB, thus proffering an explanation for increases in urinary sodium excretion. This hypothesis could be directly addressed in the controlled setting of the present study given its longitudinal, pre- and postsurgery, repeated-measure design and the fact that dietary sodium intake was standardised during 24-hour urine collections. Moreover, we sought to ascertain whether there were temporal and meal-associated changes in NT-proBNP levels after RYGB, which may be of mechanistic importance as an intermediate in the gut–kidney axis. Materials and methods The study was performed at the Department of Gastrosurgical Research & Education, Sahlgrenska University Hospital, Gothenburg, Sweden in accordance with the Declaration of Helsinki and under ethical approval from the regional ethical review board in Sweden (no: 740-10). Participants were fully briefed on the study protocol and provided written consent. Participants were recruited from clinic at the Sahlgrenska University Hospital, Gothenburg, Sweden. To be included in the study, participants needed to have a body mass index (BMI) that met the eligibility criteria for surgical intervention (participant BMI range: 39.1–44.8 kg/m2). Furthermore, recruitment was restricted to those who were nonsmokers, were not currently on any medications, with stable weight during the 3 months preceding study initiation, and not diagnosed with any obesity-related co-morbidities, including diabetes and hypertension. After enrollment, participants were prescribed multivitamin and mineral supplements but were not required to follow any presurgical weight loss regimen. Study visits were scheduled to allow for synchronization of participants with regard to phase of menstrual cycle. RYGB was performed laparoscopically and involved fashioning a gastric pouch (10–20 mL) connected to the jejunum in an antecolic–antegastric Roux-en-Y construction. Roux-limb length was 75 cm, and the entero–entero anastomosis was created 30 cm distal from the ligament of Treitz. Study visits Participants attended four 24-hour study visits; preoperatively (weight stable phase: visit 1), 10 days and 3 months after surgery (weight loss phase: visits 2 and 3), and 20 months after surgery (weight stable phase 2: visit 4). The residential setting was a 3 3 3 m hotel style room equipped to permit indirect calorimetry recordings from exhausted air leaving the room. This “metabolic chamber”
Gastric Bypass Increases Urinary Sodium Excretion / Surgery for Obesity and Related Diseases ] (2017) 00–00
design was used to assess energy expenditure, the results of which have previously been reported [16]. The evening before visits 1 and 4, participants consumed a standardized meal of mashed potatoes and meatballs between 19:00 and 20:00. The evening before visits 2 and 3, participants consumed a semiliquid meal containing 200 kcal and 300 kcal, respectively. Participants arrived at the study site at 07:30 on the morning of study visits after having fasted (11 hours) and had height, weight, and body composition determined by DEXA scanning (LUNAR radiation, Madison WI, USA). A standardized 400 kcal breakfast was then consumed outside of the chamber, and serial fasting and postprandial blood samples were collected. In the metabolic chamber, participants received a fixed lunch at 13:30, a fixed dinner at 18:00, a snack at 21:00, and a fixed breakfast the following morning at 08:40. Portion size and caloric content were reduced at visits 2 and 3 relative to visits 1 and 4 for a total calorie intake of 1000 kcal at visit 2 and 1250 kcal at visit 3 versus 1920 kcal at visits 1 and 4. Dietary intake including sodium content was thus equivalent for all participants at each visit (Table 1).
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ELISA module on the Cobas 8000 autoanalyzer (Roche Diagnostics, Hoffmann-La Roche, Basel, Switzerland). Calculation of urinary sodium excretion rate and FE-Na Urinary sodium excretion rate was determined in mEq/24 hr/kg of weight. To calculate FE-Na, the following formula was used: (Urine Na / Serum Na) / (Urine Cr / Serum Cr) 100. Calculation of creatinine clearance and estimated glomerular filtration rate Creatinine clearance was calculated using the formula (urinary creatinine/serum creatinine) (24-hour diuresis / 1440) and normalized by bodyweight to generate mL/min/kg values. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula [17], which has been validated for use in patients with obesity [18]. Statistical analyses
Determination of sodium and creatinine in urine and plasma Fasting plasma samples and aliquots of 24-hour urine collections were analyzed for sodium and creatinine by routine biochemistry on an auto-analyzer platform at the Department of Clinical Biochemistry, St Vincent’s University Hospital, Dublin, Ireland. NT-proBNP electrochemiluminescence NT-proBNP is the N-terminal cleavage product of proBNP and has a plasma half-life of 120 minutes, 6 times that of the active peptide BNP hormone, thus making its measurement a more suitable index of BNP release. NT-proBNP was measured by electrochemiluminescent
1 2 3 4 5
Results Weight loss, urinary flow rate, and urinary sodium excretion after RYGB
Table 1 Study visit protocol Participant
For inferential statistics, the sample size precluded the use of normality tests, and the data are summarized using the median and interquartile range, the latter being bracketed in the text. Time-dependent changes in the profiles of each parameter studied are presented graphically and were assessed by nonparametric repeated measures analysis of variance. Statistical comparisons between preoperative and 20-month postoperative weight stability were made by paired analyses (Wilcoxon signed-rank test) and unpaired group comparison (Mann–Whitney U test). In all cases, a value of P o .05 was considered statistically significant. All analyses were conducted using GraphPad PRISM Version 6.
Weight (kg)
BMI (kg/m2)
% BMI loss
0m
20 m
0m
20 m
0–20 m
124.1 115.6 122.2 117.8 111.4
63.0 82.5 83.1 76.2 77.9
44.8 41.4 41.3 39.1 41.9
22.3 30.3 28.1 25.5 29.5
50.1 26.8 32.0 34.9 29.6
BMI ¼ body mass index. Participants were studied for approximately 36 hours in total, including a 24-hour residential period in a metabolic chamber. Dietary intake was identical between participants at each visit.
At 20-month follow-up, the average percentage reduction in BMI was 34.7 ⫾ 9.1% (Table 2). Median urinary output at visit 1 was 1800 (1055) mL/24 hr. This fell significantly at 1 week after surgery and stabilized at 20 months after surgery at visit 4 at 1300 (1018) mL/24 hr or 20.6 (9) mL/kg/24 hr when controlled for weight (Fig. 1). Urinary sodium excretion was significantly decreased 1 week after surgery at visit 2 versus values obtained at visit 1. A significant increase versus visit 2 was observed at visit 4. When controlled for weight and compared across weight stable phases (visit 1 versus visit 4), a significant 2.3-fold
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eGFR, creatinine clearance, and FE-Na at weight stability before and after RYGB
Table 2 Weight loss after RYGB Time
Activity
Location
evening before visit 19:00 07:30 08:15 08:30 411:00
Standardized evening meal Fasting blood sampling DEXA Standardized breakfast Postprandial blood sampling Standardized lunch Standardized dinner Standardized snack Basal metabolic rate recording Standardized breakfast
Home
13:30 18:00 21:00 07:30 08:40
Research facility (outside metabolic chamber)
Research facility (Inside metabolic chamber þ24 hr urine)
RYGB ¼ Roux-en-Y gastric bypass; DEXA ¼ dual-energy X-ray absorptiometry. All patients reported marked reductions in total weight loss with attendant body mass index (BMI) reduction. The average percentage reduction in BMI was 34.7 ⫾ 9.1% (n ¼ 5).
increase in median urinary sodium excretion was evident by visit 4 1.9 (1.7) mEq/kg/24 hr versus .9(0.2) mEq/kg/24 hr (Fig. 2).
We used the Chronic Kidney Disease Epidemiology Collaboration equation to calculate eGFR. Although we used creatinine rather than cystatin C in the equation, percentage changes in serum creatinine at the fourth visit 20 months after surgery were minor (mean 6.7%, min 0 and max 10%) and no significant difference in creatinine clearance was found (1.07 [0.38] mL/min/kg versus 1.29 [0.81] mL/min/kg; Fig. 3A). Calculated eGFR was not significantly different between determinations made at visit 1 and visit 4 (95 [24.5] mL/min/1.73 m2 versus 104 [16.5] mL/min/1.73 m2; Fig. 3B). Median FE-Na values significantly increased versus baseline values from visit 1 to 20 months after surgery, doubling from .3 (.1) to .6 (.3) (Fig. 3). Relationship between NT-proBNP levels and changes in FE-Na after RYGB By visit 4 at 20 months after surgery, 4 out of 5 participants reported fasting levels of NT-proBNP that were equivalent to or elevated (1.5- to 5-fold) versus baseline at
Fig. 1. Changes in urine output after Roux-en-Y gastric bypass. (A) A 24-hour urine collection was made at each study visit, and flow rates were determined. Urinary output over 24 hours was compared at weight stability between visits 1 and visit 4 either without controlling for weight (B) or normalizing for weight (C). *P o .05 versus preoperative baseline (visit 1). #P o .05 at baseline (visit 1) versus 20-month postoperative (visit 4) (n ¼ 5).
Gastric Bypass Increases Urinary Sodium Excretion / Surgery for Obesity and Related Diseases ] (2017) 00–00
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Fig. 2. Changes in urinary sodium excretion after Roux-en-Y gastric bypass. (A) Urinary sodium concentration was calculated in 24-hour urine collections from each study visit and excretion rates determined using concentration values and flow rates. Urinary sodium excretion was compared at weight stability between visits 1 and visit 4 either without controlling for weight (B) or normalizing for weight (C). *P o .05 versus preoperative (visit 1). #P o .05 1-week postoperative (visit 2) versus 20-month postoperative (visit 4). &P o .05 at preoperative baseline (visit 1) versus 20 months’ postoperative (visit 4) (n ¼ 5).
visit 1. All patients reported a characteristic profile of shifting from either no change or a minor reduction (up to 10%) in NT-proBNP levels at 60 minutes after the preoperative test meal to values up to 10% higher than baseline 60 minutes after test meal administration 20 months after surgery. Notably, one patient reported a 50% decrease in baseline fasting NT-proBNP levels at 20 months after surgery and was the only participant not to show a marked increase in FE-Na at that time point (Fig. 4). Discussion We previously stated that long-term improvements in blood pressure in the SOS study are more marked in recipients of RYGB and when controlled for weight loss and are accompanied by small but durable increases in diuresis and urinary sodium excretion not seen with other bariatric procedures [9]. The present study sought to further investigate this phenomenon in the setting of a controlled study in which evidence of differences in renal sodium handling and NT-pro-BNP could be monitored from the preoperative period to the period of stable maximal weight
loss. The study was conducted with participants without evidence of hypertension as we hypothesised that an intrinsic physiologic shift in renal sodium handling characterized by increased FE-Na occurs after RYGB and should be best observed under controlled conditions in nonhypertensives. In summary, we report that under conditions of 24-hour residential dietary control, a cohort of 5 nonhypertensive females with obesity had significantly increased weightnormalized measures of diuresis and urinary sodium excretion. Moreover, we show that this may be dependent on altered renal tubular sodium handling because increases in FE-Na are observed in the absence of alterations in eGFR or creatinine clearance rates. We also measured fasting and postprandial NT-proBNP and confirmed previous studies that reported modest increases within the normal reference range in humans after RYGB [15]. Notably, when data are examined without adjusting for altered weight after surgery, urine volume is decreased and changes in urinary sodium excretion do not reach statistical significance. It may be argued that by factoring in BMI, an artefact is introduced that creates an apparent diuresis after weight loss. This is countered by our previous observations
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Fig. 3. Fractional excretion of sodium after Roux-en-Y gastric bypass. (A) Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate. (B) Creatinine clearance and (C) fractional excretion of sodium were assessed and compared between visits 1 and 4. *P o .05 at preoperative baseline (visit 1) versus 20-month postoperative (visit 4) (n ¼ 5).
in the SOS study showing that delta increase in diuresis at 2 years after RYGB was 200% that seen after gastric banding procedures, despite intergroup differences in BMI
Fig. 4. Fasting and postprandial N-terminal pro-brain natriuretic peptide (NT-proBNP) after Roux-en-Y gastric bypass. (A) NT-proBNP levels were measured in plasma at fasting and 60 minutes after initiation of a 400 kcal standardized breakfast at visit 1 (preoperative baseline) and visit 4 (20 months postoperative). (B) Paired comparison of percentage change in NTproBNP levels from 0 to 60 minutes during a fixed meal test at visit 1 and visit 4.
reduction being only in the region of 20%. It could be suggested that reductions in lean muscle mass after RYGB could interfere with the calculation of FE-Na by reducing serum creatinine levels. However, serum creatinine levels were not significantly decreased in this study after RYGB. How, then, are the changes in sodium excretion that occur after RYGB elicited? Plasma sodium is freely filtered at the glomerulus at a rate proportional to the glomerular filtration fraction, which under normal circumstances is approximately 20% of renal plasma flow. Approximately 99.5% of the filtered sodium load is reclaimed from the nascent urine during its journey through the renal tubule. The majority (90%) of reabsorption occurrs in the renal proximal tubule and thick ascending limb of the loop of Henle. Fine-tuning of variations in the excreted load are determined at the distal tubule, connecting tubule, and collecting duct through the actions of peptide and steroid hormones, and these regulated pathways influence circulatory volume. Under normal physiologic conditions, FE-Na, as it pertains to cardiovascular control, is usually modulated within a narrow range that oscillates around a value of .5. The balance of activity between 2 principal opposing neurohormonal systems (the renin angiotensin aldosterone system and the cardiac natriuretic peptide system) plays a critical role in determining the balance of fine-tuning of
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sodium excretion [19]. Regulation of the functioning of these systems is multi-layered, with weight and fat distribution playing an important modulatory role in the balance. Alleviation of obesity after RYGB can, via numerous mechanisms, foster reductions in blood pressure through effects on the opposing pressor and natriuretic pathways, which modulate renal sodium handling in favor of natriuresis [20]. Reductions in intra-abdominal pressure [21] and retroperitoneal and renal sinus fat [22] associated with obesity after RYGB could alleviate intrarenal pressure and oppose slow-tubular flow rate–based augmentation of sodium reabsorption and reduce renal renin release. Moreover, attenuation of renal renin release could also be affected via decreases in circulating leptin concentrations, which would serve to reverse obesity-associated increases in renal efferent sympathetic nerve activity [23]. A potential role for reductions in circulating angiotensinogen due to reduced adipose tissue could also be implicated [24]. RYGB-induced weight loss could also redress pathogenic enhancement of renal mineralocorticoid receptor activation, which is described as increasing distal tubular sodium reabsorption in obesity [25]. On the other side of the equation, RYGB-induced weight loss may reverse obesity-associated reductions in basal and volume loading–primed release of natriuretic peptides [26] and reduce obesity-associated increases in circulating neprilysin, the major peptidase involved in the degradation of natriuretic peptides [27]. Thus, although RYGB may affect blood pressure control through purely weight loss–driven pathways, the presence of an enhanced gut–kidney natriuretic axis after RYGB is a conceptually interesting proposition and may be the additional factor that explains the differential effects of restrictive versus intestinal bypass–based bariatric procedures in relation to blood pressure lowering. The potential for exaggerated activity of a gut–kidney natriuretic axis after RYGB also draws a parallel to the effect of RYGB on enteroinsular signaling, which is characterized by pronounced augmentation of the gut–pancreas insulin secretory “incretin” signal secondary to the actions of hormones such GLP-1. GLP-1 may be implicated in enhanced sodium excretion after RYGB. GLP-1 is increased after RYGB but not after purely restrictive bariatric procedures [16,28]. Infusion of GLP-1 over 3 hours doubles urinary sodium excretion [29] and is associated with a reduction in urinary Hþ excretion, implying a role for the inhibition of the proximal tubular sodium–hydrogen antiporter 3 (NHE3) in this effect. Ex vivo tubular micropuncture and gene expression/activity studies in rats support this hypothesis [30]. This response is sustained in a mouse model of obesity and diabetes in response to exendin-4 administration [31]. Oral sodium loading in rats increases both GLP-1 and natriuresis, and administration of the GLP-1 receptor agonist Exendin-4 in rats increases the FE-Na [32].
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Comparing RYGB with best medical care plus or minus exenatide (GLP-1 receptor agonist) shows a significant reduction from 2.8 to .5 in the mean number of blood pressure lowering medications required after 12 months [33]. Notably, an intermediate effect was observed when exenatide was added to usual care, implying that exaggerated postprandial gut hormone responses after RYGB (e.g., GLP-1) may be implicated in cardiovascular improvements. This is coherent with the emerging data demonstrating that at medium-term follow-up, cardiovascular mortality of patients with type 2 diabetes treated with liraglutide is reduced by 22% [34]. A gut–heart–kidney natriuretic axis involving GLP-1 stimulation of natriuretic peptide release and subsequent cyclic GMP–dependent induction of natriuresis has recently been elucidated in mice [35]. This may be mediated via inhibition of the epithelial sodium channel in the distal nephron. Thus, the existence of such an axis should be further investigated after RYGB in humans. Such studies may extend knowledge of the multifunctional nature of the altered enteroendocrine signals generated in the gut after RYGB. Although the results of the present study are interesting and appear to support and extend previous findings, questions remain as to whether the changes seen in urinary sodium excretion are sufficient to contribute to the improvements in hypertension seen after RYGB. Better understanding of this and the mechanisms involved could hold potential for guiding the development of new pharmacologic or dietary approaches to promoting natriuresis. A pertinent question in the context of diabetes is whether discontinuation of exogenous insulin or reduction in endogenous hyperinsulinemia after surgery serve to enhance or unmask the natriuretic effects of RYGB in diabetics. Exogenous insulin drives renal sodium reclamation through direct effects on renal sodium transporter expression and activity (e.g., NHE3) [36]. On the flip side, relapse of diabetes with hyperinsulinemia or reinstatement of insulin therapy may have the potential to reduce endogenous natriuretic pathway activation post-RYGB. Despite its small sample size, strengths of the present study include the controlled dietary setting, the controlled collection of the 24-hour urine sample and fasting and postprandial blood samples, and the coverage of weight stable and dynamic weight loss phases before and after surgery. The cohort data and sample bank that allowed us to address the specific research question posed here was established with the primary intention of generating data for a focused study on energy expenditure. Therefore, certain gaps in the data collection exist that limit the scope of interpretations. For example, ad libitum water intake was not measured in the study, the specific sodium content of the diet was not quantified, and blood pressure measurements were not taken during the study visits. That said, the
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N. G. Docherty et al. / Surgery for Obesity and Related Diseases ] (2017) 00–00
critical factor was to ensure that equivalent sodium loading occurred in nonhypertensives, and this was achieved with the study design. Furthermore, the lack of a control group achieving similar weight loss does limit our ability to estimate the relative contribution of bypass-specific phenomena to the overall improvements in sodium excretion occurring with weight loss. Such a comparison may be best approached through comparative experimental animal studies in which weight matching can be robustly achieved with lower variance. Calculation of eGFR, clearance, and FE-Na using cystatin C may also be preferable in studies involving significant weight loss, although in the present study the lack of significant differences in serum creatinine allows the data to be interpreted with confidence. Future studies in animal models should focus on profiling what specific changes in gene expression and protein function underpin the natriuretic effect of RYGB to narrow the list of candidate effectors to profile in the blood. Complementary clinical research studies involving direct intestinal installation of sodium chloride plus or minus different macronutrient stimuli coupled to blood sampling for gut hormones and assessment of urinary sodium excretion could follow to help pinpoint mechanisms and mediators in humans. In this context, the inclusion of peptide hormone receptor antagonists could be incorporated in crossover studies to profile the specific involvement of particular enteroendocrine hormones (e.g., use of Exendin 9–39 to block the effect of GLP-1). Conclusion The present manuscript provides evidence that FE-Na is enhanced after RYGB and may be of mechanistic importance in the better blood pressure lowering effects of this procedure versus other bariatric interventions. A credible working hypothesis for interrogation in future studies is that this phenomenon relies on enhancement of natriuretic gut– kidney signaling after intestinal bypass. Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article. Acknowledgments Financial support came from a Swedish Research Council award to L.F.(K2010-55 X-21432-01-2), The Gothenburg Medical Association (M.W.), The Sahlgreska University Hospital (L.F.), and a Science Foundation Ireland award to C.l.R. (12/YI/B2480). References [1] Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med 2007;357(8):753–61.
[2] Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357 (8):741–52. [3] Docherty NG, le Roux CW. Improvements in the metabolic milieu following Roux-en-Y gastric bypass and the arrest of diabetic kidney disease. Exp Physiol 2014;99(9):1146–53. [4] Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351(26):2683–93. [5] Hofso D, Nordstrand N, Johnson LK, et al. Obesity-related cardiovascular risk factors after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention. Eur J Endocrinol 2010;163(5):735–45. [6] Martins C, Strommen M, Stavne OA, Nossum R, Marvik R, Kulseng B. Bariatric surgery versus lifestyle interventions for morbid obesity–changes in body weight, risk factors and comorbidities at 1 year. Obes Surg 2011;21(7):841–9. [7] Ikramuddin S, Korner J, Lee WJ, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA 2013;309(21):2240–9. [8] Ahmed AR, Rickards G, Coniglio D, et al. Laparoscopic Roux-en-Y gastric bypass and its early effect on blood pressure. Obes Surg 2009;19(7):845–9. [9] Hallersund P, Sjostrom L, Olbers T, et al. Gastric bypass surgery is followed by lowered blood pressure and increased diuresis - long term results from the Swedish Obese Subjects (SOS) study. PloS One. 2012;7(11):e49696. [10] Courcoulas AP, Christian NJ, Belle SH, et al. Weight change and health outcomes at 3 years after bariatric surgery among individuals with severe obesity. JAMA 2013;310(22):2416–25. [11] Lennane RJ, Carey RM, Goodwin TJ, Peart WS. A comparison of natriuresis after oral and intravenous sodium loading in sodiumdepleted man: evidence for a gastrointestinal or portal monitor of sodium intake. Clin Sci Mol Med 1975;49(5):437–40. [12] Michell AR, Debnam ES, Unwin RJ. Regulation of renal function by the gastrointestinal tract: potential role of gut-derived peptides and hormones. Annu Rev Physiol 2008;70:379–403. [13] Celik F, Ahdi M, Meesters EW, van de Laar A, Brandjes DP, Gerdes VE. The longer-term effects of Roux-en-Y gastric bypass surgery on sodium excretion. Obes Surg 2013;23(3):358–64. [14] Taylor JA, Christenson RH, Rao K, Jorge M, Gottlieb SS. B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide are depressed in obesity despite higher left ventricular end diastolic pressures. Am Heart J 2006;152(6):1071–6. [15] Abrahamsson N, Engstrom BE, Sundbom M, Karlsson FA. Gastric bypass surgery elevates NT-ProBNP levels. Obes Surg 2013;23 (9):1421–6. [16] Werling M, Fandriks L, Olbers T, et al. Roux-en-Y gastric bypass surgery increases respiratory quotient and energy expenditure during food intake. PloS One. 2015;10(6):e0129784. [17] Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604–12. [18] Lemoine S, Guebre-Egziabher F, Sens F, et al. Accuracy of GFR estimation in obese patients. Clin J Am Soc Nephrol 2014;9 (4):720–7. [19] Rojas-Vega L, Gamba G. Mini-review: regulation of the renal NaCl cotransporter by hormones. Am J Physiol Renal Physiol 2016;310 (1):F10–4. [20] Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesityinduced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res 2015;116(6):991–1006. [21] Sugerman H, Windsor A, Bessos M, Wolfe L. Intra-abdominal pressure, sagittal abdominal diameter and obesity comorbidity. J Intern Med 1997;241(1):71–9.
Gastric Bypass Increases Urinary Sodium Excretion / Surgery for Obesity and Related Diseases ] (2017) 00–00 [22] Foster MC, Hwang SJ, Porter SA, Massaro JM, Hoffmann U, Fox CS. Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study. Hypertension 2011;58(5):784–90. [23] Carlyle M, Jones OB, Kuo JJ, Hall JE. Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension 2002;39(2 Pt 2):496–501. [24] Marcus Y, Shefer G, Stern N. Adipose tissue renin-angiotensinaldosterone system (RAAS) and progression of insulin resistance. Mol Cell Endocrinol 2013;378(1-2):1–14. [25] Nagase M, Fujita T. Role of Rac1-mineralocorticoid-receptor signalling in renal and cardiac disease. Nat Rev Nephrol 2013;9(2):86–98. [26] Savoia C, Volpe M, Alonzo A, Rossi C, Rubattu S. Natriuretic peptides and cardiovascular damage in the metabolic syndrome: molecular mechanisms and clinical implications. Clin Sci 2009;118 (4):231–40. [27] Standeven KF, Hess K, Carter AM, et al. Neprilysin, obesity and the metabolic syndrome. Int J Obes 2011;35(8):1031–40. [28] le Roux CW, Welbourn R, Werling M, et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann Surg 2007;246(5):780–5. [29] Gutzwiller JP, Tschopp S, Bock A, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab 2004;89(6):3055–61.
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[30] Crajoinas RO, Oricchio FT, Pessoa TD, et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagonlike peptide-1. Am J Physiol Renal Physiol 2011;301(2):F355–63. [31] Rieg T, Gerasimova M, Murray F, et al. Natriuretic effect by exendin4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. Am J Physiol Renal Physiol 2012;303(7):F963–71. [32] Kutina AV, Golosova DV, Marina AS, Shakhmatova EI, Natochin YV. Role of vasopressin in the regulation of renal sodium excretion: interaction with glucagon-like peptide-1. J Neuroendocrinol 2016;28(4). [33] Liang Z, Wu Q, Chen B, Yu P, Zhao H, Ouyang X. Effect of laparoscopic Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus with hypertension: A randomized controlled trial. Diabetes Res Clin Pract 2013;101(1):50–6. [34] Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Eng J Med 2016;375 (4):311–22. [35] Kim M, Platt MJ, Shibasaki T, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med 2013;19(5):567–75. [36] Klisic J, Hu MC, Nief V, et al. Insulin activates Na(þ)/H(þ) exchanger 3: biphasic response and glucocorticoid dependence. Am J Physiol Renal Physiol 2002;283(3):F532–9.