Objectives: Although several studies have explored the connection between corticosteroids and renal transplant surgical complications, these studies have overlooked several factors. In addition, no review of the literature, to our knowledge, has been conducted to evaluate corticosteroid dose and incidence of posttransplant surgical complications in these patients. Thus, our objective was to carry out a systematic investigation of the correlation between corticosteroids and surgical complications in renal transplant patients.
Materials and Methods: A systematic search was conducted on the PubMed and Embase databases from their inception until April 2023. Retrospective and prospective cohort studies were included if they met the association between corticosteroids and surgical complications. The search strategy was performed using MeSH and non-MeSH key words. Terms used in the electronic search included kidney transplant* OR kidney transplant(mesh) AND steroid* OR steroids(mesh) AND complication* OR intraope-rative complications(mesh).
Results: From 3274 articles, 8 articles were included in the systematic review. Six studies were conducted as retrospective cohorts and 2 studies as prospective cohorts. The mean age of patients included in the studies was 42.1 years. The studies were conducted between 1981 and 2023. Findings suggested that decreasing the postoperative corticosteroid dosage was associated with a lower incidence of various postoperative surgical complications.
Conclusions: We investigated the potential benefits of reducing the dose of corticosteroids following kidney transplant. Findings suggested that reducing the dose of corticosteroids following kidney transplant might be a viable strategy for minimizing the risk of surgical complications. However, it is essential to note that the optimal dosage and duration of corticosteroid therapy after kidney transplant may vary for each patient and should be carefully determined by the health care provider.

Key words : Intraoperative complications, Prednisolone, Renal transplant

Introduction

The care of patients after renal transplant has considerably improved in recent years, resulting in reduced occurrences of acute rejection episodes and life-threatening infectious complications.¹ These developments have led to shorter hospital stays, less medical supervision, and faster recovery, thereby lowering the cost of transplant surgery. However, posttransplant complications that prolong hospital stays are now more concerning than before.² In addition, it is now possible to reduce organ shortages by using an unrelated living kidney transplant, which in long-term follow-up has shown similar results to living related kidney transplant.³

After kidney transplant, corticosteroids are an essential part of immunosuppression. They possess anti-inflammatory and immunosuppressive properties, which help prevent transplant rejection. Although corticosteroids have been considered crucial in enhancing transplant survival since their introduction in the 1960s, their use can result in various postoperative surgical complications, including wound infection, incisional hernia, lymphocele, impaired wound or anastomotic healing, and bleeding.^4,5 These steroid-related side effects can lead to additional expenses, poor compliance, and decreased graft survival.^6-9

It may be necessary to monitor the side effects of oral corticosteroids throughout the disease to decide how to decrease corticosteroid doses after the surgery.¹⁰ Currently, steroid minimization protocols are being examined to decrease steroid-related complications.¹¹ Several attempts have been made to avoid or to reduce the use of steroids in favor of other immunosuppressive drugs.¹² Nevertheless, the primary concern is how reducing corticosteroids will affect graft and patient survival.

Although several studies have explored the connection between corticosteroids and renal transplant complications, these studies have overlooked several factors. In addition, to our knowledge, no review of the literature has been conducted to evaluate corticosteroid dose and incidence of posttransplant surgical complications in these patients. Thus, our objective was to carry out a systematic investigation of the correlation between corticosteroids and surgical complications in renal transplant patients.

Materials and Methods

In the study of Simforoosh and colleagues,³ patients and participants had provided informed consent during treatment to allow access to treatment

Search strategy and selection criteria
In this review, we followed the preferred reporting items outlined in the PRISMA statement.¹² The review protocol for this study was registered on PROSPERO (with registration ID pending as 444148). To conduct the review, we performed a comprehensive search in the PubMed and Embase databases.

Our search strategy utilized MeSH and non-MeSH keywords without any restrictions on language or date. The search terms included kidney transplant* OR kidney transplant(mesh) AND steroid* OR steroids(mesh) AND complication* OR intraoperative complications(mesh).

We first screened the titles and abstracts of the received studies. We then thoroughly examined the full text of the included studies based on the predetermined inclusion and exclusion criteria.

Eligibility criteria
To be included in this analysis, studies had to meet the following criteria: (1) the authors examined a correlation between corticosteroids and surgical complications, and (2) the studies had either a prospective cohort or retrospective cohort design. Conversely, studies were excluded if they fell into any of the following categories: (1) editorials, (2) nonhuman studies, (3) in vitro research, (4) case reports, case-control studies, or clinical trials, (5) ecological studies, or (6) letters lacking sufficient data.

Data extraction and quality assessment
Two authors independently retrieved and encoded all data. The differences were resolved by consensus with the third writer. The relevant data extracted included the authors, year of publication, study location, cohort name, study design, number of participants, age, patient sex, and follow-up duration. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to evaluate the quality of the studies (Table 4). Studies with a total score of 0 to 3 were classified as low-quality studies, 4 to 6 as moderate-quality studies, and 7 to 9 as high-quality studies.¹³

Statistical analyses
Because the admitted articles did not meet the conditions for a meta-analysis, we elected to perform a descriptive analysis of our results based on the reported patient characteristics, including recipient age and sex, corticosteroid dose, and surgical complications.

Results

The initial PubMed search yielded 3274 articles, and an additional 1674 articles were discovered through the Embase databases. After we eliminated 2033 duplicates, the combined search strategy resulted in 1108 articles. After we reviewed the titles and abstracts, another 1002 records were excluded, leaving 106 full-text articles for evaluation against the inclusion and exclusion criteria. Of these, 98 articles were removed as they did not contain primary quantitative data, had duplicate data, or did not meet the exclusion criteria (see Figure 1). As a result, 8 articles were included in the systematic review.

Study characteristics
Characteristics of the included studies are listed in Table 1 and Table 2. Six studies were conducted as retrospective cohorts and 2 studies as prospective cohorts. The studies were conducted between 1981 and 2023. Postoperative complications of the studied population are shown in Table 3.

In 2016, Jun and colleagues¹⁴ conducted a study involving 92 kidney transplant recipients to inves-tigate the risk factors associated with postoperative lymphocele. The participants were administered an immunosuppressive regimen consisting of calci-neurin inhibitors, mycophenolate mofetil, and corticosteroids. Although early withdrawal of steroids within 8 days was performed for 7 recipients, the specific corticosteroid doses for different groups were not provided in the study. The research revealed no significant correlation between corticosteroid dose and the occurrence of lymphocele. However, the study mentioned that there seemed to be some association between steroid pulse therapy and the size of the lymphocele, although statistical significance was lacking. The study did not provide details on demographic characteristics or the potential side effects of corticosteroids in kidney transplant recipients. The main focus of the study was to identify risk factors for postoperative lymphoceles in kidney transplant recipients and explore preventive measures, rather than to examine the relationship between corticosteroids and surgi-cal or wound complications.

In 1993, a study by Khauli and colleagues¹⁵ examined the development of lymphoceles in 118 kidney transplant recipients. The study included 96 recipients of kidneys from deceased donors and 22 recipients of kidneys from living-related donors. The participants consisted of 73 male and 43 female patients, with age ranging from 14 to 75 years (median age of 39 y). Among the patients, 7 (5.9%) received retransplants and 111 (94.1%) received primary transplants. The main focus of the study was to identify the risk factors associated with lymphoceles in kidney transplant recipients. The study found that high-dose corticosteroids, speci-fically a cumulative methylprednisolone intravenous dose of 3 g or more, significantly increased the incidence of symptomatic lymphoceles compared with low-dose steroids.

In 1997, Stephan and colleagues¹⁶ conducted a study on 102 kidney transplant recipients who received corticosteroids for several weeks to months, with varying doses depending on the group. The study mentioned that corticosteroids can increase the risk of infection and delay wound healing and suggested that higher doses of corticosteroids may be associated with increased wound complications. However, the study did not provide specific information on the relationship between corticos-teroids and surgical or wound complications. The study did mention that prednisone is part of the maintenance immunosuppression regimen for renal transplant patients but did not provide information on its relationship to surgical or wound comp-lications. The study suggested that reducing steroid administration may lower posttransplant infection rates but did not provide specific information on surgical or wound complications. Overall, although corticosteroids were discussed, the study did not provide a comprehensive overview of their rela-tionship to surgical or wound complications.

In 1995, Shoskes and colleagues¹⁷ conducted a study on 1000 renal transplant recipients, with 273 patients receiving prednisolone plus azathioprine, 102 receiving cyclosporine monotherapy, 38 receiving cyclosporine plus prednisolone, and 587 receiving triple therapy of cyclosporine plus azathioprine plus prednisolone. The mean age of the 812 patients who received the 1000 consecutive renal transplants was 40 years, and the male-to-female ratio was 1.6:1. The study mentioned the use of corticosteroids in the immunosuppressive protocols for renal transplant, stating that this practice started in the late 1970s. Most patients were given low doses of steroids via azathioprine or cyclosporin. The study found a strong correlation between high-dose steroids and complication rates, including urological complications like ureteral leak and stricture. However, the study did not provide information on specific patient groups, the relationship between corticosteroid dose and surgical complications, the side effects of corticosteroids, the length of the corticosteroid course, or the corticosteroid dose and general immunosup-pressive regimen in different groups.

A study conducted by Mundy and colleagues in 198618 investigated urological complications in 826 patients who underwent renal transplant. All patients were given azathioprine and prednisolone posttransplant, and some received antilymphocyte globulin. The study focused on 713 recipients who received “high-dose” steroid treatment (more than 0.3 mg prednisolone/kg body weight/day or equivalent for other steroids at maximum routine dosage) and 287 recipients who received “low-dose” steroid treatment. Primary ureteroneocystostomy was performed in 994 cases. The study noted that high doses of steroids were associated with a higher mortality rate in patients with complications compared with those who received low-dose treatment. Additionally, the incidence of wound complications was significantly higher in the high-dose group compared with the low-dose group (P < .01).

In 2004, Freise and colleagues¹⁹ conducted a study on 44 patients with pancreas-kidney transplant. The study provided some information on patient characteristics, including sex (26 men and 18 women), but did not provide further detailed demographic information. The study described a steroid-free maintenance immunosuppression protocol for simultaneous pancreas-kidney transp-lant and reported on the outcomes and complications associated with this protocol. The study mentioned that steroids were given at 500 mg with the first dose of thymoglobulin, but this was part of the induction therapy and not part of the maintenance immunosuppression protocol. The study did de-scribe some of the complications and side effects associated with the immunosuppressive agents used in the protocol, including gastrointestinal toxicity, leukopenia, viral infections (including polyomavirus and cytomegalovirus), wound hernias, and enteric anastomotic breakdown. The study also reported on some of the metabolic benefits observed in patients posttransplant, such as weight gain and impro-vements in cholesterol levels, but did not provide information on any potential long-term side effects of the immunosuppressive agents used in the protocol. The study mentioned that 3 patients developed a herniated wound and 1 patient had an enteric anastomotic rupture, although information on whether these complications were related to the use of corticosteroids or other factors was not mentioned.

In 2023, Simforoosh and colleagues²⁰ analyzed the data of 1231 patients who underwent kidney transplant, with 592 patients in group 1 and 639 patients in group 2. The mean age was 40 ±15 years in group 1 and 41 ±17 years in group 2, and the sex distribution was similar between the 2 groups. The study provided information on corticosteroid dosage in each group, with group 1 receiving a higher dose of prednisone initially, which was tapered to 10 mg by 3 months posttransplant. Group 2 received a lower dose that started at 50 mg, which was gradually decreased to 10 mg by day 6 post-transplant. The study aimed to investigate whether reducing the dose of corticosteroids after kidney transplant could decrease postoperative surgical complications without affecting patient and graft survival. The results indicated that lowering the dose of corticosteroids decreased serious postoperative surgical complications without negatively affecting overall patient and graft survival. The study also found that high-dose postoperative corticosteroid levels were associated with lower patient survival in the long term, potentially increasing the risk of medical comorbidities. The study reported a significant decrease in wound infection and infectious collection formation during corticosteroid dosage decrement and a considerable reduction in ureteral fistula in the low-dose group. Overall, the study suggested that postoperative corticosteroid dosage decrement could reduce postoperative surgical complications, including incisional hernia (P = .003), wound infection (P = .035), infectious collection formation (P = .004), postoperative hemorrhage (P = .005), and ureteral fistula (P = .076), without negatively impacting overall patient and graft survival.

A study conducted in 2001 by Humar and colleagues²¹ aimed to investigate the occurrence of wound complications in kidney transplant recipients and the potential effect of newer immunosuppressive drugs on these complications. The study revealed that the incidence of wound complications among kidney recipients was generally low, with risk factors, including obesity, reoperation, and advanced age. The use of mycophenolate mofetil (MMF) for maintenance immunosuppression was also iden-tified as a risk factor for wound complications. The most common complication observed after kidney transplant was wound infections, with obesity and urine leaks being risk factors. Noninfectious wound complications, such as incisional hernias and fascial dehiscence, were also prevalent, with reoperation through the initial transplant incision being the most significant risk factor. The use of MMF was also a significant risk factor for noninfectious wound complications. The study suggested that corti-costeroid dosage plays a crucial role in the occurrence of wound complications in kidney transplant recipients, with higher doses associated with a higher incidence of such complications. The study also discussed the potential side effects of corticosteroids, including impaired wound healing and increased susceptibility to infections. However, although the study highlighted important surgical complications posttransplant, it primarily focused on the impact of MMF on these complications and did not extensively address the effect of corticosteroids or the relationship between surgical complications and corticosteroid dosage.

Discussion

In this systematic review, we aimed to study the relationship between corticosteroids and surgical complications in kidney transplant recipients. Kidney transplant is a complex surgical procedure that involves the placement of a healthy kidney from a donor into a recipient. After surgery, patients are typically given corticosteroids as part of their posto-perative care to prevent organ rejection. However, high doses of corticosteroids can lead to various adverse effects, including surgical complications.

In our study, we investigated the potential benefits of decreasing the dose of corticosteroids in reducing surgical complications after kidney transplant. Findings suggested that decreasing the postoperative corticosteroid dosage was associated with a lower incidence of various postoperative surgical complications. These included incisional hernia, wound infection, which can lead to delayed healing and other complications, infectious collection formation, postoperative hemorrhage, and ureteral fistula. Findings suggested that reducing the dose of corticosteroids after kidney transplant may be a viable strategy for minimizing the risk of these complications. However, it is important to note that the optimal dosage and duration of corticosteroid therapy after kidney transplant may vary for each patient and should be carefully determined by the health care provider.

High doses of corticosteroids have been tradi-tionally administered immediately after kidney transplant, even during the tissue-healing process. This practice led us to the hypothesis that the use of high-dose steroids after surgery may increase the risk of surgical complications. Numerous studies have investigated the role of corticosteroids in posto-perative complications across different types of surgeries. For example, in a prospective study of 1243 surgeries, Hasselgren and colleagues²² found that treatment with high-dose steroids was associated with a high wound infection rate. Similarly, Golub and colleagues²³ conducted a retrospective study of 764 patients who underwent intestinal anastomoses and discovered that the use of corticosteroids was a predictor of anastomotic leakage. Another retros-pective cohort study of postoperative complications after esophagectomy by Jeong and colleagues²⁴ noted that the use of corticosteroids might be associated with graft dehiscence and fistula formation.

Weisberger and colleagues8 analyzed the effects of corticosteroid use on free flap reconstruction. The group determined that chronic use of corticosteroids increased the risk of significant bleeding complica­tions requiring blood transfusion by a factor of 4. Togo and colleagues⁷ performed a multivariate analysis and found that steroid use was a risk factor for incisional hernia after partial hepatectomy. Fink and colleagues⁹ demonstrated that patients with a history of corticosteroid use have a higher risk of vascular complications and postsurgical bleeding after transfemoral aortic valve implantation. These and other similar studies have led us to hypothesize that reducing the dose of corticosteroids after kidney transplant may help to decrease postsurgical complications, as corticosteroids are known to affect the healing process after surgery.

Simforoosh and colleagues conducted a study in which 8 cases of incisional hernia were observed in the high-dose steroid group. In contrast, no patients in the low-dose steroid group developed postoper-ative incisional hernias. Although some studies have investigated the relationship between steroid use and incisional hernia after liver transplantation,^25-27 no existing studies in the literature, to our knowledge, have specifically evaluate this rela-tionship in kidney transplant. Furthermore, the survey by Simforoosh and colleagues also found that reducing the corticosteroid dose resulted in a significant reduction in the incidence of ureteral fistula (P = .076), wound infection (P = .035), and formation of an infectious complex (P = .004).²⁰

Ahern and colleagues²⁸ conducted a study that found that recipients who received high-dose steroids had a higher incidence of surgical infections than those who received lower doses of steroids. Another study reported that patients in the low-dose steroid group had easily managed wound infections. In contrast, in the high-dose steroid group, a few resistant wound infections were observed that required prolonged and regular washing.²⁰

This review had several limitations, including reporting bias due to variations in follow-up duration and incomplete reporting of primary or secondary outcomes in most of the studies analyzed. There were also limitations when comparing postoperative complications before and after transplant, as relevant data were not available in many of the studies. Furthermore, it was not possible to adjust for confounding factors because data on potential confounders were not available in most of the studies. Finally, publication bias may be present since only studies published in English were included.

Conclusions

In our investigation of the potential benefits of reducing the dose of corticosteroids after kidney transplant, our findings suggest that decreasing the postoperative corticosteroid dosage is associated with a lower incidence of various postoperative surgical complications. These include incisional hernia, wound infection, infectious collection formation, postoperative hemorrhage, and ureteral fistula. Our findings suggest that reducing the dose of corticosteroids after kidney transplantation might be a viable strategy for minimizing the risk of these complications. However, it is essential to note that the optimal dosage and duration of corticosteroid therapy after kidney transplant may vary for each patient and should be carefully determined by the health care provider.

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