Steroid avoidance or withdrawal for pancreas and pancreas with kidney transplant recipients

People with type 1 diabetes and kidney failure have a poor survival. In the clinical course, they suffer from several diabetic vascular complications and usually have progressive kidney impairment. Pancreas transplantation improves survival and quality of life and controls blood glucose without the need for insulin therapy, making pancreas with kidney transplantation the treatment of choice in most patients with type 1 insulin-dependent diabetes and kidney failure. More than 95% of transplant recipients are treated with steroids as part of their immunosuppression. Steroid treatment has complications including: hypertension, hyperglycaemia or hyperlipidaemia, increase risk of infection, obesity, cataracts, muscle disease, bone metabolism alterations and skin problems. However, without adequate immunosuppression, transplant patients are at risk of transplant rejection and transplant failure. This review looked at two strategies - steroid avoidance and steroid withdrawal - to investigate their impact on short- and long-term outcomes. These strategies could be used in adults in the first few days after transplantation when used in combination with more powerful immunosuppressive agents. Twenty-one studies were identified and evaluated in this review although only three RCTs enrolling 144 participants met our inclusion criteria. Steroid avoidance and steroid withdrawal strategies in pancreas and pancreas with kidney transplantation were not apparently associated with increased mortality, graft loss or acute rejection, although more studies are needed.

Authors' conclusions: 

There is currently insufficient evidence for the benefits and harms of steroid withdrawal in pancreas transplantation in the three RCTs (144 patients) identified. The results showed uncertain results for short-term risk of rejection, mortality, or graft survival in steroid-sparing strategies in a very small number of patients over a short period of follow-up. Overall the data was sparse, so no firm conclusions are possible. Moreover, the 13 observational studies findings generally concur with the evidence found in the RCTs.

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Background: 

Pancreas or kidney-pancreas transplantation improves survival and quality of life for people with type 1 diabetes mellitus and kidney failure. Immunosuppression after transplantation is associated with complications. Steroids have adverse effects on cardiovascular risk factors such as hypertension, hyperglycaemia or hyperlipidaemia, increase risk of infection, obesity, cataracts, myopathy, bone metabolism alterations, dermatologic problems and cushingoid appearance. Whether avoiding steroids changes outcomes is unclear.

Objectives: 

We aimed to assess the safety and efficacy of steroid early withdrawal (treatment for less than 14 days after transplantation), late withdrawal (after 14 days after transplantation) or steroid avoidance in patients receiving a pancreas (including a vascularized organ) alone (PTA), simultaneous with a kidney (SPK) or after kidney transplantation (PAK).

Search strategy: 

We searched the Cochrane Renal Group's Specialised Register (to 18 June 2014) through contact with the Trials' Search Co-ordinator. We handsearched: reference lists of nephrology textbooks, relevant studies, recent publications and clinical practice guidelines; abstracts from international transplantation society scientific meetings; and sent emails and letters seeking information about unpublished or incomplete studies to known investigators.

Selection criteria: 

We included randomised controlled trials (RCTs) or cohort studies of steroid avoidance (including early withdrawal) versus steroid maintenance or versus late withdrawal in pancreas or pancreas with kidney transplant recipients. We defined steroid avoidance as complete avoidance of steroid immunosuppression, early steroid withdrawal as steroid treatment for less than 14 days after transplantation and late withdrawal as steroid withdrawal after 14 days after transplantation.

Data collection and analysis: 

Two authors independently assessed the retrieved titles and abstracts, and where necessary the full text reports to determine which studies satisfied the inclusion criteria. Authors of included studies were contacted to obtain missing information. Statistical analyses were performed using random effects models and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI). Cohort studies were not meta-analysed, but their findings summarised descriptively.

Main results: 

Three RCTs enrolling 144 participants met our inclusion criteria. Two compared steroid avoidance versus late steroid withdrawal and one compared late steroid withdrawal versus steroid maintenance. All studies included SPK and only one also included PTA. All studies had an overall moderate risk of bias and presented only short-term results (six to 12 months). Two studies (89 participants) compared steroid avoidance or early steroid withdrawal versus late steroid withdrawal. There was no clear evidence of an impact on mortality (2 studies, 89 participants: RR 1.64, 95% CI 0.21 to 12.75), risk of kidney loss censored for death (2 studies, 89 participants: RR 0.35, 95% CI 0.04 to 3.09), risk of pancreas loss censored for death (2 studies, 89 participants: RR 1.05, 95% CI 0.36 to 3.04), or acute kidney rejection (1 study, 49 participants: RR 2.08, 95% CI 0.20 to 21.50), however results were uncertain and consistent with no difference or important benefit or harm of steroid avoidance/early steroid withdrawal. The study that compared late steroid withdrawal versus steroid maintenance observed no deaths, no graft loss or acute kidney rejection at six months in either group and reported uncertain effects on acute pancreas rejection (RR 0.88, 95% CI 0.06 to 13.35). Of the possible adverse effects only infection was reported by one study. There were significantly more UTIs reported in the late withdrawal group compared to the steroid avoidance group (1 study, 25 patients: RR 0.41, 95% CI 0.26 to 0.66).

We also identified 13 cohort studies and one RCT which randomised tacrolimus versus cyclosporin. These studies in general showed that steroid-sparing and withdrawal strategies had benefits in lowering HbAc1 and risk of infections (BK virus and CMV disease) and improved blood pressure control without increasing the risk of rejection. However, two studies found an increased incidence of acute pancreas rejection (HR 2.8, 95% CI 0.89 to 8.81, P = 0.066 in one study and 43.3% in the steroid withdrawal group versus 9.3% in the steroid maintenance, P < 0.05 at three years in the other) and one study found an increased incidence of acute kidney rejection (18.7% in the steroid withdrawal group versus 2.8% in the steroid maintenance, P < 0.05) at three years.

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