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There was also no significant difference in the risk of allograft failure not including patient death , defined as a need for long-term dialysis or repeat transplant during a median follow-up period of These data build on previously reported 5-year outcomes from the same group. However, 5-year renal allograft survival and function rates were similar.
Those who didn't continue chronic low-dose corticosteroid therapy saw better outcomes for cardiovascular CV risk factors, including lower triglycerides, less weight gain, lower blood glucose, and less need for insulin, according to the authors.
But they stressed that a study limitation was lack of data on long-term differences in nonfatal outcomes, such as CV disease, diabetes, infections, and metabolic bone disease between the two groups of patients. Surgeries took place between and , and all patients received either a living or deceased donor kidney transplant without delayed graft function. None had short-term rejection in the first week after transplant. Half of the patients were randomized to receive the immunosuppressant drugs tacrolimus Envarsus, Protopic, Astagraf and mycophenolate mofetil with prednisone and withdraw 7 days after transplant.
Although these patients were relatively low risk to begin with, Arthur Matas, MD, of University of Minnesota in Minneapolis, pointed out that other data have suggested that the practice of early steroid cessation ESC -- withdrawing within 14 days -- has also shown some success with higher-risk groups such as Black patients, children, and even those with re-transplants or recurring disease.
I agree," Matas wrote in an invited commentary. Recipients had significantly lower rates of cataracts P Glucocorticoid avoidance protocols tend to choose low-risk individuals and utilize aggressive induction therapy [11].
In the s a multi-centre European study of cadaveric renal transplants demonstrated a one-year allograft survival rate of 77 percent with cyclosporine only, as compared with 63 percent in the azathioprine and prednisone control group [25]. Since the s a transplant group in Denmark has also successfully adopted a glucocorticoid-free IS strategy including its avoidance in treating rejection in combination with induction therapy utilizing rabbit ATG [26,27].
In a report summarizing their more recent experience, maintenance IS consisted of cyclosporine and MMF in consecutive patients [27]. Acute rejections AR , which were treated with anti-lymphocyte therapy without glucocorticoids, occurred in only 13 percent of patients.
Glucocorticoid avoidance in low-risk, living-donor recipients utilizing ATG as induction therapy, MMF, and cyclosporine [28] with steroids discontinued on postoperative day 6 showed. Patient and graft survival were comparable with national data reported by the Scientific Registry of Transplant Recipients in Data from low risk living donor patients that are not ethnically diverse or are predominantly non-sensitised cannot be extrapolated without inherent risks to other cohorts [31].
Unfortunately, long-term experience beyond 5 years with glucocorticoid-free IS is limited [12]. In a prospective, well-designed study comparing very early steroid cessation to low-dose, long-term steroid therapy in kidney recipients receiving modern maintenance immunosuppression already mentioned earlier, patients were randomly assigned to corticosteroid withdrawal at one week post-transplant or continuance of corticosteroids.
Maintenance therapy consisted of Tac, MMF, and seven days of corticosteroids followed by blinded randomization to either withdrawal or continuation tapered to 5mg by 6 months after transplant. Although some single centre studies have reported feasibility of steroid avoidance regimes in patients at increased risk, including African Americans or pre-sensitized patients with good graft survival at 3 or 5 years [34], results from single-centres require verification from registry data. In addition in light of the meta-analysis [20] which showed increased AR within 6 months in case of complete steroid avoidance, the RLBUHT protocol may need further scrutiny.
However the risk for a 2nd AR was related to whether or not steroids had been added to the maintenance protocol. Those most unlikely to have a 2nd AR — ie those recipients with very minimal-to-mild AR - the rate significantly increased if the recipient had returned to steroid-free immunosuppression [37].
In this setting, it may be useful to highlight a protocol [38] followed in the Middle East which would appear to be drawn on a combination of some of the data above. Steroids are reduced to 5 mg in 8 weeks post-transplant following categorisation of patients on their risk assessment. The general policy is to try and avoid steroid withdrawal all together except in very low immunological risk profile.
DR matching is not included in HLA matching as of yet. Intermediate and high risk patients receive ATG as induction therapy, the rest basiliximab.
This policy is based on awareness around de novo donor specific antibodies and risk of CAN — which is why steroid withdrawal or calcineurin minimisation is avoided. At King Faisal more than half of death censored graft loss is immunological in contrast to interstitial fibrosis and tubular atrophy — also known as CAN — previously believed to be related to calcineurin IS related.
An AR episode is a major risk factor for long-term graft loss [27] if the severity of the rejection episode is enough to impair the recovery of the renal function to baseline levels [39]. AR is especially common within the first months after transplantation with risk factors such as race like African American predisposing to more AR episodes and a lower graft survival following an early AR episode [40]. Antibody mediated rejections and policies around withdrawal or recommencing steroids in such patients also remain largely unanswered.
The possibility of de novo donor specific antibodies is a realistic concern when considering a steroid-free regimen [9].
The role of surveillance biopsies at predetermined time points independent of renal function or clinical status to assess graft injury [41] from subclinical antibody mediated rejection in sensitized high-risk patients [42] or subclinical BK virus nephropathy from over IS [43] or early CAN [44] is an area that may need consensus. Routine protocol biopsies may make individualization of steroid-free IS or withdrawal possible, especially in high-risk patients [44]. Trial outcomes from low-risk transplant populations cannot be generalized [45] as high-risk patients are different immunologically.
The patients who initiate steroid use later, following early withdrawal, have graft survival rates that are worse than either those who maintain steroid use or those who continue on steroid avoidance after transplant [46].
It is probably also inaccurate to conclude that complete steroid avoidance is safer than steroid withdrawal as this seems to be only based on less frequent NODAT [47]. Rapid withdrawal of steroids seems in most studies un-associated with an increased rate of AR whilst steroid withdrawal at 3 months post-transplantation—using the same maintenance IS—is.
It is possible that steroids lower cytokine production but upregulate cytokine receptor expression [9] - and when steroids are slowly withdrawn, cytokine release returns to normal in an environment of upregulated receptors. Similarly it is possible Tac exposure also increases after steroid withdrawal [9].
It is also important to balance steroid-free and calcineurin inhibitor-free approaches [9]. Steroid-free IS has the obvious advantages of eliminating steroid side effects.
Better long-term kidney allograft function when calcineurin inhibitors are minimized or eliminated is also reported. Protocols that are both steroid and calcineurin inhibitor free have high risk but in this era of newer IS drugs hopefully long-term effective immunosuppression without side effects from such medications will one day be possible. The potential benefit of eliminating steroid-related side effects for transplant recipients is obvious.
Yet concerns remain that steroid-free maintenance immunosuppression protocols may have some long-term detrimental effects. As early transplant outcomes are good, the number of patients required to power such a study would be enormous.
Very early steroid withdrawal within a week may have a short-term efficacy similar to that achieved with continuous steroid regimen but longer follow-up data along with donor specific antibody or outcomes from surveillance biopsies may be required. Surveillance biopsies may need to be incorporated routinely. Within the past decade, as a result of trials focusing on late steroid withdrawal or rapid withdrawal of prednisolone, recipients maintained on prednisone are taking far less prednisone than they would have been taking 10 years ago, and non-immunological side effects from steroid overexposure may well be of less importance today.
Order for reprints. Toggle navigation. ISSN: Author and article information. Halawa sth. DOI : Arch Clin Nephrol 4 1 : DOI: Corticosteroid use as a component of immunosuppression protocol is widespread, even though their mechanisms of action are imprecise. The burden of metabolic side effects of steroids and the impact on quality of life in kidney allograft recipients has led to attempts in minimizing steroid exposure. The concept of steroid withdrawal in patients requiring immunosuppression remains ill-defined without formally tested strategies balancing adverse events against good kidney allograft and patient outcomes.
This review is aimed at assessing steroid withdrawal at 3 transplant centre strategies in the UK, Australia and Saudi Arabia in the light of current literature. Antibody mediated rejection, donor specific antibodies or surveillance biopsies are areas of unmet needs today that require urgent attention in this era of aggressive anti-lymphocyte or anti- cytokine induction.
Since the evidence of long term patient or graft outcome reports of these corticosteroid minimization strategies is unclear, it is worth revisiting corticosteroid minimization strategies to establish evidence based practice. Main article text. Introduction Organ transplantation requires immunosuppression IS to prevent rejection, induce immunologic acceptance and reduce immune mediated damage to transplanted organs allograft.
Evolution of IS Over the decades, pharmacologic therapy originally using corticosteroids, 6-mercaptopurine and total body irradiation in the s changed to azathioprine and corticosteroids in the s leading to the first successful outcomes in unrelated kidney transplantation.
Table 1 outlines steroid minimizing strategies Steroid free maintenance regimes Lower maintenance dosages Complete avoidance Early withdrawal Late withdrawal Strategy Stoppage within 1 week post-transplant 0. Trust Clinical Policy. Protocol for immunosuppression following renal transplantation Directorates of Renal Transplant, Nephrology and Pharmacy East Coast Renal Services.
New South Wales, Australia Crit Rev Oncol Hematol Drugs Zand M Immunosuppression and immune monitoring after renal transplantation.
Semin Dial N Engl J Med Expert Review of Clinical Immunology Ann Surg J Bone Miner Res Transplant Proc KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 3: S J Am Soc Nephrol 4: Transplantation CMAJ
❿Prednisone post transplant -
Study record managers: refer to the Data Element Definitions if submitting registration or results information. Thymoglobulin rabbit antithymocyte globulin was given intravenously in the operating room at the time of transplant. Subsequent intravenous doses were administered to participants an inpatient or outpatient for a total of 3 to 5 doses. Participants also began taking Prograf tacrolimus and CellCept mycophenolate mofetil orally within 24 hours of transplant and continued indefinitely.
The steroids were initially given in the operating room intravenously at time of transplant as Solu-medrol methylprednisolone and were then switched to daily oral prednisone doses.
The participant's dose of prednisone was rapidly decreased until it was completely eliminated by day 6 post-transplant. Drug: prednisone In this group, participants had prednisone rapidly decreased until completely eliminated by day 6 after transplant. Participants began on mg of intravenous methylprednisolone on the day of transplant, followed by the following doses of oral prednisone: mg on day 1, mg on day 2, 80mg on day 3, 40mg on day 4, 20mg on day 5, none from day 6-on.
Other Names: Deltasone Steroids Methylprednisolone Corticosteroids Drug: rabbit antithymocyte globulin Participants in both groups received 3 to 5 doses of an intravenous medication to prevent rejection called Thymoglobulin rabbit antithymocyte globulin as per our standard of care.
This drug was dosed at 1. The dose was decreased in half or held if the participant had a low white blood cell count or if the participant a low platelet count. The number of doses was based on transplant kidney function and risk factors for rejection.
This medication helped to prevent rejection and was initially dosed at 0. Other Name: Prograf Drug: Mycophenolate mofetil Participants in both groups received mycophenolate mofetil by mouth twice daily indefinitely.
Dosing for patients in the Prednisone withdrawal group was mg orally twice daily. The dose was decreased or held at the discretion of the physician, for side effects such as low white blood cell count, or low platelet count, or if the participant experienced stomach side effects such as heartburn, nausea, vomiting or diarrhea.
Other Names: mmf CellCept Active Comparator: Prednisone Maintenance Participants randomized to the prednisone maintenance group, received 4 medications to prevent rejection.
Thymoglobulin rabbit antithymocyte globulin was initiated intravenously in the operating room at the time of transplant. Subsequent intravenous doses were administered an inpatient or outpatient for a total of 3 to 5 doses.
Participants began taking Prograf tacrolimus and CellCept mycophenolate mofetil orally within 24 hours of transplant and continued on them indefinitely. The steroids were initially given intravenously in the operating room at time of transplant as Solu-medrol methylprednisolone and were then switched to daily oral prednisone tablets.
Participants remained on all drugs according to their doctor's standard of care, and the prednisone was not be eliminated. Drug: rabbit antithymocyte globulin Participants in both groups received 3 to 5 doses of an intravenous medication to prevent rejection called Thymoglobulin rabbit antithymocyte globulin as per our standard of care. Other Name: Prograf Drug: Prednisone Participants in this group continued on prednisone indefinitely. Participants began with mg of intravenous methylprednisolone on the day of transplant, followed by the following doses of oral prednisone: mg on day 1, mg on day 2, 80mg on day 3, 40mg on day 4, 20 mg days15 mg day10 mg day7.
Other Names: Deltasone Steroids Methylprednisolone Corticosteroids Drug: Mycophenolate mofetil Participants in both groups received mycophenolate mofetil by mouth twice daily indefinitely. Dosing for patients in the Prednisone maintenance group was mg orally twice daily. Biopsies were only performed if clinically indicated. The cumulative number of participants with recorded rejection episodes by 6 and 12 months post-transplant would have been reported.
The Number of Participants With Graft Survival [ Time Frame: 6 and 12 months ] The number of participants who did not experience graft failure defined as return to dialysis at 6 and 12 months would have been reported.
Participant Survival [ Time Frame: 6 and 12 months ] The number of participants alive at 6 and 12 months post-transplant would have been posted as a measure of patient survival. Secondary Outcome Measures : The Number of Participants With Treatment Failures [ Time Frame: 12 months ] This measure was defined as the percentage of participants that did not remain on initial therapy ie were withdrawn from each arm of the trial Length of Hospital Stay After Transplant [ Time Frame: 12 months ] The length of the hospital stay would have assessed the number of days a participant was in the hospital after the kidney transplant was performed.
This is calculated from date of admission to date of discharge. The Number of Participants With Hospital Readmissions [ Time Frame: 12 months ] The number of readmissions during the study period for each participant would have been assessed, as well as the reason for readmissions.
The Length of Stay Associated With Hospital Readmissions [ Time Frame: 12 months ] The time from admission to discharge for each readmission for patients readmitted in the first 12 months post-transplant. This was to be performed at 3,6 and 12 months post-transplant. Participant Renal Function as Measured by 24 Hour Urine Collection [ Time Frame: 3 and 12 months post-transplant ] Results would have been reported from patients undergoing 24 hour urine collections at 3 and 12 months post-transplant.
This is a way to measure glomerular function rate GFR or renal function. Treatment of rejection episodes in each participant would have been determined by the treating transplant physician. The Number of Participants With Infections [ Time Frame: 12 months ] Participants would have been monitored throughout the study for any infectious complications as confirmed by the principal investigator.
Patients would have been monitored by urine cytology and blood polymerase chain reaction for BK virus at baseline, and months 3, 6 and 12 post-transplant. The Number of Participants With Malignancy [ Time Frame: 12 months ] Participants would have been monitored throughout the study with any reports of malignancy being confirmed by principal investigator. The Number of Participants With Hyperlipidemia [ Time Frame: 12 months ] Fasting lipid profiles were to be performed at 3,6 and 12 months post-transplant.
The Number of Participants With Bone Disease [ Time Frame: baseline within 1 month post-transplant3, 6, 12 and 24 months ] Bone densitometry by Computed tomography of peripheral skeleton and DEXA scans were performed at baseline within one month after transplant Urine and blood samples to measure markers of bone turnover: Alkaline phosphatase, pyridinoline, serum vit D 3 levels calcitriol and 25 hydroxy vit D calcidiol levels and serum osteocalcin levels were drawn at baseline, 3, 6, 12 and 24 months.
The Number of Participants With Post Transplant Diabetes Mellitus [ Time Frame: pre-transplant in living donor recipients, baseline within one month post-transplant and at 3, 6 and 12 months ] Glucose tolerance test performed in non-diabetic participants only at pre transplant in living donor recipients and at baseline within 1 mo after transplant and 6 mo and 12 months.
Blood test for hemoglobin A1C in non diabetic participants only: at baseline, 3, 6, and 12 months. Insulin and C peptide levels at baseline, 3,6 and 12 months in all participants. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below.
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Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information. Search for terms. Save this study. Warning You have reached the maximum number of saved studies Prednisone Withdrawal Versus Prednisone Maintenance After Kidney Transplant The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.
Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Results First Posted : March 21, Last Update Posted : May 15, Study Description.
The purpose of the study was to determine if rapid discontinuation of corticosteroids also known as prednisone withdrawal and maintenance immunosuppression with Prograf tacrolimus and CellCept mycophenolate mofetil while using Thymoglobulin Rabbit antithymocyte globulin will give similar safety and efficacy results compared to continuation of corticosteroids also known as prednisone maintenance and standard maintenance immunosuppression with Prograf tacrolimusCellCept mycophenolate mofetil while using Thymoglobulin Rabbit antithymocyte globulin.
Detailed Description:. Corticosteroids one specific type is prednisone have been used in clinical transplantation for more than 30 years. There are many side effects of corticosteroids including significant bone disease, diabetes elevated blood sugar levelsfluid retention and hypertension high blood pressurepsychosis, peptic ulcer disease, hyperlipidemia elevated lipid levels such as cholesterol and triglyceridesobesity overweightacne, and susceptibility to infections.
It is hoped that the new generation of potent immunosuppressive medications such as Prograf and CellCept will permit avoidance or withdrawal of corticosteroids for the majority of patients to avoid both short- and long-term complications of corticosteroid use in kidney transplant recipients.
Drug Information available for: Prednisone Tacrolimus Mycophenolate mofetil. FDA Resources. Arms and Interventions. In this group, participants had prednisone rapidly decreased until completely eliminated by day 6 after transplant.
Participants in both groups received 3 to 5 doses of an intravenous medication to prevent rejection called Thymoglobulin rabbit antithymocyte globulin as per our standard of care. Participants in both groups received tacrolimus per our standard of care. Participants in both groups received mycophenolate mofetil by mouth twice daily indefinitely.
Other Names: mmf CellCept. Participants randomized to the prednisone maintenance group, received 4 medications to prevent rejection. Participants in this group continued on prednisone indefinitely. Outcome Measures. Primary Outcome Measures : The Number of Participants With Acute Rejection Episodes [ Time Frame: 6 and 12 months post-transplant ] Acute rejection episodes would have been measured by the number of participants who underwent a kidney transplant biopsy, and had the results of the biopsy reported as acute rejection by the transplant pathologist.
The number of participants who did not experience graft failure defined as return to dialysis at 6 and 12 months would have been reported. The number of participants alive at 6 and 12 months post-transplant would have been posted as a measure of patient survival.
Secondary Outcome Measures : The Number of Participants With Treatment Failures [ Time Frame: 12 months ] This measure was defined as the percentage of participants that did not remain on initial therapy ie were withdrawn from each arm of the trial. The length of the hospital stay would have assessed the number of days a participant was in the hospital after the kidney transplant was performed. The number of readmissions during the study period for each participant would have been assessed, as well as the reason for readmissions.
The time from admission to discharge for each readmission for patients readmitted in the first 12 months post-transplant. The above methods focus on estimating or determining actual glomerular filtration rate GFR or renal function of the kidney transplant. Results would have been reported from patients undergoing 24 hour urine collections at 3 and 12 months post-transplant.
The incidence and severity of rejection episodes per participant would have been identified by kidney transplant biopsy results read by a transplant pathologist. Participants would have been monitored throughout the study for any infectious complications as confirmed by the principal investigator.
Participants would have been monitored throughout the study with any reports of malignancy being confirmed by principal investigator. Fasting lipid profiles were to be performed at 3,6 and 12 months post-transplant. Bone densitometry by Computed tomography of peripheral skeleton and DEXA scans were performed at baseline within one month after transplant Urine and blood samples to measure markers of bone turnover: Alkaline phosphatase, pyridinoline, serum vit D 3 levels calcitriol and 25 hydroxy vit D calcidiol levels and serum osteocalcin levels were drawn at baseline, 3, 6, 12 and 24 months.
Glucose tolerance test performed in non-diabetic participants only at pre transplant in living donor recipients and at baseline within 1 mo after transplant and 6 mo and 12 months. Height, weight will be used to calculate change in BMI for all participants. Eligibility Criteria. Contacts and Locations.
Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
❾-50%}Steroid withdrawal protocols in Renal Transplantation.Kidney Transplant Program - Steroid-free immunosuppression protocols - Mayo Clinic
However the risk for a 2nd AR was related to whether or not steroids had been added to the maintenance protocol. Those most unlikely to have a 2nd AR — ie those recipients with very minimal-to-mild AR - the rate significantly increased if the recipient had returned to steroid-free immunosuppression [37].
In this setting, it may be useful to highlight a protocol [38] followed in the Middle East which would appear to be drawn on a combination of some of the data above. Steroids are reduced to 5 mg in 8 weeks post-transplant following categorisation of patients on their risk assessment. The general policy is to try and avoid steroid withdrawal all together except in very low immunological risk profile.
DR matching is not included in HLA matching as of yet. Intermediate and high risk patients receive ATG as induction therapy, the rest basiliximab. This policy is based on awareness around de novo donor specific antibodies and risk of CAN — which is why steroid withdrawal or calcineurin minimisation is avoided. At King Faisal more than half of death censored graft loss is immunological in contrast to interstitial fibrosis and tubular atrophy — also known as CAN — previously believed to be related to calcineurin IS related.
An AR episode is a major risk factor for long-term graft loss [27] if the severity of the rejection episode is enough to impair the recovery of the renal function to baseline levels [39]. AR is especially common within the first months after transplantation with risk factors such as race like African American predisposing to more AR episodes and a lower graft survival following an early AR episode [40].
Antibody mediated rejections and policies around withdrawal or recommencing steroids in such patients also remain largely unanswered. The possibility of de novo donor specific antibodies is a realistic concern when considering a steroid-free regimen [9].
The role of surveillance biopsies at predetermined time points independent of renal function or clinical status to assess graft injury [41] from subclinical antibody mediated rejection in sensitized high-risk patients [42] or subclinical BK virus nephropathy from over IS [43] or early CAN [44] is an area that may need consensus.
Routine protocol biopsies may make individualization of steroid-free IS or withdrawal possible, especially in high-risk patients [44].
Trial outcomes from low-risk transplant populations cannot be generalized [45] as high-risk patients are different immunologically. The patients who initiate steroid use later, following early withdrawal, have graft survival rates that are worse than either those who maintain steroid use or those who continue on steroid avoidance after transplant [46].
It is probably also inaccurate to conclude that complete steroid avoidance is safer than steroid withdrawal as this seems to be only based on less frequent NODAT [47].
Rapid withdrawal of steroids seems in most studies un-associated with an increased rate of AR whilst steroid withdrawal at 3 months post-transplantation—using the same maintenance IS—is.
It is possible that steroids lower cytokine production but upregulate cytokine receptor expression [9] - and when steroids are slowly withdrawn, cytokine release returns to normal in an environment of upregulated receptors.
Similarly it is possible Tac exposure also increases after steroid withdrawal [9]. It is also important to balance steroid-free and calcineurin inhibitor-free approaches [9]. Steroid-free IS has the obvious advantages of eliminating steroid side effects. Better long-term kidney allograft function when calcineurin inhibitors are minimized or eliminated is also reported. Protocols that are both steroid and calcineurin inhibitor free have high risk but in this era of newer IS drugs hopefully long-term effective immunosuppression without side effects from such medications will one day be possible.
The potential benefit of eliminating steroid-related side effects for transplant recipients is obvious. Yet concerns remain that steroid-free maintenance immunosuppression protocols may have some long-term detrimental effects. As early transplant outcomes are good, the number of patients required to power such a study would be enormous. Very early steroid withdrawal within a week may have a short-term efficacy similar to that achieved with continuous steroid regimen but longer follow-up data along with donor specific antibody or outcomes from surveillance biopsies may be required.
Surveillance biopsies may need to be incorporated routinely. Within the past decade, as a result of trials focusing on late steroid withdrawal or rapid withdrawal of prednisolone, recipients maintained on prednisone are taking far less prednisone than they would have been taking 10 years ago, and non-immunological side effects from steroid overexposure may well be of less importance today.
Order for reprints. Toggle navigation. ISSN: Author and article information. Halawa sth. DOI : Arch Clin Nephrol 4 1 : DOI: Corticosteroid use as a component of immunosuppression protocol is widespread, even though their mechanisms of action are imprecise.
Search for terms. Save this study. Warning You have reached the maximum number of saved studies Prednisone Withdrawal Versus Prednisone Maintenance After Kidney Transplant The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Results First Posted : March 21, Last Update Posted : May 15, Study Description.
The purpose of the study was to determine if rapid discontinuation of corticosteroids also known as prednisone withdrawal and maintenance immunosuppression with Prograf tacrolimus and CellCept mycophenolate mofetil while using Thymoglobulin Rabbit antithymocyte globulin will give similar safety and efficacy results compared to continuation of corticosteroids also known as prednisone maintenance and standard maintenance immunosuppression with Prograf tacrolimus , CellCept mycophenolate mofetil while using Thymoglobulin Rabbit antithymocyte globulin.
Detailed Description:. Corticosteroids one specific type is prednisone have been used in clinical transplantation for more than 30 years. There are many side effects of corticosteroids including significant bone disease, diabetes elevated blood sugar levels , fluid retention and hypertension high blood pressure , psychosis, peptic ulcer disease, hyperlipidemia elevated lipid levels such as cholesterol and triglycerides , obesity overweight , acne, and susceptibility to infections.
It is hoped that the new generation of potent immunosuppressive medications such as Prograf and CellCept will permit avoidance or withdrawal of corticosteroids for the majority of patients to avoid both short- and long-term complications of corticosteroid use in kidney transplant recipients. Drug Information available for: Prednisone Tacrolimus Mycophenolate mofetil. FDA Resources. Arms and Interventions. In this group, participants had prednisone rapidly decreased until completely eliminated by day 6 after transplant.
Participants in both groups received 3 to 5 doses of an intravenous medication to prevent rejection called Thymoglobulin rabbit antithymocyte globulin as per our standard of care. Participants in both groups received tacrolimus per our standard of care. Participants in both groups received mycophenolate mofetil by mouth twice daily indefinitely. Other Names: mmf CellCept. Participants randomized to the prednisone maintenance group, received 4 medications to prevent rejection.
Participants in this group continued on prednisone indefinitely. Outcome Measures. Primary Outcome Measures : The Number of Participants With Acute Rejection Episodes [ Time Frame: 6 and 12 months post-transplant ] Acute rejection episodes would have been measured by the number of participants who underwent a kidney transplant biopsy, and had the results of the biopsy reported as acute rejection by the transplant pathologist.
The number of participants who did not experience graft failure defined as return to dialysis at 6 and 12 months would have been reported. The number of participants alive at 6 and 12 months post-transplant would have been posted as a measure of patient survival.
Mayo Clinic doctors prescribe many types of immunosuppressive anti-rejection medications, which may include steroid-free immunosuppression protocols. In the past, people with kidney transplants usually have taken steroids such as prednisone as one of their immunosuppressive medications to prevent rejection.
But steroids may cause weight gain, diabetes, high blood pressure, heart and blood vessel disease cardiovascular disease , osteoporosis, and other problems.
Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and nephrology news. Gill disclosed support from the Canadian Institutes of Health Research and relevant relationships with Astellas Pharma.
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Long-range post-kidney transplant corticosteroids may not be necessary for most patients, researchers reported. In new long-term data median There was also no significant difference in the risk of allograft failure not including patient deathdefined as a need for long-term dialysis or repeat transplant during a median follow-up period of These data build on previously reported 5-year outcomes from the same group.
However, 5-year renal allograft survival and function rates were similar. Those who didn't continue chronic low-dose corticosteroid therapy saw better outcomes for cardiovascular CV risk factors, including lower triglycerides, less weight gain, lower blood glucose, and less need for insulin, according to the authors.
But they stressed that a study limitation was lack of data on long-term differences in nonfatal outcomes, such as CV disease, diabetes, infections, and metabolic bone disease between the two groups of patients.
Surgeries took place between andand all patients received either a living or deceased donor kidney transplant without delayed graft function. None had short-term rejection in the first week after transplant.
Half of the patients were randomized to receive the immunosuppressant drugs tacrolimus Envarsus, Protopic, Astagraf and mycophenolate mofetil with prednisone and withdraw 7 days after transplant. Although these patients were relatively low risk to begin with, Arthur Matas, MD, of University of Minnesota in Minneapolis, pointed out that other data have suggested that the practice of early steroid cessation ESC -- withdrawing within 14 days -- has also shown some success with higher-risk groups such as Black patients, children, and even those with re-transplants or recurring disease.
I agree," Matas wrote in an invited commentary. He added that the success of early steroid cessation has led many transplant centers to cut down on prednisone use to just 5 mg per day. Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and nephrology news.
Gill disclosed support from the Canadian Institutes of Health Research and relevant relationships with Astellas Pharma. Share on Facebook. Opens in a new tab or window. Share on Twitter. Share on LinkedIn. Matas disclosed no relevant relationships with industry.
localhost › health › treatments › prednisone-for-organ-. Prednisone is an immunosuppressant drug used to prevent the body from rejecting a transplanted organ. It is also used to treat certain forms of arthritis. Short- and intermediate-term results have been reported after rapid discontinuation of prednisone (RDP) in kidney transplant recipients. Prednisone is similar to the steroid hormone that the body produces naturally. Corticosteroids have played a critical role in the evolution of organ transplantation. Steroids have been the cornerstone of immunosuppressive regimens to treat. The different strategies utilised to minimise steroid exposure is usually devised locally by each transplant centre. Fasting lipid profiles were to be performed at 3,6 and 12 months post-transplant. Recipients had significantly lower rates of cataracts P Glucocorticoid avoidance protocols tend to choose low-risk individuals and utilize aggressive induction therapy [11]. FDA Resources. This content does not have an Arabic version. At King Faisal more than half of death censored graft loss is immunological in contrast to interstitial fibrosis and tubular atrophy — also known as CAN — previously believed to be related to calcineurin IS related.Organ transplantation requires immunosuppression IS to prevent rejection, induce immunologic acceptance and reduce immune mediated damage to transplanted organs allograft.
IS regimes can be for induction at time of transplant, maintenance at the follow-up phase or for episodic use during periods of acute rejection AR. When attempting to use reduction of exposure to corticosteroids, 1 centre in the UK [1] for example, stratifies patients into a. Treatment of rejection episodes is subdivided into cellular rejection when IVMP is used for 3 days followed by oral prednisolone.
For acute vascular rejection, the step wise approach includes: IVMP, anti-thymocyte globulin ATG , plasmapheresis and oral prednisolone. Another centre in Australia in New South Wales [2] NSW however, minimizes exposure to corticosteroids by reducing the dose of prednisone to 5 mg within a few months following the transplant operation.
In both of the scenarios above, it is clear steroids still have a role to play either during induction or maintenance or during episodes of rejection. Both are risk stratifying transplant recipients. Both also seem to be using IL-2 blocker antibody induction for low risk patients, whilst the RLBUHT is using Campath anti-lymphocyte antibody for anything other than low risk. For the rationale for each of these approaches, around steroid avoidance or minimization, to be understood, the history of IS, the 3-signal model, actions of corticosteroids and their side effects or cost-benefits will need to be understood.
Over the decades, pharmacologic therapy originally using corticosteroids, 6-mercaptopurine and total body irradiation in the s changed to azathioprine and corticosteroids in the s leading to the first successful outcomes in unrelated kidney transplantation. In the 80s Cyclosporine reduced rejection rates greatly while OKT3 was able to reverse steroid resistant rejection.
In the 90s Tac replaced cyclosporine in most transplant centres. MMF replaced azathioprine. Sirolimus was introduced as an alternative to azathioprine or MMF. In the s belatacept was approved as a co-stimulation blocker [3- 6]. Figure 1 [7] shows the advancements of IS and the correlation to 1 year allograft survival and rejection effects of evolution of IS medication over the last few decades of renal transplantation.
The rationale for using different types of IS comes from the 3 signal model in figure 2 [8] that is widely recognized as the steps in rejection in allo-immune responses. As corticosteroids act in multiple areas rather than being a more specific IS agent, there has been debate around the risks versus benefits of steroids. Glucocorticoids bind to cytoplasmic receptors and translocate into nucleus where it alters transcription of cytokine genes besides inhibiting translocation of activating protein-1 AP-1 and nuclear factor kappa B into nucleus preventing induction of cytokine encoding genes.
The clinical implications of using corticosteroids therefore mean inhibition of cytokine production like interleukins 1, 2, 3, 4, 6, tumor necrosis factor-alpha and gamma-interferon. It also decreases activation and proliferation of lymphocytes and macrophages, prevents macrophage antigen presentation and phagocytic activity, inhibits dendritic cells, suppresses inflammatory leukotrienes and prostaglandins and alters cell trafficking by decreasing ability of leukocytes to adhere to vascular endothelium.
Side effects specific to corticosteroids are related to multiple effects of these drugs. Growth retardation in children and cardiovascular morbidity are also common side effects. Corticosteroids although inexpensive are associated with debilitating side effects. Treatment of these steroid-related side effects adds to the cost of transplants such as cataracts and avascular necrosis of the hip requiring hip surgeries. Hypertension and post-transplant diabetes PTDM trigger the highest costs. Steroid side effects also increase non-compliance leading to increased incidence of AR episodes, chronic rejection or graft loss.
There is, therefore, a hidden cost of steroid-related side effects with patients stating the IS drug they would most like not to take is prednisone. The different strategies utilised to minimise steroid exposure is usually devised locally by each transplant centre. As a general rule there are 3 strategies available:. Tapering glucocorticoids to 0. In the absence of AR, for example, the East Coast NSW Transplant Service generally reduce glucocorticoids to a maintenance dose of 5 mg per day by 6 months following kidney transplantation.
The one prospective, well-designed study that compared very early steroid cessation to low-dose, long-term steroid therapy in kidney recipients receiving modern maintenance immunosuppression was in patients [12]. Following rabbit ATG in 68 percent or IL-2 receptor antibody 32 percent as induction and maintenance with TAC, MMF and 7-days of corticosteroids, these patients were blindly randomized to either steroid withdrawal or steroid continuation at 5 mg daily by six months after transplant.
Any rejection can then potentially prime the kidney for future damage. In terms of corticosteroid-associated side effects, there were no significant differences in blood pressure, new-onset diabetes after transplant NODAT , serum cholesterol, or low-density lipoprotein LDL levels, and rates of bone fracture or cataracts.
Whilst the authors concluded very early withdrawal is safe and provides similar five-year renal allograft outcomes, this strategy resulted in double the rate of CAN compared with continuance of corticosteroid therapy. Continued maintenance therapy is probably then preferable to very early withdrawal.
The ECRS protocol follows this principle. In the current era of further information around mechanisms of CAN, the strategy of using 5mg of steroids long term would seem sensible. As any strategy requires a risk benefit assessment, toxicities around 5mg of steroids long-term needs an analysis.
There is some literature evidence that toxicity associated with chronic low-dose corticosteroids is probably overestimated.
Bone resorption resulting in bone loss is seen only with doses achieving circulation levels above physiological range Low glucocorticoid concentrations appear to stimulate osteoblast differentiation as against the inhibitory effect associated with bone loss seen with high concentrations. The risk of AR is markedly increased with the withdrawal of corticosteroids within weeks to months after transplantation [15]. Despite the Kidney Disease: Improving Global Outcomes KDIGO clinical practice guidelines suggesting corticosteroid discontinuation by the first week after transplantation in patients at low immunologic risk and who receive induction therapy [15], it is unclear if this is to be adopted without further scrutiny around the type of ethnic mix of patients in studies, length of follow-up, type of maintenance IS, biopsy data or de novo donor specific antibody data.
There is a significantly increased risk of AR and possible decreased long-term allograft survival if withdrawal is performed less than three to six months after surgery [16,17]. This adverse effect of early withdrawal upon allograft survival emerges only after extended follow-up [16]. Although less than 2 year graft survival is not compromised, a multicenter Canadian trial [18] evaluating stable transplant recipients randomly assigned at day 90 following renal transplant to placebo or alternate-day prednisone found adverse outcomes at 5 years with 73 and 85 percent allograft survival respectively, without any effect on patient survival.
In another uncontrolled trial in 30 African-Americans, excellent short-term results from steroid withdrawal within 3 months of transplantation failed to translate to better long-term allograft survival 4 years later [19]. A meta-analysis of seven randomized, prospective trials of complete avoidance of steroids or withdrawal of steroids within a 6-month period after transplantation showed an increased risk of AR.
Only using anti-lymphocyte induction agents or in low immunological risk patients was complete steroid withdrawal successful and was dependent upon the choice of maintenance IS [21, 22]. Conflicting results would suggest the need for caution in such a withdrawal regimen. A meta-analysis of 20 glucocorticoid withdrawal studies from showed a higher relative risk of graft failure of 1. Limitations of this study includes lack of randomization, heterogeneous immunosuppressive regimens, duration and timing of glucocorticoid withdrawalunclear [24] with up to 30 to 40 percent patients receiving glucocorticoids during study period, suggesting an adverse clinical event.
Recipients had significantly lower rates of cataracts P Glucocorticoid avoidance protocols tend to choose low-risk individuals and utilize aggressive induction therapy [11]. In the s a multi-centre European study of cadaveric renal transplants demonstrated a one-year allograft survival rate of 77 percent with cyclosporine only, as compared with 63 percent in the azathioprine and prednisone control group [25].
Since the s a transplant group in Denmark has also successfully adopted a glucocorticoid-free IS strategy including its avoidance in treating rejection in combination with induction therapy utilizing rabbit ATG [26,27]. In a report summarizing their more recent experience, maintenance IS consisted of cyclosporine and MMF in consecutive patients [27]. Acute rejections AR , which were treated with anti-lymphocyte therapy without glucocorticoids, occurred in only 13 percent of patients.
Glucocorticoid avoidance in low-risk, living-donor recipients utilizing ATG as induction therapy, MMF, and cyclosporine [28] with steroids discontinued on postoperative day 6 showed. Patient and graft survival were comparable with national data reported by the Scientific Registry of Transplant Recipients in Data from low risk living donor patients that are not ethnically diverse or are predominantly non-sensitised cannot be extrapolated without inherent risks to other cohorts [31].
Unfortunately, long-term experience beyond 5 years with glucocorticoid-free IS is limited [12]. In a prospective, well-designed study comparing very early steroid cessation to low-dose, long-term steroid therapy in kidney recipients receiving modern maintenance immunosuppression already mentioned earlier, patients were randomly assigned to corticosteroid withdrawal at one week post-transplant or continuance of corticosteroids.
Maintenance therapy consisted of Tac, MMF, and seven days of corticosteroids followed by blinded randomization to either withdrawal or continuation tapered to 5mg by 6 months after transplant. Although some single centre studies have reported feasibility of steroid avoidance regimes in patients at increased risk, including African Americans or pre-sensitized patients with good graft survival at 3 or 5 years [34], results from single-centres require verification from registry data.
In addition in light of the meta-analysis [20] which showed increased AR within 6 months in case of complete steroid avoidance, the RLBUHT protocol may need further scrutiny. However the risk for a 2nd AR was related to whether or not steroids had been added to the maintenance protocol. Those most unlikely to have a 2nd AR — ie those recipients with very minimal-to-mild AR - the rate significantly increased if the recipient had returned to steroid-free immunosuppression [37].
In this setting, it may be useful to highlight a protocol [38] followed in the Middle East which would appear to be drawn on a combination of some of the data above. Steroids are reduced to 5 mg in 8 weeks post-transplant following categorisation of patients on their risk assessment.
The general policy is to try and avoid steroid withdrawal all together except in very low immunological risk profile. DR matching is not included in HLA matching as of yet. Intermediate and high risk patients receive ATG as induction therapy, the rest basiliximab. This policy is based on awareness around de novo donor specific antibodies and risk of CAN — which is why steroid withdrawal or calcineurin minimisation is avoided.
At King Faisal more than half of death censored graft loss is immunological in contrast to interstitial fibrosis and tubular atrophy — also known as CAN — previously believed to be related to calcineurin IS related. An AR episode is a major risk factor for long-term graft loss [27] if the severity of the rejection episode is enough to impair the recovery of the renal function to baseline levels [39].
AR is especially common within the first months after transplantation with risk factors such as race like African American predisposing to more AR episodes and a lower graft survival following an early AR episode [40]. Antibody mediated rejections and policies around withdrawal or recommencing steroids in such patients also remain largely unanswered. The possibility of de novo donor specific antibodies is a realistic concern when considering a steroid-free regimen [9].
The role of surveillance biopsies at predetermined time points independent of renal function or clinical status to assess graft injury [41] from subclinical antibody mediated rejection in sensitized high-risk patients [42] or subclinical BK virus nephropathy from over IS [43] or early CAN [44] is an area that may need consensus. Routine protocol biopsies may make individualization of steroid-free IS or withdrawal possible, especially in high-risk patients [44]. Trial outcomes from low-risk transplant populations cannot be generalized [45] as high-risk patients are different immunologically.
The patients who initiate steroid use later, following early withdrawal, have graft survival rates that are worse than either those who maintain steroid use or those who continue on steroid avoidance after transplant [46]. It is probably also inaccurate to conclude that complete steroid avoidance is safer than steroid withdrawal as this seems to be only based on less frequent NODAT [47]. Rapid withdrawal of steroids seems in most studies un-associated with an increased rate of AR whilst steroid withdrawal at 3 months post-transplantation—using the same maintenance IS—is.
It is possible that steroids lower cytokine production but upregulate cytokine receptor expression [9] - and when steroids are slowly withdrawn, cytokine release returns to normal in an environment of upregulated receptors. Similarly it is possible Tac exposure also increases after steroid withdrawal [9]. It is also important to balance steroid-free and calcineurin inhibitor-free approaches [9].
Steroid-free IS has the obvious advantages of eliminating steroid side effects. Better long-term kidney allograft function when calcineurin inhibitors are minimized or eliminated is also reported. Protocols that are both steroid and calcineurin inhibitor free have high risk but in this era of newer IS drugs hopefully long-term effective immunosuppression without side effects from such medications will one day be possible.
The potential benefit of eliminating steroid-related side effects for transplant recipients is obvious. Yet concerns remain that steroid-free maintenance immunosuppression protocols may have some long-term detrimental effects. As early transplant outcomes are good, the number of patients required to power such a study would be enormous. Very early steroid withdrawal within a week may have a short-term efficacy similar to that achieved with continuous steroid regimen but longer follow-up data along with donor specific antibody or outcomes from surveillance biopsies may be required.
Surveillance biopsies may need to be incorporated routinely.
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