Early Steroid Withdrawal in Kidney Transplant Recipients: CON

Introduction The use of steroids for kidney transplantation changed the world of kidney care and is an integral part of the immunosuppression regimens in the current era. The long-term use of steroids may cause hyperlipidemia, obesity, new-onset diabetes after transplant, cataracts, and avascular necrosis.1 Given these side effects, in the past two decades, several studies advocated that steroid-free regimens should be adopted.2,3 However, the proper selection for steroid withdrawal is controversial. This review will discuss the possible adverse outcomes associated with steroid withdrawal among kidney transplant recipients. Steroid Withdrawal and Risk of Allograft Rejection Effect of early steroid withdrawal (ESW) on allograft: Several studies have reported that steroid withdrawal increases the risk of kidney allograft rejection and subsequent allograft failure. A systemic review of 48 randomized trials with close to 8000 recipients compared steroid avoidance and steroid withdrawal regimens with steroid maintenance regimens and found that the risk of kidney allograft rejection significantly increased among recipients where steroids were withdrawn within 14 days of the transplantation.4 Dharnidharka et al. looked at the effect of immunosuppression regimens within the first 90 days of transplant. ESW was associated with reduced risk of pneumonia (adjusted hazard ratio [aHR]=0.89, 95% confidence interval [CI], 0.83 to 0.96, P = 0.002), sepsis (aHR=0.80, 95% CI, 0.74 to 0.87, P < 0.001), and diabetes (aHR=0.77, 95% CI, 0.70 to 0.85, P < 0.001), but significantly higher risk of allograft failure (aHR=1.35, 95% CI, 1.17 to 1.57, P < 0.001).5 In another recent study, Bae et al. evaluated ESW and its association among high immunological risk recipients with high panel-reactive antibodies and reported ESW among recipients with panel-reactive antibodies >60 was associated with a substantial increase in allograft rejection (P < 0.001) and subsequent allograft failure (P = 0.02).6 In another study, Bae et al. evaluated the effect of ESW among recipients with delayed graft function. Using the Scientific Registry of Transplant Recipients, 110,019 kidney transplant recipients were assessed between 2005 and 2017. ESW was associated with an increased risk of allograft rejection (adjusted odds ratio=1.12, 95% CI, 1.02 to 1.23) and a significant increase in allograft failure (adjusted odds ratio=1.16, 95% CI, 1.08 to 1.26).7 These studies indicate that ESW was associated with an increased risk of kidney allograft rejection with a subsequent increased risk of kidney allograft failure. Effect of late steroid withdrawal on allograft: Several studies showed that even late steroid withdrawal could be associated with an increased risk of allograft rejection and subsequent graft failure. A meta-analysis of 20 steroid withdrawal studies showed that steroid withdrawal was associated with a higher risk of allograft rejection and subsequent allograft failure. Interestingly, these adverse results were worse than cyclosporine withdrawal.8 Vanrenterghem et al. conducted a study in 47 European transplant centers to investigate the discontinuation of steroids after 3 months post-transplant. Triple immunosuppression, including tacrolimus, steroids, and mycophenolate, was used for 3 months. From day 92, recipients continued triple therapy or discontinued steroids or discontinued mycophenolate. Between 3 and 6 months, the incidence of biopsy-proven rejection was higher in the steroid discontinuation group (5.9%) than the mycophenolate discontinuation group (1.8%, P = 0.044) or the control group (0.9%, P = 0.004). However, the graft survival at 6 months was similar with 94.2% (control), 92.8% (steroid discontinuation group), and 92.4% (mycophenolate discontinuation group) (P = 0.669).9 Similar results were reported by a meta-analysis, where steroid withdrawal between 3 and 6 months post-transplant was associated with significantly higher kidney allograft rejection.10 Smak Gregoor et al. evaluated 212 kidney transplant recipients who were maintained on triple immunosuppression considering mycophenolate mofetil, cyclosporine, and steroids. Recipients were randomly assigned to steroid withdrawal, cyclosporine withdrawal, or continued triple immunosuppression regimen at 6 months post-transplant. At the 2-year follow-up, biopsy-proven chronic rejection incidence was higher in the steroid withdrawal group than in the control group (21% versus 11%). However, the cyclosporine withdrawal group had a substantially higher incidence of chronic rejections as compared with the control group (14% versus 1.3%, P = 0.006).11 These studies suggest that even a late withdrawal of steroids from the immunosuppression regimen can increase kidney allograft rejection, which is summarized in Table 1. Table 1 - Steroid withdrawal and allograft rejection Studies Number of Patients Data Source Time of Steroid Withdrawal Allograft Rejection Graft Outcomes Early steroid withdrawal Bae et al. 20226 121,699 SRTR Within 30 d of the transplant Increased risk of allograft rejection among recipients with PRA >60% (P < 0.001) Increased risk of allograft failure among recipients with PRA >60% (P < 0.002) Bea et al. 20207 110,019 SRTR Steroid withdrawal at the time of discharge after transplant Increased risk of allograft rejection (aOR=1.12, 95% CI, 1.02 to 1.23) Increased risk of allograft failure (aOR=1.16, 95% CI, 1.08 to 1.26) Dharnidharka et al. 20165 45,164 USRDS Within 90 d of the transplant Increased risk of graft failure (aHR=1.35, 95% CI, 1.17 to 1.57, P < 0.001) Late steroid withdrawal Vanrenterghem et al. 20059 833 47 European centers Steroid withdrawal after 3 mo Biopsy-proven rejection was higher in steroid stop group (5.9%) than the mycophenolate group (1.8%, P = 0.044) or the control group (0.9%, P = 0.004) Graft survival at 6 mo was similar with 94.2% (control), 92.8% (steroid stop), and 92.4% (MMF stop) (P = 0.669) Smak Gregoor et al. 200211 212 Single-center study Steroid withdrawal at 6 mo post-transplant Biopsy-proven chronic rejection incidence was higher in the steroid withdrawal group than in the control group (21% versus 11%) aOR, adjusted odds ratio; CI, confidence interval; MMF, mycophenolate; PRA, panel-reactive antibodies; SRTR, Scientific Registry of Transplant Recipients; USRDS, United States Renal Data System. Steroid Withdrawal and Risk of Disease Recurrence Steroid avoidance or withdrawal may increase the risk of recurrence of GN in the transplanted kidney. Kukla et al. reported that the rapid discontinuation of steroids after the kidney transplant was significantly associated with an increased risk of recurrence of GN at 1-, 5-, and 7-year recurrence rates of GN at 6.7%, 13.7%, and 19.2%, respectively, among rapid steroid discontinuation groups compared with the recipients on maintenance steroids, the recurrence rate at 2.4%, 3.8%, and 5.3%, respectively (P < 0.0001). Overall, the discontinuation of steroids was associated with a significantly higher recurrence of GN (hazard ratio [HR]=4.86, 95% CI, 2.34 to 10.07, P < 0.0001).12 Von Visger et al. reported their observation in 124 recipients with IgA nephropathy as their primary kidney disease. In total, 60.5% of these patients received steroid-based immunosuppression, while 39.5% had either late steroid withdrawal or ESW. IgA nephropathy recurrence was significantly higher in patients managed with steroid-free (HR=8.59, 95% CI, 3.03 to 24.38, P < 0.001) and sirolimus-based (HR=3, 95% CI, 1.16 to 7.75, P < 0.024) immunosuppression regimens.13 Using the Australia & New Zealand Dialysis and Transplant Registry, Clayton et al. evaluated the effect of steroid use on kidney allograft failure due to the recurrence of IgA nephropathy. Prevalence of steroid use was 92% at the baseline, 84% at 1 year, and 64% at 5 years. After adjusting for age, sex, HLA-mismatch, dialysis duration, and transplant era, steroid use was strongly associated with a reduced risk of IgA recurrence by 50% (HR=0.50, 95% CI, 0.30 to 0.84). Furthermore, the overall 10-year cumulative incidence of allograft failure from recurrent IgA nephropathy was 4.3%. The study concluded that the risk of allograft failure from recurrent disease should be considered while tailoring immunosuppression for patients with IgA nephropathy.14 These studies are summarized in Table 2. Table 2 - Steroid withdrawal and risk of GN recurrence Studies Number of Patients Data Source Recurrence of GN Graft Outcomes Von Visger et al. 201413 124 patients Single-center study Higher incidence of GN recurrence in the steroid withdrawal group (HR=8.59, 95% CI, 3.03 to 24.38, P < 0.001) At 60 mo, graft survival was 72% in patients on steroids versus 44% in patients who were steroid-free (P = 0.03) Kukla et al. 201112 2164 Single-center study Higher incidence of GN recurrence in the steroid withdrawal group (HR=4.86, 95% CI, 2.34 to 10.07, P < 0.0001) No difference in graft outcomes Clayton et al. 201114 1521 ANZDATA registry Steroid use was strongly associated with a reduced risk of IgA recurrence by 50% (HR=0.50, 95% CI, 0.30 to 0.84) Steroids were only associated with less graft failure from recurrence in those with IgAN (P for interaction = 0.0002) ANZDATA, Australia & New Zealand Dialysis and Transplant Registry; CI, confidence interval; HR, hazard ratio. Advantages of Low-Dose Steroid Continuation There may be several advantages to continuing low doses of steroids after kidney transplantation. Reduced risk of rejection: As discussed above, the continuation of low-dose steroids reduces the risk of kidney allograft rejection.2 Modulation of calcineurin inhibitors (CNI): The maintenance of low doses of steroids may provide an opportunity to lower the CNI dose, which may have beneficial long-term effects, such as decreased rates of nephrotoxicity, neurotoxicity, or diabetes. Woodle et al. compared three induction regimens: alemtuzumab/belatacept, antithymocyte globulin, or antithymocyte globulin/tacrolimus. All recipients underwent ESW. A significant difference was observed in biopsy-proven acute T-cell–mediated rejection among the three (10.3% versus 18.3% versus 1.9%, respectively, P < 0.0001). This shows that simultaneous withdrawal of CNIs and steroids is associated with a higher risk of rejection.3 Reduced risk of cytopenia: Several maintenance and induction immunosuppressive medications, such as mycophenolate or azathioprine, have bone marrow suppressive effects, leading to anemia and leukopenia.15 Low-dose steroids lessen the risk of cytopenia.16 Furthermore, if the dose of mycophenolate or azathioprine needs to be reduced for cytopenia or any other comorbidities (e.g., infections, diarrhea), a low dose of steroids may prevent rejections. Steroid withdrawal in kidney transplant recipients remains controversial. Although withdrawal of steroids may have several metabolic advantages, it may be associated with the increased risk of allograft rejection and recurrence of primary GN, which subsequently is related to poor kidney allograft outcomes. Low-dose continuation of steroids may have less metabolic effects with reduced risk of allograft rejection and recurrence of GN. After carefully assessing the immunological risk, a decision should be made about steroid withdrawal. Large interventional mechanistic clinical trials are needed to better understand the group of kidney transplant recipients who may benefit from steroid withdrawal. Until then, we support low-dose steroid continuation.