1 Running Head: The effect of lowering the dose of corticosteroid in post-operative complications of kidney transplant patients. Lowering the Dose of Corticosteroid Regimen in Kidney Transplantation: Is It Effective in Decreasing Post-operative Surgical Complications? Nasser simforoosh1, Amirhossein Nayebzade2*, Mehdi Dadpour3, Atefe Eslami4 Nasser Simforoosh : MD; Email: n.simforoosh@gmail.com; ORCID: 000-0003-4135-342X; Urology and nephrology research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Amirhossein Nayebzade : MD; E.mail: nayebzade.amir@gmail.com; ORCID: 0000-0003- 1607-8104; Urology and nephrology research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Mehdi Dadpour : MD; E.mail: mehdi_dadpour@yahoo.com; ORCID: 0000-0003-3550-3778; Urology and nephrology research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Atefe Eslami : MD; E.mail: atefe.esl7020@gmail.com; ORCID: 0000-0001-8027-6258; Urology and nephrology research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Corresponding author: Amirhossein Nayebzade : MD; E.mail: nayebzade.amir@gmail.com; ORCID: 0000-0003- 1607-8104; Urology and nephrology research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Email : nayebzade.amir@gmail.com Key words: kidney transplantation; corticosteroid; administration and dosage; postoperative complications; survival analysis https://journals.sbmu.ac.ir/urolj/index.php/uj/article/view/6858 mailto:n.simforoosh@gmail.com https://journals.sbmu.ac.ir/urolj/index.php/uj/article/view/6858 2 ABSTRACT Purpose: To investigate the impact of reducing post-operative oral corticosteroid regimen on associated postoperative surgical complication rate, patient and graft survival in kidney transplant patients. Materials and Methods: In this retrospective cohort study, we enrolled patients who received kidney transplant during two periods of distinct corticosteroid protocols. 592 patients in group 1 received prednisone 2 mg/kg (maximum dose 120 mg) on post-operative days (POD) 1, 2 and 3, 1mg/kg for a week, and tapered it to 10 mg by 3 months post-transplant and sustained the daily 10mg from 3 months post-transplant as maintenance therapy. 639 patients in group 2 received prednisone 50 mg on POD 1, 40mg on POD 2, 30mg on POD 3, 20mg on POD 4, 15mg on POD 5 and continued with 10mg daily from POD 6, as maintenance therapy. The two groups were similar in terms of other immunosuppression drug regimen. Results: 75 (12.7%) patients in group 1 and 24 (3.4%) patients in group 2 developed corticosteroid-related postoperative surgical complications (P < .001). Wound infection (P = .035), incisional hernia (P = .003), infectious collection (P = .004), post-op hemorrhage (P = .005) and ureteral fistula (P = .076) occurred with lower frequency in group 2. Patient survival (1-year: 97.3% vs 97.1%, respectively; P = .85, 5-year: 89.9% vs 94.9%, respectively; P = .06) and graft survival (1-year: 94.6% vs 93.3%, respectively; P = .29, 5-year: 81.2% vs 85.1%, respectively; P = .39) were similar in both groups. Conclusion: Post-operative corticosteroid dosage decrement through our protocol would lessen the serious associated postoperative surgical complications, without negative impacts on overall patient and graft survival. 3 INTRODUCTION Corticosteroids are an important part of the immunosuppression regimen following kidney transplantation. Corticosteroids are used to prevent graft rejection through the capability of immunosuppression and anti-inflammatory effect. Since its introduction in the 1960s, it has been accepted that corticosteroid has been playing a significant role in increasing the graft survival (1, 2). However, taking corticosteroid may be associated with various post-operative surgical complications including wound infection, incisional hernia, lymphocele, wound or anastomosis healing impairment and bleeding, probably due to interference with the tissue healing process (3- 7). Occurrence of these steroid-related side effects is accompanied with additional costs, post- transplant noncompliance and decreased graft survival (8). It is interesting to know that prednisone is the immunosuppressive drug that the kidney transplant recipients who survived, would most like not to take (9). Monitoring the side effects of oral corticosteroids alongside with the disease process seems necessary to decide how to reduce the dose of corticosteroids, post-operatively (10). Nowadays, to minimize the steroid-related complications, steroid minimization protocols are taken into consideration. (8). Many efforts have been made either to avoid taking steroids or decrease the dosage through other immunosuppressive drugs replacement (11, 12). However, the main concern in this respect is how corticosteroid minimization would affect the graft and the patient survival. In this study, we aimed to investigate if decreasing post-operative oral corticosteroid regimen following kidney transplantation would reduce the postoperative surgical complication rate, with no change in patient and graft survival. 4 Materials and Methods Study Population In this retrospective cohort study, we enrolled patients who received kidney transplant during two periods of distinct corticosteroid protocols in our center between 2013 and 2019. A total number of 592 patients who received first kidney transplantation between Jan 2013 and Jan 2016 (group 1) were compared to 639 patients receiving kidney alone transplant between Jan 2016 and Jan 2019 (group 2). The follow-up of all patients in both groups started at the time of surgery and continued until the end of 2022. Exclusion criteria Exclusion criteria were patients with multi-organ transplantation, repeated kidney transplantation in the same recipients, history of corticosteroid usage for whatever reason like autoimmune disease and loss to follow up. Immunosuppression protocols In group 1, patients received prednisone 2 mg/kg (maximum dose 120 mg) on post-operative days (POD) 1,2 and 3, 1 mg/kg for a week, and tapered to 10 mg by 3 months post-transplant and continued with 10mg daily from 3 months post-transplant as maintenance therapy. In group 2, patients received prednisone 50 mg on POD 1, 40mg on POD 2, 30mg on POD 3, 20mg on POD 4, 15mg on POD 5 and continued with 10mg daily from POD 6, as maintenance therapy. All patients in both groups were similar in chronic immunosuppression maintenance including Mycophenolate Mofetil and Tacrolimus. Evaluations 5 We used electronic medical records and organ transplant tracking record database to extract the variables. All the kidney transplantation survival data in our center are registered in Collaborative Transplant Study (CTS) of Heidelberg, prospectively. The primary goal of this study is to evaluate and compare the associated postoperative surgical complications including incisional hernia, lymphocele information requiring percutaneous drainage or exploration, hemorrhage which lead to exploration; nephrectomy or anastomosis repair, infectious collection formation, wound infection, ureteral stenosis and ureteral fistula leading to exploration between the two groups. The secondary goal is to compare the patient and graft survival between these two groups. The study protocol was approved by the institutional board of research and committee of medical ethics (code: IR.SBMU.MSP.REC.1398.690). This study was conducted in accordance with the Declaration of Helsinki. Statistical Analysis All the statistical analyses were performed using SPSS software version 25.0 (IBM, Chicago, Illinois, USA). Data are shown as mean ± standard deviation (SD) and frequency (percentage) for quantitative and qualitative variables, respectively. The normality of data distribution was assessed using the Kolmogorov-Smirnov test. The independent sample T test or Mann-Whitney test was also used to compare the mean outcome quantities between the two groups studied. Chi Square test or Fisher exact test (where the 20% of expected cell counts were less than 5) was also used to compare qualitative factors between the two groups. Kaplan-Meier survival analysis along with log rank test was performed by CTS of Heidelberg to compare patient and graft survival between the study groups. Univariable and multivariable Logistic regression analysis was used to assess the effect of variables on binary outcomes. The normality of data distribution 6 was assessed using the Kolmogorov-Smirnov test and also graphically through Q-Q plot. In this study, P-value of less than 0.05 was considered as statistically significant. RESULTS In this study, we evaluated the data of 1231 patients who underwent kidney transplantation. Table 1 shows the patients characteristics of group 1 and 2, separately. A total number of 99 (8.04%) patients including 75 (12.7%) in group 1 and 24 (3.8%) in group 2 developed corticosteroid-associated postoperative surgical complications (P < .001). Wound infection (P = .035), incisional hernia (P = .003), infectious collection formation (P = .004) and post-op hemorrhage (P = .005) occurred with significantly lower frequency in group 2. Ureteral fistula was also decreased in group 2 but not significant (9 in group 1 versus 3 in group 2, P = .076). Table 2 shows the types of postoperative complications among group 1 and 2, separately. After adjusting the covariates, in a multivariate logistic regression, the corticosteroid dosage group was an independent predictor for infectious collection formation (OR[CI]: 0.05[0.007- 0.37]; p = .004), wound infection (OR[CI]: 0.45[0.21-0.94]; P = .035) and postoperative bleeding (OR[CI]: 0.12[0.028-0.530]; P = .005). We did not perform multivariate analysis for incisional hernia because it did not occur to any patient in the low-dose group at all (Table 3). Figure 1a shows the Kaplan-Meier overall patient survival, comparing group 1 with group 2. Patient survival was similar between two groups, 1-year survival: 97.3% vs 97.1%, respectively; (P = .85), 3-year survival: 94.3% vs 95.5%, respectively; (P = .38), 5-year survival: 89.9% vs 94.9%, respectively; (P = .06). Figure 1b shows the Kaplan-Meier graft survival comparing the two groups. Graft survival was also similar between the two groups. 1-year survival: 94.6% vs 7 93.3%, respectively; (P = .29), 3-year survival: 88.2% vs 89.1%, respectively; (P = .81), 5-year survival: 81.2% vs 85.1%, respectively; (P = .39). DISCUSSION Steroids are used against inflammation, edema and autoimmunity and have a role in the treatment of a wide range of diseases. Considering its benefits, in this study we intended to address its disadvantages including post-surgical complications following kidney transplantation. Tissue-healing process following vascular anastomosis, ureterovesical reimplantation and abdominal wall repairment begins immediately in kidney transplant patients. It is proven that corticosteroids would affect all major steps of healing process including inflammatory, proliferative and remodeling phases. By inhibiting vascular permeability and leukocyte adhesion, steroids impair the initiation of tissue matrix layout and healing process (13, 14). Conventionally, high-dose corticosteroids are used immediately following kidney transplantation, just when the tissue-healing process has begun. This effect led us to the hypothesis that using high dose steroids post-operatively might increase surgical complications. Many studies have evaluated the role of corticosteroids in postoperative complications in different types of surgeries. Hasselgren et al. (6) found out in a prospective study of 1243 different surgeries that treatment with high-dose steroids is associated with high wound infection rate. Golub et al. (15) in a retrospective study of 764 patients who underwent intestinal anastomoses found out that the use of corticosteroids could predict anastomotic leakage. In a retrospective cohort study of post-operative complications after esophagectomy, Jeong et al. (16) realized that using corticosteroids may be related to graft dehiscence and fistula. Weisberger et al. (5) analyzed the impact of corticosteroid use on free flap reconstruction and concluded that chronic corticosteroid usage conferred 8 increased major bleeding complications requiring blood transfusion by a factor of four. In a multivariate analysis, Togo et al. (4) discovered that steroid use is a risk factor for incisional hernia following partial hepatectomy. Fink et al. (7) showed that patients with history of using corticosteroids are at a higher risk of vascular complications and post-surgical bleeding following transfemoral aortic valve implantation. Based on the findings of these studies and other similar studies, and in agreement with the association of corticosteroids usage and post- operative healing process, we hypothesized that we could reduce the post-surgical complications by corticosteroid dosage decrement following kidney transplantation. In this study, we experienced 8 incisional hernias in group 1 (high-dose steroid), some of whom were inoperable (figure 1), while no patients in group 2 (low-dose steroid) suffered an incisional hernia post-operatively (P < .05). Some studies address the issue of association between steroid usage and incisional hernia following liver transplantation (17-20) but to our best knowledge, there is no study in the literature having specifically evaluated this relationship in kidney transplant recipients. In addition, we observed a considerable decrease of ureteral fistula in the low-dose group (9 versus 3, P = .076). Given that ureteral fistula is a rare complication following transplantation, we believe that with a larger sample size, a significant p-value may be achievable. Collins et al. (21) showed that the use of corticosteroid may interfere with the healing of vesicovaginal and urethrovaginal fistula when an early repair is attempted but to our best knowledge, no study has been designed to evaluate the association of corticosteroid dosage and ureteral fistula following kidney transplantation yet. We observed a significant decrease of wound infection and infectious collection formation during corticosteroid dosage decrement (22 versus 11 P = .035, 17 versus 1 P = .04, respectively). Ahern et al. (22) in a study about general infectious complications associated with renal transplant, concluded that the incidence of serious 9 infections was higher in recipients receiving high-dose steroid versus recipients receiving lower doses of steroids. Wound infections were easily managed in low-dose steroid groups patients, while we faced a few refractory wound infections among high-dose steroid group, which needed to be left open and required regular washing for a long time period. We did not observe changes in lymphocele formation incidence in different corticosteroid dosage recipients. In a univariate analysis, Khauli et al. (23) detected high-dose corticosteroid as a risk factor for lymphocele development beside acute tubular necrosis and rejection in kidney recipients. However, in the multivariate analysis only rejection rather than corticosteroid dosage was a predictor for lymphocele formation in their study. Our results showed that our corticosteroid minimization protocol would reduce the serious postoperative surgical complication rate, without negative impacts on patient and graft survival. There are some studies in the literature, which are comparable to our results regarding corticosteroid dosage decrement and survivals. In a comparative study about patient and graft survival among 1689 patients with historical approach and 2097 patients in early steroid withdrawal group following kidney transplantation, Adebiyi et al. (24) showed no difference in patient survival but better death-censored graft survival in the second group. In a large study, Luan et al. (25) evaluated the data of 95,755 kidney transplant recipients, 16,491 (17.2%) of whom were steroid-free at discharge. It was interesting to notice that steroid-free regimen was associated with a reduced risk for graft failure and death. In a study about corticosteroid minimization protocol, Jaber et al. (26) found out that early steroid withdrawal (day 6, postoperatively) would not affect the graft survival. In a 15-year period kidney transplantation study, Serrano et al. (27) evaluated 1553 patients and concluded that rapid discontinuation of prednisone does not lead to a decrease in patient or graft survival. These two 10 recent studies evaluated the association of corticosteroid dosage decrement and medical steroids side effects, the patient and graft survival. Along with reducing medical steroid-associated side effects, similar to us, they found out that reducing steroid dosage would not adversely impact on patient and graft survival. They, however, did not investigate the relationship between corticosteroid dosage decrement and post-operative surgical complications. Our patient survival Kaplan-Meier curves (fig 1a) show that as the follow-up time increases, patient survival decreases further in high-dose corticosteroid group than low-dose corticosteroid group. In other words, high-dose post-operative corticosteroid is associated with lower patient survival in the long term, probably through increasing the risk of medical comorbidities including diabetes mellitus, osteoporosis, ischemic heart disease. Based on our results, early steroid decrement has promising outcomes and deserves more attention in renal transplant patients to prevent serious post-transplant surgical complications, a goal that has been underappreciated in the literature. Nevertheless, it is evident that careful monitoring of the patient and graft function seems to be necessary. We perform kidney transplantation from living or deceased donor in our center (28, 29) and including a high proportion of living donors in this study is different in comparison to many other studies. Retrospective nature is the main limitation of this study and prospective studies through randomized clinical trial settings seem to be mandatory to confirm our findings. Large OR estimates and CI due to low rate of some surgical complications were another limitation of this study. CONCLUSION Reducing the dose of corticosteroid through our protocol seems to be beneficial following kidney transplantation. Our study indicates that post-operative corticosteroid dosage decrement would 11 lessen the post-operative surgical complications including incisional hernia, wound infection, infectious collection formation, post-operative hemorrhage and ureteral fistula without negative impacts on overall patient and graft survival. ACKNOWLEDGEMENT We would like to thank Collaborative Transplant Study (CTS) team, Heidelberg University Hospital, for their assistance with Kaplan-Meier survival analysis. CONFLICT OF INTEREST All authors declare that they have no conflict of interests. REFERENCES 1 Tarantino A, Montagnino G, Ponticelli C. Corticosteroids in kidney transplant recipients. Safety issues and timing of discontinuation. Drug safety 1995; 13 (3): 145-156. 2 Citterio F. Steroid side effects and their impact on transplantation outcome. Transplantation 2001; 72 (12 Suppl): S75-80. 3 Yasir M, Goyal A, Sonthalia S. Corticosteroid Adverse Effects. 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Causative factors, surgical treatment and outcome of incisional hernia after liver transplantation. Br J Surg 2002; 89 (8): 1049-1054. 20 Gómez R, Hidalgo M, Marques E et al. Incidence and predisposing factors for incisional hernia in patients with liver transplantation. Hernia 2001; 5 (4): 172-176. 21 Collins CG, Collins JH, Harrison BR et al. Early repair of vesicovaginal fistula. American Journal of Obstetrics and Gynecology 1971; 111 (4): 524-528. 22 Ahern MJ, Comite H, Andriole VT. Infectious complications associated with renal transplantation: an analysis of risk factors. Yale J Biol Med 1978; 51 (5): 513-525. 23 Khauli RB, Stoff JS, Lovewell T et al. Post-transplant lymphoceles: a critical look into the risk factors, pathophysiology and management. J Urol 1993; 150 (1): 22-26. 24 Adebiyi O, Umukoro P, Sharfuddin A et al. Patient and Graft Survival Outcomes During 2 Eras of Immunosuppression Protocols in Kidney Transplantation: Indiana University Retrospective Cohort Experience. Transplantation proceedings 2021; 53 (10): 2841-2852. 25 Luan FL, Steffick DE, Gadegbeku C et al. Graft and patient survival in kidney transplant recipients selected for de novo steroid-free maintenance immunosuppression. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2009; 9 (1): 160-168. 26 Jaber JJ, Feustel PJ, Elbahloul O et al. Early steroid withdrawal therapy in renal transplant recipients: a steroid-free sirolimus and CellCept-based calcineurin inhibitor- minimization protocol. Clinical transplantation 2007; 21 (1): 101-109. 27 Serrano OK, Kandaswamy R, Gillingham K et al. Rapid Discontinuation of Prednisone in Kidney Transplant Recipients: 15-Year Outcomes From the University of Minnesota. Transplantation 2017; 101 (10): 2590-2598. 13 28 Simforoosh N, Bassiri A, Ziaee SA et al. Laparoscopic versus open live donor nephrectomy: the first randomized clinical trial. Transplant Proc 2003; 35 (7): 2553- 2554. 29 Simforoosh N, Basiri A, Tabibi A et al. Technical Challenges and Innovations in Kidney Transplantation: Experience With Over 5000 Cases. Exp Clin Transplant 2020; 18 (Suppl 1): 10-15. 14 Tables Table1. Patients’ characteristics of group 1 and 2. Group 1 Group 2 p-value Number (n) 592 639 Age (±SD) 40 (±15) 41 (±17) 0.148 Sex (F/M) 206/386 213/426 0.588 BMI (±SD) 24.30 (±4.89) 24.54 (±5.11) 0.386 Pre-op DM (%) 112 (19%) 129 (20.2%) 0.585 Pre-op HTN 412 (69.7%) 450 (70.4%) 0.786 Donour type (living/cadaver) 309/283 320/319 0.458 Table2. Types of postoperative complications among group 1 and 2. Group 1 Group 2 p-value Odds ratio (95%CI) Lymphocele 5 (0.8%) 4 (0.6%) 0.654 0.740 (0.198-2.767) Incisional hernia 8 (1.4%) 0 (0%) 0.003 - Infectious collection 17 (2.9%) 1 (0.2%) 0.004 0.053 (0.007-0.400) Ureteral fistula 9 (1.5%) 3 (0.5%) 0.076 0.306 (0.082-1.134) Ureteral stenosis 6 (1%) 3 (0.5%) 0.275 0.461 (0.115-1.850) Wound infection 22 (3.7%) 11 (1.7%) 0.035 0.454 (0.218-0.944) Hemorrhage (anastomosis leakage) 15 (2.5%) 2 (0.3%) 0.005 0.121 (0.028-0.530) any kind of side effects 75 (12.7%) 24 (3.8%) <0.001 0.269 (0.167-0.432) 15 Table3. Multivariable logistic regression of the postoperative complications after adjusting the covariates. p-value Odds ratio (95%CI) Lymphocele .557 .67(.17, 2.55) Infectious collection .004 .05(.007, .37) Ureteral fistula .084 .31(.08, 1.16) Ureteral stenosis .241 .43(.10, 1.75) Wound infection .035 .45(.21, .94) Hemorrhage (anastomosis leakage) .005 .12(.02, .53) overall complications <.001 .27(.68, 1.67) Figures Figure 1a. The Kaplan-Meier overall patient survival, comparing group 1 with group 2. Note: Patient survival was similar between two groups. Figure 1b. The Kaplan-Meier graft survival comparing the two groups. Note: Graft survival was also similar between the two groups.