Rapid Discontinuation Of Prednisone Research Articles

Rapid discontinuation of prednisone in kidney transplant recipients from at-risk subgroups: an OPTN/SRTR analysis.

Although rapid discontinuation of prednisone (RDP) after kidney transplantation has been successful in low-risk recipients, there is concern about RDP use in recipients at increased risk for rejection or recurrent disease. Using SRTR, we compared outcomes for RDP versus maintenance prednisone-treated recipients for alladult 1st and 2nd transplants (n=169479) and the following 1st transplant subgroups: African American (AA); highly sensitized; those with a potentially recurrent disease; and pediatric recipients. For all adult 1st LD and DD transplants, RDP was associated with better patient and graft survival. For all LD subgroups, RDP and maintenance prednisone were associated with similar patient, graft, and death-censored (DC) graft survival. For 1st transplantDD subgroups, RDP was associated with better patient survival in AA, those with potentially recurrent disease, and pediatric recipients; graft survival with RDP was better in AAs. For adult 2nd DD transplants, RDP was associated with worse DC-graft survival. Importantly, for all differences, the effect size was small. With the exception of 2nd DD transplants, RDP protocols can be used without decreasing patient or graft survival for subgroups of 1st DD and LD kidney transplant recipients and for 2nd LD transplant recipients, at increased risk of rejection or recurrent disease.

Rapid Discontinuation of Prednisone in Kidney Transplant Recipients: 15-Year Outcomes From the University of Minnesota.

Short- and intermediate-term results have been reported after rapid discontinuation of prednisone (RDP) in kidney transplant recipients. Yet there has been residual concern about late graft failure in the absence of maintenance prednisone. From October 1, 1999, through June 1, 2015, we performed a total of 1553 adult first and second kidney transplants-1021 with a living donor, 532 with a deceased donor-under our RDP protocol. We analyzed the 15-year actuarial overall patient survival (PS), graft survival (GS), death-censored GS (DCGS), and acute rejection-free survival (ARFS) rates for RDP compared with historical controls on maintenance prednisone. For living donor recipients, the actuarial 15-year PS rates were similar between groups. But RDP was associated with increased GS (P = 0.02) and DCGS (P = 0.01). For deceased donor recipients, RDP was associated with significantly better PS (P < 0.01), GS (P < 0.01) and DCGS (P < 0.01). There was no difference between groups in the rate of acute or chronic rejection, or in the mean estimated glomerular filtration rate at 15 years. However, RDP-treated recipients had significantly lower rates of avascular necrosis, cytomegalovirus, cataracts, new-onset diabetes after transplant, and cardiac complications. Importantly, for recipients with GS longer than 5 years, there was no difference between groups in subsequent actuarial PS, GS, and DCGS. In summary, at 15 years postkidney transplant, RDP did not lead to decreased in PS or GS, or an increase in graft dysfunction but as associated with reduced complication rates.

Incidence of BK Is Higher in Recipients On Tacrolimus vs. Cyclosporine On Rapid Steroid Discontinuation Protocols.

Background: BK nephropathy is an important cause of kidney allograft failure. Yet, little data exists on the risks of individual immunosuppressive drugs, either with or without prednisone maintenance therapy. Routine monitoring for BK viremia (BKV) began (at our institution) in 2008. We studied incidence of BKV in recipients on a rapid discontinuation of prednisone (RDP) protocol including either CSA or FK (polyclonal Ab, CNI, MMF, and RDP). Multivariate analysis (MVA) was done to determine risk factors for BKV. Variables included in the analysis were: recipient race and gender, age>50, DD vs. LD, donor race and gender, dialysis prior the transplant, CNI (FK vs CSA) and incident of acute rejection. Results: Between 2008 and November, 2013, 415 recipients (FK =172; CSA = 287) were screened for BKV using BK PCR. Recipients demographics are shown in table 1: significant differences existed between groups in donor source (p=.04) and dialysis prior to tx (p=.02)Table: No Caption available.There were no difference between groups in patient or graft survival or in acute rejection rates. A total of 39 recipients (8.4%) developed BKV (TAC, 21; CSA, 18). Cumulative incidence at 5 years was 13.2 % in TAC and 7.6% in CSA (Figure). Kaplan-Meier BK free survival curves in recipients on FK+MMF (blue) and CSA+MMF (red).Figure: No Caption available.By MVA the only risk factor for BKV was maintenance FK vs. CSA (p=0.03; HR 1.96, CI 1.0-3.6). Of note, recipients on FK had significant higher MPA levels at 1 month posttxt (3.0±1.8 vs. 1.7± 1.5, p <0.0001); Addition of 1 month MPA levels >3 mcg/ml to the MVA model did not show significance. 5 years graft survival was 86% on CSA +MMF and 83% on FK+MMF (NS). Conclusion: Recs on RDS protocol receiving FK +MMF combination have higher risk for BK. Exposure to MMF is higher in recs on TAC, but did not show to be a significant risk factor in MVA.

Calcineurin inhibitors in HLA-identical living related donor kidney transplantation

Given the nephrotoxicity of calcineurin inhibitors (CNIs), we asked whether their addition improved living related donor (LRD) human leukocyte antigen (HLA) identical kidney transplant recipient outcomes. We performed a comprehensive literature review and a single-center study comparing patient survival (PS) and graft survival (GS) of LRD HLA-identical kidney transplants for three different immunosuppression eras: Era 1 (up to 1984): anti-lymphocyte globulin (ALG) induction and maintenance immunosuppression with prednisone and azathioprine (AZA) (n = 114); Era 2a (1984-99): CNI added; evolution from ALG to thymoglobulin; AZA to mycophenolate (n = 262). Era 2b (1999-2011): rapid discontinuation of prednisone (thymoglobulin induction, CNI and mycophenolate) in recipients having first or second transplant and not previously on prednisone (n = 77). Demographics differed by era: recipient (P < 0.0001) and donor age (P < 0.0001) increased and the proportion of Caucasian donors (P = 0.02) and recipients (P = 0.003) decreased with each advancing era. There was no significant difference in PS (P = 0.6); cause of death (P = 0.5); death-censored GS (P = 0.8) or graft loss from acute rejection by era. Graft loss from chronic allograft nephropathy (P = 0.02) and hypertension (P = 0.005) were greater in the CNI eras. There were no significant differences in the 1/creatinine slopes between eras for the first (P = 0.6), second (P = 0.9) or >2 years post-transplant (P = 0.4). Literature review revealed no clear benefits for CNI in these human leukocyte antigen (HLA) identical LRD graft recipients. This study confirmed that there are no benefits of CNIs for HLA-identical LRD recipients. Moreover, we did find evidence of potential harm. Thus, monotherapy or early discontinuation of CNI should be given consideration in these patients.

Prospective Randomized Trial of Maintenance Immunosuppression With Rapid Discontinuation of Prednisone in Adult Kidney Transplantation

Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n=440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n=151); high-level tacrolimus (TAC, 8-12 μg/L) and low-level sirolimus (SIR, 3-7 μg/L) (TACH/SIRL, n=149) or low-level TAC (3-7 μg/L) and high-level SIR (8-12 μg/L) (TACL/SIR(H) , n=140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p=0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p=0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.

Ten-Year Outcome after Rapid Discontinuation of Prednisone in Adult Primary Kidney Transplantation

Rapid discontinuation of prednisone after kidney transplantation potentially allows for minimization of steroid-related side effects. Although intermediate-term data with rapid discontinuation of prednisone have been promising, concern still exists regarding long-term outcomes. The 10-year experience is reported herein. Between October 1, 1999 and December 31, 2010, 1241 adult primary kidney transplants (791 living donor and 450 deceased donor) were performed using a protocol in which prednisone is discontinued after postoperative day 5. The 10-year actuarial recipient and graft survival rates and prednisone-related side effects were studied. Ten-year actuarial patient survival was 71% for living donor transplants and 62% for deceased donor transplants; 10-year graft survival was 61% for living donor transplants and 51% for deceased donor transplants, and was comparable to 10-year Scientific Registry of Transplant Recipients national data. Ten-year death-censored graft survival was 79% for living donor transplants and 80% for deceased donor transplants. Ten-year acute rejection rates were 25% for deceased donor transplants and 31% for living donor transplants; 10-year chronic rejection (interstitial fibrosis/tubular atrophy) rates were 39% for deceased donor transplants and 47% for living donor transplants. For nondiabetic recipients of living donor or deceased donor allografts, the incidence of new-onset diabetes was significantly lower than in historical controls on prednisone (P<0.001). We also found significantly reduced rates of cataracts, avascular necrosis, and cytomegalovirus infection in some subgroups. Prednisone-related side effects can be minimized in a protocol incorporating rapid discontinuation of prednisone for maintenance immunosuppression. Ten-year patient and graft outcomes remain acceptable.

Validation of genetic variants associated with early acute rejection in kidney allograft transplantation

Numerous reports have identified genetic variants associated with kidney transplant outcome, but only a few have been validated in subsequent studies. We analyzed the association of 21 previously reported genetic variants associated with acute rejection (AR), in an effort to validate these associations in our kidney transplant population. All recipients (n = 585) received Ab induction, rapid discontinuation of prednisone, and calcineurin inhibitors with either mycophenolate mofetil or sirolimus. Both univariate analysis and logistic regression were used for determining the association between the genotypes and AR. Univariate analysis detected one significant single-nucleotide polymorphism (p = 0.03), rs1801133, within the methylenetetrahydrofolate reductase (MTHFR) gene associated with AR. Logistic regression analysis identified two variants associated with AR, the 32-bp deletion within chemokine (C-C motif) receptor 5 gene (rs333) and the p.222A/V variant (rs1801133) within the MTHFR gene. Although our analysis utilized a much larger cohort than used in previous reports, we were only able to detect an association with two of these variants. The lack of validation for the other 19 variants may be due to the small effect size, or that, they are not associated with AR. These results stress the need for larger cohorts for both future studies as well as for validation studies.

Pediatric Kidney Transplantation Using a Novel Protocol of Rapid (6-Day) Discontinuation of Prednisone: 2-Year Results

There are few prospective studies of prednisone-free immunosuppression (IS) in pediatric kidney transplant (KTx) recipients. We studied the outcomes of a protocol using rapid discontinuation of prednisone (RDP, <1 week) and thymoglobulin induction. Twenty-one RDP recipients (mean age 14+/-3 years) received KTx between May 2002 and December 2005 and were matched with controls (n=39) for age, race, and donor source. For the RDP group, IS consisted of prednisone tapered off over 6 days, thymoglobulin, mycophenolate mofetil, and cyclosporine A (CsA). In controls, IS consisted of thymoglobulin, maintenance prednisone, azathioprine, and CsA. For the RDP group, graft survival at 1 and 2 years was 90% and 86%; for the controls, graft survival at 1 and 2 years was 92%, and 90% (P=0.86). For the RDP group, the incidence of acute rejection at 1 and 2 years was 14% and 19%; for controls, the incidence of acute rejection at 1 and 2 years was 23%, and 31% (P=0.17). Of the 18 RDP recipients with functioning grafts, 89% remain prednisone-free at follow-up. There was no significant difference between groups in recipient survival rates, incidence of hypertension, chronic allograft nephropathy, or cytomegalovirus disease. RDP using thymoglobulin, mycophenolate mofetil, and CsA in selected pediatric KTx recipients is associated with recipient and graft survival rates and acute rejection incidence comparable with quadruple drug therapy.

Kidney Transplant Half-Life (t [½]) After Rapid Discontinuation of Prednisone

Protocols incorporating rapid discontinuation of prednisone (RDP) after kidney transplantation have been associated with good short-term results. However, concern remains that RDP will be associated with decreased long-term graft survival rates. We compared kidney transplant half-life (t1/2) for recipients treated with antibody induction, calcineurin inhibitor, antimetabolite, and RDP versus historical controls treated with antibody induction, calcineurin inhibitor, antimetabolite, and maintenance prednisone. For both living and deceased donor recipients, we found no difference between groups. We also found no differences in rate of graft loss to acute rejection or to tubular atrophy and interstitial fibrosis. Our study suggests that long-term graft outcome is not decreased when using RDP protocols versus chronic maintenance prednisone.

Minimization of steroids in kidney transplantation.

The goal of steroid minimization trials has been to minimize or eliminate steroid-related side-effects while simultaneously not increasing the rate of acute rejection (AR) and chronic graft loss. Early trials of late steroid withdrawal (> or =3 months post-transplant) were associated with significantly increased AR rates and late graft loss. More recent trials of rapid discontinuation of prednisone (RDP) (< or =7 days post-transplant) have been associated with little or no increase in AR rates and no difference in graft survival (versus maintenance prednisone). Of note, induction therapy appears to be important for success; however, it is not clear if any single maintenance protocol is superior. Intermediate-term follow-up (5-7 years) is now available for some randomized and nonrandomized trials; graft survival and renal function remain excellent. Most of these trials have been done in low immunologic risk recipients, but there are reports of success of RDP in children, black recipients, sensitized recipients, recipients with potentially recurring disease, and kidney-pancreas recipients. Of critical importance, steroid-related side-effects have been minimized. Steroid minimization protocols can clearly be recommended for low-risk patients; additional trials are necessary for those at higher risk. Additional research is also necessary on integrating calcineurin inhibitor minimization with steroid minimization.

Steroid Avoidance Regimens: A Comparison of Outcomes with Maintenance Steroids versus Continued Steroid Avoidance in Recipients Having an Acute Rejection Episode

Roughly 15% of kidney transplant recipients on a rapid discontinuation of prednisone (RDP) protocol have > or =1 episode of acute rejection (AR). One clinically important question is whether long-term maintenance steroids should be introduced in those recipients having AR. Of 842 adult kidney transplant recipients on an RDP protocol, 149 (17.7%) have had at least 1 AR episode. Of these, 51 (34%) started on maintenance prednisone (5 mg/day) after treatment of the AR, while 98 (66%) remained steroid free. Demographics for the two groups were similar. With mean follow-up of 26 months, 48 (32%) of the recipients have had a 2nd AR episode: 15 (29.4%) in those on maintenance steroids vs. 33 (33.7%) in those remaining steroid free (p = 0.12). Graft survival was not significantly different between the two groups. Multivariate analysis of risk factors for a 2nd episode found the histologic appearance of the initial AR episode to be the most significant risk factor. But, whether steroids were added to the maintenance regimen or not, also seemed to have an impact (RR = 2.1, p = 0.07). At present there is evidence to suggest that some SA patients should start on maintenance steroids after AR. However, longer follow-up with more patients is necessary.

Steroid minimization in liver transplant recipients: impact on hepatitis C recurrence and post‐transplant diabetes

Steroid minimization regimens have become increasingly popular for kidney transplant recipients. We studied outcomes for liver transplant recipients with a regimen using rapid discontinuation of prednisone (RDP). The study group consisted of 83 recipients transplanted between June 2004 and January 2006. Immunosuppression consisted of tacrolimus, MMF, and two doses of basiliximab with six d of steroids. Patients with underlying autoimmune disorders (PSC, autoimmune hepatitis) were not included as they were maintained on steroids. The control group consisted of 83 recipients transplanted between January 2002 and May 2004. Immunosuppression consisted of tacrolimus, MMF and steroids, with no antibody induction. Mean MELD score at time of transplant was significantly higher in the steroid free group vs. the control group (28 vs. 23, p = 0.02); mean donor age was also higher (42 vs. 37 yr, p = 0.02). Other characteristics including recipient age, cold ischemic time, donor source, and cause of liver disease were similar (p = ns). Mean length of follow-up was 16.1 months in the RDP group and 32 months in the control group; a minimum of six months follow up was present for all patients. Patient and graft survival rates were not statistically different in the two groups (p = ns). Biopsy proven rejection was low in both groups and not significantly different (at one yr post-transplant 11% in the RDP group vs. 12% in control, p = 0.53). Based on protocol biopsy data, histologic recurrence of hepatitis C was demonstrated in 56% of the control group hepatitis C positive recipients vs. 39% in the RDP group (p = 0.05). There was a significantly lower incidence of post-transplant diabetes (PTDM) in the RDP vs. control group (at 6 months post-transplant 12% vs. 32%, p = 0.004). Rapid discontinuation of prednisone in liver transplant recipients is not associated with an increased risk of rejection, and may be associated with lower morbidity, especially PTDM and hepatitis C recurrence.

Evolution of immunosuppression at the University of Minnesota

Immunosuppressive protocols at the University of Minnesota have evolved from identical immunosuppression for all recipients (prednisone, azathioprine, and antilymphocyte globulin) to differing protocols for living (triple therapy) and cadaver (sequential therapy) donor recipients, and then to our current protocol in which all recipients receive induction therapy with rapid discontinuation of prednisone. At the same time, progress has been made in the prevention and treatment of cytomegalovirus infection along with numerous parallel improvements in patient care, including in anesthesia, dialysis, and intensive care unit care. The net result has been an incremental improvement in recipient and graft survival.

Rapid Discontinuation of Steroids in Living Donor Kidney Transplantation: A Pilot Study

Steroids are associated with significant postoperative complications (hypertension, cosmetic changes, bone loss, hyperlipidemia, diabetes, and cataracts). Most develop early; in addition, late post-transplant steroid withdrawal in kidney transplant recipients has been associated with increased acute rejection (AR). To obviate these problems, we studied outcome of a protocol of rapid discontinuation of prednisone (RDS) (steroids stopped on POD6). Between November 1, 1999 and October 31, 2000, 51 adult living donor (LD) first transplant recipients (2 HLA-id, 28 non-id relative, 21 LURD) were immunosuppressed with thymoglobulin (1.25 mg/kg intraoperatively and then qdx4); prednisone (P) (500 mg methylprednisolone intraoperatively, 1 mg/kg x 1 day, 0.5 mg/kg x 2 days, 0.25 mg/kg x 2 days, then d/c); MMF, 1 g b.i.d.; and CSA, 4 mg/kg b.i.d. adjusted to achieve levels of 150-200 ng/mL (by HPLC). Exclusion criteria were delayed graft function or primary disease requiring P. Minimum follow-up was 5.5 months (range 5.5 to 17.5 months). Outcome was compared vs. previous cohorts of LD recipients immunosuppressed with P/AZA/CSA (n = 171) or P/MMF/CSA (n = 43) (both without antibody induction). For the RDS group, average CSA level (+/- S.E.) at 3 and 6 months was 190 +/- 12 and 180 +/- 9; avg. MMF dose, 1.7 +/- 0.1 g and 1.7 +/- 0.1 g. There was no significant difference in 6- and 12-month actuarial patient survival, graft survival and rejection-free graft survival between recipients on the RDS protocol vs. historical controls. For RDS recipients, actuarial 6- and 12-month rejection-free graft survival was 87%. Of the 51 RDS recipients, five (10%) have had AR (at 20 days, 1 month, 3 months, 3 months, and 3.5 months post-transplant). After treatment, all five were maintained on 5 mg P; there have been no second AR episodes. Two additional recipients were started on 5 mg P due to low white blood count (WBC) and low/no MMF. Of the 51 grafts, one has failed (death with function). Average serum Cr level (+/- S.E.) at 3 and 6 months for RDS recipients was 1.7 +/- 0.5 (NS vs. historical controls). For low-risk LD recipients, a kidney transplant with an RDS protocol does not increase risk of AR or graft loss. Future studies will need to be done to assess AR rates with an RDS protocol in cadaver transplant recipients and in recipients with delayed graft function.