Long‐term dosing patterns of enteric‐coated mycophenolate sodium or mycophenolate mofetil with tacrolimus after renal transplantation

MORE was a four‐yr, prospective, observational study at 40 transplant centers in the US. Data were analyzed to evaluate changes in mycophenolic acid (MPA) dosing over time in 904 de novo kidney transplant recipients receiving enteric‐coated mycophenolate sodium (EC‐MPS, n = 616) or mycophenolate mofetil (MMF, n = 288) with tacrolimus. Induction therapy and steroid treatment were similar in the two subpopulations. The proportion of patients receiving the maximal recommended MPA dose was 80.5%, 43.9%, 39.2%, 34.6%, and 30.1% at baseline and years 1, 2, 3, and 4, respectively. More patients received the maximal recommended MPA dose with EC‐MPS vs. MMF at month 1 (79.2% vs. 71.7%, p = 0.016), month 3 (68.5% vs. 56.9%, p = 0.001), and month 6 (52.9% vs. 44.0%, p = 0.028). Multivariate analysis showed the risk of biopsy‐proven acute rejection, graft loss or death to be similar for EC‐MPS vs. MMF. Estimated glomerular filtration rate (GFR) was similar with EC‐MPS vs. MMF at all time points. There were no significant differences in any category of adverse event between the EC‐MPS and MMF cohorts during follow‐up, including gastrointestinal events. In conclusion, MPA dose was maintained more effectively in the first six months after kidney transplantation using EC‐MPS vs. MMF, without an increase in adverse events.     

Long‐term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four‐yr analysis of the Mycophenolic acid Observational REnal transplant (MORE) study

Mycophenolic acid Observational REnal transplant (MORE) was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA). Four‐yr data on 904 patients receiving tacrolimus and enteric‐coated mycophenolate sodium (EC‐MPS) or mycophenolate mofetil (MMF) were analyzed to evaluate immunosuppression and graft outcomes in African American (AA, n = 218) vs. non‐AA (n = 686) patients. Mean tacrolimus dose was higher in AA vs. non‐AA patients but mean tacrolimus trough concentration was similar. Use of the recommended MPA dose in AA patients decreased from 78.9% at baseline to 33.1% at year 3. More AA patients received the recommended MPA dose with EC‐MPS than MMF at month 6 (56.2% vs. 35.7%, p = 0.016) and month 36 (46.6% vs. 16.7%, p = 0.029), with no safety penalty. Significantly, more AA patients received corticosteroids than non‐AA patients. Biopsy‐proven acute rejection was higher in AA vs. non‐AA patients (18.9% vs. 10.7%, p = 0.003), as was graft loss (10.9% vs. 4.4%, p = 0.003); differences were confirmed by Cox regression analysis. Patient survival was similar. Estimated GFR was comparable in AA vs. non‐AA patients. Kidney allograft survival remains lower for AA vs. non‐AA recipients even under the current standard of care.     

Everolimus with low‐dose tacrolimus in simultaneous pancreas and kidney transplantation

The efficacy and safety of everolimus (EVR) in simultaneous pancreas and kidney transplantation (SPKT) is unclear. We retrospectively evaluated 25 consecutive SPKT recipients at our center from November 2011 to March 2013. All patients received dual induction (Thymoglobulin/basiliximab) and low‐dose tacrolimus plus corticosteroids. Nine patients who received EVR were compared with 14 patients who received enteric‐coated mycophenolate sodium (EC‐MPS); two patients who received sirolimus were excluded from the analysis. With a median follow‐up of 14 months, the pancreas graft survival rate was 100% in both groups, and the kidney graft survival rate was 100% and 93% in EVR and EC‐MPS patients, respectively. One EC‐MPS patient lost her kidney graft from proteinuric kidney disease. Another EC‐MPS patient received treatment for clinically diagnosed pancreas and kidney graft rejection. No rejection was observed in EVR patients. Serum creatinine and HbA1c levels were similar between the groups. There was no significant difference of surgical or medical complications. In conclusion, EVR seems to provide comparable short‐term outcome to EC‐MPS when combined with low‐dose tacrolimus/steroids and dual induction therapy. A larger study with a longer follow‐up is required to further assess this combination.     

Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses

This study compared the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate and no CMV pharmacological prophylaxis. We randomized 288 patients to receive a single 3 mg/kg dose of antithymocyte globulin, tacrolimus, everolimus, and prednisone (r‐ATG/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (BAS/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (BAS/MPS, n = 101). The primary end‐point was the incidence of first CMV infection/disease in the intention‐to‐treat population at 12 months. Patients treated with r‐ATG/EVR showed a 90% proportional reduction (4.7% vs. 37.6%, HR 0.10, 95% CI 0.037–0.29; p < 0.001), while those treated with BAS/EVR showed a 75% proportional reduction (10.8% vs. 37.6%, HR 0.25, 95% CI 0.13–0.48; p < 0.001) in the incidence of CMV infection/disease compared to BAS/MPS. There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 15.8%, p = 0.403), wound‐healing complications, delayed graft function, and proteinuria. Mean estimated glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p = 0.021). In de novo kidney transplant recipients receiving no pharmacological CMV prophylaxis, reduced‐dose tacrolimus and everolimus was associated with a significant reduction in the incidence of CMV infection/disease compared to standard tacrolimus dose and mycophenolate ( ClinicalTrials.gov NCT01354301).     

Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients

Tedesco‐Silva H, Felipe CR, Park SI, Pinheiro‐Machado PG, Garcia R, Slade A, Schmouder R, Medina‐Pestana JO. Randomized crossover study to assess the inter‐ and intrasubject variability of morning mycophenolic acid concentrations from enteric‐coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients.
Clin Transplant 2010: 24: E116–E123.
© 2009 John Wiley & Sons A/S. Abstract: The delayed release of mycophenolic acid (MPA) from enteric‐coated mycophenolate sodium (EC‐MPS, myfortic^®) may have an impact on the variability of MPA trough (C_{0 h}) levels. A randomized, two‐period crossover study was performed in 24 maintenance renal transplants to evaluate the inter‐ and intrasubject variability of MPA predose levels from EC‐MPS and mycophenolate mofetil (MMF, CellCept^®), both in combination with cyclosporine. Patients received EC‐MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at ?1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1–80.3) and 54.4% (40.0–86.8) for EC‐MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1–72.9) and 42.8% (37.9–49.2). High MPA C_{0 h} levels >10 μg/mL were rarely observed with both EC‐MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)_{0–3 h} was comparable between treatments, while MPA C_{0 h} was on average 46% higher with EC‐MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC‐MPS and MMF therapy given the large intrasubject variability in MPA C_{0 h} levels with both treatments.     

Four-year experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies

van Hooff JP, Alloway RR, Trune?ka P, Mourad M. Four‐year experience with tacrolimus once‐daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies.
Clin Transplant 2011: 25: E1–E12. © 2010 John Wiley & Sons A/S. Abstract: Introduction: This study assessed the long‐term effects of prolonged‐release tacrolimus (Advagraf^® [Tacrolimus QD]), which has been developed to provide similar efficacy and safety to twice‐daily tacrolimus (Prograf^® [Tacrolimus BID]) with the added benefit of once‐daily dosing. Methods: Adult participants from four phase II de novo (kidney, liver) or Tacrolimus BID to QD conversion (kidney, heart) studies were enrolled into the follow‐up study. Patients remained on the immunosuppressive regimen they were receiving on entry, unless medical needs required otherwise. The primary endpoint was patient and graft survival, and secondary endpoints were biopsy‐confirmed acute rejection (BPAR) and safety. Results: The full analysis set comprised 240 patients. Tacrolimus mean total daily dose and whole‐blood trough levels decreased over time, particularly in de novo patients. At four yr, Kaplan–Meier estimates of patient and graft survival were over 90%. Freedom from BPAR was 90.9/92.6% and 100/87.0% in the de novo kidney/liver and conversion kidney/heart patients, respectively. There were 13 deaths, and 20% patients withdrew from the study, mainly because of adverse events. Conclusions: The efficacy and safety of Tacrolimus QD was maintained for four yr in kidney, liver, and heart transplant recipients. Therefore, this formulation offers a convenient alternative to Tacrolimus BID.     

Fibrosis Progression According to Epithelial‐Mesenchymal Transition Profile: A Randomized Trial of Everolimus Versus CsA

Markers of epithelial‐mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open‐label, 12‐month trial, de novo kidney transplant patients received cyclosporine, enteric‐coated mycophenolate sodium (EC‐MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT? based on month 3 biopsy, then randomized to start everolimus with half‐dose EC‐MPS (720 mg/day) and cyclosporine withdrawal (CNI‐free) or continue cyclosporine with standard EC‐MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3–12) in EMT+ patients. 194 patients were randomized (96 CNI‐free, 98 CNI); 153 (69 CNI‐free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI‐free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy‐proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI‐free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI‐free protocol, in which everolimus exposure was relatively low and administered with half‐dose EC‐MPS, CNI‐free patients were overwhelmingly under‐immunosuppressed and experienced an increased risk of BPAR.

     

Eight‐year results of the Spiesser study,a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation

We present the results at 8 years of the Spiesser study, a randomized trial comparing de novo sirolimus and cyclosporine in kidney transplant recipients at low immunologic risk. We assessed estimated glomerular filtration (eGFR), graft, patient, and death‐censored graft survival (log‐rank compared), de novo DSA appearance, risk of malignancy, post‐transplant diabetes mellitus (PTDM), and anemia. Intent‐to‐treat and on‐treatment analyses were performed. Graft survival was similar in both groups (sirolimus: 73.3%, cyclosporine: 77.7, P = 0.574). No difference was observed between treatment groups concerning patient survival (P = 0.508) and death‐censored graft survival (P = 0.858). In conditional intent‐to‐treat analysis, mean eGFR was greater in sirolimus than in cyclosporine group (62.5 ± 27.3 ml/min vs. 47.8 ± 17.1 ml/min, P = 0.004), in particular because graft function was excellent in patients maintained under sirolimus (eGFR = 74.0 ml/min). Importantly, no detrimental impact was observed in patients in whom sirolimus has been withdrawn (eGFR = 49.5 ml/min). Overall, 17 patients showed de novo DSAs, with no difference between the two groups (P = 0.520). Malignancy did not differ by treatment. An initial maintenance regimen based on sirolimus provides a long‐term improvement in renal function for kidney transplant patients, especially for those maintained on sirolimus.     

Gastrointestinal side effects in liver transplant recipients taking enteric‐coated mycophenolate sodium vs. mycophenolate mofetil

In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric‐coated mycophenolate sodium (EC‐MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC‐MPS to MMF in liver transplant patients in a de novo study (Study I—randomized, prospective, double‐blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC‐MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC‐MPS instead of MMF.     

De Novo Donor‐Specific HLA Antibodies Are Associated With Rapid Loss of Graft Function Following Islet Transplantation in Type 1 Diabetes

Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor‐specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed‐meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1–3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post–first transplant; two post–second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C‐peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300–1090); DSA positive 106(34–235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03).     

De novo membranous nephropathy and antibody‐mediated rejection in transplanted kidney

Honda K, Horita S, Toki D, Taneda S, Nitta K, Hattori M, Tanabe K, Teraoka S, Oda H, Yamaguchi Y. De novo membranous nephropathy and antibody‐mediated rejection in transplanted kidney.
Clin Transplant 2011: 25: 191–200. © 2010 John Wiley & Sons A/S. Abstract: Background: The etiology of de novo membranous nephropathy (MN) after kidney transplantation is still uncertain. Immunological response to various allograft antigens is speculated to be a candidate for the etiology. Methods: Seventeen patients with post‐transplant de novo MN were studied clinically and pathologically in comparison with control post‐transplant patients without MN. Double immunofluorescent staining was performed to identify the presence of donor‐specific human leukocyte antigen (HLA) combined with IgG in the deposits on glomerular capillary walls. Results: De novo MN occurs in relatively late period after transplantation (102.1 ± 68.3 months), presenting various degree of proteinuria. Histological findings associated with antibody‐mediated rejection (AMR), such as peritubular capillaritis and C4d deposition in peritubular capillary, were more frequently observed in the patients with de novo MN than the non‐MN control patients. Donor‐specific antibody (DSA) was detected in five patients at the time of biopsy. In one case of de novo MN with DSA, a donor‐derived HLA was identified in the subepithelial deposits on the glomerular capillary walls combined with IgG deposition. Conclusions: DSA and AMR might play some roles for the pathogenesis in some patients with de novo MN after kidney transplantation.     

Experience with belatacept rescue therapy in kidney transplant recipients

In kidney transplant recipients with chronic graft dysfunction, long‐term immunosuppression with calcineurin inhibitors (CNIs) or mTOR inhibitors (mTORi) can be challenging due to adverse effects, such as nephrotoxicity and proteinuria. Seventy‐nine kidney transplant recipients treated with CNI‐based or mTORi‐based maintenance immunosuppression who had CNI‐induced nephrotoxicity or severe adverse events were switched to belatacept. Mean time from transplantation to belatacept conversion was 69.0 months. Mean estimated glomerular filtration rate (eGFR) ± standard deviation at baseline was 26.1 ± 15.0 ml/min/1.73 m², increasing to 34.0 ± 15.2 ml/min/1.73 m² at 12 months postconversion (P < 0.0005). Renal function improvements were also seen in patients with low eGFR (<25 ml/min/1.73 m²) or high proteinuria (>500 mg/l) at conversion. The Kaplan–Meier estimates for patient and graft survival at 12 months were 95.0% and 85.6%, respectively. The discontinuation rate due to adverse events was 7.9%. One case of post‐transplant lymphoproliferative disorder occurred at 17 months postconversion. For comparison, a historical control group of 41 patients converted to mTORi‐based immunosuppression because of biopsy‐confirmed CNI‐induced toxicity was examined; eGFR increased from 27.6 ± 7.2 ml/min/1.73 m² at baseline to 31.1 ± 11.9 ml/min/1.73 m² at 12 months (P = 0.018). Belatacept‐based immunosuppression may be an alternative regimen for kidney transplant recipients with CNI‐ or mTORi‐induced toxicity.     

A single center's clinical experience with quadruple immunosuppression including ATG or IL2 antibodies and mycophenolate mofetil in simultaneous pancreas–kidney transplants

Acute rejection remains a major problem in simultaneous pancreas–kidney (SPK) transplant and occurs in 60–100% of the cases.
With the introduction of mycophenolate mofetil (MMF) replacing azathioprine (AZA) as a basis immunosuppressant, reduced rates of rejection have been reported. This study investigates the frequency and clinical relevance of allograft rejection in SPK patients receiving anti‐thymocyte globulin (ATG) or Basiliximab® induction therapy and cyclosporine Neoral® (CyA), MMF, steroid basis immunosuppression.
Between December 1996 and October 1999, 21 consecutive patients (15 males, 6 females) received a SPK transplant at our institution with a mean±standard deviation (SD) age of 42±6 yr. Of these, 14 patients were treated with anti‐thymocyte globulin (ATG) Fresenius® (rabbit) 3–5 mg/kg for 6±2 d, cyclosporine Neoral (CyA) (trough levels 350–400 ng/mL), MMF 3 g/d and low dose steroid therapy. Seven SPK patients were treated with Basiliximab (Simulect®, Novartis 20 mg on d 0 and d 4 post‐transplant) instead of ATG. The patients had an average human leucocyte antigen (HLA) mismatch of 3.9/6 and a negative cross match. All patients remained on triple drug therapy. Three patients were switched to tacrolimus instead of Neoral for CyA intolerance. The mean±SD cold ischemia time (CIT) of the organs was 10.1±2.4 h for the pancreas and 10.5±2.6 h for the kidney.
Results: Biopsy‐proven rejection occurred in the kidney of 1 ATG patient (8%), which responded to steroid bolus therapy. One of the patients (14%) with Basiliximab induction developed renal allograft rejection, which was resolved after a 6‐d course of anti‐CD3 mAb (OKT3) treatment. All patients (100%) were free from rejection in the pancreas, as measured by urine amylase levels and glycemic control without the need for exogenous insulin with a mean glycosylated hemoglobin (HBA₁C) of 5.1±0.7% and serum creatinine with a mean of 1.24±0.24 mg/dL in a mean follow‐up period of 17±15 months (median 12, range 2–37).
Conclusion: Triple drug immunosuppression including cyclosporine, MMF and low dose steroids with ATG or interleukin 2 (IL2) receptor antibodies induction therapy appears to be a very suitable immunosuppressive regimen for combined pancreas–kidney transplant (PKT) with a marked reduction in the incidence of rejection.     

Impact of de novo donor‐specific anti‐HLA antibodies on grafts outcomes in simultaneous pancreas–kidney transplantation

De novo donor‐specific antibodies (dDSA) relevance in simultaneous pancreas–kidney (SPK) transplantation has been scarcely investigated. We analyzed dDSA relationship with grafts outcomes in a long‐term follow‐up SPK‐transplanted cohort. In 150 patients that received SPK transplant between 2000 and 2013, post‐transplant anti‐human leukocyte antigen (HLA) antibodies were screened and identified using Luminex‐based assays in sera collected at 3, 6, and 12 months, then yearly. dDSA were detected in 22 (14.7%) patients at a median 3.1 years after transplant. Pretransplant anti‐HLA sensitization (OR = 4.64), full HLA‐DR mismatch (OR = 4.38), and previous acute cellular rejection (OR = 9.45) were significant risk factors for dDSA. dDSA were significantly associated with kidney (in association with acute rejection) and pancreas graft failure. In dDSA+ patients, those with at least one graft failure presented more frequently dDSA against class II or I + II (P = 0.011) and locusDQ (P = 0.043) and had a higher median dDSA number (P = 0.014) and strength (P = 0.030). Median time between dDSA emergence and pancreas and kidney graft failure was 5 and 12 months, respectively. Emergence of dDSA increased the risk of grafts failure in SPK‐transplanted patients. Full HLA‐DR mismatch was associated with dDSA emergence. dDSA characteristics might help identify patients at a higher risk of graft failure.     

Everolimus Versus Mycophenolate Mofetil in Heart Transplantation: A Randomized,Multicenter Trial

In an open‐label, 24‐month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced‐dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard‐dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12‐month composite incidence of biopsy‐proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow‐up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: –7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24‐month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12‐month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced‐dose cyclosporine offers similar efficacy to MMF with standard‐dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.     

The Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Recipients: One‐Year Results of a Scandinavian Randomized Trial

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12‐month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7–11 weeks after HTx or standard cyclosporine immunosuppression. Ninety‐five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm³ and 13.8 ± 28.0 mm³ [all p‐values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor‐1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus‐based CNI‐free can potentially be considered in suitable de novo HTx recipients.     

DQ molecules are the principal stimulators of de novo donor‐specific antibodies in nonsensitized pediatric recipients receiving a first kidney transplant

Data on the different HLA‐antibody (Ab) categories in pediatric kidney recipients developing de novo donor‐specific Abs (DSA) after transplantation are scarce. We retrospectively evaluated 82 consecutive nonsensitized pediatric recipients of a first kidney graft for de novo HLA Ab occurrence and antigen specificity. At a median follow‐up of 6 years, 29% of patients developed de novo DSA, while 45% had de novo non‐DSA. DSA appeared at 25‐month median time post‐transplant and were mostly directed toward HLA‐DQ antigens. Considering each HLA antigen, the estimated rate of DQ DSA (7.55 per 100 person‐years) was much higher than the rates observed for non‐DQ DSA. The HLA‐DQ Ab recognized determinants of the DQβ chain in 70% of cases, α chain in 25% of cases, and both chains in one patient. Non‐DSA peaked earlier than DSA, and were largely directed against HLA class I specificities that belonged to HLA‐A‐ and HLA‐B‐related cross‐reacting epitope groups (CREG) in 56% of cases. Our results indicate a need for evaluating HLA‐DQ compatibilities in kidney allocation, in order to minimize post‐transplant development of de novo DSA, known to be responsible for antibody‐mediated rejection and graft loss.     

Genetic Variation in Caveolin‐1 Correlates With Long‐Term Pancreas Transplant Function

Pancreas transplantation is a successful treatment for a selected group of people with type 1 diabetes. Continued insulin production can decrease over time and identifying predictors of long‐term graft function is key to improving survival. The aim of this study was to screen subjects for variation in the Caveolin‐1 gene (Cav1), previously shown to correlate with long‐term kidney transplant function. We genotyped 435 pancreas transplant donors and 431 recipients who had undergone pancreas transplantation at the Oxford Transplant Centre, UK, for all known common variation in Cav1. Death‐censored cumulative events were analyzed using Kaplan–Meier and Cox regression. Unlike kidney transplantation, the rs4730751 variant in our pancreas donors or transplant recipients did not correlate with long‐term graft function (p = 0.331–0.905). Presence of rs3801995 TT genotype (p = 0.009) and rs9920 CC/CT genotype (p = 0.010) in our donors did however correlate with reduced long‐term graft survival. Multivariate Cox regression (adjusted for donor and recipient transplant factors) confirmed the association of rs3801995 (p = 0.009, HR = 1.83;[95% CI = 1.16–2.89]) and rs9920 (p = 0.037, HR = 1.63; [95% CI = 1.03–2.73]) with long‐term graft function. This is the first study to provide evidence that donor Cav1 genotype correlates with long‐term pancreas graft function. Screening Cav1 in other datasets is required to confirm these pilot results.     

Transplantation with pancreas after living donor kidney vs. living donor kidney alone in type 1 diabetes mellitus recipients*

Sampaio MS, Poommipanit N, Cho YW, Shah T, Bunnapradist S. Transplantation with pancreas after living donor kidney vs. living donor kidney alone in type 1 diabetes mellitus recipients.
Clin Transplant 2010: 24: 812–820. © 2009 John Wiley & Sons A/S. Abstract: Living donor kidney transplantation (LDKT) in type 1 diabetic recipients (T1DM) may be followed by a pancreas after living donor kidney (PALK). The impact of the PALK is largely unknown. Adult T1DM living donor kidney recipients (1997–2007) listed for pancreas transplantation were divided into those who subsequently received pancreas transplantation and those who did not (living donor kidney transplant alone [LDKA]). Outcomes were compared. A sub‐analysis was performed in recipients with at least one yr of kidney graft survival and limiting PALK to those who underwent pancreas transplantation in the first year. Of 4554 recipients, 23% received PALK. PALK had more favorable baseline characteristics. At the end of eight yr, we found significantly superior patient (85% vs. 75%) and kidney graft survival (75% vs. 62%) in PALK group. The adjusted hazard ratios of PALK (LDKA as reference) were 0.65 (95%CI: 0.52–0.81) for death and 0.63 (0.54–0.76) for renal graft loss. In sub‐group analysis, there was a trend toward decreased death in PALK (HR = 0.78: 0.57–1.07). In conclusion, only 23% of those wait‐listed received a pancreas with patient and kidney survival superior to LDKA. Pancreas transplant in the first year after kidney transplant was associated with a trend toward better long‐term patient survival.     

De Novo Donor‐Specific HLA Antibodies Decrease Patient and Graft Survival in Liver Transplant Recipients

The role of de novo donor‐specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre‐ and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1‐year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.