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Bariatric surgery is associated with improvement in kidney outcomes
clinical investigation
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Bariatric surgery is associated with improvement in kidney outcomes Alex R. Chang1, Yuan Chen2, Christopher Still3, G. Craig Wood3, H. Lester Kirchner4, Meredith Lewis4, Holly Kramer5, James E. Hartle1, David Carey4, Lawrence J. Appel2,6 and Morgan E. Grams2,7 1
Division of Nephrology, Geisinger Health System, Danville, Pennsylvania, USA; 2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA; 3Obesity Institute, Geisinger Health System, Danville, Pennsylvania, USA; 4 Biomedical & Translational Informatics, Geisinger Health System, Danville, Pennsylvania, USA; 5Division of Nephrology, Loyola University Medical Center, Chicago, Illinois, USA; 6Division of General Internal Medicine, Johns Hopkins University, Baltimore, Maryland, USA; and 7 Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Severe obesity is associated with increased risk of kidney disease. Whether bariatric surgery reduces the risk of adverse kidney outcomes is uncertain. To resolve this we compared the risk of estimated glomerular filtration rate (eGFR) decline of ‡30% and doubling of serum creatinine or end-stage renal disease (ESRD) in 985 patients who underwent bariatric surgery with 985 patients who did not undergo such surgery. Patients were matched on demographics, baseline body mass index, eGFR, comorbidities, and previous nutrition clinic use. Mean age was 45 years, 97% were white, 80% were female, and 33% had baseline eGFR <90 ml/min per 1.73 m2. Mean 1-year weight loss was 40.4 kg in the surgery group compared with 1.4 kg in the matched cohort. Over a median follow-up of 4.4 years, 85 surgery patients had an eGFR decline of ‡30% (22 had doubling of serum creatinine/ESRD). Over a median follow-up of 3.8 years, 177 patients in the matched cohort had an eGFR decline of ‡30% (50 had doubling of serum creatinine/ESRD). In adjusted analysis, bariatric surgery patients had a significant 58% lower risk for an eGFR decline of ‡30% (hazard ratio 0.42, 95% confidence interval 0.32–0.55) and 57% lower risk of doubling of serum creatinine or ESRD (hazard ratio 0.43, 95% confidence interval: 0.26–0.71) compared with the matched cohort. Results were generally consistent among subgroups of patients with and without eGFR <90 ml/min per 1.73 m2, hypertension, and diabetes. Thus, bariatric surgery may be an option to prevent kidney function decline in severely obese individuals. Kidney International (2016) j.kint.2016.02.039
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http://dx.doi.org/10.1016/
KEYWORDS: bariatric surgery; gastric bypass; GFR; glomerular filtration rate; kidney function; morbid obesity; Roux-en-Y surgery; weight loss Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Correspondence: Alex R. Chang, 100 N. Academy Ave., Danville, Pennsylvania 17822, USA. E-mail: [email protected] Received 1 September 2015; revised 11 February 2016; accepted 18 February 2016 Kidney International (2016) -, -–-
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besity (body mass index [BMI] $30 kg/m2) affects more than 1 in 3 adults in the United States and is associated with the development of numerous chronic conditions including hypertension, diabetes, cardiovascular disease, cancer, and chronic kidney disease (CKD).1,2 The risk of end-stage renal disease (ESRD) is particularly elevated in patients with severe obesity.3,4 Compared with patients with a BMI of 18.5 to 24.9, patients with a BMI of 35 to 39.9 or a BMI $40 kg/m2 had a 512% and 607% increased risk of ESRD, respectively.3 Potential mediators of this relationship include increased blood pressure, blood glucose, inflammation, dysregulated production of adipocytokines, and the adverse effects of glomerular hyperfiltration. Bariatric surgery is very effective for inducing sustained weight loss, lowering blood pressure, improving glycemic control, and causing diabetes remission.5–7 However, evidence of the effects of bariatric surgery on CKD outcomes is sparse. Previous studies have been limited by small sample sizes or relatively short duration of follow-up.8–11 The long-term effects of surgical weight loss on kidney function are uncertain. Using a cohort of bariatric surgery patients and a propensity-matched cohort of obese patients who did not undergo surgery, we examined the incidence rates of kidney function decline during follow-up of up to 9 years.
RESULTS Baseline characteristics
Overall, baseline characteristics of participants in the surgery and matched nonsurgery cohorts were similar (Table 1 and Supplementary Figure S1). Mean values of age, weight, and eGFR were 45 years, 129 kg, and 97 ml/min per 1.73 m2 for both groups. The majority of patients were female (surgery patients, 79%; nonsurgery patients, 80%) and white (97% for both groups). Both groups had similar prevalence of hypertension (surgery patients, 62%; nonsurgery patients, 61%), diabetes (surgery patients, 38%; nonsurgery patients, 36%), and metabolic syndrome (surgery patients, 74%; nonsurgery patients, 76%) with small but significant differences in systolic blood pressure (surgery patients, 133 mm Hg; nonsurgery patients, 129 mm Hg). The prevalence of eGFR <60 ml/min per 1.73 m2 (5% for both groups) and an 1
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AR Chang et al.: Bariatric surgery and kidney outcomes
Table 1 | Baseline characteristics of bariatric surgery patients and matched controls Matched surgery Matched control patients patients P value N Age, yr Female Black Weight, kg BMI, kg/m2 SBP, mm Hg DBP, mm Hg eGFR, ml/min per 1.73 m2 <60 60–89 >90 Smoking status Current Former Never Diagnosesa Hypertension Type 1 diabetes Type 2 diabetes Dyslipidemia Metabolic syndrome Kidney calculus Gout Heart failure MI History of AKI Taking a statin Taking an ACEI or ARB Taking a diuretic Taking metformin Taking insulin Visit to a nutrition clinic Surgery type Roux-en-Y Sleeve
985 45.5 (11.1) 79 2.8 129.0 (26.4) 46.4 (7.8) 132.7 (16.9) 76.9 (9.6) 97.2 (19.5) 4.7 27.5 67.8
985 45.0 (12.0) 80.4 2.6 128.7 (26.5) 46.4 (8.3) 129.2 (15.5) 77.3 (10.3) 97.2 (20.1) 4.6 27.6 67.8
6.5 30.5 46.2
6.8 30.6 47.2
61.9 1.9 37.8 53.4 73.7 3.0 2.6 3.0 0.8 0.1 22.8 23.2 26.2 27.2 8.2 99.6
61.2 2.2 35.6 54.1 76.4 2.6 2.6 3.0 1.1 0.1 23 22.8 29.1 25.8 8.8 99.6
0.3 0.4 0.8 0.8 0.9 <0.001 0.4 0.9 0.9 1 1 0.9
0.7 0.6 0.3 0.8 0.2 0.6 1 1 0.5 1 0.9 0.8 0.1 0.5 0.6 1
96.5 3.5
Values are presented as mean (SD) or percentage. ACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; SBP, systolic blood pressure. a Diagnoses were identified from International Classification of Diseases, Ninth Revision, codes except for metabolic syndrome, which was determined based on diagnosis codes, use of antihypertensive and diabetes medications, and fasting laboratory values.
eGFR of 60 to 89 ml/min per 1.73 m2 (28% for both groups) was similar. Nearly all patients in both groups (99.6%) visited a nutrition clinic at Geisinger. The vast majority of surgery patients underwent Roux-en-Y bypass surgery (96.5%) with a small minority undergoing gastric sleeve surgery (3.5%).
nonsurgery-matched cohort experienced minimal weight loss (1.4 kg at 1 year, 1.3 kg at 5 years). The surgery group had a small decline in systolic blood pressure during follow-up, whereas the nonsurgery cohort had stable blood pressure (Supplementary Figure S2). There were also smaller increases in the prevalence of hypertension and diabetes in the surgery group than the non-surgery group (Supplementary Figures S3 and S4). Risk of an eGFR decline of ‡30%
A total of 85 patients in the surgery group and 177 patients in the nonsurgery cohort had an eGFR decline of $30%. Corresponding incidence rates of an eGFR decline of $30% were 20.2 per 1000 person-years in the surgery group and 48.2 per 1000 person-years in the nonsurgery-matched cohort (Table 2). Individuals who underwent bariatric surgery had a 58% lower risk (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.32–0.55, P < 0.001) of the development of an eGFR decline of $30% compared with the nonsurgery patients. Adjustment for incident hypertension and incident diabetes only slightly attenuated the protective association between bariatric surgery and an eGFR decline of $30% (HR 0.46, 95% CI 0.36–0.60, P < 0.001). On stratified analysis, bariatric surgery was associated with a significantly lower risk of an eGFR decline of $30% in both patients with a baseline eGFR <90 ml/min per 1.73 m2 (HR 0.37, 95% CI 0.24–0.56, P < 0.001) and patients with a baseline eGFR of $90 ml/min per 1.73 m2 (HR 0.46, 95% CI 0.33–0.65, P < 0.001; P value for interaction ¼ 0.4). Similarly, the association between bariatric surgery and a lower risk of an eGFR decline persisted in subgroups by hypertension and diabetes status (P value for interaction terms > 0.05). In patients with and without hypertension, bariatric surgery was associated with a 60% and 52% decreased risk of an eGFR decline of $30%, respectively (HR 0.40, 95% CI 0.30–0.54, P < 0.001; HR 0.48, 95% CI 0.29–0.80, P ¼ 0.005). In patients with and without diabetes, bariatric surgery was associated with a 55% and 64% decreased risk of an eGFR decline of $30%, respectively (HR 0.45, 95% CI 0.32–0.64, P < 0.001; HR 0.36, 95% CI 0.24–0.54, P < 0.001). On sensitivity analysis requiring at least 2 follow-up eGFR levels demonstrating a $30% decline, the median time between creatinine measurements was 142 days (interquartile range, 52–448). Results appeared similar, if not stronger; individuals who underwent bariatric surgery had a 66% decreased risk of an eGFR decline of $30% compared with the nonsurgery cohort (HR 0.34, 95% CI 0.23–0.48, P < 0.001) (Supplementary Figure S5).
Trajectories of weight, blood pressure, and prevalence of diabetes
Risk of doubling of serum creatinine or ESRD
The median duration of follow-up for the surgery and nonsurgery matched cohort was 4.4 (interquartile range, 2.1–6.3) years and 3.8 (interquartile range, 1.7–6.6) years, respectively. After 1 year, weight decreased by an average of 40.4 kg in the surgery group (Figure 1). At the end of 5 years, the surgery group regained an average of 6.2 kg, such that the average 5-year weight loss was 34.2 kg. On average, the
A total of 22 patients in the surgery group and 50 patients in the nonsurgery matched cohort experienced either doubling of serum creatinine or ESRD. Specifically, ESRD eventually occurred in 8 surgery patients and 10 nonsurgery patients. The incidence rates of doubling of serum creatinine or ESRD were 5.0 per 1000 person-years in the surgery group and 12.4 per 1000 person-years in the nonsurgery patients
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AR Chang et al.: Bariatric surgery and kidney outcomes
Figure 1 | Trajectories of weight and eGFR in bariatric surgery patients and matched controls. Trajectories of weight and estimated glomerular filtration rate (eGFR) were adjusted for propensity score and baseline weight and eGFR, respectively, in mixed effects models with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds.
(Table 2). Bariatric surgery patients had a 57% lower risk of doubling of serum creatinine or ESRD (HR 0.43, 95% CI 0.26–0.71, P ¼ 0.002) (Figure 2). Adjustment for incident hypertension and incident diabetes resulted in minimal attenuation of the association between bariatric surgery and doubling of serum creatinine or ESRD (HR 0.49, 95% CI 0.30–0.82, P ¼ 0.006). Trajectories of eGFR
Patients undergoing bariatric surgery experienced an initial average increase in eGFR of 4.6 ml/min per 1.73 m2 at 1 year; at the end of 5 years, the mean eGFR had declined by 0.7 ml/min per 1.73 m2 compared with baseline. In contrast, nonsurgery patients experienced a mean decrease in the eGFR of 1.5 ml/min per 1.73 m2 at 1 year and a mean
decrease in the eGFR of 6.3 ml/min per 1.73 m2 at the end of 5 years compared with baseline. The trajectory of eGFR varied slightly by baseline eGFR, particularly in the short term (Figure 3). Surgery patients with a baseline eGFR <90 ml/min per 1.73 m2 experienced a mean increase in the eGFR of 13.8 ml/min per 1.73 m2 after 1 year, which persisted at 5 years (7.8 ml/min per 1.73 m2 greater than baseline). Matched nonsurgery patients with a baseline eGFR <90 ml/min per 1.73 m2 experienced an increase in the eGFR of 4.6 ml/min per 1.73 m2 after 1 year and a 5-year eGFR decline of 1.1 ml/min per 1.73 m2. In contrast, surgery patients with a baseline eGFR of $90 ml/min per 1.73 m2 experienced no significant change in the eGFR after 1 year and a 5-year eGFR decline of 4.8 ml/min per 1.73 m2. Matched nonsurgery patients with a
Table 2 | Incidence rates of and hazard ratios of kidney outcomes in bariatric surgery patients and matched controls eGFR decline ‡30% Model 1a
No surgery Surgery
Model 2b
Model 3c
Event/N
IR (per 1000 PY)
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
177/985 85/985
48.2 (41.6–55.9) 20.2 (16.4–25.0)
Ref. 0.42 (0.32–0.54)
<0.001
Ref. 0.42 (0.32–0.55)
<0.001
Ref. 0.46 (0.36–0.60)
<0.001
Doubling of serum creatinine or ESRD Model 1a
No surgery Surgery
Model 2b
Model 3c
Event/N
IR (per 1000 PY)
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
50/985 22/985
12.4 (9.4–16.4) 5.0 (3.3–7.7)
Ref. 0.42 (0.26–0.70)
<0.001
Ref. 0.43 (0.26–0.71)
0.002
Ref. 0.49 (0.30–0.82)
0.006
CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio; IR, incidence rate; PY, patient-year; Ref., reference. a Model 1 is adjusted for baseline eGFR. b Model 2 is adjusted for baseline eGFR and propensity score. c Model 3 is adjusted for baseline eGFR, propensity score, incident hypertension, and incident diabetes. Kidney International (2016) -, -–-
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Figure 2 | Kaplan-Meier curves estimating time to kidney outcomes by surgery group and control group. The estimated glomerular filtration rate (eGFR) decline $30% outcome was defined as having a follow-up outpatient eGFR $30% lower than the baseline eGFR value. ESRD was defined as eGFR <15 ml/min/1.73 m2 or treated ESRD per US Renal Data System registry. Shaded areas represent 95% confidence interval bounds.
baseline eGFR of $90 ml/min per 1.73 m2 experienced a decrease in the eGFR of 4.5 ml/min per 1.73 m2 after 1 year and a 5-year eGFR decline of 8.7 ml/min per 1.73 m2. Trajectories for patients with and without hypertension were similar as were trajectories for patients with and without diabetes (Supplementary Figures S6 and S7).
DISCUSSION
Using data from 985 patients undergoing bariatric surgery and 985 matched controls with up to 9 years of follow-up, we found that severely obese patients who underwent bariatric surgery had a 58% lower risk of an eGFR decline of $30% and a 57% lower risk of doubling of serum creatinine or
Figure 3 | Trajectories of eGFR stratified by baseline eGFR. Trajectories of estimated glomerular filtration rate (eGFR) for patients with baseline eGFR $90 and <90 were examined using mixed effects models adjusted for propensity score and baseline eGFR, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. 4
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ESRD compared with matched nonsurgery patients. The protective effect associated with bariatric surgery persisted in patients with and without a baseline eGFR <90 ml/min per 1.73 m2, hypertension, and diabetes. Our findings expand on previous short-term studies investigating the effects of bariatric surgery on measured glomerular filtration rate (mGFR), all of which have been limited by small sample sizes.8,10–12 In studies examining mGFR in patients with normal or supranormal kidney function, the mGFR (indexed for body surface area; expressed as ml/min per 1.73 m2) did not change 1 year after surgery, although the unindexed mGFR (ml/min) decreased significantly.10,11 This observed decrease in the unindexed mGFR has been construed as resolution of glomerular hyperfiltration, potentially resulting in decreased intraglomerular pressure and kidney injury.10,11,13 Our study using longitudinal eGFR values suggests that bariatric surgery may also have long-term benefits for the kidneys, decreasing the risk of an eGFR decline of $30% and a doubling of serum creatinine or ESRD. Previous studies in patients with a decreased eGFR examined more extensively the possible mechanisms of bariatric surgery’s effect on kidney function but were limited by small sample size and short duration of follow-up.8,12,14 One study of 13 patients with CKD who underwent bariatric surgery found that indexed mGFR and eGFR increased, leptin and adiponectin levels normalized, and C-reactive protein decreased 12 months after surgery.12 Inflammation and dysregulated adipocytokines have both been postulated to have adverse effects on the kidneys.15–18 Our study evaluated kidney function trajectories in patients with and without bariatric surgery and suggests that the beneficial effect of bariatric surgery persists up to 5 years later in patients with and without a baseline eGFR <90 ml/min per 1.73 m2, hypertension, and diabetes. Interestingly, the association between bariatric surgery and a decreased risk of kidney function decline remained significant in the current study, even after accounting for incident hypertension and diabetes. One notable caveat is that we used International Classification of Diseases, Ninth Revision, Clinical Modification codes, which may have limited sensitivity.19 Still, our findings support the possibility that severe obesity may have adverse effects via mechanisms distinct from the effect of bariatric surgery on hypertension and dysglycemia, such as inflammation,17,18 relative decreases in podocyte density,20 and dysregulation of adipocytokines.15,21,22 Although we had insufficient data to evaluate these relationships, bariatric surgery has been shown to reduce albuminuria and markers of inflammation and normalize adipocytokine levels both in patients with normal and with decreased kidney function.10,18,22–24 Decreased consumption of sodium, protein, other nutrients, or total calories could also play a role in decreased risk of kidney function decline after bariatric surgery.25,26 There is some evidence that associations between bariatric surgery and kidney outcomes may vary by type of surgery.27 Kidney International (2016) -, -–-
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A study of 674 patients without baseline CKD found that surgeries that were more malabsorptive in nature (biliopancreatic diversion/duodenal switch and “very long limb Roux-en-Y surgery”) were associated with a higher risk of incident CKD.27 In contrast, the authors found a nonsignificant trend toward the benefit of routine Roux-en-Y surgery for the risk of CKD, although the study was limited by the use of diagnosis codes of CKD rather than laboratory values.27 As nearly all of the patients in our study underwent Roux-en-Y gastric bypass surgery, our findings may not be generalizable to other types of bariatric surgery. Although bariatric surgery has been shown to decrease blood pressure and improve glycemic control5,6 and quality of life,6 limited data exist on the long-term outcomes and complications of bariatric surgery.7 Malabsorptive procedures such as Roux-en-Y surgery and the even more malabsorptive duodenal switch can decrease fat and calcium absorption, resulting in increased risk for hyperoxaluria and kidney stones.27–29 Oxalate nephropathy, characterized by tubulointerstitial injury and tubular calcium oxalate deposits, is a rare complication of malabsorptive surgeries.30 Other risks of bariatric surgery include perioperative complications, anemia, and vitamin and mineral deficiencies.31 The major limitation of our study is the use of a creatinine-based eGFR, although this is the clinical standard. In the African-American Study of Kidney Disease and Hypertension, we found that the relationship between changes in weight and kidney function differs when using eGFR compared with GFR measured by iothalamate clearance.32 This difference is likely explained by the correlation between serum creatinine and muscle mass,33,34 which decreases after bariatric surgery along with a decrease in fat mass.35 Thus, serum creatinine would be expected to overestimate the GFR in the setting of large weight loss.11,12 However, results were very similar, even when we used a more robust renal endpoint, doubling of serum creatinine, or ESRD. Other filtration markers that are less influenced by changes in muscle mass such as cystatin C, beta-trace protein, or b2-microglobulin were not measured. Another limitation was the lack of albuminuria assessment in the vast majority of patients, although we did include many risk factors for albuminuria in our propensity score. Future studies measuring markers of filtration, kidney damage, and inflammation may further enhance our understanding of weight change and kidney function. In the absence of a randomized trial, residual confounding remains possible. We may not have been able to account for differences as to why some patients had bariatric surgery and others did not. However, we used propensity scores to carefully match a well-characterized bariatric surgery cohort with a control group drawn from a pool of 135,626 patients, accounting for many potential confounders, including health care utilization. We included only patients receiving primary care within the Geisinger Health System, thus optimizing capture of these potential confounders and providing a large number of follow-up outpatient serum creatinine values 5
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available in our cohort (surgery patients: mean 9.7 creatinine values, control patients: mean 8.8 creatinine values). Further, we are unlikely to miss cases of ESRD because ascertainment of ESRD status was determined by linkage to the U.S. Renal Data System. In summary, among severely obese patients, bariatric surgery is associated with a lower risk of kidney function decline. This association persisted in patients with and without decreased baseline kidney function, hypertension, and diabetes. Bariatric surgery may be a possible treatment option to prevent and slow the progression of CKD in severely obese patients. METHODS Study population We identified 1814 individuals 18 years of age and older receiving primary care between January 1, 2004 and December 31, 2013 in the Geisinger Health System who underwent bariatric surgery. The Geisinger Health System is a fully integrated rural health care system serving 44 counties in central and northeastern Pennsylvania. We excluded patients who were missing baseline or follow-up weight or serum creatinine values (n ¼ 396); had a baseline BMI <30 kg/m2 (n ¼ 2), a history of ESRD (n ¼ 4), or a baseline eGFR <15 ml/min per 1.73 m2 (n ¼ 2) or were of a race other than African-American or white (n ¼ 16), resulting in 1394 bariatric surgery patients. We matched these surgery patients with a cohort of 135,626 individuals 18 years of age and older with a BMI of $35 kg/m2 who never underwent bariatric surgery and received primary care during the same time period in the Geisinger Health System. This study was reviewed and deemed exempt by the Geisinger Medical Center Institutional Review Board. Development of propensity scores and matching protocol Propensity scores for bariatric surgery were calculated in the 137,020 patients using logistic regression and the following covariates: baseline year, follow-up time, age, sex, race, and baseline characteristics, which included weight; the square of weight; BMI; eGFR; the square of eGFR; smoking status; metabolic syndrome; the use of metformin, insulin, statins, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers, visit to a nutrition clinic, and International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic coded history of hypertension, type 1 diabetes, type 2 diabetes, dyslipidemia, kidney calculus, gout, congestive heart failure, urethral disorders, myocardial infarction, and acute kidney injury. Metabolic syndrome was defined using the National Cholesterol Education Program’s Adult Treatment Panel III report criteria; all individuals were presumed to have an increased waist circumference.36,37 Laboratory data for metabolic syndrome were imputed using the most recent data within 1 year before the baseline date. For bariatric surgery patients, baseline was considered the date of surgery. For nonsurgery patients, baseline was considered the second creatinine measurement. This determination was made to minimize length-time bias (i.e., to avoid oversampling nonsurgery patients with more frequent contact with the medical system). In addition, the distribution of the year of the baseline visit was most similar between surgery patients and nonsurgery patients when the second creatinine value was used. Separate propensity scores were created for patients with a baseline eGFR <90 ml/min per 1.73 m2 6
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and patients with a baseline eGFR of $90 ml/min per 1.73 m2 to optimize matching for eGFR-stratified analyses. We used the propensity scores to match patients undergoing bariatric surgery 1:1 with patients who did not undergo surgery. This nonsurgery cohort was selected without replacement using caliper sizes of one-half of the SD of the propensity scores.38 Nonsurgery matches were successfully identified for 985 of 1394 bariatric surgery patients. The 409 surgery patients who were not matched generally had more comorbid conditions than the matched surgery patients (Supplementary Table S1). Measurement of kidney function We used the electronic health record to calculate the eGFR using the CKD-EPI formula based on serum creatinine,34 which was measured at a single laboratory using the isotope-dilution mass spectrometry– traceable Roche enzymatic method (Roche Diagnostics, Indianapolis, IN) according to manufacturer specifications. No changes in assay or calibration techniques occurred during the study period. For bariatric surgery patients, baseline eGFR was defined as the value on the day of surgery. If this value was not available, we imputed a baseline eGFR as the most recent value up to 1 year before the surgery date. Outcomes Outpatient eGFR values from the electronic health record and data from the U.S. Renal Data System were used to determine outcomes for bariatric surgery patients and matched controls. ESRD was defined as an eGFR <15 ml/min per 1.73 m2 or ESRD requiring dialysis or transplantation per the US Renal Data System registry. Patients were censored at a renal outcome or last available creatinine value before the end date of the study, December 31, 2013. Recognizing that creatinine-based eGFR may be influenced by changes in muscle mass,11,39 we used an eGFR decline of $30% as our primary endpoint because recent studies have provided evidence that an eGFR decline of $30% may be an acceptable endpoint for CKD progression.40,41 On sensitivity analyses, we required at least 2 follow-up eGFR values with a $30% decline. Secondary outcomes included the composite endpoint of doubling of serum creatinine or ESRD and eGFR trajectory. In eGFR trajectory analyses, eGFR was imputed as 10 ml/min per 1.73 m2 for the incident ESRD record, and future eGFR data were censored. Statistical analysis We compared baseline characteristics between patients who underwent bariatric surgery and their matched controls using the McNemar c2 test and paired t tests for categorical and continuous variables, respectively. We calculated incidence rates of the categorical outcomes (eGFR decline $30%, doubling of serum creatinine, or ESRD) using Poisson regression, used Kaplan-Meier methods to estimate incidence over time, and used log-rank tests to compare survival curves. We used Cox proportional hazards regression models adjusted for baseline eGFR and propensity scores to investigate the association between bariatric surgery and risk of kidney outcomes. To assess whether the proportional hazards assumption was satisfied, we examined plots of Schoenfeld residuals of the covariates versus time. Trajectories of weight and eGFR over time were examined using mixed-effects models adjusted for propensity scores, with a random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Because trajectories of weight and eGFR were nonlinear, we modeled time using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th Kidney International (2016) -, -–-
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percentiles (0, 0.9, 2.4, 4.1, 7.6 years, respectively), allowing slopes to vary from each time point to the next. A priori subgroup analyses included stratification by a baseline eGFR <90 ml/min per 1.73 m2, hypertension, and diabetes status. We then examined the change in coefficient associated with bariatric surgery when incident hypertension and diabetes were added to the Cox models and modeled trajectories of systolic blood pressure and prevalence of hypertension and diabetes over time. All analyses were performed using Stata version 13.0 (College Station, TX). P values <0.05 were considered statistically significant. DISCLOSURE
All the authors declared no competing interests. ACKNOWLEDGMENTS
Some data presented in this article were given in an oral presentation at the American Society of Nephrology Kidney Week on November 14, 2014, in Philadelphia, PA. AC is supported by National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant K23 DK106515-01. MG is supported by NIH/NIDDK grant K08 DK092287. DC, CS, and GCW are supported by NIH/NIDDK grant P30 DK072488. The data reported here were supplied by the U.S. Renal Data System. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government. SUPPLEMENTARY MATERIAL Figure S1. Distribution of propensity scores in matched surgery and control patients. Controls were selected by matching patients without bariatric surgery with those with bariatric surgery using caliper sizes one-half the SD of the propensity scores. Matched controls were successfully identified for 985 of 1394 bariatric surgery patients. Figure S2. Trajectories of systolic blood pressure. Trajectories of systolic blood pressure were examined, using mixed-effects models adjusted for propensity score, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Figure S3. Prevalence of ICD-9 diagnosis of hypertension over time. Prevalence of hypertension over time was examined, using mixedeffects models adjusted for propensity score, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Figure S4. Prevalence of ICD-9 diagnosis of diabetes over time. Prevalence of diabetes over time was examined, using mixed-effects models adjusted for propensity score, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Figure S5. Kaplan-Meier curves estimating time to eGFR decline $30% requiring 2 qualifying eGFR values. Outcome defined as having 2 follow-up outpatient eGFRs of $30% lower than the baseline eGFR value. Shaded areas represent 95% confidence interval bounds. Figure S6. Trajectories of eGFR stratified by hypertension status. Trajectories of eGFR for patients stratified by baseline hypertension were examined, using mixed-effects models adjusted for propensity score and baseline eGFR, with random intercept and slopes Kidney International (2016) -, -–-
for each individual, allowing unstructured correlation between the random effects. The upper red and blue lines represent individuals without hypertension, and the lower red and blue lines represent individuals with hypertension. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Figure S7. Trajectories of eGFR stratified by diabetes status. Trajectories of eGFR for patients stratified by baseline diabetes were examined, using mixed effects models adjusted for propensity score and baseline eGFR, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. The upper red and blue lines represent individuals without diabetes, and the lower red and blue lines represent individuals with diabetes. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Table S1. Baseline characteristics of unmatched surgery patients. Supplementary material is linked to the online version of the paper at www.kidney-international.org.
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18. Fenske WK, Dubb S, Bueter M, et al. Effect of bariatric surgeryinduced weight loss on renal and systemic inflammation and blood pressure: a 12-month prospective study. Surg Obes Relat Dis. 2013;9: 559–568. 19. Navaneethan SD, Jolly SE, Schold JD, et al. Development and validation of an electronic health record-based chronic kidney disease registry. Clin J Am Soc Nephrol. 2011;6:40–49. 20. Wiggins JE, Goyal M, Sanden SK, et al. Podocyte hypertrophy, “adaptation,” and “decompensation” associated with glomerular enlargement and glomerulosclerosis in the aging rat: prevention by calorie restriction. J Am Soc Nephrol. 2005;16:2953–2966. 21. Sharma K. The link between obesity and albuminuria: adiponectin and podocyte dysfunction. Kidney Int. 2009;76:145–148. 22. Kopp HP, Krzyzanowska K, Mohlig M, et al. Effects of marked weight loss on plasma levels of adiponectin, markers of chronic subclinical inflammation and insulin resistance in morbidly obese women. Int J Obes (Lond). 2005;29:766–771. 23. Agrawal V, Khan I, Rai B, et al. The effect of weight loss after bariatric surgery on albuminuria. Clin Nephrol. 2008;70:194–202. 24. Illan-Gomez F, Gonzalvez-Ortega M, Orea-Soler I, et al. Obesity and inflammation: Change in adiponectin, C-reactive protein, tumour necrosis factor-alpha and interleukin-6 after bariatric surgery. Obes Surg. 2012;22:950–955. 25. Friedman AN, Quinney SK, Inman M, et al. Influence of dietary protein on glomerular filtration before and after bariatric surgery: a cohort study. Am J Kidney Dis. 2014;63:598–603. 26. Hao CM, Haase VH. Sirtuins and their relevance to the kidney. J Am Soc Nephrol. 2010;21:1620–1627. 27. Lieske JC, Mehta RA, Milliner DS, Rule AD, Bergstralh EJ, Sarr MG. Kidney stones are common after bariatric surgery. Kidney Int. 2015;87: 839–845. 28. Kumar R, Lieske JC, Collazo-Clavell ML, et al. Fat malabsorption and increased intestinal oxalate absorption are common after Roux-en-Y gastric bypass surgery. Surgery. 2011;149:654–661. 29. Park AM, Storm DW, Fulmer BR, et al. A prospective study of risk factors for nephrolithiasis after Roux-en-Y gastric bypass surgery. J Urol. 2009; 182:2334–2339.
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30. Nasr SH, D’Agati VD, Said SM, et al. Oxalate nephropathy complicating Roux-en-Y gastric bypass: an underrecognized cause of irreversible renal failure. Clin J Am Soc Nephrol. 2008;3:1676–1683. 31. Dimick JB, Nicholas LH, Ryan AM, et al. Bariatric surgery complications before vs after implementation of a national policy restricting coverage to centers of excellence. JAMA. 2013;309:792–799. 32. Chang A, Greene TH, Wang X, et al. The effects of weight change on glomerular filtration rate. Nephrol Dial Transplant. 2015;39:1870–1877. 33. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem. 1992;38:1933–1953. 34. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–612. 35. Pourhassan M, Bosy-Westphal A, Schautz B, et al. Impact of body composition during weight change on resting energy expenditure and homeostasis model assessment index in overweight nonsmoking adults. Am J Clin Nutr. 2014;99:779–791. 36. Hinnouho GM, Czernichow S, Dugravot A, et al. Metabolically healthy obesity and risk of mortality: does the definition of metabolic health matter? Diabetes Care. 2013;36:2294–2300. 37. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation. 2002;106:3143–3421. 38. Rubin DB, Thomas N. Matching using estimated propensity scores: relating theory to practice. Biometrics. 1996;52:249–264. 39. Perrin N, Berg UB. Estimated glomerular filtration rates cannot replace measured GFR in type 1 diabetes patients with hyperfiltration. Acta Paediatr. 2015;104:730–737. 40. Coresh J, Turin TC, Matsushita K, et al. Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA. 2014;311:2518–2531. 41. Levey AS, Inker LA, Matsushita K, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis. 2014;64:821–835.
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Bariatric surgery is associated with improvement in kidney outcomes Alex R. Chang1, Yuan Chen2, Christopher Still3, G. Craig Wood3, H. Lester Kirchner4, Meredith Lewis4, Holly Kramer5, James E. Hartle1, David Carey4, Lawrence J. Appel2,6 and Morgan E. Grams2,7 1
Division of Nephrology, Geisinger Health System, Danville, Pennsylvania, USA; 2Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA; 3Obesity Institute, Geisinger Health System, Danville, Pennsylvania, USA; 4 Biomedical & Translational Informatics, Geisinger Health System, Danville, Pennsylvania, USA; 5Division of Nephrology, Loyola University Medical Center, Chicago, Illinois, USA; 6Division of General Internal Medicine, Johns Hopkins University, Baltimore, Maryland, USA; and 7 Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Severe obesity is associated with increased risk of kidney disease. Whether bariatric surgery reduces the risk of adverse kidney outcomes is uncertain. To resolve this we compared the risk of estimated glomerular filtration rate (eGFR) decline of ‡30% and doubling of serum creatinine or end-stage renal disease (ESRD) in 985 patients who underwent bariatric surgery with 985 patients who did not undergo such surgery. Patients were matched on demographics, baseline body mass index, eGFR, comorbidities, and previous nutrition clinic use. Mean age was 45 years, 97% were white, 80% were female, and 33% had baseline eGFR <90 ml/min per 1.73 m2. Mean 1-year weight loss was 40.4 kg in the surgery group compared with 1.4 kg in the matched cohort. Over a median follow-up of 4.4 years, 85 surgery patients had an eGFR decline of ‡30% (22 had doubling of serum creatinine/ESRD). Over a median follow-up of 3.8 years, 177 patients in the matched cohort had an eGFR decline of ‡30% (50 had doubling of serum creatinine/ESRD). In adjusted analysis, bariatric surgery patients had a significant 58% lower risk for an eGFR decline of ‡30% (hazard ratio 0.42, 95% confidence interval 0.32–0.55) and 57% lower risk of doubling of serum creatinine or ESRD (hazard ratio 0.43, 95% confidence interval: 0.26–0.71) compared with the matched cohort. Results were generally consistent among subgroups of patients with and without eGFR <90 ml/min per 1.73 m2, hypertension, and diabetes. Thus, bariatric surgery may be an option to prevent kidney function decline in severely obese individuals. Kidney International (2016) j.kint.2016.02.039
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http://dx.doi.org/10.1016/
KEYWORDS: bariatric surgery; gastric bypass; GFR; glomerular filtration rate; kidney function; morbid obesity; Roux-en-Y surgery; weight loss Copyright ª 2016, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Correspondence: Alex R. Chang, 100 N. Academy Ave., Danville, Pennsylvania 17822, USA. E-mail: [email protected] Received 1 September 2015; revised 11 February 2016; accepted 18 February 2016 Kidney International (2016) -, -–-
O
besity (body mass index [BMI] $30 kg/m2) affects more than 1 in 3 adults in the United States and is associated with the development of numerous chronic conditions including hypertension, diabetes, cardiovascular disease, cancer, and chronic kidney disease (CKD).1,2 The risk of end-stage renal disease (ESRD) is particularly elevated in patients with severe obesity.3,4 Compared with patients with a BMI of 18.5 to 24.9, patients with a BMI of 35 to 39.9 or a BMI $40 kg/m2 had a 512% and 607% increased risk of ESRD, respectively.3 Potential mediators of this relationship include increased blood pressure, blood glucose, inflammation, dysregulated production of adipocytokines, and the adverse effects of glomerular hyperfiltration. Bariatric surgery is very effective for inducing sustained weight loss, lowering blood pressure, improving glycemic control, and causing diabetes remission.5–7 However, evidence of the effects of bariatric surgery on CKD outcomes is sparse. Previous studies have been limited by small sample sizes or relatively short duration of follow-up.8–11 The long-term effects of surgical weight loss on kidney function are uncertain. Using a cohort of bariatric surgery patients and a propensity-matched cohort of obese patients who did not undergo surgery, we examined the incidence rates of kidney function decline during follow-up of up to 9 years.
RESULTS Baseline characteristics
Overall, baseline characteristics of participants in the surgery and matched nonsurgery cohorts were similar (Table 1 and Supplementary Figure S1). Mean values of age, weight, and eGFR were 45 years, 129 kg, and 97 ml/min per 1.73 m2 for both groups. The majority of patients were female (surgery patients, 79%; nonsurgery patients, 80%) and white (97% for both groups). Both groups had similar prevalence of hypertension (surgery patients, 62%; nonsurgery patients, 61%), diabetes (surgery patients, 38%; nonsurgery patients, 36%), and metabolic syndrome (surgery patients, 74%; nonsurgery patients, 76%) with small but significant differences in systolic blood pressure (surgery patients, 133 mm Hg; nonsurgery patients, 129 mm Hg). The prevalence of eGFR <60 ml/min per 1.73 m2 (5% for both groups) and an 1
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Table 1 | Baseline characteristics of bariatric surgery patients and matched controls Matched surgery Matched control patients patients P value N Age, yr Female Black Weight, kg BMI, kg/m2 SBP, mm Hg DBP, mm Hg eGFR, ml/min per 1.73 m2 <60 60–89 >90 Smoking status Current Former Never Diagnosesa Hypertension Type 1 diabetes Type 2 diabetes Dyslipidemia Metabolic syndrome Kidney calculus Gout Heart failure MI History of AKI Taking a statin Taking an ACEI or ARB Taking a diuretic Taking metformin Taking insulin Visit to a nutrition clinic Surgery type Roux-en-Y Sleeve
985 45.5 (11.1) 79 2.8 129.0 (26.4) 46.4 (7.8) 132.7 (16.9) 76.9 (9.6) 97.2 (19.5) 4.7 27.5 67.8
985 45.0 (12.0) 80.4 2.6 128.7 (26.5) 46.4 (8.3) 129.2 (15.5) 77.3 (10.3) 97.2 (20.1) 4.6 27.6 67.8
6.5 30.5 46.2
6.8 30.6 47.2
61.9 1.9 37.8 53.4 73.7 3.0 2.6 3.0 0.8 0.1 22.8 23.2 26.2 27.2 8.2 99.6
61.2 2.2 35.6 54.1 76.4 2.6 2.6 3.0 1.1 0.1 23 22.8 29.1 25.8 8.8 99.6
0.3 0.4 0.8 0.8 0.9 <0.001 0.4 0.9 0.9 1 1 0.9
0.7 0.6 0.3 0.8 0.2 0.6 1 1 0.5 1 0.9 0.8 0.1 0.5 0.6 1
96.5 3.5
Values are presented as mean (SD) or percentage. ACEI, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; BMI, body mass index; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; SBP, systolic blood pressure. a Diagnoses were identified from International Classification of Diseases, Ninth Revision, codes except for metabolic syndrome, which was determined based on diagnosis codes, use of antihypertensive and diabetes medications, and fasting laboratory values.
eGFR of 60 to 89 ml/min per 1.73 m2 (28% for both groups) was similar. Nearly all patients in both groups (99.6%) visited a nutrition clinic at Geisinger. The vast majority of surgery patients underwent Roux-en-Y bypass surgery (96.5%) with a small minority undergoing gastric sleeve surgery (3.5%).
nonsurgery-matched cohort experienced minimal weight loss (1.4 kg at 1 year, 1.3 kg at 5 years). The surgery group had a small decline in systolic blood pressure during follow-up, whereas the nonsurgery cohort had stable blood pressure (Supplementary Figure S2). There were also smaller increases in the prevalence of hypertension and diabetes in the surgery group than the non-surgery group (Supplementary Figures S3 and S4). Risk of an eGFR decline of ‡30%
A total of 85 patients in the surgery group and 177 patients in the nonsurgery cohort had an eGFR decline of $30%. Corresponding incidence rates of an eGFR decline of $30% were 20.2 per 1000 person-years in the surgery group and 48.2 per 1000 person-years in the nonsurgery-matched cohort (Table 2). Individuals who underwent bariatric surgery had a 58% lower risk (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.32–0.55, P < 0.001) of the development of an eGFR decline of $30% compared with the nonsurgery patients. Adjustment for incident hypertension and incident diabetes only slightly attenuated the protective association between bariatric surgery and an eGFR decline of $30% (HR 0.46, 95% CI 0.36–0.60, P < 0.001). On stratified analysis, bariatric surgery was associated with a significantly lower risk of an eGFR decline of $30% in both patients with a baseline eGFR <90 ml/min per 1.73 m2 (HR 0.37, 95% CI 0.24–0.56, P < 0.001) and patients with a baseline eGFR of $90 ml/min per 1.73 m2 (HR 0.46, 95% CI 0.33–0.65, P < 0.001; P value for interaction ¼ 0.4). Similarly, the association between bariatric surgery and a lower risk of an eGFR decline persisted in subgroups by hypertension and diabetes status (P value for interaction terms > 0.05). In patients with and without hypertension, bariatric surgery was associated with a 60% and 52% decreased risk of an eGFR decline of $30%, respectively (HR 0.40, 95% CI 0.30–0.54, P < 0.001; HR 0.48, 95% CI 0.29–0.80, P ¼ 0.005). In patients with and without diabetes, bariatric surgery was associated with a 55% and 64% decreased risk of an eGFR decline of $30%, respectively (HR 0.45, 95% CI 0.32–0.64, P < 0.001; HR 0.36, 95% CI 0.24–0.54, P < 0.001). On sensitivity analysis requiring at least 2 follow-up eGFR levels demonstrating a $30% decline, the median time between creatinine measurements was 142 days (interquartile range, 52–448). Results appeared similar, if not stronger; individuals who underwent bariatric surgery had a 66% decreased risk of an eGFR decline of $30% compared with the nonsurgery cohort (HR 0.34, 95% CI 0.23–0.48, P < 0.001) (Supplementary Figure S5).
Trajectories of weight, blood pressure, and prevalence of diabetes
Risk of doubling of serum creatinine or ESRD
The median duration of follow-up for the surgery and nonsurgery matched cohort was 4.4 (interquartile range, 2.1–6.3) years and 3.8 (interquartile range, 1.7–6.6) years, respectively. After 1 year, weight decreased by an average of 40.4 kg in the surgery group (Figure 1). At the end of 5 years, the surgery group regained an average of 6.2 kg, such that the average 5-year weight loss was 34.2 kg. On average, the
A total of 22 patients in the surgery group and 50 patients in the nonsurgery matched cohort experienced either doubling of serum creatinine or ESRD. Specifically, ESRD eventually occurred in 8 surgery patients and 10 nonsurgery patients. The incidence rates of doubling of serum creatinine or ESRD were 5.0 per 1000 person-years in the surgery group and 12.4 per 1000 person-years in the nonsurgery patients
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Figure 1 | Trajectories of weight and eGFR in bariatric surgery patients and matched controls. Trajectories of weight and estimated glomerular filtration rate (eGFR) were adjusted for propensity score and baseline weight and eGFR, respectively, in mixed effects models with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds.
(Table 2). Bariatric surgery patients had a 57% lower risk of doubling of serum creatinine or ESRD (HR 0.43, 95% CI 0.26–0.71, P ¼ 0.002) (Figure 2). Adjustment for incident hypertension and incident diabetes resulted in minimal attenuation of the association between bariatric surgery and doubling of serum creatinine or ESRD (HR 0.49, 95% CI 0.30–0.82, P ¼ 0.006). Trajectories of eGFR
Patients undergoing bariatric surgery experienced an initial average increase in eGFR of 4.6 ml/min per 1.73 m2 at 1 year; at the end of 5 years, the mean eGFR had declined by 0.7 ml/min per 1.73 m2 compared with baseline. In contrast, nonsurgery patients experienced a mean decrease in the eGFR of 1.5 ml/min per 1.73 m2 at 1 year and a mean
decrease in the eGFR of 6.3 ml/min per 1.73 m2 at the end of 5 years compared with baseline. The trajectory of eGFR varied slightly by baseline eGFR, particularly in the short term (Figure 3). Surgery patients with a baseline eGFR <90 ml/min per 1.73 m2 experienced a mean increase in the eGFR of 13.8 ml/min per 1.73 m2 after 1 year, which persisted at 5 years (7.8 ml/min per 1.73 m2 greater than baseline). Matched nonsurgery patients with a baseline eGFR <90 ml/min per 1.73 m2 experienced an increase in the eGFR of 4.6 ml/min per 1.73 m2 after 1 year and a 5-year eGFR decline of 1.1 ml/min per 1.73 m2. In contrast, surgery patients with a baseline eGFR of $90 ml/min per 1.73 m2 experienced no significant change in the eGFR after 1 year and a 5-year eGFR decline of 4.8 ml/min per 1.73 m2. Matched nonsurgery patients with a
Table 2 | Incidence rates of and hazard ratios of kidney outcomes in bariatric surgery patients and matched controls eGFR decline ‡30% Model 1a
No surgery Surgery
Model 2b
Model 3c
Event/N
IR (per 1000 PY)
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
177/985 85/985
48.2 (41.6–55.9) 20.2 (16.4–25.0)
Ref. 0.42 (0.32–0.54)
<0.001
Ref. 0.42 (0.32–0.55)
<0.001
Ref. 0.46 (0.36–0.60)
<0.001
Doubling of serum creatinine or ESRD Model 1a
No surgery Surgery
Model 2b
Model 3c
Event/N
IR (per 1000 PY)
HR (95% CI)
P value
HR (95% CI)
P value
HR (95% CI)
P value
50/985 22/985
12.4 (9.4–16.4) 5.0 (3.3–7.7)
Ref. 0.42 (0.26–0.70)
<0.001
Ref. 0.43 (0.26–0.71)
0.002
Ref. 0.49 (0.30–0.82)
0.006
CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio; IR, incidence rate; PY, patient-year; Ref., reference. a Model 1 is adjusted for baseline eGFR. b Model 2 is adjusted for baseline eGFR and propensity score. c Model 3 is adjusted for baseline eGFR, propensity score, incident hypertension, and incident diabetes. Kidney International (2016) -, -–-
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Figure 2 | Kaplan-Meier curves estimating time to kidney outcomes by surgery group and control group. The estimated glomerular filtration rate (eGFR) decline $30% outcome was defined as having a follow-up outpatient eGFR $30% lower than the baseline eGFR value. ESRD was defined as eGFR <15 ml/min/1.73 m2 or treated ESRD per US Renal Data System registry. Shaded areas represent 95% confidence interval bounds.
baseline eGFR of $90 ml/min per 1.73 m2 experienced a decrease in the eGFR of 4.5 ml/min per 1.73 m2 after 1 year and a 5-year eGFR decline of 8.7 ml/min per 1.73 m2. Trajectories for patients with and without hypertension were similar as were trajectories for patients with and without diabetes (Supplementary Figures S6 and S7).
DISCUSSION
Using data from 985 patients undergoing bariatric surgery and 985 matched controls with up to 9 years of follow-up, we found that severely obese patients who underwent bariatric surgery had a 58% lower risk of an eGFR decline of $30% and a 57% lower risk of doubling of serum creatinine or
Figure 3 | Trajectories of eGFR stratified by baseline eGFR. Trajectories of estimated glomerular filtration rate (eGFR) for patients with baseline eGFR $90 and <90 were examined using mixed effects models adjusted for propensity score and baseline eGFR, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. 4
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ESRD compared with matched nonsurgery patients. The protective effect associated with bariatric surgery persisted in patients with and without a baseline eGFR <90 ml/min per 1.73 m2, hypertension, and diabetes. Our findings expand on previous short-term studies investigating the effects of bariatric surgery on measured glomerular filtration rate (mGFR), all of which have been limited by small sample sizes.8,10–12 In studies examining mGFR in patients with normal or supranormal kidney function, the mGFR (indexed for body surface area; expressed as ml/min per 1.73 m2) did not change 1 year after surgery, although the unindexed mGFR (ml/min) decreased significantly.10,11 This observed decrease in the unindexed mGFR has been construed as resolution of glomerular hyperfiltration, potentially resulting in decreased intraglomerular pressure and kidney injury.10,11,13 Our study using longitudinal eGFR values suggests that bariatric surgery may also have long-term benefits for the kidneys, decreasing the risk of an eGFR decline of $30% and a doubling of serum creatinine or ESRD. Previous studies in patients with a decreased eGFR examined more extensively the possible mechanisms of bariatric surgery’s effect on kidney function but were limited by small sample size and short duration of follow-up.8,12,14 One study of 13 patients with CKD who underwent bariatric surgery found that indexed mGFR and eGFR increased, leptin and adiponectin levels normalized, and C-reactive protein decreased 12 months after surgery.12 Inflammation and dysregulated adipocytokines have both been postulated to have adverse effects on the kidneys.15–18 Our study evaluated kidney function trajectories in patients with and without bariatric surgery and suggests that the beneficial effect of bariatric surgery persists up to 5 years later in patients with and without a baseline eGFR <90 ml/min per 1.73 m2, hypertension, and diabetes. Interestingly, the association between bariatric surgery and a decreased risk of kidney function decline remained significant in the current study, even after accounting for incident hypertension and diabetes. One notable caveat is that we used International Classification of Diseases, Ninth Revision, Clinical Modification codes, which may have limited sensitivity.19 Still, our findings support the possibility that severe obesity may have adverse effects via mechanisms distinct from the effect of bariatric surgery on hypertension and dysglycemia, such as inflammation,17,18 relative decreases in podocyte density,20 and dysregulation of adipocytokines.15,21,22 Although we had insufficient data to evaluate these relationships, bariatric surgery has been shown to reduce albuminuria and markers of inflammation and normalize adipocytokine levels both in patients with normal and with decreased kidney function.10,18,22–24 Decreased consumption of sodium, protein, other nutrients, or total calories could also play a role in decreased risk of kidney function decline after bariatric surgery.25,26 There is some evidence that associations between bariatric surgery and kidney outcomes may vary by type of surgery.27 Kidney International (2016) -, -–-
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A study of 674 patients without baseline CKD found that surgeries that were more malabsorptive in nature (biliopancreatic diversion/duodenal switch and “very long limb Roux-en-Y surgery”) were associated with a higher risk of incident CKD.27 In contrast, the authors found a nonsignificant trend toward the benefit of routine Roux-en-Y surgery for the risk of CKD, although the study was limited by the use of diagnosis codes of CKD rather than laboratory values.27 As nearly all of the patients in our study underwent Roux-en-Y gastric bypass surgery, our findings may not be generalizable to other types of bariatric surgery. Although bariatric surgery has been shown to decrease blood pressure and improve glycemic control5,6 and quality of life,6 limited data exist on the long-term outcomes and complications of bariatric surgery.7 Malabsorptive procedures such as Roux-en-Y surgery and the even more malabsorptive duodenal switch can decrease fat and calcium absorption, resulting in increased risk for hyperoxaluria and kidney stones.27–29 Oxalate nephropathy, characterized by tubulointerstitial injury and tubular calcium oxalate deposits, is a rare complication of malabsorptive surgeries.30 Other risks of bariatric surgery include perioperative complications, anemia, and vitamin and mineral deficiencies.31 The major limitation of our study is the use of a creatinine-based eGFR, although this is the clinical standard. In the African-American Study of Kidney Disease and Hypertension, we found that the relationship between changes in weight and kidney function differs when using eGFR compared with GFR measured by iothalamate clearance.32 This difference is likely explained by the correlation between serum creatinine and muscle mass,33,34 which decreases after bariatric surgery along with a decrease in fat mass.35 Thus, serum creatinine would be expected to overestimate the GFR in the setting of large weight loss.11,12 However, results were very similar, even when we used a more robust renal endpoint, doubling of serum creatinine, or ESRD. Other filtration markers that are less influenced by changes in muscle mass such as cystatin C, beta-trace protein, or b2-microglobulin were not measured. Another limitation was the lack of albuminuria assessment in the vast majority of patients, although we did include many risk factors for albuminuria in our propensity score. Future studies measuring markers of filtration, kidney damage, and inflammation may further enhance our understanding of weight change and kidney function. In the absence of a randomized trial, residual confounding remains possible. We may not have been able to account for differences as to why some patients had bariatric surgery and others did not. However, we used propensity scores to carefully match a well-characterized bariatric surgery cohort with a control group drawn from a pool of 135,626 patients, accounting for many potential confounders, including health care utilization. We included only patients receiving primary care within the Geisinger Health System, thus optimizing capture of these potential confounders and providing a large number of follow-up outpatient serum creatinine values 5
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available in our cohort (surgery patients: mean 9.7 creatinine values, control patients: mean 8.8 creatinine values). Further, we are unlikely to miss cases of ESRD because ascertainment of ESRD status was determined by linkage to the U.S. Renal Data System. In summary, among severely obese patients, bariatric surgery is associated with a lower risk of kidney function decline. This association persisted in patients with and without decreased baseline kidney function, hypertension, and diabetes. Bariatric surgery may be a possible treatment option to prevent and slow the progression of CKD in severely obese patients. METHODS Study population We identified 1814 individuals 18 years of age and older receiving primary care between January 1, 2004 and December 31, 2013 in the Geisinger Health System who underwent bariatric surgery. The Geisinger Health System is a fully integrated rural health care system serving 44 counties in central and northeastern Pennsylvania. We excluded patients who were missing baseline or follow-up weight or serum creatinine values (n ¼ 396); had a baseline BMI <30 kg/m2 (n ¼ 2), a history of ESRD (n ¼ 4), or a baseline eGFR <15 ml/min per 1.73 m2 (n ¼ 2) or were of a race other than African-American or white (n ¼ 16), resulting in 1394 bariatric surgery patients. We matched these surgery patients with a cohort of 135,626 individuals 18 years of age and older with a BMI of $35 kg/m2 who never underwent bariatric surgery and received primary care during the same time period in the Geisinger Health System. This study was reviewed and deemed exempt by the Geisinger Medical Center Institutional Review Board. Development of propensity scores and matching protocol Propensity scores for bariatric surgery were calculated in the 137,020 patients using logistic regression and the following covariates: baseline year, follow-up time, age, sex, race, and baseline characteristics, which included weight; the square of weight; BMI; eGFR; the square of eGFR; smoking status; metabolic syndrome; the use of metformin, insulin, statins, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers, visit to a nutrition clinic, and International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic coded history of hypertension, type 1 diabetes, type 2 diabetes, dyslipidemia, kidney calculus, gout, congestive heart failure, urethral disorders, myocardial infarction, and acute kidney injury. Metabolic syndrome was defined using the National Cholesterol Education Program’s Adult Treatment Panel III report criteria; all individuals were presumed to have an increased waist circumference.36,37 Laboratory data for metabolic syndrome were imputed using the most recent data within 1 year before the baseline date. For bariatric surgery patients, baseline was considered the date of surgery. For nonsurgery patients, baseline was considered the second creatinine measurement. This determination was made to minimize length-time bias (i.e., to avoid oversampling nonsurgery patients with more frequent contact with the medical system). In addition, the distribution of the year of the baseline visit was most similar between surgery patients and nonsurgery patients when the second creatinine value was used. Separate propensity scores were created for patients with a baseline eGFR <90 ml/min per 1.73 m2 6
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and patients with a baseline eGFR of $90 ml/min per 1.73 m2 to optimize matching for eGFR-stratified analyses. We used the propensity scores to match patients undergoing bariatric surgery 1:1 with patients who did not undergo surgery. This nonsurgery cohort was selected without replacement using caliper sizes of one-half of the SD of the propensity scores.38 Nonsurgery matches were successfully identified for 985 of 1394 bariatric surgery patients. The 409 surgery patients who were not matched generally had more comorbid conditions than the matched surgery patients (Supplementary Table S1). Measurement of kidney function We used the electronic health record to calculate the eGFR using the CKD-EPI formula based on serum creatinine,34 which was measured at a single laboratory using the isotope-dilution mass spectrometry– traceable Roche enzymatic method (Roche Diagnostics, Indianapolis, IN) according to manufacturer specifications. No changes in assay or calibration techniques occurred during the study period. For bariatric surgery patients, baseline eGFR was defined as the value on the day of surgery. If this value was not available, we imputed a baseline eGFR as the most recent value up to 1 year before the surgery date. Outcomes Outpatient eGFR values from the electronic health record and data from the U.S. Renal Data System were used to determine outcomes for bariatric surgery patients and matched controls. ESRD was defined as an eGFR <15 ml/min per 1.73 m2 or ESRD requiring dialysis or transplantation per the US Renal Data System registry. Patients were censored at a renal outcome or last available creatinine value before the end date of the study, December 31, 2013. Recognizing that creatinine-based eGFR may be influenced by changes in muscle mass,11,39 we used an eGFR decline of $30% as our primary endpoint because recent studies have provided evidence that an eGFR decline of $30% may be an acceptable endpoint for CKD progression.40,41 On sensitivity analyses, we required at least 2 follow-up eGFR values with a $30% decline. Secondary outcomes included the composite endpoint of doubling of serum creatinine or ESRD and eGFR trajectory. In eGFR trajectory analyses, eGFR was imputed as 10 ml/min per 1.73 m2 for the incident ESRD record, and future eGFR data were censored. Statistical analysis We compared baseline characteristics between patients who underwent bariatric surgery and their matched controls using the McNemar c2 test and paired t tests for categorical and continuous variables, respectively. We calculated incidence rates of the categorical outcomes (eGFR decline $30%, doubling of serum creatinine, or ESRD) using Poisson regression, used Kaplan-Meier methods to estimate incidence over time, and used log-rank tests to compare survival curves. We used Cox proportional hazards regression models adjusted for baseline eGFR and propensity scores to investigate the association between bariatric surgery and risk of kidney outcomes. To assess whether the proportional hazards assumption was satisfied, we examined plots of Schoenfeld residuals of the covariates versus time. Trajectories of weight and eGFR over time were examined using mixed-effects models adjusted for propensity scores, with a random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Because trajectories of weight and eGFR were nonlinear, we modeled time using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th Kidney International (2016) -, -–-
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percentiles (0, 0.9, 2.4, 4.1, 7.6 years, respectively), allowing slopes to vary from each time point to the next. A priori subgroup analyses included stratification by a baseline eGFR <90 ml/min per 1.73 m2, hypertension, and diabetes status. We then examined the change in coefficient associated with bariatric surgery when incident hypertension and diabetes were added to the Cox models and modeled trajectories of systolic blood pressure and prevalence of hypertension and diabetes over time. All analyses were performed using Stata version 13.0 (College Station, TX). P values <0.05 were considered statistically significant. DISCLOSURE
All the authors declared no competing interests. ACKNOWLEDGMENTS
Some data presented in this article were given in an oral presentation at the American Society of Nephrology Kidney Week on November 14, 2014, in Philadelphia, PA. AC is supported by National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant K23 DK106515-01. MG is supported by NIH/NIDDK grant K08 DK092287. DC, CS, and GCW are supported by NIH/NIDDK grant P30 DK072488. The data reported here were supplied by the U.S. Renal Data System. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government. SUPPLEMENTARY MATERIAL Figure S1. Distribution of propensity scores in matched surgery and control patients. Controls were selected by matching patients without bariatric surgery with those with bariatric surgery using caliper sizes one-half the SD of the propensity scores. Matched controls were successfully identified for 985 of 1394 bariatric surgery patients. Figure S2. Trajectories of systolic blood pressure. Trajectories of systolic blood pressure were examined, using mixed-effects models adjusted for propensity score, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Figure S3. Prevalence of ICD-9 diagnosis of hypertension over time. Prevalence of hypertension over time was examined, using mixedeffects models adjusted for propensity score, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Figure S4. Prevalence of ICD-9 diagnosis of diabetes over time. Prevalence of diabetes over time was examined, using mixed-effects models adjusted for propensity score, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Figure S5. Kaplan-Meier curves estimating time to eGFR decline $30% requiring 2 qualifying eGFR values. Outcome defined as having 2 follow-up outpatient eGFRs of $30% lower than the baseline eGFR value. Shaded areas represent 95% confidence interval bounds. Figure S6. Trajectories of eGFR stratified by hypertension status. Trajectories of eGFR for patients stratified by baseline hypertension were examined, using mixed-effects models adjusted for propensity score and baseline eGFR, with random intercept and slopes Kidney International (2016) -, -–-
for each individual, allowing unstructured correlation between the random effects. The upper red and blue lines represent individuals without hypertension, and the lower red and blue lines represent individuals with hypertension. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Figure S7. Trajectories of eGFR stratified by diabetes status. Trajectories of eGFR for patients stratified by baseline diabetes were examined, using mixed effects models adjusted for propensity score and baseline eGFR, with random intercept and slopes for each individual, allowing unstructured correlation between the random effects. The upper red and blue lines represent individuals without diabetes, and the lower red and blue lines represent individuals with diabetes. Time was modeled using restricted cubic splines with 5 knots at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. Shaded areas represent 95% confidence interval bounds. Table S1. Baseline characteristics of unmatched surgery patients. Supplementary material is linked to the online version of the paper at www.kidney-international.org.
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