Immunosuppression: practice and trends

Over the past decade, immunosuppression therapy has undergone striking changes in the scale and pace by which new immunosuppressive molecules and antibodies have become incorporated into daily transplant medicine. An organ-by-organ review of data reveals several trends. The highest use of induction therapy (over 70% of patients) was reported for simultaneous pancreas kidney (SPK) and pancreas after kidney (PAK) transplants in 2002; use of induction therapy was less common in liver transplants (only 18%). Corticosteroids served as discharge maintenance immunosuppression in over 87% of the recipients of kidney, SPK, PAK and thoracic transplants, and in over 70% of pancreas transplant alone (PTA) recipients. Corticosteroid use in intestine transplants was reported in 64% of recipients in 2002. A shift in the calcineurin inhibitor used for maintenance immunosuppression from cyclosporine to tacrolimus for the majority of patients had occurred for kidney, PAK, SPK, PTA, liver, lung, and heart-lung by 2001. For heart transplants, cyclosporine remained the calcineurin inhibitor of choice; tacrolimus remained the predominant calcineurin inhibitor agent for intestine (since 1994). Use of antibody treatment for rejection during the first post-transplant year for most organs declined. Short-term outcomes have improved, based on the observation that rates of rejection within the first year post-transplant have diminished.     

Immunosuppression: Evolution in Practice and Trends, 1994–2004

Over the last 10 years, there have been important changes in immunosuppression management and strategies for solid-organ transplantation, characterized by the use of new immunosuppressive agents and regimens. An organ-by-organ review of OPTN/SRTR data showed several important trends in immunosuppression practice. There is an increasing trend toward the use of induction therapy with antibodies, which was used for most kidney, pancreas after kidney (PAK), simultaneous pancreas-kidney (SPK) and pancreas transplant alone (PTA) recipients in 2004 (72–81%) and for approximately half of all intestine, heart and lung recipients. The highest usage of the tacrolimus/mycophenolate mofetil combination as discharge regimen was reported for SPK (72%) and PAK (64%) recipients. Maintenance of the original discharge regimen through the first 3 years following transplantation varied significantly by organ and drug. The usage of calcineurin inhibitors for maintenance therapy was characterized by a clear transition from cyclosporine to tacrolimus. Corticosteroids were administered to the majority of patients; however, steroid-avoidance and steroid-withdrawal protocols have become increasingly common. The percentage of patients treated for acute rejection during the first year following transplantation has continued to decline, reaching 13% for those who received a kidney in 2003, 48% of which cases were treated with antibodies.     

Trends in adult post-kidney transplant immunosuppressive use in Australia, 1991-2005

Aim: Kidney transplant outcomes have improved over the past 15 years, partly due to improvements in immunosuppression. We used data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry to examine trends in immunosuppressive use post transplant. Methods: All adult (recipient age 16+ years) kidney‐only transplants performed in Australia from April 1991 to December 2005 were followed to graft loss or December 2005. Immunosuppressive use at induction, 1, 3 and 5 years post transplant were analysed by transplant cohort. Results: Calcineurin‐inhibitors (CNI) were used in most recipients for induction and maintenance immunosuppression, with increasing tacrolimus use. Induction cyclosporin dose increased since 2001 (from 5.8 to 7.9 mg/kg per day), but maintenance cyclosporin and tacrolimus dose decreased (from 3.8 to 3.0 mg/kg per day cyclosporin at 1 year post transplant). CNI‐free induction increased since 2002 (from 1.4% to 8.4%), while CNI‐free maintenance increased throughout the study period. Mycophenolates were the predominant antimetabolite used. Steroid‐free maintenance decreased (from 22.7% to 8.7% at 1 year post transplant), as did median prednisolone doses (from 0.12 to 0.09 mg/kg per day at 1 year post transplant). Sirolimus or everolimus are increasingly used for CNI‐sparing rather than as antimetabolites substitutes. OKT3 or antithymocyte globulin induction decreased, while anti‐CD25 antibody usage increased from 9.5% to 57.1% since 2000. Conclusion: There is a trend to more potent induction immunosuppression with tacrolimus, mycophenolates and anti‐CD‐25 antibodies, but with CNI avoidance or minimization during maintenance phase. While steroid avoidance/cessation decreased, maintenance steroid dose has also decreased. Anti‐CD25 antibodies are now used in >50% of recipients.     

Prednisone-Free Maintenance Immunosuppression—A 5-Year Experience

Concern persists that prednisone-free maintenance immunosuppression in kidney transplant recipients will be associated with an increase in late allograft dysfunction and graft loss. We herein report 5-year follow-up of a trial of prednisone-free maintenance immunosuppression. From October 1, 1999, through January 31, 2005, at our center, 589 kidney transplant recipients were treated with a protocol incorporating discontinuation of their prednisone on postoperative day 6. At 5 years, actuarial patient survival was 91%; graft survival, 84%; death-censored graft survival, 92%; acute rejection-free graft survival, 84% and chronic rejection-free graft survival, 87%. The mean serum creatinine level (+/-SD) at 1 year was 1.6 +/- 0.6; at 5 years, 1.7 +/- 0.8. In all, 86% of kidney recipients with functioning grafts remain prednisone-free as of April 30, 2005. As compared with historical controls, recipients on prednisone-free maintenance immunosuppression had a significantly lower rate of a number of complications, including cataracts (p < 0.001), posttransplant diabetes mellitus (p < 0.001), avascular necrosis (p = 0.001), and fractures (p = 0.004). We conclude that prednisone-related side effects can be minimized in a protocol incorporating prednisone-free maintenance immunosuppression. Five-year graft outcome remains good.     

Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply

Given the current climate of drug shortages in the United States, this review summarizes available comparative literature on the use of alternative immunosuppressive agents in adult solid organ transplant recipients including kidney, pancreas, liver, lung, and heart, when immediate-release tacrolimus (IR-TAC) is not available. Alternative options explored include extended-release tacrolimus (ER-TAC) formulations, cyclosporine, belatacept, mammalian target of rapamycin inhibitors, and novel uses of induction therapy for maintenance immunosuppression. Of available alternatives, only ER-TAC formulations are of non-inferior efficacy compared to IR-TAC when used de novo or after conversion in stable kidney transplant recipients (KTRs). All other alternatives were associated with higher rates of biopsy-proven rejection, but improved tolerance from classic adverse effects of IR-TAC including nephrotoxicity and development of diabetes. While most alternative therapies are approved in KTRs, access via third-party payors is an obstacle in non-KTRs. In the setting of IR-TAC shortage, alternate therapeutic options may be plausible depending on the organ population and individual patient situation to ensure appropriate, effective immunosuppression for each patient.     

Lymphomas After Solid Organ Transplantation: A Collaborative Transplant Study Report

We used the Collaborative Transplant Study database to analyze the incidence, risk, and impact of malignant lymphomas in approximately 200,000 organ transplant recipients. Over a 10-year period, the risk in renal transplant recipients was 11.8-fold higher than that in a matched nontransplanted population (p<0.0001). The majority of lymphomas were diagnosed after the first post-transplant year. Heart-lung transplants showed the highest relative risk (RR 239.5) among different types of organ transplants. In kidney recipients, immunosuppression with cyclosporine did not confer added risk compared with azathioprine/steroid treatment, whereas treatment with FK506 increased the risk approximately twofold. Induction therapy with OKT3 or ATG, but not with anti-IL2 receptor antibodies, increased the risk of lymphoma during the first year. Antirejection therapy with OKT3 or ATG also increased the risk. First-year mortality in renal and heart transplant patients with lymphoma was approximately 40% and 50%, respectively, and showed no improvement in recent years. A pattern of preferential localization to the vicinity of the transplant was noted, and the prognosis of the patient was related to localization. This study highlights the continuing risk for lymphoma with time post-transplantation, the contribution of immunosuppression to increased risk, and continuing poor outcomes in patients with post-transplant lymphoma.     

Prevention of acute rejection with antithymocyte globulin, avoiding corticosteroids, and delaying cyclosporin after renal transplantation.

BACKGROUND: Despite their well-known side-effects, corticosteroids (Cs) are currently used after kidney transplantation. Avoidance of Cs may improve patient quality of life and eventual long-term survival. We report on a regimen using antithymocyte globulin (ATG) and mycophenolate mofetil (MMF) for induction, and cyclosporin (CsA) plus MMF for maintenance treatment of recipients of primary kidney transplantation. METHODS: We studied 11 consecutive, non-sensitized renal transplant patients (nine cadaver and two living donors). Initial immunosuppression consisted of ATG (1.5 mg/kg/day, i.v.) given for 10 days and MMF (1.0 g/b.i.d.). CsA (8 mg/kg, in two divided doses) was started on post-operative day 11. Cs were only allowed in the case of MMF discontinuation, for the treatment of acute rejection, and in the event of recurrence of the primary glomerulonephritis. RESULTS: All patients completed the entire 10-day ATG course. Main side-effects included fever (>38 degrees C) and serum sickness, observed in 73 and 27% of the patients respectively. The incidence of acute rejection was 27% (three of 11 patients). In two patients with acute rejection, serum sickness was concomitantly diagnosed and renal histology was partially compatible with immune-complex disease. The remaining patient had two episodes of low-grade rejection. All rejection episodes were rapidly reversed. Two patients (18%) were treated with ganciclovir for cytomegalovirus (CMV) infection. Two patients (18%) are currently receiving Cs for recurrence of the native glomerulonephritis and two rejection episodes respectively. All patients are currently alive with functioning kidneys (average follow-up of 8.4 months; average creatinine level of 128 micromol/l). CONCLUSION: This pilot study suggests that ATG induction in combination with MMF and delayed introduction of CsA, in the absence of Cs, is not well tolerated in recipients of kidney transplants. An earlier introduction of calcineurin inhibitors and/or a shorter course of ATG may reduce the incidence of fever and serum sickness secondary to ATG.     

Transplant immunology

The immune response to an allogeneic transplanted organ is T-cell dependent. It is governed partially by the context in which the T-cell encounters the antigen and can range from apoptosis, anergy, and neglect to full activation. The current armamentarium of immunosuppressive agents acts to inhibit the various steps of this T-cell activation pathway; at the level of the T-cell receptor (monoclonal antibodies such as OKT3), intracellular signally (calcineurine-inhibitors), DNA synthesis (azathioprine), or to cause lymphocyte depletion (ATG, ALG). Most protocols use a combination of agents for induction and maintenance immunosuppression. Although successful in preventing and treating allograft rejection, they are not without side effects. With improved patient and graft survival rates, adverse events such as hypertension, nephrotoxicity, hyperglycaemia, and lymphoproliferative disease become increasingly important issues. Newer drugs (IL-2 receptor antagonists, mycophenolate mofetil, rapamycin) have been introduced in an attempt to spare or avoid these adverse effects. Inducing graft tolerance and long-term drug-free survival is the goal of transplant immunologists. Postulated mechanisms include clonal deletion, anergy, and immunoredirection. Although a number of methods have been tested experimentally, none has been proven to induce tolerance for routine clinical use. Immunosuppression remains the cornerstone of the success of organ transplantation. Until investigators are able to induce tolerance in their transplant recipients or develop a tolerance assay, they would need to continue to tailor their immunosuppressive therapy according to the risk profile of the individual recipient.     

Corticosteroid elimination in simultaneous liver–kidney transplantation recipients

Abstract: Background: Simultaneous liver–kidney transplantation (SLK) has more than doubled since 2002. While less common in kidney transplant alone recipients (KTA), corticosteroid discontinuation is performed routinely in liver transplantation, raising the question of optimal immunosuppression for SLK recipients. Methods: A retrospective case series of 16 SLK recipients under a steroid withdrawal protocol was performed to compare short‐term outcomes to a contemporaneous cohort of 32 KTA recipients. Results: In 69% of SLK recipients, corticosteroids were eliminated compared to 3% of KTA recipients, p < 0.0001. When comparing SLK and KTA recipients one yr post‐transplant, there were no significant differences in renal graft rejection (23.1% vs. 6.3%), death‐censored renal graft survival (100% vs. 97%), estimated glomerular filtration rate (74.4 vs. 62.6 mL/min), serum creatinine (1.10 vs. 1.39 mg/dL), or maintenance immunosuppression, respectively. Conclusions: Corticosteroids may be withdrawn safely in SLK recipients with one‐yr renal outcomes comparable to a KTA cohort.     

Ochroconis gallopava: a dematiaceous mold causing infections in transplant recipients

The dematiaceous mold Ochroconis gallopava is increasingly recognized as a human pathogen. Infection is almost always associated with immunosuppression. We describe a case with a unique presentation in a kidney transplant recipient and retrospectively review all 10 cases of O. gallopava at our institution over 18 yr, all in organ transplant recipients. Sixty percent of infections at our institution occurred in the last five yr studied. Infection generally occurred late after transplantation, and pulmonary infection was the most common manifestation. Use of almetuzumab for induction was associated with infection in the first six months post-transplant (p = 0.03). Attributable mortality at six months was 20%. Ochroconis gallopava is a rare but important pathogen in immunosuppressed individuals and organ transplantation is the most common underlying condition. Pulmonary involvement is the most common manifestation among patients with organ transplant. Optimal therapy remains undefined. Prognosis in organ transplant recipients is good if infection is diagnosed prior to dissemination.     

The janus face of immunosuppression - de novo malignancy after renal transplantation: the experience of the Transplantation Center Munich

After decades of successful organ transplantation clinicians continue to be troubled by the increasing incidence of cancers under maintenance immunosuppression. In this study, we examined rates of malignancies in 2419 renal transplant recipients transplanted in our institution between 1978 and 2005. In renal transplant recipients the cumulative incidence of cancer after 25 years was 49.3% for all tumors and 39.7% excluding non-melanoma skin cancers, compared with 21% for a normal sex- and age-matched population. The most frequent tumors observed were non-melanoma skin cancers (20.5%), kidney cancers (12.0%), and cancers of the pharynx, larynx, or oral cavity (8.2%). The general increase of cancer risk was 4.3-fold. Independent risk factors for the development of a tumor were male gender, older recipient age, the presence of preformed antibodies before transplantation, and the time on immunosuppression. Interestingly, the use of IL-2-receptor antagonists significantly reduced the tumor risk of transplant recipients. The tumor risk between immunosuppressive drugs typically used for maintenance immunosuppression was not significantly different. However, mammalian target of rapamycin (mTOR) inhibitor-based immunosuppressive protocols showed a clear tendency for lower malignancy rates. De novo malignancies following renal transplantation represent a serious problem endangering the prognosis of otherwise successfully transplanted patients. Future studies will have to address whether optimized immunosuppressive regimens including mTOR-inhibitors are capable of reducing the incidence or preventing the development of posttransplant malignancies.     

Zygomycosis and other rare filamentous fungal infections in solid organ transplant recipients.

Fungi cause severe infections in solid organ transplant (SOT) recipients. Recently, a shift towards non-Aspergillus filamentous fungal infections (nAFFI) was noticed. In a series of 2878 SOTs (kidney, pancreas, islets, liver, heart, lung, and bowel) performed between January 1995 and December 2006 at the Innsbruck medical university, eleven cases of nAFFI were diagnosed. The encountered species included Zygomyzetes (n = 8), and Alternaria alternate, Pseudallescheria boydii, Trichoderma spp. (one each); there were three liver and three heart, one intestinal, pancreas, lung, bilateral forearm and renal recipient each. Five patients died from nAFFI (zygomycosis: 4, Pseudallerichia boydii: 1); four were diagnosed postmortem. In five cases infection was surgically treated in combination with antifungals. Risk factors for nAFFI were renal failure (73%) and intensified immunosuppression (73%); two cases were associated with post-transplant lymphoproliferative disorder, one with graft versus host disease. An increase in the incidence of nAFFI was observed parallel to introduction of caspofungin and voriconazole (three cases until 12/2003, seven cases thereafter). NAFFI are increasingly found in SOT recipients. If diagnosed in time, the outcome seems acceptable. Intensified immunosuppression and exposure to antifungals not active against zygomycetes may be risk factors. Surgical therapy may play an important role in these infections.     

Living related renal transplantation--the use of advanced age donors

AIM: Efforts to increase the donor pool and available organs included some unconventional kidney transplantation. One of these was including elderly donors for both, living and cadaver kidney transplantation. The aim of the study was to review our single centre experience with living donor transplants from elderly advanced age donors. PATIENTS AND METHODS: During a period of 7 years, 71 living related renal transplantations were performed. Twenty-six of them were over 65 (mean 69+/-4, range 65 to 81), but 10 were over 70 years of age. The survival rate was compared with 45 transplants from younger donors (mean age 51+/-6, range 24 to 59). The cold and warm ischemia time, the preservation procedure and blood vessels anastomosis time were comparable in both donor groups. The immunosuppression included sequental quadruple protocol with ATG, PRED, AZA and CyA replacing ATG after 7 days. The triple drug (AZA, PRED, CyA) maintenance therapy was applied to all recipients. RESULTS: Kaplan-Meier 1-, 3- and 5-year graft survival was 88.0%, 79.2% and 68%, respectively, for advanced donor age group and 90.2%, 82.4% and 74%, respectively, for younger donor group. The difference was slightly statistically significant (p < 0.05). In 6 patients who received graft from elderly donors, a delayed graft function was observed, whereas only in one in the younger donor group. CONCLUSION: Despite the worse results in the elderly donors' transplants, we consider the advanced age donors as an important source of kidneys contributing to solving the actual organ shortage, especially in our region.     

Impact of Induction Immunosuppression on the Recurrence of Primary IgA Nephropathy

ObjectiveThe objective of this study was to analyze the impact of induction immunosuppression on the incidence of recurrent IgA nephropathy (IgAN).MethodsWe conducted recurrence-free survival analysis of recipients of a first kidney transplant for IgAN who received a graft between 1995 and 2015. Kaplan-Meier and Cox regression analyses were used to sort the significant risk factors for recurrence. A total of 226 recipients with biopsy-proven IgAN received a kidney transplant, and 218 recipients were enrolled.ResultsAmong the recipients, 29 cases of IgAN recurrence were observed. The recipients were categorized into 3 groups according to induction immunosuppression: no induction (group 1, n = 72), anti-CD25 (group 2, n = 86), and antithymocyte globulin (ATG, group 3, n = 60). The 5- and 10-year cumulative IgAN recurrence rates were 9.7% and 21.0%, respectively. Recipients receiving ATG (group 3) exhibited significantly higher 4- and 5-year recurrence-free graft survival rates (both 96.4%) than recipients who received anti-CD25 (group 2, both 85.1%, P = .03). However, the induction therapy used (ATG or basiliximab) was not the risk factor for IgAN recurrence.ConclusionsTherefore, we concluded that ATG induction seems to postpone IgAN recurrence. These findings should be evaluated with well-designed prospective studies.     

The impact of induction on survival after lung transplantation: an analysis of the International Society for Heart and Lung Transplantation Registry

Abstract: Background: The use of induction immunosuppression after lung transplantation remains controversial. In this study, we examined the impact of induction on survival after lung transplantation. Methods: We performed a retrospective cohort study of 3970 adult lung transplant recipients reported to the ISHLT Registry. We divided the cohort into three groups based on the use of induction: none, interleukin‐2 receptor antagonists (IL‐2 RA), and polyclonal antithymocyte globulins (ATG). We estimated graft survival using the Kaplan‐Meier method and constructed a multivariable Cox proportional hazards model to examine the impact of induction on graft survival in the context of other variables. Results: During the study period, 2249 patients received no induction, 1124 received IL‐2 RA, and 597 received ATG. Four years after transplantation, recipients treated with IL‐2 RA had better graft survival (64%) than those treated with ATG (60%) and those who did not receive induction (57%; log rank p = 0.0067). This survival advantage persisted in the multivariable model for single and bilateral recipients treated with IL‐2 RA compared to those who did not receive induction (RR = 0.82, p = 0.007). Similarly, bilateral recipients treated with ATG had a survival advantage over bilateral recipients who did not receive induction (RR = 0.78, p = 0.043), but single lung recipients treated with ATG did not have a survival advantage over single lung recipients who did not receive induction (RR = 1.06, p = 0.58). Conclusions: Induction with lL‐2 RA for single and bilateral lung recipients and induction with ATG for bilateral recipients are associated with a survival benefit, independent of other variables that might impact survival.     

Calcineurin-inhibitor avoidance in elderly renal allograft recipients using ATG and basiliximab combined with mycophenolate mofetil

In old recipients of renal allografts from old donors, benefits of calcineurin-inhibitors (CNI) are curtailed by nephrotoxicity. Intending to improve the outcome of these recipients, we analyzed a CNI-free immunosuppressive regimen consisting of anti-thymocyte globulin (ATG), basiliximab, mycophenolate mofetil (MMF) and steroids. Kidney allograft recipients with low immunological risk (panel reactive antibodies <30%) were eligible for this study. Immunosuppression induction included ATG (4 mg/kg, day 0), basiliximab (20 mg, day 0 + 4) and steroids, followed by MMF (TL 2-6 microg/ml) and steroid maintenance treatment. Patient and graft survival rates respectively were 89.3% and 85.4% (12 months), and 86.6% and 76.8% (24 months). Delayed graft function occurred in 44.6%. S-creatinine at 12 months was 1.85 +/- 0.94 mg/dl. Thirty patients (53.6%) showed biopsy-proven rejections (6x Banff 3, 13x Banff 4I and 16x Banff 4II), 77% of which were steroid-sensitive, 23% required antibody treatment. After 12 months, 83% of the patients had an MMF-based immunosuppression, 43% were CNI-free. Cytomegalovirus (CMV) infections occurred in 28, tissue-invasive disease in three patients. Despite acceptable renal graft survival and function in some of patients with marginal organs, high incidences of rejections and CMV infections suggest the feasibility of CNI-avoidance using an MMF-based protocol only in carefully selected patients.     

The use of contaminated donor organs in transplantation

Introduction. Organ transplantation has become an accepted means of treating end‐stage organ disease in recent years with acceptable patient and graft survival. Transplant recipients have an increased risk of infectious complications due to multiple factors including decreased host resistance from chronic end‐stage organ failure as well as from the immunosuppression required to prevent graft rejection.
Hypothesis. Therefore, the use of contaminated allografts could result in life‐threatening infections in organ recipients.
Method. In this study, transplant patients receiving organs from donors with positive blood or urine cultures, from 1993 to 1997, were retrospectively reviewed.
Results. There was a total of 599 organ donors in our state. Forty‐six (7.5%) had positive blood cultures and 25 (4.5%) had positive urine cultures. A total of 179 patients received organs from these contaminated donors, 36 of which were transplanted at our center. In this group, there were 16 kidney, 9 liver, and 11 heart transplants. Both donors and recipients received prophylactic broad‐spectrum antibiotics, which were adjusted based on culture and sensitivity results. The most common organisms isolated from the blood were staphylococci followed by streptococci and Gram‐negative organisms. Three of the 9 liver transplant patients in the series died with a mortality of 33%. Two of the 3 patients who died had sepsis but the responsible organisms were different from those recovered from the donor. The rest (66%) did well and have acceptable liver function. None of the 16 renal transplant recipients developed an infection and all survived. One patient developed acute irreversible rejection requiring transplant nephrectomy. There was one death in the heart transplant group resulting in a mortality of 9%. This death was not attributed to infectious processes. Three of 11 heart transplant patients grew organisms in the post‐operative period that were similar to those found in the corresponding donors. However, no patient suffered significant morbidity or mortality from these infections and all recovered. The recipients of contaminated organs had levels of organ function similar to those of randomly chosen recipients of non‐contaminated organs, and both groups had similar lengths of hospital stay.
Conclusion. Only 3 of 36 organ recipients had infections caused by organisms found in the contaminated donor organs for a rate of 8%. Contaminated donor organs seem to fare as well as non‐contaminated donor organs and there was no increase in morbidity or mortality. Contamination of organs should not be an absolute contraindication to the use of these organs in transplantation.     

Excellent clinical outcomes in primary kidney transplant recipients treated with steroid-free maintenance immunosuppression

Steroid-free maintenance immunosuppression is desirable to eliminate the side effects of chronic corticosteroid use. Complete steroid avoidance or rapid post-transplant steroid withdrawal has recently been used in renal transplant recipients with encouraging results. The present study evaluated the outcome of a steroid-free maintenance immunosuppressive protocol in kidney transplant recipients with at least one-yr follow up. Between April 2002 and October 2004, a total of 301 primary kidney transplant recipients received steroid-free maintenance immunosuppression. The regimen consisted of induction with thymogobulin and prednisone for the first five d. Patients were maintained on Sirolimus and Neoral. Neoral dose was adjusted to target C2 levels and the Sirolimus dose was adjusted to a target rapamycin trough level. All primary kidney transplants (n = 502) performed in the two yr (starting January 2000) prior to institution of the steroid-free regimen and thus maintained on a steroid-based immunosuppressive protocol were used for comparison. One-year patient and death censored graft survival were 93.1% and 98.1% for the steroid-free group vs. 95.2% and 95.2% for the comparator groups (p = ns). The incidence of biopsy-proven acute rejection was 4.9% in the steroid-free group vs. 9.4% in the comparator group (p < 0.01). Two (0.7%) of 301 patients in the steroid-free group lost their grafts because of acute rejection compared with nine (1.8%) patients in the comparator group (p < 0.05). At one-yr post-transplant the mean serum creatinine level was not different between the two groups. There were no significant differences in mean serum cholesterol and triglycerides levels as well as the percentage of patients on lipid lowering agents between the groups. White blood cell counts, daily doses of Neoral and weight gain were significantly lower in the steroid-free group vs. the comparator group. However, more patients in the steroid-free group required erythropoietin and iron therapy for anemia (p < 0.001). We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of Neoral and Sirolimus.     

Determining the conversion ratios for oral versus sublingual administration of tacrolimus in solid organ transplant recipients

Tacrolimus is utilized as maintenance immunosuppression in solid organ transplant (SOT). Current literature has reported conflicting conversion ratios when transitioning between oral and sublingual tacrolimus, and the exact conversion ratio has not been fully established in SOT. The purpose of this study was to determine the conversion ratios between oral and sublingual tacrolimus needed to achieve equivalent whole blood concentrations in heart, kidney, liver, and lung transplant recipients. A retrospective, single‐center analysis was conducted at Mayo Clinic in Florida. One hundred and eighteen hospitalized SOT recipients who received oral and sublingual tacrolimus during the same inpatient admission from June 1, 2012, through June 1, 2017, were reviewed. The median conversion ratio of sublingual to oral tacrolimus was 1.34 (IQR: 1.03‐1.93) in all SOT, 1.25 (IQR: 1.08‐1.64) in heart transplant, 1.23 (IQR: 1.1‐2.06) in kidney transplant, 1.64 (IQR: 1.27‐2.29) in liver transplant, and 1.34 (IQR: 0.94‐1.93) in lung transplant. A slightly higher dose of oral tacrolimus is needed in the majority of solid organ recipients in our population when converting between sublingual to oral tacrolimus administration.     

Should heart,lung, and liver transplant recipients receive immunosuppression induction for kidney transplantation?

Ranney DN, Englesbe MJ, Muhammad W, Al‐Holou SN, Park JM, Pelletier SJ, Punch JD, Lynch RJ. Should heart, lung, and liver transplant recipients receive immunosuppression induction for kidney transplantation?
Clin Transplant 2010: 24: 67–72. © 2009 John Wiley & Sons A/S. Abstract: As the outcomes of heart, liver, and lung transplantation continue to improve, more patients will present for subsequent renal transplantation. It remains unclear whether these patients benefit from induction immunosuppression. We retrospectively reviewed induction on solid organ graft recipients who underwent renal transplant at our center from January 1, 1995 to March 30, 2007. Induction and the non‐induction groups were compared by univariate and Kaplan–Meier analyses. There were 21 patients in each group, with mean follow‐up of 4.5–6.0 years. Forty‐seven percent of patients receiving induction had a severe post‐operative infection, compared with 28.6% in the non‐induction group (p = NS). The one yr rejection rate in the induction group was 9.5% compared with 14.3% for non‐induction (p = NS). One‐yr graft survival was 81.0% and 95.2% in the induction and non‐induction group (p = NS). In summary, there is a trend toward lower patient and graft survival among patients undergoing induction. These trends could relate to selection bias in the decision to prescribe induction immunosuppression, but further study is needed to better define the risks and benefits of antibody‐induction regimens in this population.