Steroid-based Regimen Research Articles

Outcomes of pediatric deceased donor kidney transplant in northeast Thailand.

Kidney transplantation (KT) is the best therapy in children with end-stage renal disease (ESRD), however, improving long-term graft survival remains challenging. The aim of this study was to determine graft survival and potential risk factors in pediatric patients who undergo deceased donor KT with a steroid-based regimen. The medical records of children who underwent their first deceased donor KT in Srinagarind Hospital (Khon Kaen, Thailand) between 2001 and 2020 were reviewed. Seventy-two patients were studied. Male adolescents were the predominant recipients and the majority of donors were young adult males. Non-glomerular disease, particularly hypoplastic/dysplastic kidney disease, was the major cause of ESRD (48.61%). The mean cold ischemic time (CIT) was 18.29 ± 5.29h. Most of the recipients had more than 4 human leukocyte antigen (HLA) mismatched loci with positive HLA-DR mismatch (52.78%). Induction therapy was administered in 76.74% of recipients. Tacrolimus plus mycophenolate sodium and prednisolone was the most common immunosuppressive maintenance regimen (69.44%). Graft failure occurred in 18 patients, mostly due to graft rejection (50%). Graft survival at 1, 3, and 5 years after KT were 94.40%, 86.25%, and 74.92%, respectively. The only significant risk factor of graft failure in this study was delayed graft function (DGF) (adjusted HR=3.55; 95%CI: 1.14, 11.12; p=.029). Patient survival at 1, 3, and 5 years was 100%, 98.48%, and 96.19%, respectively. The short-term outcomes of pediatric KT from deceased donors were satisfactory; however, prevention of DGF would result in better outcomes.

Long-Term Safety, Clinical and Immunological Outcomes in Primary Membranous Nephropathy with Severe Renal Impairment Treated with Cyclophosphamide and Steroid-Based Regimen

Introduction and Aims: Therapy of primary membranous nephropathy (PMN) with progressive advanced kidney dysfunction is challenging with limited literature and no clear therapeutic strategies. This is due to the scant evidence of effectiveness and uncertainty around the risk-benefit profile of immunosuppression (ImS) when eGFR is less than 30 mL/min. We aimed to determine long-term clinical outcomes in patients with PMN and severe renal impairment treated with combined cyclophosphamide and steroids. Methods: The study is a single-center retrospective longitudinal cohort study. All patients (between 2004 and 2019) with biopsy confirmed PMN who initiated combination therapy with steroids and cyclophosphamide and had an eGFR of ≤30 mL/min/1.73 m² at the time of initiation of therapy were included for analysis. Clinical and laboratory parameters including anti-PLA₂R-Ab were monitored as per standard clinical guidance. Primary outcome was achievement of partial remission. Secondary outcomes included immunological remission, need for renal replacement therapy, and adverse effects. Results: Eighteen patients with median age of 68 (IQR 58–73) years and 5:1 M:F ratio received the combination therapy when eGFR was ≤30 mL/min/1.73 m² (CKD-EPI). At time of ImS, median eGFR and uPCR were 23 (IQR 18–27) mL/min/1.73 m² and 8.4 (IQR 6.9–10.7) g/g, respectively. Median follow-up was for 67 (IQR 27–80) months. 16 patients (89%) achieved partial remission and 7 (39%) achieved complete remission. eGFR increased by 7 mL/min/1.73 m² (27%) after 1 year of starting ImS treatment and 12 mL/min/1.73 m² at end of follow-up. Two patients (11%) developed end-stage renal disease needing renal replacement therapy. 67% achieved both immunological and clinical remission. At the end of the follow-up period, 2 (11%) patients required hospitalization secondary to infections, 4 (22%) patients developed cancer and 4 patients died (22%). Conclusion: Combination therapy with cyclophosphamide and steroids is effective in achieving partial remission and improving renal function in PMN with advanced renal dysfunction. Prospective controlled studies are required to provide further evidence to rationalize treatment and improve outcomes in such patients.

A systematic review and network meta-analysis of the safety of early interventional treatments in rheumatoid arthritis

ObjectivesTo evaluate the safety of treatment strategies in patients with early RA.MethodsSystematic searches of MEDLINE, EMBASE and PubMed were conducted up to September 2020. Double-blind randomized controlled trials (RCTs) of licensed treatments conducted on completely naïve or MTX-naïve RA patients were included. Long-term extension studies, post-hoc and pooled analyses and RCTs with no comparator arm were excluded. Serious adverse events, serious infections and non-serious adverse events were extracted from all RCTs, and event rates in intervention and comparator arms were compared using meta-analysis and network meta-analysis (NMA).ResultsFrom an initial search of 3423 studies, 20 were included, involving 9202 patients. From the meta-analysis, the pooled incidence rates per 1000 patient-years for serious adverse events were 69.8 (95% CI: 64.9, 74.8), serious infections 18.9 (95% CI: 16.2, 21.6) and non-serious adverse events 1048.2 (95% CI: 1027.5, 1068.9). NMA showed that serious adverse event rates were higher with biologic monotherapy than with MTX monotherapy, rate ratio 1.39 (95% CI: 1.12, 1.73). Biologic monotherapy rates were higher than those for MTX and steroid therapy, rate ratio 3.22 (95% CI: 1.47, 7.07). Biologic monotherapy had a higher adverse event rate than biologic combination therapy, rate ratio 1.26 (95% CI: 1.02, 1.54). NMA showed no significant difference between strategies with respect to serious infections and non-serious adverse events rates.ConclusionThe study revealed the different risk profiles for various early RA treatment strategies. Observed differences were overall small, and in contrast to the findings of established RA studies, steroid-based regimens did not emerge as more harmful.

New-onset diabetes after transplantation among renal transplant recipients at a new transplant center; King Fahad Specialist Hospital-Dammam, Saudi Arabia.

New-onset diabetes after transplant (NODAT) has been reported to occur in 4%-25% of renal transplant recipients. Its development has also been shown to be associated with an adverse impact on patient survival and an increased risk of graft rejection and graft loss, as well as an increased incidence of infectious complications. The study aims to describe the incidence of NODAT and its important risk factors in a single center. We conducted a retrospective analysis of data from all kidney transplant recipients in our center, transplanted between September 2008 and May 2013. Out of 311 patients, 77 had diabetes mellitus (DM) before transplantation and were excluded, leaving 234 patients as the study population. NODAT was diagnosed based on the WHO definition for DM: any two readings of fasting blood sugar >7 mmol/L or random blood sugar >11 or the use of hypoglycemic medications after 1st posttransplant month. The mean age of the study patients was 36 years ± 14 years; 55.5% were male, 69% had living-related transplant, 31% had deceased donor transplant, 98% were on tacrolimus-based immunosuppression regimen, 2% on cyclosporine and all patients were on the steroid-based regimen. The 1 and 5-year cumulative incidence of NODAT was 14.1% and 27.5%, respectively. The median duration to onset of NODAT was 2.5 months. The body mass index of >30 kg/m2 and age >60 years at the time of transplant were significantly associated with the occurrence of NODAT. Our finding of incidence was not different from what has been reported in the literature. Larger prospective and multicenter studies are needed.

Current Australasian practice for diagnosis and management of idiopathic pulmonary fibrosis: Where are we now?

Recent international consensus statements have refined evidence-based guidelines for the diagnosis and management of idiopathic pulmonary fibrosis (IPF). This study sought to investigate how closely these guidelines are adhered to and to compare current practices with those of a similar cohort 15 years ago. A questionnaire on IPF diagnosis and management was distributed to respiratory physicians practising in Australia and New Zealand, in 2012-2013, and results were compared with a similar survey conducted in 1999. A total of 172 and 144 questionnaires were completed in 1999 and 2012-2013, respectively. The most important investigations in both survey populations were high-resolution computed tomography scans, spirometry, diffusing capacity for carbon monoxide, chest X-ray, static lung volumes and autoimmune serology. In 1999, physicians were more likely to perform arterial blood gases, bronchoalveolar lavage and transbronchial lung biopsy. In the 2012-2013 cohort, 6-min walk tests and pulse oximetry were more widely utilized. Treatment choices differed considerably between the two survey populations. In 1999, the majority would offer a steroid-based regimen, whereas most would not use any specific treatment or would refer for trial participation in 2012-2013. Approach to IPF diagnosis and management is not uniform and has changed over 15 years. Surveyed respiratory physicians were generally practising in accordance with clinical guidelines, although significant variation in practice was identified in both cohorts. This study identifies the need to standardize care of IPF patients across Australia and New Zealand.

Still's Disease in a Pediatric Patient after Liver Transplantation

Still's disease (SD) is a multisystemic inflammatory disease characterized by persistent arthritis and in many cases with fever of unknown origin. Diagnosis of SD is challenging because of nonspecific characteristics and especially in the case of a patient with solid organ transplantation and immunosuppressive therapy where multiple causes of fever are possible. There is no diagnostic test for SD, even though some useful diagnostic criteria or laboratory findings, such as serum ferritin levels, have been proposed, and useful imaging studies for the diagnosis or followup of SD have not been developed. We report the case of a 9-year-old child who presented with high grade fever associated with joint pain after a history of liver transplantation and immunosuppressive therapy. Laboratory tests showed increased acute phase reactants, elevated ferritin, and leukocytosis. An 18 F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) was performed identifying abnormal hypermetabolic areas localized in spleen, transplanted liver, and bone marrow secondary to inflammatory process. All infectious, autoimmune, and malignant causes were ruled out. A diagnosis of SD was performed and a steroid-based regimen was initiated with adequate response and no evidence of recurrence. To our knowledge this is the first case of SD following a solid organ transplant.

Development and Validation of Limited Sampling Strategies for Tacrolimus and Mycophenolate in Steroid-Free Renal Transplant Regimens

1) To develop and validate limited sampling strategies (LSSs) for tacrolimus (TAC) and mycophenolic acid (MPA) in renal transplant recipients not receiving corticosteroids; and 2) to evaluate predictive performance of published LSSs (for steroid-based regimens) in a steroid-free population. On administration of steady-state morning TAC and mycophenolate mofetil doses, 12-hour serial blood samples from 28 stable renal transplant recipients were collected and measured by validated high-performance liquid chromatography methods and area under the curve (AUC) by trapezoidal rule. TAC LSSs were developed and validated by multiple regression analysis by a two-group method (index n = 18; validation n = 10) and MPA LSSs by the jackknife method (n = 28). Potential LSSs were those with r ≥ .8 (TAC) or r ≥ 0.7 (MPA) and < 3 time points within 2 hours (TAC) or 4 hours (MPA) postdose. Predictive performance was calculated and other published TAC and MPA LSSs tested using preset criteria for bias and precision of within ± 15%. For TAC, three three-concentration, one two-concentration, and one one-concentration model met preset criteria. The best equations were: TAC AUC = 10.338 + 7.739C0 + 3.589C2 (r = 0.956, bias = -3.4%, precision = 4.7%) and TAC AUC = 29.479 + 5.016C2 (r = 0.862, bias = 3.2%, precision = 9.7%). For MPA, only one model was identified: MPA AUC = 9.328 + 1.311C1 + 1.455C2 + 2.901C4 (r = 0.838, bias = -3.8%, precision = 14.9%). One published TAC (and no MPA) LSS in renal transplant recipients on steroid-based regimens met criteria. To the authors' knowledge, these LSSs are the first to be developed and validated in steroid-free renal transplant recipients and can be used to accurately predict TAC and MPA AUCs for steroid-free regimens. Because the commonly used MPA LSS is based on a steroid regimen and not predictive for steroid-free patients, the newly derived MPA LSS is being applied at the authors' institution. Other renal transplant centers may also wish to validate this equation in their own patients.

Steroid Refractoriness, but Not Rapidity of Response, to Induction Therapy Predicts for Outcome Post-Autologous Stem Cell Transplant (ASCT) in Patients (Pts) with Multiple Myeloma (MM)

Introduction: Goals of induction therapy in younger, newly diagnosed MM pts are to ameliorate symptoms, improve performance status, and initiate disease control enabling the move toward ASCT. It is controversial whether more intensive induction regimens which lead to greater depth or more rapid onset of response translate to improved survival outcomes post-transplant. As a result, conservative steroid-based regimens such as high-dose dexamethasone (HDD) or VAD are still frequently used as standard induction therapy despite response rates of only 50–60%. Patients who do not respond appropriately to these conservative regimens can typically be salvaged successfully with the addition of novel agents such as thalidomide and proceed to ASCT. This approach allows for efficient use of novel agents that in many parts of the world are not easily accessed for first-line use. To validate this approach, we performed a retrospective review of 183 MM patients who received conservative induction therapy (HDD, VAD) and correlated induction parameters (rapidity of response, use of salvage induction therapy) with transplant outcomes.Methods: 183 MM patients who received HDD or VAD induction prior to proceeding to ASCT over a 7 year period (Feb 2000–Oct 2006) were reviewed. No pts received tandem transplants. HDD (40mg daily PO days 1–4, 9–12, 17–20 on a 28 day cycle) was used in 42 pts (33%) and VAD (vincristine, adriamycin, HDD) in 141 pts (77%). At our institution, a 50% or greater decrease in the monoclonal protein (PR) with induction therapy is targeted in order to proceed to transplant.Results: Median age for all 183 pts at time of transplant was 59 years (33–75); 60% male; 174 pts (95%) Salmon-Durie stage II–III. MM subtypes included: IgG 132(72%), IgA 39(21%), light chains only 7(4%). Median hemoglobin at diagnosis was 104 g/L, serum creatinine 89μmol/L, β2-microglobulin 248 nmol/L (normal <200) and albumin 35 g/L. Response to induction therapy was assessed with each cycle to evaluate the rapidity of response. Response (PR or CR) by cycle: cycle 1 – 65 pts (35.5%), cycle 2 – 33 pts (18%), cycle 3 – 28 pts (15.3%), cycle 4 – 17 pts (9.3%) and over 4 cycles – 40 pts (22%). Half of the pts (98 pts; 54%) achieved at least a PR by cycle 2 (early responders) with 46% of pts responding after 2 cycles (late responders). Rapidity of induction response did not translate into a significant difference in post-transplant PFS (median PFS from transplant 20.7 vs 20.0 mos for early vs. late responders, P=0.56; median OS from transplant: 64.4 vs. 51.3 mos respectively, P=0.37). 46 pts (25%) failed their first induction regimen: primary nonresponders in 33 pts (18%); responsive but progressed before ASCT in 13 pts (7%). However, all responded subsequently to a salvage induction regimen (most commonly VAD, thalidomide+HDD, cyclophosphamide+prednisone) and proceeded to ASCT. Pts requiring salvage induction had inferior survival outcomes post-transplant compared to pts requiring only one induction regimen: median PFS from transplant 16.3 vs. 21.8 mos, P=0.02; median OS from transplant 46.2 vs. 69.4 mos, P=0.0005. Pts requiring more than one induction regimen had delayed time from induction to ASCT (9.4 vs 6.7 mos; p=0.01). Median follow-up from ASCT was 33 mos. For all pts, the median PFS was 20.3 mos (95% CI: 17.0–24.4); median OS was 63.9 mos (95% CI: 50.3–90.5) from transplant. Pts requiring more than one induction regimen had significantly lower serum albumin levels than those responding to first induction, but no other differences in baseline prognostic factors were identified (Salmon-Durie stage, serum creatinine, B2-microglobulin, LDH, presence of cytopenias).Conclusions: Early response to dexamethasone-based induction therapy does not correlate with PFS or OS post-ASCT.Patients who fail initial dexamethasone-based induction therapy have worse post-transplant outcomes than initial responders, despite ultimately achieving a successful response pre-transplant. Whether the poor outcomes are due to delayed time to transplant, identification of biologically aggressive disease or intrinsic “steroid-refractoriness” remain to be clarified.Our data support the use of novel induction regimens able to achieve high response rates in order to avoid the need for salvage induction before proceeding to transplant.

Beneficial Outcomes of a Steroid-Free Regimen With Thymoglobulin Induction in Pancreas-Kidney Transplantation

Backgound Steroid-free immunosuppressive regimens are becoming more common in pancreas transplantation, with persistent concerns regarding its safety and efficacy. Methods We performed a retrospective chart review of 87 pancreas transplant recipients—22 simultaneous pancreas-kidney transplants, 48 pancreas-after-kidney transplants, and 17 pancreas transplant alone—who underwent transplantation within the period of January 2000 to November 2006 and who received induction therapy with thymoglobulin followed by maintenance immunosuppression with tacrolimus and mycophenolate mofetil. We compared one group on a steroid-free regimen ( n = 25) with another on a steroid-based regimen ( n = 62). Results At 6 months, there was no kidney graft loss and no significant difference between groups (steroid-free vs steroid-based groups) in patient survival (100% vs 96.8%), pancreas graft survival (96.0% vs 93.5%), acute rejection (4.0% vs 11.3%), hospitalization for any cause (60.0% vs 51.6%), infection requiring hospitalization (16.0% vs 32.3%), or incidence of BK viremia (0% vs 3.2%). CMV viremia occurred less in the steroid-free group (0% vs 17.7% in the steroid-based group, P = .024). The estimated glomerular filtration rate (eGFR) at 6 months was higher in the steroid-free group (74.8 vs 55.7 mL/min/1.73 m 2 in the steroid-based group, P = .001), with fewer occurrences of a 25% decline in eGFR (33.3% among the steroid-free group vs 61.7% among steroid-based group, P = .019), despite similar average tacrolimus exposure (11.7 ± 3.7 vs 12.2 ± 2.7 ng/dL, P = .478). Conclusions A steroid-free regimen with thymoglobulin induction followed by tacrolimus and mycophenolate mofetil for maintenance in pancreas transplantation was safe and effective in preventing rejection, with reduced incidence of CMV infection and better-preserved kidney function.

Recent Trends and Results for Organ Donation and Transplantation in the United States, 2005

Recent Trends and Results for Organ Donation and Transplantation in the United States, 2005

Pilot Study of Rapid Steroid Elimination With Alemtuzumab Induction Therapy in Kidney and Pancreas Transplantation

This study evaluates our initial experience using alemtuzumab induction with rapid corticosteroid elimination in kidney (KTX) and pancreas transplant (PTX) patients. Data were collected retrospectively for all patients who received single-dose alemtuzumab (30 mg IV intraoperatively) with steroid pretreatment and a control group who received alternate day rabbit antithymocyte globulin (rATG) induction with a steroid-based regimen. Patients in both groups received tacrolimus (TAC) and mycophenolate mofetil (MMF). There were 16 patients in each group, including 9 deceased donor KTXs, 5 living donor KTXs, 1 simultaneous K-PTX, and 1 sequential PTX after KTX. Demographic, immunologic, and transplant characteristics were similar between groups. Nine patients (56%) in the alemtuzumab group compared to five (25%) in the control group developed neutropenia requiring MMF or valganciclovir dose reduction (or both). Absolute lymphocyte counts at 3 months were 340 ± 200/mm 3 and 890 ± 544/ mm 3 in the alemtuzumab and control groups, respectively ( P = .001). There were two biopsy-proven acute rejection episodes (12.5%) in each group, and no difference in the incidence of infection. Creatinine clearance at 6 months was 58 mL/min in each group. Patient and kidney graft survival rates were both 94% in the alemtuzumab group (one death from cardiac arrest), compared with 100% patient and kidney graft survival rates in the control group ( P = NS), with a mean follow-up of 9 and 11 months, respectively. The results of this pilot study suggest that similar short-term outcomes can be achieved using a rapid steroid elimination protocol with alemtuzumab induction therapy compared to rATG with steroids in patients receiving TAC and MMF maintenance therapy.

Increased expression of cytotoxic effector molecules: different interpretations for steroid-based and steroid-free immunosuppression.

Cytotoxic T lymphocyte (CTL) effector molecules have been studied as markers of acute rejection in renal allograft recipients on steroid-based immunosuppression. We hypothesized that basal CTL gene expression may vary with time post-transplantation as well as with different immunosuppression protocols (steroid-based or steroid-free). Variations in CTL gene expression may thus impact on the ability to predict acute allograft rejection. We used the non-invasive method of quantitative competitive-reverse transcription-polymerase chain reaction (QC-RT-PCR) to quantify the amounts of CTL effector molecules (granulysin, GL; perforin, P; granzyme B, GB) in serial peripheral blood lymphocyte (PBL) samples from steroid-free and steroid-based adult and pediatric renal allograft recipients. Patients on both protocols were clinically monitored by protocol biopsies at 1, 3, 6, and 12 months post-transplantation and for graft function at 1 yr post-transplantation in a separate clinical study. Steroid-free patients with stable graft function showed an increase in GL, P, and GB gene expression over time post-transplantation with the increase being seen largely by the first post-transplant month. A further increase in GL expression was noted at the end of the first post-transplant year in the absence of acute rejection, whereas GB and P levels were unchanged. At comparative time-points post-transplantation, CTL genes were found to be higher in steroid-free patients with stable graft function, compared to steroid-based recipients with either clinically stable graft function or acute rejection. This study suggests that levels of CTL gene expression, although important in a steroid-based regimen to monitor the risk of acute rejection, may not be similarly applied in patients on steroid-free immunosuppression. The early increase in levels seen in steroid-free patients appears to correlate with the total absence of steroids. As steroid-free patients seem to have a lower incidence of acute rejection and better long-term graft function at 1 yr, the early increase in CTL genes in the absence of acute rejection may suggest an early adaptive immune activation response, promoting early graft acceptance in this protocol.