Effect of bariatric surgery on normal and abnormal renal function

Surgery for Obesity and Related Diseases 7 (2011) 459 – 464

Original article

Effect of bariatric surgery on normal and abnormal renal function D. P. Schuster, M.D.a,b,*, M. Teodorescu, M.D.b, D. Mikami, M.D.b, K. Foreman, R.N., C.P.N.b, P. Rogers, B.S.c, B. J. Needleman, M.D.b a

Division of Endocrinology and Metabolism, Department of Internal Medicine, Ohio State University Hospitals, Columbus, Ohio b Division of Gastrointestinal and General Surgery, Department of Surgery, Ohio State University Hospitals, Columbus, Ohio c Information Warehouse, Ohio State University Hospitals, Columbus, Ohio Received June 22, 2010; accepted November 12, 2010

Abstract

Background: Obesity has been associated with hypertension, diabetes mellitus, and metabolic syndrome, risk factors for chronic kidney disease. In addition, obesity has been found to have an independent, negative effect on renal function and the progression of renal insufficiency. Methods: The serum creatinine (CR) in 813 patients who had undergone obesity surgery from 2003 to 2009 at a large academic medical center and had been followed up for ⱖ24 months was retrospectively monitored. Renal function, as measured by the CR level, was assessed at baseline and at 6, 12, and ⱖ24 months of follow-up. The groups were stratified by the baseline CR as follows: normal (CR ⬍1.3 mg/dL), mild impairment (CR 1.3–1.6 mg/dL), and moderate impairment (CR ⬎1.6 mg/dL). Results: Of the 813 patients, 757 had a CR ⬍1.3 mg/dL at baseline. Of those 757 patients, 97.6% had maintained a CR of ⬍1.3 mg/dL, 1.3% had a CR of 1.3–1.6 mg/dL, 1.1% had a CR of ⬎1.6 mg/dL (n ⫽ 757) at 6 months of follow-up. At 1 year of follow-up, 99% had maintained a CR of ⬍1.3 mg/dL and 1% had a CR of ⬎1.3% (n ⫽ 509). At 2 years of follow-up, 100% had a CR value of ⬍1.3 mg/ dL (n ⫽ 388). Of the remaining 56 patients, 71.4% had been classified as having mild impairment (CR 1.3–1.6 mg/dL) and 28.5% as having moderate impairment (CR ⬎1.6 mg/dL) before weight loss surgery. Examination of the CR values at ⱖ2 years after weight loss surgery demonstrated that 76.7% had a normal CR level, 12.5% had mild impairment, and 10.7% had moderate impairment. Conclusion: Bariatric surgery does not have a negative effect on renal function as measured by the CR, whether CR at baseline is ⬍1.3 or ⱖ1.3 mg/dL when monitored for ⱖ24 months. For those with impaired renal function and a CR ⱖ1.3 mg/dL, improvement in CR was seen in 76.7% at ⱖ2 years postoperatively, at a point at which the weight loss velocity, hydration, and nutritional status have stabilized. The weight loss associated with bariatric surgery could potentially have a positive effect on renal function at ⱖ24 months, such as was found in the present study by a stable or reduced CR level. The etiology for this might be a direct effect of weight loss on impaired renal function or an indirect effect by reducing the rates of co-morbidities, such as diabetes mellitus and hypertension, both risk factors for renal disease. Additional prospective studies, including weight-matched controls, are needed. (Surg Obes Relat Dis 2011;7:459 – 464.) © 2011 American Society for Metabolic and Bariatric Surgery. All rights reserved.

Keywords:

Bariatric surgery; Creatinine; Renal function

*Correspondence: D. P. Schuster, M.D., Departments of Internal Medicine and Surgery, Ohio State University Hospitals, 491 McCampbell Hall, 1581 Dodd Drive, Columbus, OH 43210. E-mail: [email protected]

Obesity has been linked to a growing number of metabolic and medical co-morbid conditions, including diabetes mellitus (DM), hypertension (HTN), and obstructive sleep apnea, and has been increasingly linked to chronic renal failure. Although the primary effect on renal function seems to be related to co-morbid conditions, especially DM and

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D. P. Schuster et al. / Surgery for Obesity and Related Diseases 7 (2011) 459 – 464

HTN, obesity alone now appears to be a direct and independent risk factor for renal failure [1–5]. After adjusting for the covariants of age, gender, smoking, DM, and baseline glomerular filtration rate, Fox et al. [6] demonstrated a 23% increase in the risk of development of chronic kidney disease with each standard deviation increase in the body mass index (BMI). Hsu et al. [5] reported a greater relative risk (RR) of end-stage renal disease (ESRD) for obese subjects than those of normal weight (overweight, RR 1.87; class 1 obesity, RR 3.57; class 2 obesity, RR 6.12; and morbid obesity, RR 7.07). These associations remain significant after adjustment for DM and HTN [5]. Similarly, participants in health screening programs in the United States have demonstrated a significant positive relationship between BMI and the risk of developing ESRD [7]. Additionally, the age of onset of overweight or obesity before 20 years of age has been shown to play a role in the later development of declining renal function, with and without the presence of DM and HTN [2]. Systemic illnesses, as a sequelae of obesity, such as DM and HTN, play a significant role in the development of ESRD [8]. In an analysis of risk, Ejerblad et al. [2] found the strongest correlation of increased BMI with the risk of diabetic nephropathy and the second strongest correlation with hypertensive nephrosclerosis. Within the Framingham study, obesity alone was thought to account for 78% of essential HTN in men and 65% in women [9]. Furthermore, it has been estimated that DM and HTN together account for ⬎70% of all cases of ESRD [10]. Finally, in the setting of pre-existing renal disease, obesity has been shown to worsen IgA nephropathy, urate nephropathy, and others [11–14]. Renal disease in the setting of obesity often manifests itself as proteinuria, hyperfiltration, and an increased glomerular filtration rate (GFR) [12–14]. However, pathologic changes within the nephron can be seen before overt proteinuria and renal disease [13,14]. Serra et al. [12] provided early insight into the renal structural changes in the setting of morbid obesity. This group performed renal biopsies on morbidly obese patients without overt kidney disease, who were undergoing bariatric surgery. The findings were significant for structural lesions, including enlarged glomeruli, mesangial hypercellularity, podocyte hypertrophy, and/or focal segmental glomerulosclerosis [12]. Although the increase in chronic renal failure has paralleled the increase in the rates of obesity, the mechanisms that lead to renal damage in obesity are not completely understood. Increased renal blood flow, an increased GFR with vasodilation of glomerular afferent arterioles, and microalbuminuria have been demonstrated in the presence of obesity [15,16]. Weight loss and renal function Weight loss has been shown to improve renal function, with decreased proteinuria, decreased glomerular hyperfil-

tration, decreased inflammation, improved blood pressure control, and improved blood glucose control in obese individuals with and without overt kidney disease [17]. However, achieving and maintaining weight loss has continued to be a challenge, especially in a population with limited mobility, limited dietary choices, and/or numerous chronic medical conditions, including renal failure. Given the potential benefits of weight reduction in the setting of chronic renal disease, the National Kidney Foundation has published clinical practice guidelines recommending weight loss for Stage 1– 4 kidney disease if DM is present, a BMI ⬎30 kg/m2, or increased waist circumference. For patients with Stage 5 kidney disease, weight loss has been recommended if obesity precludes transplantation. In the transplant population, it is known that graft survival will be negatively affected by morbid obesity. Given the high failure rate of medical weight loss, bariatric surgery remains the best option for durable weight loss. Numerous studies have demonstrated improvements in blood pressure control, DM, and renal function after bariatric surgery [18 –21]. Whether those with impaired renal function will benefit in the long term from this intervention remains unclear. The objective of the present retrospective chart review was to examine the effect of surgery-induced weight loss on creatinine (CR) in the setting of both normal and impaired renal function at 6, 12, and ⱖ24 months postoperatively. We had few patients with data available at 5 years postoperatively; however, given that the numbers were small, the CR values were combined and analyzed for the 24 – 60-month period as 1 group. Methods After obtaining exempt status from the institutional review board, we conducted a retrospective study of 813 patients who had undergone Roux-en-Y gastric bypass (RYGB) for weight loss from January 2003 to December 2009. The patients were excluded if a baseline CR was not found. The surgical eligibility for bariatric surgery as defined by the National Institutes of Health consensus statement was met [22]. The data were collected from the clinic visit records conducted at baseline and 6, 12, and ⱖ24 months postoperatively. Method for CR measurement All CR measurements were performed at the Ohio State University Hospitals chemistry laboratory (Columbus, OH). The Synchron system (Beckman Coulter, Inc., Fullerton, CA) (isotope dilution mass spectroscopy method) was used to determine the CR concentration using the Jaffe rate method [23]. In this method, a precise volume of the sample (16.5 ␮L serum or 5.5 ␮L urine) is injected into a reaction cup containing an alkaline picrate solution. The CR from the sample combines with the reagent to produce a red color

D. P. Schuster et al. / Surgery for Obesity and Related Diseases 7 (2011) 459 – 464

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complex. Absorbance readings are taken at 520 nm 19 –25 seconds after sample injection. The absorbance rate has been shown to be a direct measure of the concentration of CR in the sample [24]. Sensitivity was defined as the lowest measurable concentration that could be distinguished from 0 with 95% confidence. The sensitivity for this analyte determination was .1 mg/dL (8.84 ␮mol/L) for serum or plasma and 10 mg/dL (.88 mmol/L) for urine. A significant change in the renal function was defined by a difference of ⱖ.1 mg/dL in the postoperative serum CR, as predicted by the reproducibility of the CR assay.

with our clinical experience of early issues with postoperative complications, dehydration, and associated acute renal insufficiency, with decreased occurrence rates during the first 12 months and the return of normal renal function as a function of hydration. The etiology of the low follow-up rate is unclear. As a tertiary care referral center, many of the patients live ⬎1 hour from the medical center and, if doing well and without ongoing medical issues complicating their case, will return to their local provider for follow-up care and will return to the bariatric surgery clinic less consistently.

Statistical analysis

Characteristics of 56 subjects with impaired renal function

The Statistical Package for Social Sciences (PASW Statistics, version 18.0, SPSS, Chicago, IL) was used to perform and interpret the statistical analyses for the present retrospective study. P ⬍ .05 was considered significant. All the variables with a normal distribution are expressed as the mean ⫾ SD. The significance differences in the study population were determined using analysis of covariance and chi-square analysis. Results Clinical characteristics of study population The study population was defined as all patients who had undergone RYGB from January 2003 to December 2009, for whom a baseline CR was available. A total of 813 patients were examined, of whom 77% were women and 23% were men. Their mean age was 45 ⫾ 10 years. Laparoscopic RYGB was performed in 88%, and 12% underwent an open technique. The patients were divided into 3 groups according to their baseline serum CR level: normal (⬍1.3 mg/dL), mild impairment (1.3–1.6 mg/dL), and moderate impairment (⬎1.6 mg/dL) [25,26]. Characteristics of 757 subjects with normal renal function The normal renal function group (n ⫽ 757) included 79.1% women and 20.9% men. Their mean age was 45 ⫾ 10 years. The mean baseline serum CR was .84 ⫾ .15 mg/dL, and 88% had undergone laparoscopic RYGB and 12% open RYGB. Follow-up At 6 months of follow-up, 97.6% had maintained a CR of ⬍1.3 mg/dL, 1.3% had a CR of 1.3–1.6 mg/dL, and 1.1% had a CR of ⬎1.6 mg/dL (n ⫽ 757). Of the 509 patients with a CR level available at 1 year of follow-up, 99% had maintained a CR of ⬍ 1.3 mg/dL (n ⫽ 509). Of the 388 patients with a CR level available at ⱖ24 months, 100% had a CR value of ⬍1.3 mg/dL. Although no specific conclusions can be drawn from these data, the trend was consistent

The group with impaired renal function was further divided into those with mild renal impairment (CR 1.3–1.6 mg/dL) and those with moderate renal impairment (CR ⬍1.6 mg/dL). No statistically significant differences were found in age, gender, ethnicity, BMI, the co-morbidities of DM or HTN, or surgical approach between the 2 groups (Table 1). Just as for the normal renal function group, the impaired renal function group was examined at baseline and 6, 12, and ⱖ24 months postoperatively. As a group, 69.9% of the subjects with some degree of renal impairment had improvement in their serum CR by the 6-month post-RYGB visit by ⱖ.1 mg/dL (Table 2). In the original group of 56 subjects with renal impairment, 71.4% were classified as having mild impairment and 28.5% has having moderate impairment before their weight loss surgery. The CR values in this patient population at ⱖ2 years after weight loss surgery demonstrated that 76.7% had a CR value in the normal range, 12.5% had a CR level of Table 1 Clinical characteristics for subjects with renal impairment Characteristic

Patients (n) Age (y) Gender (n) Female Male Ethnicity (%) White Black Other BMI (kg/m2) Surgical approach (%) Laparoscopic Open DM (%) HTN (%) Both DM and HTN (%)

Renal insufficiency (mg/dL) 1.3–1.6

⬎1.6

40 54.5 ⫾ 7.5

16 49.5 ⫾ 10.69

27 13

10 6

65 32.5 2.5 50.7 ⫾ 10.8

62.5 31.3 6.3 53.1 ⫾ 8.4

80 20 67.5 77.5 57.5

81.3 18.8 68.8 87.5 62.5

BMI ⫽ body mass index; DM ⫽ diabetes mellitus; HTN ⫽ hypertension.

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Table 2 Changes in renal function postoperatively for those with renal impairment preoperatively Follow-up

Mild impairment (CR 1.3–1.6 mg/dL)

Moderate impairment (CR ⬎1.6 mg/dL)

Baseline 6 mo 1 yr ⬎2 yr

1.42 ⫾ .14 (n⫽40) 1.21 ⫾ .41 (n⫽40) 1.12 ⫾ .5 (n⫽24) 1.2 ⫾ .6 (n⫽21)

2.19 ⫾ .19 (n⫽16) 2.24 ⫾ .42 (n⫽16) 2.04 ⫾ .38 (n⫽13) 2.67 ⫾ .69 (n⫽10)

Data presented as mean ⫾ standard error of mean.

1.3–1.6 mg/dL, and 10.7% had a CR level of ⬎1.6 mg/dL. This did not reflect the changes in the individual subject values but the group as a whole (Fig. 1). The improvement in renal function was not preempted by the presence of DM or HTN, or both. No statistical significance was found between those with and without DM, those with or without HTN, or those with or without both DM and HTN and an improvement in CR at 6 months or 1 year (chi-square test). Discussion In the present retrospective analysis of renal function according to the CR value in subjects who had undergone weight loss surgery, the CR values remained stable or had improved in the overwhelming majority, in the setting of both baseline normal renal function and renal impairment. Given the potential for known underlying glomerular disease in this morbidly obese population, including enlarged glomeruli, mesangial hypercellularity, podocyte hypertrophy, and/or focal segmental glomerulosclerosis, maintaining normal renal function with weight loss surgery could be an indirect indicator of glomerular protection. For those with normal renal function, it appears that bariatric surgery did not result in a statistically significant change in the CR value in the acute (6 month) or chronic (12 and 24 months) setting. It is important to remember that this value does not take into account the potential reduction in CR that might be associated with weight loss; therefore, we could not comment directly on whether renal function improved, stayed the same, or, even, potentially worsened. The GFR is an indirect marker of renal function and CR, a naturally occurring substance in the body, is used to approximate the GFR using a measure known as the CR clearance. However, the 24-hour CR clearance is a function of muscle mass and therefore affected by any process that results in a change in the muscle mass, such as the weight loss that occurs because of bariatric surgery. This issue has been problematic for any CR-based approximation of the GFR, including the Modification of Diet in Renal Disease study group formula and the isotope dilution mass spectroscopy formula, 2 commonly used formulas. Thus, limitations exists to these methods of renal function assessment; however,

the modalities have been commonly used owing to the ease of use and availability in large populations. More exact evaluations of renal function have included continuous inulin infusion with calculation of the GFR and evaluation of the 24-hour protein excretion. These measurements have been examined in other studies of weight loss, including weight loss from very low calorie diets and bariatric surgery and have demonstrated overall improvement in renal function after the intervention, as measured by reductions in proteinuria, the albumin/CR ratio, and CR clearance. These findings of improved renal function will be particularly important when considering the risk of the potential progression of renal disease in the setting of untreated obesity. However, the studies [27–30] reported were small and/or had a short follow-up duration compared with our retrospective study. Our data, from a large population and study period of ⱖ24 months, have supported these findings, indicative of the potential for sustained or improved renal function, despite the reduced reliability of the screening test, such as CR. In addition, bariatric surgery, in the setting of a known underlying renal impairment, did not have a significant negative effect on CR, and possibly renal function, during the study period. In contrast, most of those patients demonstrated significant improvement in their serum CR (Fig. 1). The improvement in CR was often enough of a change in value to move the subject into a different category of previously defined renal function. It is likely that the improvement in CR value was multifactorial, due in part to weight loss with loss of muscle mass and also to the improved blood pressure control, improved diabetic control, an increased ability to exercise, and so forth. Also, the presence of DM or HTN did not reduce the likelihood of CR improvement. However, we are unable to determine whether the absence of DM allowed a greater degree of improvement in serum CR. Similarly, the presence of HTN, or both

Fig. 1. Change in renal status after bariatric surgery.

D. P. Schuster et al. / Surgery for Obesity and Related Diseases 7 (2011) 459 – 464

DM and HTN, did not preclude the improvement in renal function. The benefits of weight loss on the stabilization of renal function have been seen in both nonoperative and surgical weight loss interventions [17]; however, medical weight loss can be challenging in the morbidly obese population, especially in the setting of renal impairment. Conventional weight loss diets consisting of high-fiber, low-energy consumption and exercise have demonstrated some success; however, these are often not suited to the patient with chronic kidney disease. As seen in the general population, nonoperative weight loss has had a high rate of failure in attaining and maintaining meaningful weight loss. A few studies have suggested that bariatric surgery could be a safe and effective method of weight loss for the patient with chronic renal insufficiency. In studies examining renal function after bariatric surgery, glomerular hyperfiltration improved with a reduction in the GFR, microalbuminuria was reduced, and renal function was stabilized. Despite studies that have demonstrated improved renal function with bariatric surgery in the morbidly obese population, such as the present study, no large, long-term prospective trials have yet been published on this issue. Finally, it is important to remember the risks of bariatric surgery in patients with chronic kidney disease, including an increased risk of infection and the presence of additional co-morbid conditions. Special attention to the risks of dehydration, rhabdomyolysis, and hyperoxaluria might be necessary in the patient with renal impairment. Nevertheless, including renal disease/dysfunction in the discussion of the risk/benefit ratio of bariatric surgery is a must. The limitations of the present study included the issues associated with any retrospective analysis. These included, primarily, the inconsistency in the follow-up, particularly in the normal renal function group, the incomplete data set regarding complications and the resolution of co-morbidities, and using CR as the only marker of renal function. We believe that the most reliable CR level is that measured at ⱖ24 months postoperatively, when the velocity of weight loss velocity has slowed and the patients have learned to manage their fluid status, making the CR less volatile and thus more predictable as an indirect marker of renal function. Despite these limitations and considering the consistency of improved CR, particularly in the impaired renal function groups and the known outcomes of declining renal function in the morbidly obese population over time, we believe these data draw attention to renal disease in the setting of morbid obesity and the potential efficacy of weight loss surgery on protecting renal function in the setting of normal and impaired renal function. Conclusion Given that the rate of overweight and obesity in the United States was 66.3% according to the Centers for Dis-

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ease Control and Prevention 2003–2004 data, that 16% of the adult population had chronic kidney disease according to the National Health and Nutrition Examination Survey 1999 –2004 data, and that the risk of ESRD increases with increasing BMI, weight loss is an appropriate and necessary treatment modality for all these patients. Therefore, given the efficacy of bariatric surgery on weight loss, this treatment modality should be considered as an early, viable method of treatment of obesity and renal impairment and might prevent the development and/or progression to overt renal disease in the “at risk” morbidly obese population. Additional long-term, prospective studies examining the primary and secondary prevention of obesity-related renal disease in the morbidly obese population are needed. Mechanistic studies examining renal failure and obesity and studies, including weight-matched control studies, will provide better insight into the effect of bariatric surgery on renal function improvement compared with the natural progression of obesity-related renal dysfunction.

Disclosures The authors have no commercial associations that might be a conflict of interest in relation to this article.

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