American Journal of Transplantation 2014; 14: 2384–2390 Wiley Periodicals Inc.
C
Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12829
Brief Communication
Laparoscopic Sleeve Gastrectomy as a Weight Reduction Strategy in Obese Patients After Kidney Transplantation I. Golomb1,*, J. Winkler2, A. Ben-Yakov3, C. C. Benitez4 and A. Keidar1,3 1
Bariatric Clinic, Beilinson Medical Center, Petah-Tikva, Israel 2 Department of Nephrology, Beilinson Medical Center, Petah-Tikva, Israel 3 Department of Surgery, Beilinson Medical Center, Petah-Tikva, Israel 4 Department of Surgery, Hospital Mexico, San Jose, Costa Rica Corresponding author: Inbal Golomb, [email protected]
Morbid obesity is associated with increased graft loss and shortened graft survival in kidney transplant patients. Treating obesity in transplant patients may improve graft outcomes. Laparoscopic sleeve gastrectomy (LSG), an effective bariatric operation, is relatively unlikely to interfere with absorption of anti-rejection medications. Data on relevant renal function parameters were collected from all LSGs performed on renal transplant patients at our center (n ¼ 10). The procedure was successful in eight patients, with no mortality, graft rejection or dysfunction. The median age and follow-up were 57 years and 14 months, respectively. Seven patients had over 1 year of follow-up. The median preoperative weight and BMI were 119 kg (96– 152) and 42 kg/m2 (37–49), respectively. The median hospital stay was 4 days. The median postoperative weight and BMI at 6 months and 1 year were 86 kg and 31 kg/m2 and 83 kg and 29 kg/m2, respectively. Urinary protein excretion and serum creatinine decreased significantly in all patients (p < 0.05). One patient developed two complications, acute renal failure and sleeve stricture, both of which resolved with treatment. LSG provided effective weight loss in renal transplant patients without adverse effects on graft function and immunosuppression. Abbreviations: %EWL, percentage excess weight loss; BPD/DS, biliopancreatic diversion and duodenal switch; LSG, laparoscopic sleeve gastrectomy Received 20 January 2014, revised and accepted for publication 14 May 2014
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Introduction Obesity has been proven to induce or exacerbate morbidities, such as type II diabetes mellitus, dyslipidemia and hypertension, which are currently the leading causes of end-stage renal failure (1). Among other reasons, the prevalence of obesity has been on the rise in the renal transplant population because of the increasing proportion of patients who develop end-stage renal disease due to obesity-mediated diseases (2). Furthermore, weight gain following transplantation is very common, occurring in most kidney transplant recipients (3). Pfeiffer et al (4) found that the prevalence of obesity increased from 19% before the transplantation to 36% at 1 year after transplantation. An increase in body weight has been noted both in obese and nonobese patients undergoing renal transplantation. Johnson et al (5) and Thoma et al (6) described a mean body weight gain of 15.3% and 10.9% at 5 years after transplantation, respectively. In addition to its indirect effect through obesity-mediated diseases, obesity is an independent risk factor for renal dysfunction. According to the Framingham Offspring Study, the odds of chronic renal disease increased by 1.23-fold for each unit increase in BMI, even after adjusting for age, diabetes, smoking and baseline GFR (7). Obesity is especially dangerous in kidney transplant patients, since it is associated with an increased risk of mortality, complications and graft loss (8). Specifically, morbidly obese recipients are more likely to incur adverse graft events, such as bleeding, delayed graft function, prolonged hospitalization and early graft loss (9). Overall, obese patients have significantly worse short-term and long-term graft survival than normal-weight recipients (10). It follows, therefore, that effective treatment of obesity in renal transplant patients may improve graft outcome. Bariatric surgery is currently the most effective means of weight loss (11). There is, however, little documentation on bariatric surgeries in renal transplant patients. To the best of our knowledge, there are no published studies on laparoscopic sleeve gastrectomy (LSG) in this population. It has been established that weight loss positively affects renal function (12). Furthermore, a few studies have shown that bariatric surgeries lead to a reduction in serum creatinine, albuminuria and proteinuria and creatinine
Sleeve Gastrectomy in Transplant Patients
clearance, which are typically high in the obese population (12–15). Renal transplant patients are considered as having high surgical risk due to immunosuppression and multiple comorbidities. Nonetheless, with greater experience in bariatric surgery, the doctors can conduct surgery with reasonable safety on patients who had previously been considered inoperable. We examined the effectiveness and safety of LSG in renal transplant patients in this retrospective analysis.
Methods This retrospective review of prospectively collected data was conducted to analyze outcomes of LSG performed on morbidly obese renal transplant patients. The study included 10 patients who underwent LSG between November 2011 and July 2013. During this period, all renal transplant patients who had over 1 year of follow-up and who were still suffering from morbid obesity were offered a surgical approach for weight loss. Those who were interested were referred by their nephrologist to the Bariatric Surgery Clinic for management of morbid obesity if conservative approaches had failed. All 10 study patients fulfilled the criteria for bariatric surgery established by the NIH Consensus Conference (16). Our routine preoperative workup consisted of the regular battery of tests for bariatric surgery candidates and upper endoscopy when indicated. Demographic details and current comorbidities were recorded, as were the dosage of immunosuppressive drugs and function of the renal graft. LSG was performed using five ports. A 32-French bougie was inserted into the pylorus. Longitudinal stomach division was performed starting 1–2 cm proximal to the pylorus by consecutive application of an endoscopic stapler (green and gold cartridge, Echelon, Ethicon Endosurgery, or violet load, Tristapler; Covidien, Mansfield, MA) parallel to the bougie, up to the gastroesophageal junction. The staple line was not oversewn. Methylene blue dye (100 cc) was used to test for leaks. A drain was left along the suture line for 2 days. On the first postoperative day, all patients underwent a contrast swallow study to rule out leakage, and began ingesting clear liquids if the results were negative. The patients were scheduled for follow-up visits at the bariatric clinic at 2 and 6 weeks, 3, 6 and 12 months and annually thereafter. The patients also had separate follow-up visits at the transplant clinic at 2 weeks, 1, 2 and 3 months and every 3 months thereafter. Every visit included blood tests for plasma levels of immunosuppressive drugs (calcineurin inhibitor trough). In addition, renal function tests, including serum creatinine and 24-h urine samples were collected for urinary protein and creatinine clearance measurements. Descriptive and comparative statistics were performed using SPSS v21 (SPSS, Inc., Chicago, IL). Continuous variables are reported as mean and range unless otherwise specified, and were compared using the Student t-test. A p-value 0.05 was considered significant in all cases.
Results Ten renal transplant patients (four females and six males, median age 57 years) underwent LSG. Eight of the patients were treated with hemodialysis prior to transplantation for a median of 3 years (0.3–8), one patient received only peritoneal dialysis for 1 year prior to transplantation and one American Journal of Transplantation 2014; 14: 2384–2390
patient was never on dialysis of any kind. Four of the transplantations were from a deceased donor, and all of those procedures were conducted at our medical center. Six of the transplantations from a living donor included one in our medical center and five in medical centers abroad. The median weight and BMI at the transplantation were 102 kg (84–142) and 36 kg/m2 (30–48), respectively. The median interval between the transplantation and LSG was 6 years (0.4–8). Nine of the 10 patients gained weight during this period, and their mean body weight increased by 13%. The median preoperative (pre-LSG) weight and BMI were 119 kg (96–152) and 42 kg/m2 (37–49), respectively. The median operation time was 60 min (range 50–80), and the median hospital stay was 4 days (2–7). Follow-up data were calculated for nine patients since one patient had a complication that required conversion to a gastric bypass. Seven patients had 1 year of follow-up or more, and the median follow-up was 14 months (5–20). At 3, 6 and 12 months post-LSG (seven patients), the median weight and BMI were 93 kg and 33 kg/m2; 86 kg and 31 kg/m2; and 83 kg and 29 kg/m2, respectively. Table 1 displays the patients’ demographic data, etiology of end-stage renal disease, weight and BMI before the transplant, pre-LSG and post-LSG. The median percentage excess weight loss (%EWL) was 54% at 3 months, 57% at 6 months and 75% at 1 year. Figure 1 displays the weight follow-up. Most of the preoperative comorbidities underwent remission or improvement (i.e. decrease of medication dosage or an improvement in lab results). Table 2 displays the patients’ full data on obesity-related comorbidities, including relevant test results and medications. The procedure was successful in 8 of the 10 patients. One patient (failed banding with super super-morbid obesity) experienced no significant weight loss and underwent a second-stage biliopancreatic diversion and duodenal switch (BPD/DS) 14 months later and was excluded from the follow-up since then. Another patient had two perioperative complications. The minor complication was acute renal failure with an elevation of serum creatinine level to 2.4 mg/dL due to recurrent vomiting secondary to a sleeve stricture, which was successfully treated with hydration. The major complication was sleeve stricture, which was initially treated unsuccessfully by pneumatic dilatation and finally required conversion to a gastric bypass 6 weeks after the primary operation. No mortality or graft rejection/dysfunction was encountered. Immunosuppressive protocol included a combination of tacrolimus, mycophenolic acid and prednisone. Renal function was closely monitored. Table 3 displays the patients’ measurements of protein in 24-h urine collection and dosage of immunosuppressive drugs before and after the surgery. The median creatinine level decreased from a median 1.44 mg/dL (0.78–1.88) before the operation to 1.29 mg/dL, 1.03 mg/dL and 1.25 at 3, 6 and 12 months of follow-up respectively. This result reached a level of 2385
2386
– – – 29.1
significance (p ¼ 0.04). Preoperative and postoperative creatinine clearance data were available for only five patients. The median level decreased from 98 to 76 mL/ min. Urinary protein excretion (measured by 24-h urine collection) was measured in all patients and it decreased from a median 391 mg/24 h (140–1197) to 207 mg/24 h (95– 336) (p ¼ 0.05).
29.1 – 32.4 31.2
Discussion To the best of our knowledge, this is the first study to describe LSG as a stand-alone operation in obese patients following renal transplant. In 1996, Marterre et al (17) described gastric bypass in three renal transplant patients and observed improvements in hypertension and hyperlipidemia as well as elevation in cyclosporine dosage. In 2010, Szomstein et al (18) described gastric bypass in four renal transplant patients and LSG in one patient and observed no changes in immunosuppressive drug dosage or in renal function. Lin et al (19) recently reported nine sleeve gastrectomies in patients after liver transplantation, eight of which were laparoscopic and observed no difficulty in maintaining immunosuppression and no need for dose escalation. Three of their patients had early complications, all of which required reoperation. Al-Nowaylati et al (20) reported seven gastric bypasses following liver transplantation, of which six required elevation in the dosage of immunosuppressive medications.
51 55 60 57 8 9 10 Median
F F M
F M M F 52 62 39 63 4 5 6 7
ESRD, end-stage renal disease; LSG, laparoscopic sleeve gastrectomy. Patient #9 was excluded from follow-up due to conversion to a gastric bypass.
6 8 7 6 Living donor (abroad) Deceased donor Living donor (abroad)
84.5 102.7 142 102.9
33.2 36.4 48.0 36.2
98 116 125 119
38.6 41.1 42.3 41.6
74 – 96 86
– – – 83
34.2 23.6 32.0 29.1 31.2 27.3 38.6 32.3 7 6 1 5
M M M 1 2 3
63 59 49
Glomerulonephritis, pyelonephritis Diclophenac sodium overdose Diabetic nephropathy and hypertension Chronic interstitial nephritis Diabetic nephropathy Diabetic nephropathy Unknown (mild diabetes, untreated) IgA nephropathy Diabetic nephropathy Diabetic nephropathy
Deceased Deceased Deceased Living donor
donor donor donor (abroad)
93 103 119 90
34.2 36.1 39.3 38.4
101 120 136 96
37.1 42.0 44.9 41.0
85 78 117 75.6
93 67.5 97 68
28.1 48.4 27.7 83 150 79 29.1 46.8 30.5 86 145 87 39.9 49.1 42.0 118 152 120 34.8 43.9 29.5 4 1 7 Living donor (abroad) Living donor (abroad) Living donor
103 136 84.3
Weight BMI Weight BMI Weight BMI (kg) (kg/m2) (kg) (kg/m2) (kg) (kg/m2) BMI (kg/m2) Weight (kg) Transplant Etiology of ESRD
Interval between transplantation and surgery (years) Age at surgery Patient no. (years) Gender
12 months post-LSG 6 months post-LSG Pre-LSG Pretransplantation
Table 1: Patients’ characteristics: age, gender, information on transplantation (including etiology of end-stage renal disease), weight and BMI at transplantation, LSG and follow-up duration
Golomb et al
LSG was recently accepted by the American Society for Metabolic and Bariatric Surgery as a first-stage operation for high-risk patients (21). We selected LSG as the procedure of choice in transplant patients in this study for several reasons. LSG has been demonstrated as having a relatively shorter operative time, a lower overall morbidity and to be less technically challenging than gastric bypass (22,23), all of which are critical in patients at high risk for complications. Another major advantage of LSG in renal transplant patients is that it is a purely restrictive and nonmalabsorptive procedure. Therefore, we assumed that there would be less likelihood of causing significant alterations in the absorption of medications than a Roux-en-Y gastric bypass and biliopancreatic diversion, both having malabsorptive and restrictive components. This is a major advantage, especially in patients that are dependent on immunosuppressive medication. Laparoscopic adjustable gastric banding also offers some of these benefits, but the presence of a foreign body poses a risk of infection and stomach erosion in the immunosuppressed population. LSG has recently been described as the procedure of choice in pretransplant candidates (24) and in patients who had undergone a liver transplant (19), and we believe it is the most appropriate procedure for obese patients with a renal transplant. The %EWL reported in LSG varies widely, from 33% to 90% (25). We found that the median 1 year %EWL in renal American Journal of Transplantation 2014; 14: 2384–2390
Sleeve Gastrectomy in Transplant Patients
WEIGHT AT 3, 6 AND 12 MONTHS 160 140 120 KG
100 80 60 40 20 0 PRE LSG
1
2
3 MONTHS
3
4
5
6 MONTHS
6
7
8
12 MONTHS
9
10
median
Figure 1: Graph showing weight before the surgery, and at 3, 6 and 12 months (seven patients) following it. Each curve represents a single patient and the bold curve represents the median.
transplant patients (57%) is similar to that produced by LSG in the general bariatric patient population. This similarity is important, given that obesity is a major risk factor for mortality, complications, shortened graft survival and graft loss (8,10). Three of our patients required adjustments in the dosage of tacrolimus (Table 3). Two of them (patients #4 and #8) required dosage elevation of 1 mg/day and one required a decrease of 2 mg/day (patient #2). The levels of these drugs are very closely monitored and often adjusted. Table 4 lists the calcineurin inhibitor blood levels. Our findings of a decrease in 24-h proteinuria, serum creatinine are in concordance with published values (12– 15). It should be noted that proteinuria is a marker of poor long-term allograft prognosis and an independent risk factor for mortality in renal transplant population (26). Hence, reduction in proteinuria due to weight loss is likely to have a beneficial long-term effect on graft survival. Obese patients tend to suffer from hyperfiltration and increased GFR (12,27). As GFR is usually reduced after kidney transplantation, the patients in this group did not have hyperfiltration according to the accepted criteria. It is reasonable to assume that the measurements that were taken prior to the surgery were affected by the relatively high perfusion caused by obesity. We assume that the decrease in creatinine clearance is a consequence of the reduction in renal ultrafiltration caused by weight loss and does not represent kidney injury. The importance of the decrease in creatinine is not clear since it could result from reduced creatinine generation due to the reduction in body mass. It is difficult to deduce from these results whether there was an improvement of graft function, but it is clear that American Journal of Transplantation 2014; 14: 2384–2390
LSG has no significant deleterious effect on renal function. The effect of obesity on graft survival has profound consequences, including potential ramifications for the availability of transplant procedures to obese patients and therefore, it has been the subject of considerable debate. In 2002, Howard et al (28) reported that obesity does not predict bad outcomes in kidney transplant recipients. However, the preponderance of evidence shows that obesity, and especially in the extreme (BMI > 36), constitutes a risk factor for graft loss and patient death (8,29,30). Consequently, bariatric surgeries in these patients can yield dramatic positive changes to their quality of life and may make the difference between losing the transplanted kidney and returning to the lengthy transplant waiting list and leading a productive and relatively healthy life with a functioning graft. Our study provides preliminary results in a novel field, but there are several limitations that need to be considered. The first lies in the paucity of some important data regarding renal function. Also, the long-term efficacy of LSG in the transplant population cannot be deduced by our small sample size and the relatively short follow-up. Real proof of the positive effect of bariatric surgery on graft survival requires longer follow-up (5–10 years) and a larger study group. Graft function, graft survival and the complication rate in this group should be compared to a group of renal transplant patients with similar initial BMIs who did not undergo bariatric surgery. In spite of the above-cited limitations, these initial results suggest that LSG is an effective and safe procedure in the renal transplant population. The surgery induced effective weight loss and remission of obesity-related comorbidities 2387
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231, 9.7, 150 insulin units a day
5
220, 7.9, insulin 70 units a day 141,175, simvastatin 20 mg 1
227, 135, rosuvastatin 40 mg 1
203, 187, simvastatin 40 mg 1 155, 152, simvastatin 40 mg 1
163, 89, simvastatin 20 mg 1 203, 235, simvastatin 10 mg 1 159, 207, atorvastatin 20 mg 1 155, 159, atorvastatin 20 mg 1, ezetrol 10 mg 1
119, 273, atorvastatin 40 mg 1
triglycerides, medications)
Yes, furosemide 40 mg 1
Yes, bisoprolol 2.5 mg 1, valsartan 160 mg 2, furosemide 40 mg 2 doxazosin 4 mg 1, vasodip 10 mg 2 Yes, valsartan 160 mg 2
Yes, furosemide 40 mg 2, valsartan 160 mg 2, normiten 25 mg 1 N/A
Yes, enalapril 10 mg 2
N/A
N/A
Yes, enalapril 10 mg 3
medications)
12.1, no medications
8.5, no medications
6.7, allopurinol 100 mg 2
9.4, no medications
8.8, allopurinol 100 mg 1
7.5, no medications
4.3, allopurinol 100 mg 2 N/A
8.3, no medications
medications)
65, 7, no medications
89, 5.5, no medications
110, 7.3, 20 insulin units a day
N/A
165, 9.5, 50 insulin units a day
190, 6.6, 32 insulin units a day 83, 5.2, no medications
N/A
109, 6.5, 30 insulin units a day
HbA1C, medications)
HTN, hypertension; LSG, laparoscopic sleeve gastrectomy; N/A, diseases from which the patient did not suffer; T2DM, type II diabetes mellitus. Patient #9 was excluded from follow-up due to conversion to a gastric bypass.
9 10
113, 6.2, no medications
85, 7.3, insulin 52 units a day
7
8
N/A
6
4
109, 7.3, 50 insulin units a day 109, 6.1, no medications
171, 7.2, 58 insulin units a day, metformin 850 mg 2 N/A
HbA1C, medications)
3
2
1
Patient no.
Uric acid (plasma level,
T2DM (plasma HTN (has HTN,
glucose levels,
Lipids (total cholesterol,
T2DM (plasma
glucose levels,
Pre-LSG
134, 98, no medications
218, 93, rosuvastatin 40 mg 1
197, 92, simvastatin 40 mg 1 161, 209, simvastatin 20 mg 1
134, 123, atorvastatin 20 mg 1 155, 93, atorvastatin 40 mg 1
157, 93, simvastatin 20 mg 1 123, 100, no medications
148, 170, no medications
triglycerides, medications
Lipids (total cholesterol,
Uric acid
6.7, allopurinol 100 mg 2
Yes, normiten 12.5 mg 1, valsartan 160 mg 1, valsartan 80 mg 1, furosemide 20 mg 1 N/A
8.3, no medications
6.5, no medications
Yes, valsartan 80 mg 2 No, no medications
8.1, allopurinol 100 mg 2
Yes, bisprolol 1.25 mg 1, valsartan 160 mg 2, furosemide 40 mg 1
7, no medications
5.8, no medications
5.1, allopurinol 100 mg 1 N/A
7.8, no medications
medications)
(plasma level,
No, no medications
N/A
N/A
Yes, enalapril 5 mg 2
medications)
HTN (has HTN,
6 months post-LSG
Table 2: Full data on obesity-related comorbidities, including results of blood tests and medication before the surgery and at 6 months of follow-up
Golomb et al
American Journal of Transplantation 2014; 14: 2384–2390
Sleeve Gastrectomy in Transplant Patients Table 3: Measurement of protein in the 24-h urine collection and dosage of immunosuppressive drugs before and after the surgery Patient no.
Age (years)
1
63
2
59
3
49
4
52
5
62
6
39
7
63
8
51
9
55
10
60
Median
57
Protein in urine (mg/24 h) pre-LSG
Immunosuppressive drugs pre-LSG Tacrolimus 2.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 5.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 2.5 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 2.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 1080 mg, prednisone 15 mg Tacrolimus 2 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 720 mg Tacrolimus 3 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 1.5 mg, prednisone 5 mg
494.3 314 877 140 160 581 1197 175.3 1350
Immunosuppressive drugs post-LSG Tacrolimus 2.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 2.5 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 4.5 mg, mycophenolic acid 720mg, prednisone 5mg Tacrolimus 2.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 1080 mg, prednisone 15 mg Tacrolimus 2 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 4.5 mg, mycophenolic acid 720 mg –
391 391
Tacrolimus 1.5 mg, prednisone 5 mg
Protein in urine (mg/24 h) post-LSG 104 150 207 230 95 359 314 203 – 336 207
Patient #9 was excluded from follow-up due to conversion to a gastric bypass.
without adverse effects on graft function and immunosuppression. These findings are especially important when considering the high prevalence of obesity among renal transplant patients and its association with increased risk of mortality and complications, increased graft loss rates and shortened graft survival.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Table 4: Levels of calcineurin inhibitors in the plasma (ng/dL) before the surgery, and at 3, 6 and 12 months Patient no. 1 2 3 4 5 6 7 8 9 10
Pre-LSG
3 months post-LSG
6 months post-LSG
12 months post-LSG
5.2 8 4.8 5.4 4.7 8.1 13.5 6.2 – 6.5
4.5 9.2 9.4 5 4.2 6 6.1 6.4 – 5
4.6 5.9 7.5 6.9 3.9 7.8 12 3.6 – 4.6
4.7 6.5 3.4 5.8 5.1 6.7 3.5 – – –
LSG, laparoscopic sleeve gastrectomy. Patient #9 was excluded from follow-up due to conversion to a gastric bypass.
American Journal of Transplantation 2014; 14: 2384–2390
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American Journal of Transplantation 2014; 14: 2384–2390
C
Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.12829
Brief Communication
Laparoscopic Sleeve Gastrectomy as a Weight Reduction Strategy in Obese Patients After Kidney Transplantation I. Golomb1,*, J. Winkler2, A. Ben-Yakov3, C. C. Benitez4 and A. Keidar1,3 1
Bariatric Clinic, Beilinson Medical Center, Petah-Tikva, Israel 2 Department of Nephrology, Beilinson Medical Center, Petah-Tikva, Israel 3 Department of Surgery, Beilinson Medical Center, Petah-Tikva, Israel 4 Department of Surgery, Hospital Mexico, San Jose, Costa Rica Corresponding author: Inbal Golomb, [email protected]
Morbid obesity is associated with increased graft loss and shortened graft survival in kidney transplant patients. Treating obesity in transplant patients may improve graft outcomes. Laparoscopic sleeve gastrectomy (LSG), an effective bariatric operation, is relatively unlikely to interfere with absorption of anti-rejection medications. Data on relevant renal function parameters were collected from all LSGs performed on renal transplant patients at our center (n ¼ 10). The procedure was successful in eight patients, with no mortality, graft rejection or dysfunction. The median age and follow-up were 57 years and 14 months, respectively. Seven patients had over 1 year of follow-up. The median preoperative weight and BMI were 119 kg (96– 152) and 42 kg/m2 (37–49), respectively. The median hospital stay was 4 days. The median postoperative weight and BMI at 6 months and 1 year were 86 kg and 31 kg/m2 and 83 kg and 29 kg/m2, respectively. Urinary protein excretion and serum creatinine decreased significantly in all patients (p < 0.05). One patient developed two complications, acute renal failure and sleeve stricture, both of which resolved with treatment. LSG provided effective weight loss in renal transplant patients without adverse effects on graft function and immunosuppression. Abbreviations: %EWL, percentage excess weight loss; BPD/DS, biliopancreatic diversion and duodenal switch; LSG, laparoscopic sleeve gastrectomy Received 20 January 2014, revised and accepted for publication 14 May 2014
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Introduction Obesity has been proven to induce or exacerbate morbidities, such as type II diabetes mellitus, dyslipidemia and hypertension, which are currently the leading causes of end-stage renal failure (1). Among other reasons, the prevalence of obesity has been on the rise in the renal transplant population because of the increasing proportion of patients who develop end-stage renal disease due to obesity-mediated diseases (2). Furthermore, weight gain following transplantation is very common, occurring in most kidney transplant recipients (3). Pfeiffer et al (4) found that the prevalence of obesity increased from 19% before the transplantation to 36% at 1 year after transplantation. An increase in body weight has been noted both in obese and nonobese patients undergoing renal transplantation. Johnson et al (5) and Thoma et al (6) described a mean body weight gain of 15.3% and 10.9% at 5 years after transplantation, respectively. In addition to its indirect effect through obesity-mediated diseases, obesity is an independent risk factor for renal dysfunction. According to the Framingham Offspring Study, the odds of chronic renal disease increased by 1.23-fold for each unit increase in BMI, even after adjusting for age, diabetes, smoking and baseline GFR (7). Obesity is especially dangerous in kidney transplant patients, since it is associated with an increased risk of mortality, complications and graft loss (8). Specifically, morbidly obese recipients are more likely to incur adverse graft events, such as bleeding, delayed graft function, prolonged hospitalization and early graft loss (9). Overall, obese patients have significantly worse short-term and long-term graft survival than normal-weight recipients (10). It follows, therefore, that effective treatment of obesity in renal transplant patients may improve graft outcome. Bariatric surgery is currently the most effective means of weight loss (11). There is, however, little documentation on bariatric surgeries in renal transplant patients. To the best of our knowledge, there are no published studies on laparoscopic sleeve gastrectomy (LSG) in this population. It has been established that weight loss positively affects renal function (12). Furthermore, a few studies have shown that bariatric surgeries lead to a reduction in serum creatinine, albuminuria and proteinuria and creatinine
Sleeve Gastrectomy in Transplant Patients
clearance, which are typically high in the obese population (12–15). Renal transplant patients are considered as having high surgical risk due to immunosuppression and multiple comorbidities. Nonetheless, with greater experience in bariatric surgery, the doctors can conduct surgery with reasonable safety on patients who had previously been considered inoperable. We examined the effectiveness and safety of LSG in renal transplant patients in this retrospective analysis.
Methods This retrospective review of prospectively collected data was conducted to analyze outcomes of LSG performed on morbidly obese renal transplant patients. The study included 10 patients who underwent LSG between November 2011 and July 2013. During this period, all renal transplant patients who had over 1 year of follow-up and who were still suffering from morbid obesity were offered a surgical approach for weight loss. Those who were interested were referred by their nephrologist to the Bariatric Surgery Clinic for management of morbid obesity if conservative approaches had failed. All 10 study patients fulfilled the criteria for bariatric surgery established by the NIH Consensus Conference (16). Our routine preoperative workup consisted of the regular battery of tests for bariatric surgery candidates and upper endoscopy when indicated. Demographic details and current comorbidities were recorded, as were the dosage of immunosuppressive drugs and function of the renal graft. LSG was performed using five ports. A 32-French bougie was inserted into the pylorus. Longitudinal stomach division was performed starting 1–2 cm proximal to the pylorus by consecutive application of an endoscopic stapler (green and gold cartridge, Echelon, Ethicon Endosurgery, or violet load, Tristapler; Covidien, Mansfield, MA) parallel to the bougie, up to the gastroesophageal junction. The staple line was not oversewn. Methylene blue dye (100 cc) was used to test for leaks. A drain was left along the suture line for 2 days. On the first postoperative day, all patients underwent a contrast swallow study to rule out leakage, and began ingesting clear liquids if the results were negative. The patients were scheduled for follow-up visits at the bariatric clinic at 2 and 6 weeks, 3, 6 and 12 months and annually thereafter. The patients also had separate follow-up visits at the transplant clinic at 2 weeks, 1, 2 and 3 months and every 3 months thereafter. Every visit included blood tests for plasma levels of immunosuppressive drugs (calcineurin inhibitor trough). In addition, renal function tests, including serum creatinine and 24-h urine samples were collected for urinary protein and creatinine clearance measurements. Descriptive and comparative statistics were performed using SPSS v21 (SPSS, Inc., Chicago, IL). Continuous variables are reported as mean and range unless otherwise specified, and were compared using the Student t-test. A p-value 0.05 was considered significant in all cases.
Results Ten renal transplant patients (four females and six males, median age 57 years) underwent LSG. Eight of the patients were treated with hemodialysis prior to transplantation for a median of 3 years (0.3–8), one patient received only peritoneal dialysis for 1 year prior to transplantation and one American Journal of Transplantation 2014; 14: 2384–2390
patient was never on dialysis of any kind. Four of the transplantations were from a deceased donor, and all of those procedures were conducted at our medical center. Six of the transplantations from a living donor included one in our medical center and five in medical centers abroad. The median weight and BMI at the transplantation were 102 kg (84–142) and 36 kg/m2 (30–48), respectively. The median interval between the transplantation and LSG was 6 years (0.4–8). Nine of the 10 patients gained weight during this period, and their mean body weight increased by 13%. The median preoperative (pre-LSG) weight and BMI were 119 kg (96–152) and 42 kg/m2 (37–49), respectively. The median operation time was 60 min (range 50–80), and the median hospital stay was 4 days (2–7). Follow-up data were calculated for nine patients since one patient had a complication that required conversion to a gastric bypass. Seven patients had 1 year of follow-up or more, and the median follow-up was 14 months (5–20). At 3, 6 and 12 months post-LSG (seven patients), the median weight and BMI were 93 kg and 33 kg/m2; 86 kg and 31 kg/m2; and 83 kg and 29 kg/m2, respectively. Table 1 displays the patients’ demographic data, etiology of end-stage renal disease, weight and BMI before the transplant, pre-LSG and post-LSG. The median percentage excess weight loss (%EWL) was 54% at 3 months, 57% at 6 months and 75% at 1 year. Figure 1 displays the weight follow-up. Most of the preoperative comorbidities underwent remission or improvement (i.e. decrease of medication dosage or an improvement in lab results). Table 2 displays the patients’ full data on obesity-related comorbidities, including relevant test results and medications. The procedure was successful in 8 of the 10 patients. One patient (failed banding with super super-morbid obesity) experienced no significant weight loss and underwent a second-stage biliopancreatic diversion and duodenal switch (BPD/DS) 14 months later and was excluded from the follow-up since then. Another patient had two perioperative complications. The minor complication was acute renal failure with an elevation of serum creatinine level to 2.4 mg/dL due to recurrent vomiting secondary to a sleeve stricture, which was successfully treated with hydration. The major complication was sleeve stricture, which was initially treated unsuccessfully by pneumatic dilatation and finally required conversion to a gastric bypass 6 weeks after the primary operation. No mortality or graft rejection/dysfunction was encountered. Immunosuppressive protocol included a combination of tacrolimus, mycophenolic acid and prednisone. Renal function was closely monitored. Table 3 displays the patients’ measurements of protein in 24-h urine collection and dosage of immunosuppressive drugs before and after the surgery. The median creatinine level decreased from a median 1.44 mg/dL (0.78–1.88) before the operation to 1.29 mg/dL, 1.03 mg/dL and 1.25 at 3, 6 and 12 months of follow-up respectively. This result reached a level of 2385
2386
– – – 29.1
significance (p ¼ 0.04). Preoperative and postoperative creatinine clearance data were available for only five patients. The median level decreased from 98 to 76 mL/ min. Urinary protein excretion (measured by 24-h urine collection) was measured in all patients and it decreased from a median 391 mg/24 h (140–1197) to 207 mg/24 h (95– 336) (p ¼ 0.05).
29.1 – 32.4 31.2
Discussion To the best of our knowledge, this is the first study to describe LSG as a stand-alone operation in obese patients following renal transplant. In 1996, Marterre et al (17) described gastric bypass in three renal transplant patients and observed improvements in hypertension and hyperlipidemia as well as elevation in cyclosporine dosage. In 2010, Szomstein et al (18) described gastric bypass in four renal transplant patients and LSG in one patient and observed no changes in immunosuppressive drug dosage or in renal function. Lin et al (19) recently reported nine sleeve gastrectomies in patients after liver transplantation, eight of which were laparoscopic and observed no difficulty in maintaining immunosuppression and no need for dose escalation. Three of their patients had early complications, all of which required reoperation. Al-Nowaylati et al (20) reported seven gastric bypasses following liver transplantation, of which six required elevation in the dosage of immunosuppressive medications.
51 55 60 57 8 9 10 Median
F F M
F M M F 52 62 39 63 4 5 6 7
ESRD, end-stage renal disease; LSG, laparoscopic sleeve gastrectomy. Patient #9 was excluded from follow-up due to conversion to a gastric bypass.
6 8 7 6 Living donor (abroad) Deceased donor Living donor (abroad)
84.5 102.7 142 102.9
33.2 36.4 48.0 36.2
98 116 125 119
38.6 41.1 42.3 41.6
74 – 96 86
– – – 83
34.2 23.6 32.0 29.1 31.2 27.3 38.6 32.3 7 6 1 5
M M M 1 2 3
63 59 49
Glomerulonephritis, pyelonephritis Diclophenac sodium overdose Diabetic nephropathy and hypertension Chronic interstitial nephritis Diabetic nephropathy Diabetic nephropathy Unknown (mild diabetes, untreated) IgA nephropathy Diabetic nephropathy Diabetic nephropathy
Deceased Deceased Deceased Living donor
donor donor donor (abroad)
93 103 119 90
34.2 36.1 39.3 38.4
101 120 136 96
37.1 42.0 44.9 41.0
85 78 117 75.6
93 67.5 97 68
28.1 48.4 27.7 83 150 79 29.1 46.8 30.5 86 145 87 39.9 49.1 42.0 118 152 120 34.8 43.9 29.5 4 1 7 Living donor (abroad) Living donor (abroad) Living donor
103 136 84.3
Weight BMI Weight BMI Weight BMI (kg) (kg/m2) (kg) (kg/m2) (kg) (kg/m2) BMI (kg/m2) Weight (kg) Transplant Etiology of ESRD
Interval between transplantation and surgery (years) Age at surgery Patient no. (years) Gender
12 months post-LSG 6 months post-LSG Pre-LSG Pretransplantation
Table 1: Patients’ characteristics: age, gender, information on transplantation (including etiology of end-stage renal disease), weight and BMI at transplantation, LSG and follow-up duration
Golomb et al
LSG was recently accepted by the American Society for Metabolic and Bariatric Surgery as a first-stage operation for high-risk patients (21). We selected LSG as the procedure of choice in transplant patients in this study for several reasons. LSG has been demonstrated as having a relatively shorter operative time, a lower overall morbidity and to be less technically challenging than gastric bypass (22,23), all of which are critical in patients at high risk for complications. Another major advantage of LSG in renal transplant patients is that it is a purely restrictive and nonmalabsorptive procedure. Therefore, we assumed that there would be less likelihood of causing significant alterations in the absorption of medications than a Roux-en-Y gastric bypass and biliopancreatic diversion, both having malabsorptive and restrictive components. This is a major advantage, especially in patients that are dependent on immunosuppressive medication. Laparoscopic adjustable gastric banding also offers some of these benefits, but the presence of a foreign body poses a risk of infection and stomach erosion in the immunosuppressed population. LSG has recently been described as the procedure of choice in pretransplant candidates (24) and in patients who had undergone a liver transplant (19), and we believe it is the most appropriate procedure for obese patients with a renal transplant. The %EWL reported in LSG varies widely, from 33% to 90% (25). We found that the median 1 year %EWL in renal American Journal of Transplantation 2014; 14: 2384–2390
Sleeve Gastrectomy in Transplant Patients
WEIGHT AT 3, 6 AND 12 MONTHS 160 140 120 KG
100 80 60 40 20 0 PRE LSG
1
2
3 MONTHS
3
4
5
6 MONTHS
6
7
8
12 MONTHS
9
10
median
Figure 1: Graph showing weight before the surgery, and at 3, 6 and 12 months (seven patients) following it. Each curve represents a single patient and the bold curve represents the median.
transplant patients (57%) is similar to that produced by LSG in the general bariatric patient population. This similarity is important, given that obesity is a major risk factor for mortality, complications, shortened graft survival and graft loss (8,10). Three of our patients required adjustments in the dosage of tacrolimus (Table 3). Two of them (patients #4 and #8) required dosage elevation of 1 mg/day and one required a decrease of 2 mg/day (patient #2). The levels of these drugs are very closely monitored and often adjusted. Table 4 lists the calcineurin inhibitor blood levels. Our findings of a decrease in 24-h proteinuria, serum creatinine are in concordance with published values (12– 15). It should be noted that proteinuria is a marker of poor long-term allograft prognosis and an independent risk factor for mortality in renal transplant population (26). Hence, reduction in proteinuria due to weight loss is likely to have a beneficial long-term effect on graft survival. Obese patients tend to suffer from hyperfiltration and increased GFR (12,27). As GFR is usually reduced after kidney transplantation, the patients in this group did not have hyperfiltration according to the accepted criteria. It is reasonable to assume that the measurements that were taken prior to the surgery were affected by the relatively high perfusion caused by obesity. We assume that the decrease in creatinine clearance is a consequence of the reduction in renal ultrafiltration caused by weight loss and does not represent kidney injury. The importance of the decrease in creatinine is not clear since it could result from reduced creatinine generation due to the reduction in body mass. It is difficult to deduce from these results whether there was an improvement of graft function, but it is clear that American Journal of Transplantation 2014; 14: 2384–2390
LSG has no significant deleterious effect on renal function. The effect of obesity on graft survival has profound consequences, including potential ramifications for the availability of transplant procedures to obese patients and therefore, it has been the subject of considerable debate. In 2002, Howard et al (28) reported that obesity does not predict bad outcomes in kidney transplant recipients. However, the preponderance of evidence shows that obesity, and especially in the extreme (BMI > 36), constitutes a risk factor for graft loss and patient death (8,29,30). Consequently, bariatric surgeries in these patients can yield dramatic positive changes to their quality of life and may make the difference between losing the transplanted kidney and returning to the lengthy transplant waiting list and leading a productive and relatively healthy life with a functioning graft. Our study provides preliminary results in a novel field, but there are several limitations that need to be considered. The first lies in the paucity of some important data regarding renal function. Also, the long-term efficacy of LSG in the transplant population cannot be deduced by our small sample size and the relatively short follow-up. Real proof of the positive effect of bariatric surgery on graft survival requires longer follow-up (5–10 years) and a larger study group. Graft function, graft survival and the complication rate in this group should be compared to a group of renal transplant patients with similar initial BMIs who did not undergo bariatric surgery. In spite of the above-cited limitations, these initial results suggest that LSG is an effective and safe procedure in the renal transplant population. The surgery induced effective weight loss and remission of obesity-related comorbidities 2387
2388
231, 9.7, 150 insulin units a day
5
220, 7.9, insulin 70 units a day 141,175, simvastatin 20 mg 1
227, 135, rosuvastatin 40 mg 1
203, 187, simvastatin 40 mg 1 155, 152, simvastatin 40 mg 1
163, 89, simvastatin 20 mg 1 203, 235, simvastatin 10 mg 1 159, 207, atorvastatin 20 mg 1 155, 159, atorvastatin 20 mg 1, ezetrol 10 mg 1
119, 273, atorvastatin 40 mg 1
triglycerides, medications)
Yes, furosemide 40 mg 1
Yes, bisoprolol 2.5 mg 1, valsartan 160 mg 2, furosemide 40 mg 2 doxazosin 4 mg 1, vasodip 10 mg 2 Yes, valsartan 160 mg 2
Yes, furosemide 40 mg 2, valsartan 160 mg 2, normiten 25 mg 1 N/A
Yes, enalapril 10 mg 2
N/A
N/A
Yes, enalapril 10 mg 3
medications)
12.1, no medications
8.5, no medications
6.7, allopurinol 100 mg 2
9.4, no medications
8.8, allopurinol 100 mg 1
7.5, no medications
4.3, allopurinol 100 mg 2 N/A
8.3, no medications
medications)
65, 7, no medications
89, 5.5, no medications
110, 7.3, 20 insulin units a day
N/A
165, 9.5, 50 insulin units a day
190, 6.6, 32 insulin units a day 83, 5.2, no medications
N/A
109, 6.5, 30 insulin units a day
HbA1C, medications)
HTN, hypertension; LSG, laparoscopic sleeve gastrectomy; N/A, diseases from which the patient did not suffer; T2DM, type II diabetes mellitus. Patient #9 was excluded from follow-up due to conversion to a gastric bypass.
9 10
113, 6.2, no medications
85, 7.3, insulin 52 units a day
7
8
N/A
6
4
109, 7.3, 50 insulin units a day 109, 6.1, no medications
171, 7.2, 58 insulin units a day, metformin 850 mg 2 N/A
HbA1C, medications)
3
2
1
Patient no.
Uric acid (plasma level,
T2DM (plasma HTN (has HTN,
glucose levels,
Lipids (total cholesterol,
T2DM (plasma
glucose levels,
Pre-LSG
134, 98, no medications
218, 93, rosuvastatin 40 mg 1
197, 92, simvastatin 40 mg 1 161, 209, simvastatin 20 mg 1
134, 123, atorvastatin 20 mg 1 155, 93, atorvastatin 40 mg 1
157, 93, simvastatin 20 mg 1 123, 100, no medications
148, 170, no medications
triglycerides, medications
Lipids (total cholesterol,
Uric acid
6.7, allopurinol 100 mg 2
Yes, normiten 12.5 mg 1, valsartan 160 mg 1, valsartan 80 mg 1, furosemide 20 mg 1 N/A
8.3, no medications
6.5, no medications
Yes, valsartan 80 mg 2 No, no medications
8.1, allopurinol 100 mg 2
Yes, bisprolol 1.25 mg 1, valsartan 160 mg 2, furosemide 40 mg 1
7, no medications
5.8, no medications
5.1, allopurinol 100 mg 1 N/A
7.8, no medications
medications)
(plasma level,
No, no medications
N/A
N/A
Yes, enalapril 5 mg 2
medications)
HTN (has HTN,
6 months post-LSG
Table 2: Full data on obesity-related comorbidities, including results of blood tests and medication before the surgery and at 6 months of follow-up
Golomb et al
American Journal of Transplantation 2014; 14: 2384–2390
Sleeve Gastrectomy in Transplant Patients Table 3: Measurement of protein in the 24-h urine collection and dosage of immunosuppressive drugs before and after the surgery Patient no.
Age (years)
1
63
2
59
3
49
4
52
5
62
6
39
7
63
8
51
9
55
10
60
Median
57
Protein in urine (mg/24 h) pre-LSG
Immunosuppressive drugs pre-LSG Tacrolimus 2.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 5.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 2.5 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 2.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 1080 mg, prednisone 15 mg Tacrolimus 2 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 720 mg Tacrolimus 3 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 1.5 mg, prednisone 5 mg
494.3 314 877 140 160 581 1197 175.3 1350
Immunosuppressive drugs post-LSG Tacrolimus 2.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 2.5 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 4.5 mg, mycophenolic acid 720mg, prednisone 5mg Tacrolimus 2.5 mg, mycophenolic acid 1080 mg, prednisone 5 mg Tacrolimus 3.5 mg, mycophenolic acid 1080 mg, prednisone 15 mg Tacrolimus 2 mg, mycophenolic acid 720 mg, prednisone 5 mg Tacrolimus 4.5 mg, mycophenolic acid 720 mg –
391 391
Tacrolimus 1.5 mg, prednisone 5 mg
Protein in urine (mg/24 h) post-LSG 104 150 207 230 95 359 314 203 – 336 207
Patient #9 was excluded from follow-up due to conversion to a gastric bypass.
without adverse effects on graft function and immunosuppression. These findings are especially important when considering the high prevalence of obesity among renal transplant patients and its association with increased risk of mortality and complications, increased graft loss rates and shortened graft survival.
Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Table 4: Levels of calcineurin inhibitors in the plasma (ng/dL) before the surgery, and at 3, 6 and 12 months Patient no. 1 2 3 4 5 6 7 8 9 10
Pre-LSG
3 months post-LSG
6 months post-LSG
12 months post-LSG
5.2 8 4.8 5.4 4.7 8.1 13.5 6.2 – 6.5
4.5 9.2 9.4 5 4.2 6 6.1 6.4 – 5
4.6 5.9 7.5 6.9 3.9 7.8 12 3.6 – 4.6
4.7 6.5 3.4 5.8 5.1 6.7 3.5 – – –
LSG, laparoscopic sleeve gastrectomy. Patient #9 was excluded from follow-up due to conversion to a gastric bypass.
American Journal of Transplantation 2014; 14: 2384–2390
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