Summary
Obesity causes hyperfiltration. Patients lose a substantial amount of weight after bariatric surgery. This weight loss includes a decrease in muscle mass, as evidenced by a decrease in creatinine excretion. Hyperfiltration also improves but is not detected by changes in serum creatinine due to concurrent decreases in creatinine generation.
Keywords: bariatric surgery, creatinine generation, estimated GFR, gastric bypass, iothalamate clearance, obesity, proteinuria
Obesity (body mass index (BMI) greater than 30 kg/m2) is associated with glomerular hyperfiltration, glomerular hypertrophy, and proteinuria, all potentially harmful 1. Although bariatric surgery can achieve sustained long-term weight loss, is recommended by consensus guidelines 2, and is associated with overall decreased mortality 3, the renal effects of this acute weight loss on glomerular hyperfiltration are not clearly established, and the accuracy of the equations that are used to estimate GFR (eGFR) before and after the procedure is unclear.
Subjects with a BMI in excess of 40 kg/m2 undergoing bariatric surgery were recruited 4. Comprehensive evaluation including 24-hour urine collection, serum creatinine, and dietary intake assessment by food frequency questionnaire 7 were conducted at an outpatient visit prior to, and at 6 and 12 months after surgery. eGFR was calculated by the 2009 CKD-EPI equation 5, while GFR was measured (mGFR) using renal iothalamate clearance 8. Body surface area was estimated from height and weight 6.
Statistical analysis employed as a mixed effects models to test for an overall (fixed) time effect (baseline, 6 months, 12 months) with random repeated subject effects. Paired t-tests were also done to assess specific differences from baseline. Associations between quantitative factors were done using Pearson’s correlation coefficient. Multiple readings were corrected using generalized estimating equations. Analyses were done using SAS, version 9.1 (SAS institute, Cary, NC). Continuous data are presented as mean plus or minus standard deviation.
Eleven Caucasian women aged 50 ± 12 years (range 28–68 years) participated (Table 1), 9 of whom underwent standard RYGB and 2 a biliopancreatic diversion/ duodenal switch. Preoperative BMI was 46 ± 5 kg/m2, and 2 patients had diabetes. BMI decreased to 33 ± 5 and 28 ± 2 kg/m2 at 6 and 12 months after surgery (P<0.001). At baseline 7 of 11 patients required a median of 1 (0:2.5; p25:p75) antihypertensive medications, while at 12 months only 4 of 11 required 0 (0:1) agents (p<0.05). Baseline diabetes in 2 patients (on metformin only) resolved by 12 months. Serum creatinine decreased slightly, but not significantly, while urinary creatinine excretion fell from 1342 ± 434 mg/24h to 1019 ± 213 and 1035 ± 255 mg/24h at 6 and 12 months, respectively (P<0.05 vs baseline for both; Table 1). Therefore, creatinine and iothalamate clearance decreased by 22 and 31 ml/min, respectively (p=0.2 and 0.02) (Figure 1). Urine albumin excretion fell slightly (4 mg) at 12 months (P=0.4) (Figure S1).
Table 1.
Patient characteristics at baseline, and 6 and 12 months after bariatric surgery
| Baseline | 6 mo | 12 mo | |
|---|---|---|---|
| Female/male | 11/0 | - | - |
| Age (y) | 49.5 (11.5) | - | - |
| Diabetes (Y/N) | 2/9 | - | - |
| Hemoglobin A1C (non- diabetics) | 5.4 (0.3) | 5.0 (0.5) | 5.2 (0.5) |
| Hemoglobin A1C (diabetics) | 9.1 (3.7) | 6.2 (0.8) | 6.6 (1.3) |
| Hypertension (Y/N) | 7/4 | - | - |
| Weight (kg) | 121.2 (18.4) | 87.1 (18.2)** | 75.7 (9.2)** |
| BMI (kg/m2) | 45.7 (5.0) | 32.5 (5.2)** | 28.4 (2.0)** |
| Systolic BP | 124 (13) | 120 (16) | 118 (10) |
| Diastolic BP | 70 (8) | 69 (10) | 69 (11) |
| Serum creatinine (mg/dl) | 0.8 (0.2) | 0.8 (0.1) | 0.7 (0.1) |
| Urine creatinine (mg/24 h) | 1342 (434) | 1019 (213) | 1035 (255) |
| Creatinine clearance (ml/min) | 120 (64) | 95 (30) | 98 (27) |
| Iothalamate clearance (ml/min) | 121 (32) | 93 (34) | 90 (24)* |
| Uncorrected CKD EPI eGFR (ml/min) | 108 (28) | 102 (29) | 94 (20) |
| Adjusted iothalamate clearance (ml/min/1.73 m2) | 95 (26) | 83 (22) | 85 (20) |
| CKD EPI eGFR (ml/min/1.73m2) | 84 (20) | 92 (19) | 90 (16) |
| Urine albumin (mg/24 h) | 20.5 (10.4) | 14.8 (11.4) | 17.1 (10.9) |
| Food Frequency Questionnaire | |||
| Calories (kcal/24 h) | 2248 (816) | 1209 (795)* | 1509 (784)* |
| Carbohydrates (g/24 h) | 285 (116) | 157 (114)* | 200 (130)* |
| Fat (g/24 h) | 79.5 (35) | 39 (25)* | 51 (25)* |
| Protein (g/24 h) | 108 (51) | 65 (42) | 71 (38) |
| Sugar (g/24 hrs) | 129 (75) | 90 (79)* | 105 (87) |
| Diet-dependent urine variables | |||
| Urine Sodium (mEq/24 h) | 170 (104) | 94 (40)* | 136 (60) |
| Urine Sulfate (mmol/24 h) | 23 (12) | 11 (5)* | 14 (6)* |
| Urine Uric Acid (mg/24 h) | 670 (360) | 360 (129)* | 404 (135)* |
| Urine Phosphorous (mg/day) | 897 (417) | 446 (172)* | 553 (168)* |
| Urine Volume (ml/24 h) | 2091 (768) | 1317 (540)* | 1596 (569) |
Values expressed as mean (SD)
P< 0.05 vs baseline
P<0.001 vs baseline
Figure 1. Changes in measured GFR.
Each line is an individual patient.
Overall, mGFR correlated with urinary creatinine excretion (r=0.69, p<0.001, Figure S2A), more than with weight (r=0.48, p=0.005; Figure S2B). The large fall in creatinine excretion associated with a decrease in serum creatinine and consequent rise in eGFR (+10.3 ml/min/1.73 m2, p=0.2). However, BSA corrected mGFR fell after RYGB (10 ml/min/1.73m2), while BSA corrected eGFR slightly increased (6 ml/min/1.73m2, Figure S3A). Thus eGFR underestimated GFR at baseline, but overestimated it postoperatively.
Total calorie and protein intakes decreased postoperatively (Table 1). Urinary sodium excretion, a direct reflection of dietary intake, and sulfate and uric acid excretions, correlates of dietary protein intake, were all less after bariatric surgery. The baseline to 12 month decrease in protein intake did not correlate significantly with the decrease in GFR (r=0.13, p=0.5) or the decrease in sodium intake (r=0.13, p=0.5). Furthermore, dietary protein did not correlate with urinary creatinine excretion (r=0.10; P=0.5).
Therefore, this prospective cohort study demonstrates that mGFR fell in a cohort of female patients during the first year after bariatric surgery. Importantly, serum creatinine and eGFR calculated from serum creatinine did not detect this change in kidney function because of a large decrease in creatinine generation. Although volume depletion may have contributed to the postoperative fall in mGFR, especially at six months, by 12 months urine volume and sodium both rebounded close to baseline values yet lower mGFR persisted (Table 1). Our data also suggest that urinary creatinine excretion has a stronger effect on GFR than weight (Figure S2). Although not always recognized, morbidly obese persons often have larger amounts of body fat and muscle mass. Thus, metabolism related to increased muscle mass may be a more important determinant of glomerular filtration than metabolism related to adipose tissue. These changes in muscle mass relative to body weight also have important implications on the use of the equations used to estimate GFR. Pre-operatively the CKD EPI equation significantly underestimated GFR in this obese population, while it overestimated GFR when the patients lost weight and muscle mass postoperatively.
The primary limitation of the current study is the small number of subjects and the fact that all were female. As such these findings should be validated in larger cohorts containing both men and women. However, a strength is the detailed information available over the first year after surgery, including mGFR at three time points, 24-hour urine collections, and matched quantitative dietary information.
Supplementary Material
Acknowledgments
This work was supported by NIH grant DK-77669 (RK), the Mayo Clinic O’Brien Urology Research Center (U54 DK100227), the Rare Kidney Stone Consortium (U54DK083908), a member of the NIH Rare Diseases Clinical Research Network (RDCRN), funded by the NIDDK and the National Center for Advancing Translational Sciences (NCATS). Funders of this study did not have any role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.
Footnotes
The authors have no commercial conflicts of interest regarding this study.
Contributions: research idea and study design: MLC, RK, JCL; data acquisition: MLC, RK, JCL; data analysis/interpretation: EB, MLC, RK, JCL, ADR, MGS; statistical analysis: EB; supervision or mentorship: N/A. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. JCL takes responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted, and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
References
- 1.Moriya T, Tsuchiya A, Okizaki S, Hayashi A, Tanaka K, Shichiri M. Glomerular hyperfiltration and increased glomerular filtration surface are associated with renal function decline in normo- and microalbuminuric type 2 diabetes. Kidney international. 2012 Mar;81(5):486–493. doi: 10.1038/ki.2011.404. [DOI] [PubMed] [Google Scholar]
- 2.Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary. Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults. Am J Clin Nutr. 1998 Oct;68(4):899–917. doi: 10.1093/ajcn/68.4.899. [DOI] [PubMed] [Google Scholar]
- 3.Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007 Aug 23;357(8):741–752. doi: 10.1056/NEJMoa066254. [DOI] [PubMed] [Google Scholar]
- 4.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 May;149(5):654–661. doi: 10.1016/j.surg.2010.11.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604–612. doi: 10.7326/0003-4819-150-9-200905050-00006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Int Med. 1971;17:863–871. [Google Scholar]
- 7.Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T. Measurement characteristics of the Women’s Health Initiative food frequency questionnaire. Ann Epidemiol. 1999 Apr;9(3):178–187. doi: 10.1016/s1047-2797(98)00055-6. [DOI] [PubMed] [Google Scholar]
- 8.Wilson D, Bergert J, Larson T, Liedtke R. GFR determined by nonradiolabeed iothalamate using capillary electrophoresis. Am J Kid Dis. 1997;30:646–652. doi: 10.1016/s0272-6386(97)90488-1. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.