Introduction
] Patients with obesity are predisposed to diabetic nephropathy, hypertensive nephrosclerosis and focal and segmental glomerulosclerosis, which accelerates the progression of chronic kidney failure.
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Moreover, although obesity is not an absolute contra-indication for kidney transplantation (KT), patients with obesity have reduced access to receive KT[
] since it is associated with a higher incidence of posttransplant complications, such as surgical site infection, new onset of diabetes after transplantation and delayed graft function (DGF).
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] To the kidney transplant recipients, BS improved renal function, graft survival and decreased obesity-related comorbidities such as diabetes mellitus and hypertension.
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To the kidney transplant candidates, BS has been proven to be effective in weight loss and improving eligibility for KT.[
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] Meanwhile, the question on what is the optimal timing of BS in the kidney transplant population has not been answered unequivocally. A systematic review which enrolled 15 clinical studies with a total of 119 patients who underwent BS either before or after transplant showed that it was the safest to perform BS after transplant.[
] However, a certain group of patients also benefited from pre-transplant BS, as complication rates were acceptable and BS improved eligibility for kidney transplant.
To our knowledge, there has been no clinical trial to directly compare the outcomes of patients who underwent both operations in different order. The aim of this study is to assess short- and long-term outcomes of ESRD patients who underwent both BS and KT, trying to determine the optimal timing of BS for ESRD patients with obesity.
Materials and Methods
Study design
In this retrospective cohort study, all patients ≥18 years who have undergone both KT and BS between January 2000 and January 2020 were screened using the transplant database of Erasmus Medical Center (EMC) and University Medical Center Groningen (UMCG). All the individuals accepting BS prior to KT were to lose weight to be eligible for transplant. These patients were stratified into two groups according to the sequence of the two operations, group 1: patients who underwent KT before BS (KT first group), group 2: patients who underwent BS before KT (BS first group). A standardized immunosuppressive protocol was applied after transplantation. All patients had induction therapy with basiliximab (20mg) on postoperative day (POD) 0 and 4, tacrolimus (0.1mg per kg per day to maintain trough levels of 7-10ng/mL), mycophenolate mofetil (500mg twice daily) and prednisolone (20mg daily). ABO incompatible, cross-match positive, or high panel reactive antibody patients were treated according to local protocol. All patients were followed up until death or June 2021. All clinical data was obtained from the electronic patient dossier of EMC and UMCG. Patient demographics, co-morbidities, surgical details, postoperative complications and follow-up results were recorded. This study was approved by the Ethics Committee of the Erasmus Medical Center Rotterdam (MEC-2018-1699) and conducted in accordance with the provisions of the declaration of Helsinki.
Kidney transplantation related outcome
Patient and graft survival, duration of hospital stay and postoperative complications were analyzed. Patient survival was defined as the time from transplantation to death or the last follow-up. Uncensored graft survival was defined as the time from transplantation to graft failure or death or the last follow-up with a functioning graft. Death-censored graft survival was defined as the time from transplantation to graft failure or the last follow-up with a functioning graft, with censoring death with a functioning graft. Postoperative complications were recorded up to 90 days after transplantation except for the incidence of incisional hernia and rejection, which was recorded throughout the follow-up after transplantation. Allograft rejection was based on renal graft biopsy-proven diagnosis (Category 2, 3 and 4 according to Banff classification). DGF was defined as the need for dialysis in the first posttransplant week or failure of creatinine to decrease in the first 24 hours. Primary nonfunction (PNF) was defined as the absence of graft function immediately after transplantation and dialysis for 3 months post-transplant. Graft failure was defined as the need for retransplant or long-term dialysis.
Bariatric surgery related outcome
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%EWL was calculated using the formula:
. Postoperative complications were registered up to 90 days and classified according to the Clavien-Dindo classification.[
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Statistical analysis
Baseline characteristics and both outcomes of KT and BS were compared between the two groups. Continuous variables were reported as mean ± standard deviation (SD) if normally distributed or median with interquartile range (IQR) if data was skewed using Kolmogorov-Smirnov test. Categorical variables were described as numbers and percentages. Continuous variables were compared using student’s t-test or Mann–Whitney U test. Categorical variables were compared using
test or Fisher’s exact test. Kaplan-Meier curves and log-rank test were used to compare patient and graft survival. Since the age at transplantation was statistically inconsistent between the two groups, the propensity score matching (PSM) was used to avoid the age-related bias when analyzing transplant related outcomes. The nearest neighbor-matching algorithm with a maximum caliper of 0.25 was used to match patients in KT first group with comparable patients in BS first group according to the age at transplantation. Statistical analyses and Kaplan-Meier curves were performed using Stata/SE 16.0. The bar graph was plotted using GraphPad Prism 9.3.1. A p-value of < 0.05 was considered statistically significant.
Discussion
In this retrospective cohort study, we compared baseline characteristics, postoperative complications, and outcomes between patients with either a KT first or BS first approach. Our analysis showed that death-uncensored graft survival in the KT first group was significantly higher than the BS first group, but there was no significant difference in patient survival, death-censored graft survival or post-transplant complications. Both pre- and post-transplant BS achieved remarkable weight loss and the incidence of postoperative complications is acceptable.
] However, when it comes to patients with ESRD, another study showed that BS only improved transplant candidacy and stable weight loss, but not renal function[
]. Moreover, pre-transplant BS may have prolonged time on dialysis to establish sufficient weight loss and recover from long-term complications, which remains an independent predictor of mortality after KT.[
] When transplant is technically feasible despite being overweight, patients with an expected long waiting time because of blood type O or B, might decide to have BS first. However, because kidney donors are so scarce, the opportunity to receive a donor kidney may often postpone the consideration of BS. In our study, patients with severe obesity (BMI ≥ 40 kg/m2) were more likely to have BS before transplant, which caused higher baseline BMI in the BS first group.
] Although the findings of the two studies are different, both show that patients undergoing BS after KT benefit more.
] The study by Yemini et al. observed that tacrolimus blood concentrations declined slightly but remained within therapeutic range without serious rejection among transplanted patients who underwent laparoscopic Roux-en-Y gastric bypass.[
] However, it is not advisable to increase the tacrolimus dose solely based on bodyweight. Our previous experience found that such practices resulted in overexposure in more than half of overweight patients.[
] In this data, graft rejection occurred in 7 (33.3%) patients receiving Roux-en-Y gastric bypass and 8 (32.0%) patients receiving other types of BS (RR 1.04, 95% CI 0.45-2.39, P=0.923). Although not significantly different, more research into the pharmacokinetics of immunosuppressive agents among transplant recipients with obesity is needed.
] Furthermore, Roux-en-Y gastric bypass is associated with oxalate nephropathy and graft loss.
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In a systematic review evaluating the risk of hyperoxaluria in patient who underwent BS, it was concluded that Roux-en-Y gastric bypass was associated with increased urine oxalate and these patients had a significantly higher risk of stone formation.[
] In our study, oxalate deposits were found in four patients, all of whom had undergone Roux-en-Y gastric bypass. One of them lost the graft due to oxalate nephropathy. For this reason, sleeve gastrectomy may be a preferred choice compared to Roux-en-Y gastric bypass. Dietary interventions such as a low oxalate and salt diet show promising results in decreasing oxaluria and calcium oxalate relative supersaturation indexes.[
] Our colleagues first proposed that a systematic low-oxalic acid diet with supplementation of calcium, cholestyramine and sodium bicarbonate and intensifying dialysis effectively prevented oxalate nephropathy in a cohort of patients with enteric hyperoxaluria.[
] It may be beneficial for the transplant candidates and recipients who have undergone Roux-en-Y gastric bypass to adhere to such a low-oxalic acid diet.
] Compared to patients with class Ⅱ (BMI 35-39.9 kg/m2) and class Ⅲ obesity (BMI ≥ 40 kg/m2) who received RAKT alone, estimated blood loss, readmission rates, incidence of surgical complications and graft survival at one-year follow-up were comparable. Also, renal graft function was similar, indicating that performing kidney transplantation and sleeve gastrectomy simultaneously does not have a negative effect on graft function. As long-term data is not yet available, it is premature to conclude that simultaneous KT and BS should become the gold standard in ESRD patients.
Our study is limited by several factors. Firstly, the present study is a retrospective cohort analysis, of which a potential selection bias is unavoidable. To minimize this bias, we combined the data of two high volume transplant centers, which resulted in one of the largest cohorts of ESRD patients who underwent both BS and KT. However, the baseline BMI of patients in the BS first group was still higher and they may have a potentially higher risk of postoperative complications. Secondly, in this population of ESRD patients with obesity, some died after BS while awaiting KT. Unfortunately, these data were not collected prospectively. Thirdly, as the study involves patients over a 21-year period, the safety and public acceptance of BS have been tremendously improved. This dynamic change should be also taken into consideration when evaluating the robustness of the results.