Biopsy-proven Acute Rejection Episodes Research Articles

Mizoribine Versus Mycophenolate Mofetil in Combination Therapy With Tacrolimus for De Novo Kidney Transplantation: Evaluation of Efficacy and Safety

The present study compared the efficacy and safety of mizoribine (MZR) with mycophenolate mofetil (MMF) in kidney transplantation. This multicenter, randomized clinical trial. Employed doses of study drug tailored to the immunosuppressive need. The primary efficacy outcome was the incidence of biopsy-proven acute rejection episodes (BPAR). The safety of the study drug was assessed using the incidences of adverse events, drug discontinuations, and abnormal laboratory results. The 7 (6.4%) BPARs above grade II were observed in the MZR group noninferior to the 2 (1.8%) in the MMF group (95% confidence interval, −0.007–0.097 > noninferiority limit [−0.2]). BPAR was significantly decreased in the MZR group after the dose change (17/41 [41.4%] vs 8/69 [11.6%]; P < .0001) and the incidence of BPAR was similar between the MZR and MMF groups after the dose change (P = .592). The uric acid level was significantly elevated in the MZR group (P = .002). In conclusion, the efficacy and safety of MZR were similar and statistically noninferior to MMF in combination therapy with tacrolimus.

Serum Level of Soluble Fibrinogen-Like Protein 2 in Renal Allograft Recipients With Acute Rejection: A Preliminary Study

BackgroundSoluble fibrinogen-like protein 2 (sfgl2), which is mainly secreted by T cells, is a novel effector of regulatory T cells with immunosuppressive functions. The aim of this study was to investigate serum levels of sfgl2 among renal allograft recipients. MethodsFrom November 2010 to August 2011 we retrospectively divided 47 renal allograft recipients into an acute rejection (n = 19) versus a stable group (n = 28) according to allograft biopsy results, using the Banff 2007 classification. The acute rejection group was subdivided into grade I (n = 8) versus grade II T-cell–mediated (n = 6) or antibody-mediated rejection episodes (n = 5). Peripheral blood samples were collected at the time of biopsy. Fourteen healthy volunteers were included as normal group controls. Serum levels of sfgl2 were analyzed by enzyme-linked immunosorbent assay. ResultsSerum levels of sfgl2 were increased among renal allograft recipients suffering from biopsy-proven acute rejection episodes (61.91 ± 45.68 ng/mL), versus those with stable allografts (38.59 ± 19.92 ng/mL, P < .05) or healthy volunteers (29.10 ± 18.08 ng/mL, P < .05). The sfgl2 level was significantly higher among patients with antibody-mediated (118.48 ± 55.54 ng/mL) than T-cell–mediated acute rejection episodes (41.71 ± 16.44 ng/mL, P < .01). Serum sfgl2 levels were remarkably elevated in patients with grade II (51.87 ± 19.13 ng/mL) versus grade I T-cell–mediated rejection (34.10 ± 9.26 ng/mL, P < .05). ConclusionsSerum sfgl2 levels were increased among renal allograft recipients with acute rejection episodes to an extent dependent upon the pathological type and severity of the response.

The Effect of Acute Rejection Episodes According to Banff 2009 on Long-Term Outcome of Patients after Kidney Transplantation

Background: The effect of the most recent Banff-09 classification on graft outcomes is not well described. We undertook a retrospective analysis to determine whether the time and severity of acute transplant rejection according to the Banff-09 classification are risk factors of long-term allograft survival. Methods: 409 adult patients (pts) with at least 1 episode of biopsy proven acute rejection (BPAR) were enrolled in this study. All pts received kidney transplantation (Tx) in our centre between 01.01.1996 and 31.12.2010. In retrospect all biopsies were reclassified by the most recent Banff 2009 criteria. Only the highest BPAR was documented for each recipient with more than one BPAR. All pts were divided into two groups according to the time of first BPAR episode: group early (≤12 months post Tx) vs. late, (>12 months post Tx). Graft survival and death-censored graft survival (recipient survival) analysis were performed using the Kaplan-Meier method. Results: Eight-year allograft survival and recipient survival differed significantly (p< 0.005) between early and late rejections: it was 79.9% and 84.2% in the early group vs 54.7%, 82.1% in the late group, respectively. Similarly we observed significant differences of graft survival between early and late groups for pts with borderline changes (95.3% vs 66.6%), interstitial rejection (78.0% vs 50.0%), and vascular rejection (67.2% vs 33.3%). Recipient survival was statistically different between early and late groups for patients with borderline changes (92.4% vs 87.2%), and vascular rejection (82.4% vs 66.7%). Regarding to the severity of BPAR, there were significant differences (p< 0,001) among the eight-year graft survival (borderline 84.2% vs. grade I 70.7% grade II 62.0%) and recipient survival (borderline 90.6% vs. grade I vs 84.4% grade II 80.0%). Recipients with borderline changes had similar graft and recipient survival with pts having grade IA rejection, but had better long-term graft and recipient survival than pts with grade IB and vascular rejection. Graft and recipient survival were similar between pts with interstitial rejection and vascular rejection but pts with IA rejection had higher recipient survival than IB rejection, and pts with IIA rejection had higher graft survival than IIB rejection. Conclusions: Late occurrence of acute rejection results in inferior allograft and patient survival. In addition, more severe rejections according to the most recent Banff 2009 classification are associated with a worse long-term survival.

The Effect of Acute Rejection Episodes According to Banff 2009 on Long-Term Outcome of Patients after Kidney Transplantation

Background: The effect of the most recent Banff-09 classification on graft outcomes is not well described. We undertook a retrospective analysis to determine whether the time and severity of acute transplant rejection according to the Banff-09 classification are risk factors of long-term allograft survival. Methods: 409 adult patients (pts) with at least 1 episode of biopsy proven acute rejection (BPAR) were enrolled in this study. All pts received kidney transplantation (Tx) in our centre between 01.01.1996 and 31.12.2010. In retrospect all biopsies were reclassified by the most recent Banff 2009 criteria. Only the highest BPAR was documented for each recipient with more than one BPAR. All pts were divided into two groups according to the time of first BPAR episode: group early (≤12 months post Tx) vs. late, (>12 months post Tx). Graft survival and death-censored graft survival (recipient survival) analysis were performed using the Kaplan- Meier method. Results: Eight-year allograft survival and recipient survival differed significantly (p< 0.005) between early and late rejections: it was 79.9% and 84.2% in the early group vs 54.7%, 82.1% in the late group, respectively. Similarly we observed significant differences of graft survival between early and late groups for pts with borderline changes (95.3% vs 66.6%), interstitial rejection (78.0% vs 50.0%), and vascular rejection (67.2% vs 33.3%). Recipient survival was statistically different between early and late groups for patients with borderline changes (92.4% vs 87.2%), and vascular rejection (82.4% vs 66.7%). Regarding to the severity of BPAR, there were significant differences (p< 0,001) among the eight-year graft survival (borderline 84.2% vs. grade I 70.7% grade II 62.0%) and recipient survival (borderline 90.6% vs. grade I vs 84.4% grade II 80.0%). Recipients with borderline changes had similar graft and recipient survival with pts having grade IA rejection, but had better long-term graft and recipient survival than pts with grade IB and vascular rejection. Graft and recipient survival were similar between pts with interstitial rejection and vascular rejection but pts with IA rejection had higher recipient survival than IB rejection, and pts with IIA rejection had higher graft survival than IIB rejection. Conclusions: Late occurrence of acute rejection results in inferior allograft and patient survival. In addition, more severe rejections according to the most recent Banff 2009 classification are associated with a worse long-term survival.

Deceased Donors Renal Transplantation from Older Donors to Increase the Donor Pool

Background: Use of kidneys from donors aged 70 years and older is controversial. The organ shortage has led many transplant centers to accept kidneys from old, suboptimal deceased donors, and make increasing use of old-for-old allocation systems. We herein describe our institutional experience with outcomes of transplanting deceased-donor kidneys from older donors(>70 years). Material and methods: Between June 2004 and September 2011, twenty deceased donor renal transplants (DDRTx) were performed at our center using grafts from deceased donor 70 years and older. Kidneys allocated to dual or single grafting according to pre-transplant biopsy. Mean age of recipients was 47.60 ± 11.38 years, 13 were males. Mean donor age was 76.49 ± 4.9 years; 10 were males. Commonest cause of donor death was cerebrovascular/road traffic accidents. Mean dialysis duration pre-transplantation was 19.5 ± 6.5 months. Mean HLA match was 1 ± 0.8. Most common recipient diseases leading to ESRD were chronic glomerulonephritis(25%), diabetes(20%), and hypertension(20%). Post-transplant immunosuppression consisted of a calcineurin inhibitor-based regimen. Results: Over a mean follow-up of 2.8 ± 1.7 years, patient and graft survival rates were 75 % (n=15) and 80 % (n=16), respectively, with a mean serum creatinine of 1.78 ± 0.56 mg/dL; 20% of patients had biopsy-proven acute rejection episodes. A total of 25% (n=5) patients were died, mainly due to infections. Patient and graft survival, rejection and infection rates were similar in older and young donors RTx groups (p < 0.05). Conclusion: DDRTx from older donors achieves acceptable graft function with patient/graft survival, provided that organs allocated to dual or single grafting according to pre-transplant biopsy, encouraging the use of this approach even in low-income countries.

Significance of CD4 T-Cell Adenosine Triphosphate Levels Monitoring in Elderly Renal Transplant Recipients

ObjectivesTo find the significance of CD4 T-cell adenosine triphosphate (ATP) levels in elderly renal recipients in correlation with drug doses, levels, and clinical parameters. MethodsDrug doses and levels, CD4 T-cell ATP levesl (162 sequential samples), and other clinical data were collected and assessed among 31 elderly renal recipients who underwent transplantations from November 2007 to March 2011. ResultsAmong subjects with stable clinical status, the main ATP levels pretransplantation were not significantly different from those posttransplantation: 302.4 ± 97.5 ng/mL versus 288.8 ± 102.6 ng/mL (P > .05). There was no relationship between ATP levels and tacrolimus concentrations or doses. In 12 patients experiencing infection, the ATP levels were significantly lower then those of subjects showing a stable clinical status: 127.3 ± 92.8 versus 288.8 ± 102.6 ng/mL (P < .01). Six patients with biopsy-proven acute rejection episodes did not show significantly higher ATP levels compared with those who were clinically stable: 26.2 ± 224.8 versus 288.8 ± 102.6 (P > .05). ConclusionsCD4 T-cell ATP levels were valuable to monitor immunosuppression among elderly renal transplant recipients.

Does Rapamycin Still Have a Role? Experience and Lessons from the Last Decade

Background: Rapamycin, an mTor inhibitor, is a potent immunosuppressant agent in solid organ transplantation. Initial enthusiasm on its efficacy and reduced nephrotoxcity was tempered by unacceptable and widely publicised side effects leading to increasingly sporadic usage by transplant centres. It appears to have a niche for specific and varied indications, particularly as ‘rescue therapy’ and in situations where its anti-neoplastic or anti-fibrotic properties may confer an advantage rather than as primary maintenance immunosuppression. We aimed to assess the frequency and pattern of Rapamycin use focusing primarly on indications, usage length, outcomes and complications, in three large North of England centres since its introduction into clinical practice in 1997. Methods: All Patients who have had Rapamycin at any point following transplantation were identified through laboratory records of assays done at 3 follow up centres. A retrospective analysis was then done of a database of 1412 patients receiving either a kidney or pancreas transplant between 1997 and 2011. 123 patients received Rapamycin with data on the indications, pattern and length of usage available in 91 patients (8.7%). These comprised 2 distinct groups: Rapamycin as de novo immunosuppression (primarily in clinical trials with Mycophenolae Mofetil and steroid) or as a modification of therapy at a later date due to distinct clinical indications. End points including Biopsy proven acute rejection (BPAR), complication rates, proteinuria (>1g/24hr) and mortality were reviewed in this cohort of patients. Results: 36 patients received de novo Rapamycin treatment (Trial 35/36; non trial 1/36 - previous PTLD) 13 (36%) of these patients required immunosuppression modulation (recurrent BPAR, 38%; 10 single episodes of BPAR), impaired wound healing (23%), interstitial pneumonitis (15%) and mouth ulcers (7.6% each). Complications which did not require immunosuppressive changes included hyperlipidaemia (>6mmol/l, 83%), mouth ulceration (19%), and lymphocoele (22%). The incidence of neoplasia was 5% and mortality 14%. Rapamycin associated significant proteinurian was 5%. 53 patients were converted to Rapamycin as ‘rescue therapy’ (median interval 6 years post-transplant (range 1/12 to 42 years); indications including: allograft nephropathy 17/53 (32%), anti-neoplastic 14/53 (11 skin cancer, 1 PTLD, 1 small bowel lymphoma, 1 renal cell Ca; 26%), and intolerance of other drugs 9/53 (17%). 19/53 (36%) had changes due to intolerance (infection (11%); mouth ulcers (17%); BPAR (5%), or chest infections (interstitial pneumonitis or PCP pneumonia; 4%.) Other adverse effects included hyperlipidaemia (22%) and mouth ulcers (15%). The incidence of significant proteinuria was 20% with a mortality rate of 13%. Conclusion: Rapamycin has been sparingly used in the last decade due to severe adverse outcomes associated with de novo usage. Trends have developed for its use for allied benefits, particularly including anti-fibrotic and neoplastic properties and as rescue therapy for toxicity rather than as defined maintenance immunosuppression. This study highlights that despite not fulfilling original indications, it has a role for both maintenance and rescue therapy. Its side effect profile ensures that it is better tolerated than originally perceived thereby ensuring its continued importance in the armamentarium of immunosuppressant agents.

Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation

In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent.

Deceased Donor Renal Transplantation from Older Donors to Increase the Donor Pool

Background Use of kidneys from donors aged 70 years and older is controversial. Organ shortage has led many transplant centers to accept kidneys from old, suboptimal deceased donors and make increasing use of old-for-old allocation systems. We describe our institutional experience with outcomes from transplanting deceased-donor kidneys from older donors (≥70 years). Material and methods 20 deceased donor renal transplants (DDRTx) were performed at our center using grafts from deceased donors 70 years and older between June 2004 and September 2011. Kidneys were allocated to dual or single grafting according to pre-transplant biopsy. Mean age of recipients was 47.60 ± 11.38 years, 13 of whom were males. Mean donor age was 76.49 ± 4.9 years; 10 of whom were males. The most common cause of donor death was cerebrovascular/road traffic accidents. Mean dialysis duration pre-transplantation was 19.5 ± 6.5 months. Mean HLA (Human Leukocyte Antigens) match was 1 ± 0.8. Most common recipient diseases leading to ESRD were chronic glomerulonephritis (25%), diabetes (20%), and hypertension (20%). Post-transplant immunosuppression consisted of a calcineurin inhibitor-based regimen. Results Over a mean follow-up of 2.8 ± 1.7 years, patient and graft survival rates were 75% (n = 15) and 80% (n = 16), respectively, with a mean serum creatinine of 1.78 ± 0.56 mg/dl; 20% of the patients had biopsy-proven acute rejection episodes. A total of 25% (n = 5) patients died, mainly due to infections. Conclusions DDRTx from older donors achieves acceptable graft function with patient/graft survival, provided that organs are allocated to dual or single grafting according to pre-transplant biopsy. These findings encourage the use of this approach even in low-income countries.

Deceased donor renal transplantation from older donors to increase the donor pool

Use of kidneys from donors aged 70 years and older is controversial. Organ shortage has led many transplant centers to accept kidneys from old, suboptimal deceased donors and make increasing use of old-for-old allocation systems. We describe our institutional experience with outcomes from transplanting deceased-donor kidneys from older donors (=70 years). 20 deceased donor renal transplants (DDRTx) were performed at our center using grafts from deceased donors 70 years and older between June 2004 and September 2011. Kidneys were allocated to dual or single grafting according to pre-transplant biopsy. Mean age of recipients was 47.60 ± 11.38 years, 13 of whom were males. Mean donor age was 76.49 ± 4.9 years; 10 of whom were males. The most common cause of donor death was cerebrovascular/road traffic accidents. Mean dialysis duration pre-transplantation was 19.5 ± 6.5 months. Mean HLA (Human Leukocyte Antigens) match was 1 ± 0.8. Most common recipient diseases leading to ESRD were chronic glomerulonephritis (25%), diabetes (20%), and hypertension (20%). Post-transplant immunosuppression consisted of a calcineurin inhibitor-based regimen. Over a mean follow-up of 2.8 ± 1.7 years, patient and graft survival rates were 75% (n = 15) and 80% ( n = 16), respectively, with a mean serum creatinine of 1.78 ± 0.56 mg/dl; 20% of the patients had biopsy-proven acute rejection episodes. A total of 25% (n = 5) patients died, mainly due to infections. DDRTx from older donors achieves acceptable graft function with patient/graft survival, provided that organs are allocated to dual or single grafting according to pre-transplant biopsy. These findings encourage the use of this approach even in low-income countries.

Spousal Versus Living Unrelated Renal Transplantation: A Retrospective Analysis of Allograft Outcomes

ObjectiveTo compare the outcomes of spousal and living unrelated donor (LUD) allografts. Patients and methodsThe 378 ABO-compatible living and cadaveric kidney transplantations between February 2005 and August 2010 included 25 wife-to-husband (group 1), 15 husband-to-wife (group 2), and 20 LUD cases (group 3). Donor nephrectomy was performed by open surgery. Induction therapy with antithymocyte globulin or anti-interleukin-2 receptor antibody was followed by maintenance regimens using cyclosporine (CsA) or tacrolimus (Tac) plus mycophenolate mofetil (MMF) and corticosteroids. We compared spousal donor and LUDs in terms of clinical characteristics as well as graft and patient survival rates. ResultsFifty-six (93.3%) patients underwent induction therapy with either antithymocyte globulin (n = 30) or anti-interleukin-2 receptor antibody (n = 26). Maintenance immunosuppression was administered with Tac + MMF (n = 37; 61.6%) or CsA + MMF (n = 23; 38.4) with corticosteroids. Mean follow-up was 34 ± 16 months. There were four graft losses and five patient deaths. There were no significant differences between spousal and living unrelated transplants in terms of clinical characteristics or biopsy-proven acute rejection episodes. The Kaplan-Meier analysis showed 3-year patient survival rates of 94%, 100%, and 88% in group 1, group 2, and group 3, respectively (P > .05). Overall graft survival rates were 94%, 100%, and 77% in group 1, group 2, and group 3, respectively (P > .05). Graft and patient survival rates were similar at 3 years for wife-to-husband, husband-to-wife, or LUDs. ConclusionIn conclusion, family members should be encouraged as LUD or spousal donors, based on similar patient and graft survival rates.

Kidney Transplantation From Donation After Cardiac Death Donors in China—A Single-Center Experience

ObjectiveTo report clinical outcomes of kidney transplantation from cardiac death donors (DCD) in China, and to investigate its feasibility to expand the organ donor pool. Patients and methodsWe retrospectively studied clinical data of 46 DCD kidneys from 31 donors from February 2007 to August 2011. Recipients were followed for patient and graft survival. ResultsWe discarded the organs from 3 of 29 (10.3%) DCD donors and 7 of 42 (16.7%) kidneys that displayed renal thrombosis. Of the 39 recipients engrafted with DCD kidneys successfully, the mean follow-up was 16 months, (range = 50 days to 43 months). Delayed graft function (DGF) occurred in 15 (38.5%) recipients, who except one recovered within 3 months. Three biopsy-proven acute rejection episodes were observed in two recipients (5.1%). All patients survived through the follow-up. The graft survival rate was 97.4% at 12 months and 94.9% at 24 months. A 45-year-old male recipient who received a pair of grafts from a 6-year-old child survived with good renal function. ConclusionAlthough kidney transplantations from DCD donors showed a higher rate of DGF with a longer duration of graft recovery, we achieved favorable short-term clinical outcome in terms of graft survival and function. Donation after cardiac death can expand the organ donor pool in China.

A 39-Month Follow-up Study to Evaluate the Safety and Efficacy in Kidney Transplant Recipients Treated With Modified-Release Tacrolimus (FK506E)-Based Immunosuppression Regimen

BackgroundWe initially performed a study to evaluate the safety and efficacy of modified-release tacrolimus (FK506E) in a phase 3, 2-arm, 6-month, randomized, open-label, multicenter trial in Korean living donor de novo kidney transplant recipients. We then performed an extended study to evaluate the long-term safety and efficacy of a FK506E-based regimen up to 45 months posttransplantation in recipients already treated with FK506E. MethodsInitial study was designed as a randomized, open-label, comparative, multicenter study in de novo living donor kidney transplant recipients. The patients were randomized to an FK506E versus a control (FK506) group (1:1). Recipients who completed a 6-month FK506E treatment study were enrolled in the 39-month follow-up study. Primary end-points were patient and graft survivals at posttransplantation 45 months. Secondary end-point was the incidence of a clinical or biopsy-proven acute rejection episode between 6 and 45 months posttransplantation. ResultsIn the initial 6-month de novo study 124 enrolled patients were randomized into either the FK506E (n = 62) or the control group (n = 62). The incidence of an acute rejection episode was 19.4% (n = 12) in the FK506E versus 16.1% (n = 10) in the control group (P = .638). There was no mortality or graft failure among the 44 recipients enrolled in this additional 39-month follow-up study. There was 1 patient with biopsy-proven acute cellular rejection episode (2.3%) who underwent steroid pulse therapy with renal function recovery. At the time of study completion 40/44 recipients (90.9%) maintained FK506E treatment. ConclusionThis 39-month study following the initial 6-month FK506E study period showed an FK506E-based immunosuppressive regimen in living donor kidney transplantation recipients to be safe and effective.

Clinical Outcome of Renal Transplantation in End-Stage Renal Disease Patients With Positive Pretransplantation Hepatitis B Surface Antigen

BackgroundRenal transplantation (RTx) is the best therapeutic modality for patient suffering from end-stage renal disease (ESRD) with positive pretransplantation hepatitis B surface antigen (HbsAg). We report 11 years of single-center experience on RTx vis-à-vis patient/graft survival, graft function in terms of serum creatinine (SCr), and rejection episodes in 35 ESRD patients with pretransplantation HbsAg positivity. Patients and MethodsThirty-five ESRD patients with pretransplantation HbsAg positivity underwent RTx at our center between 2000 and 2010. Mean recipient age was 36.06 ± 12.22 years; 30 were males and 5 were females. Mean donor age was 43.51 ± 13.63 years; 13 were males and 22 were females. The majority of donors were parents (31.42%) and spouses (22.85%). Mean HLA match was 2 ± 1.37. The most common recipient diseases leading to ESRD were chronic glomerulonephritis (51%) and diabetes (17.5%). Posttransplantation immunosuppression consisted of a calcineurin inhibitor–based regimen. ResultsOver mean follow-up of 6.16 ± 3.69 years, patient and graft survival rates were 71.42% and 71.42%, respectively, with mean SCr of 1.92 ± 0.62 mg% with 20% biopsy-proven acute rejection episodes. In total, 10 (28.57%) patients were lost, mainly to infections. ConclusionRTx for ESRD with pretransplantation HbsAg positivity has acceptable graft function and patient/graft survival over 11 years follow-up and should be encouraged.

Efficacy of Anti-Interleukin-2 Receptor Antibody in Reducing the Incidence of Acute Rejection After Renal Transplantation

Dear Editor, Acute rejection (AR) in kidney transplant recipients is a major risk factor for chronic allograft failure and reduction in early and long term mean graft survival. New immunosuppressant agents have been developed to reduce the incidence of these episodes (1). Immunobiological drugs such as monoclonal anti-interleukin-2 receptor antibodies have shown promise in this direction; they have a more restrict immunosuppressive effect, are not related to interleukin release syndrome and are related to lower rates of CMV infection than polyclonal antibodies (2). In his trial Saghafi et al. (3) showed a reduction of Biopsy-Proven Acute Rejection (BPAR) episodes in non-related living donor kidney transplant recipients performing anti-interleukin-2 receptor, daclizumab, as an induction drug in addition to standard therapy with cyclosporine, mycophenolate and prednisone. The induction group had a statistically significant (20.8%) reduction in rejection episodes compared to control group using only standard therapy after a six month follow up (3). Resembling data had already been shown in previous studies, Vincent et al. showed similar reduction in incidence of BPAR in low immunologic risk deceased donor kidney recipients and the same rate of bacterial infections and/or viral infections, including CMV, malignances and adverse event as placebo group (4). Another study showed a reduction in the incidence of BPAR in deceased and living kidney recipients of about 14 % in the group that underwent induction therapy with daclizumab with no increase in infections and adverse events (1). Saghafi et al. in accordance with other authors showed daclizumab as an effective induction treatment option for low immunologic risk living donor kidney recipients. However, missing data about safety drug profile such as incidence of infection, adverse events, CMV infection, and early and late cyclosporine trough levels are not reported in the text. There are several studies confirming that induction therapy with either monoclonal or polyclonal antibodies in addition to standard therapy reduces the incidence of acute rejection but none of these studies have shown statistically significant improving in long term graft survival. New trials such as ELITE-symphony (5) study performing inteleukin-2 receptor antibody as a calcineurin inhibitor sparing agent showed promising results when comparing classical treatment protocol with standard cyclosporine dose, mycophenolate and corticosteroids with daclizumab, corticosteroids and mycophenolate and low dose cyclosporine or low dose tacrolimus or low dose sirolimus. This study found better outcomes in term of lower incidence of acute rejection, adverse events, infections and a better allograft survival rates in daclizumab and low dose tacrolimus group (5). Improving long-term outcomes in renal transplantation is still a field of challenge and numbness but the use of induction agents in adjunction with other drugs for reducing their side effects is a promising strategy for better graft and patient survival. Perhaps, most important induction therapy importance is in minimizing exposure to other immunosuppressive therapy and its side effects and this topic deserves research.

Outcome of Renal Transplantation in Alport's Syndrome: A Single-Center Experience

BackgroundAnti-glomerular basement membrane (anti-GBM) nephritis post–renaltransplantation (RTx) is known to cause graft loss in Alport's syndrome (AS). We evaluated theresults of RTx in AS patients vis à vis patient and graft survivals, incidence of anti-GBM nephritis, andcauses of graft failure. Materials and methodsBetween 1993 and 2009 we performed 31 RTx on AS patients (28 males and three females)of overall mean age of 22 ± 7.9 yearsfrom six deceased and 27 living donors. Two patients underwent second RTx. ResultsOver a follow-up of 1, 3, 5, and10 years, the mean serum creatinines (mg/dL) were 1.51 ± 0.52, 1.59 ± 0.26, 1.61 ± 0.30, and 1.63 ±0.32, respectively. Patient survivals at 1, 5, and 10 years were 89.71%, 81.32% and 81.32% withgraft survival for all periods of 81.2%. Twenty-one percent experienced biopsy-proven acute rejection episodes. Graftfailures were due to anti-GBM nephritis in 12.2% (n = 4), chronic allograft nephropathy in 3.2%(n = 1), and acute rejection or cyclosporine toxicity 3.2% (n = 1 each). The mean duration to graftloss was 4.9 ± 2.4 months. ConclusionGraft and patientsurvivals were acceptable among transplant recipients with AS despite the risk of anti-GBM nephritis.

Renal function and safety in stable kidney transplant recipients converted from immediate-release to prolonged-release tacrolimus

This multicenter, open, phase IIIb study assessed short-term efficacy, safety and dose adjustments in adult stable renal transplant recipients converted from tacrolimus twice-daily (BID) to once-daily (QD). Patients receiving unchanged tacrolimus BID for ≥ 12 weeks were enrolled, and after 6-weeks, converted from tacrolimus BID to QD (morning dose) on a 1 : 1 (mg : mg) total daily dose basis, for a further 12 weeks. Primary endpoint: change in steady-state creatinine clearance between treatment phases. Secondary endpoints: biopsy-proven acute rejection (BPAR), patient and graft survival, safety. 128 patients enrolled (mean age 48.9 years; time post-transplant 48.9 months); 91 evaluated for the primary endpoint. Mean total daily dose was 0.06 mg/kg (BID) and 0.07 mg/kg (QD); 79.1% required one/no dose changes post-conversion to maintain recommended blood-trough levels; average dose increase was small (0.6-0.7 mg/day) with more dose increases in patients on the lowest tacrolimus BID doses. Renal function remained stable and non-inferiority of tacrolimus QD against tacrolimus BID was demonstrated. There were no BPAR episodes; patient and graft survival were 100%. Adverse events were few; none led to dose modifications/discontinuation. Tacrolimus BID to tacrolimus QD conversion is straightforward and does not compromise renal function in stable kidney transplant patients in the short term.

Efficacy and Safety of Early Cyclosporine Conversion to Sirolimus with Continued MMF—Four-Year Results of the Postconcept Study

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function. We previously reported that conversion from cyclosporine A (CsA) to sirolimus (SRL) 3 months after transplantation significantly improved renal function at 1 year. In the Postconcept trial, 77 patients in the SRL group and 85 in the CsA group were followed for 48 months. Renal function (Cockcroft and Gault) was significantly better at month 48 (M48) in the SRL group both in the intent-to-treat population (ITT): 62.6 mL/min/1.73 m(2) versus 57.1 mL/min/1.73 m(2) (p = 0.013) and in the on-treatment population (OT): 67.5 mL/min/1.73 m(2) versus 57.4 mL/min/1.73 m(2) (p = 0.002). Two biopsy proven acute rejection episodes occurred after M12 in each group. Graft and patient survival were comparable (graft survival: 97.4 vs. 100%; patient survival: 97.4 vs. 97.6%, respectively). The incidence of new-onset diabetes was numerically increased in the SRL group (7 vs. 2). In OT, three cancers occurred in the SRL group versus nine in the CsA group and mean proteinuria was increased in the SRL group (0.42 ± 0.44 vs. 0.26 ± 0.37; p = 0.018). In summary, the renal benefits associated with conversion of CsA to SRL, at 3 months posttransplantation, in combination with MMF were maintained for 4 years posttransplantation.

Regression of new-onset diabetes mellitus after conversion from tacrolimus to cyclosporine in liver transplant patients: Results of a pilot study

New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation. To evaluate the impact of conversion from tacrolimus to cyclosporine in liver transplant patients presenting NODM. In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study. At month 12, NODM had significantly resolved (FBG<7 mmol/L without treatment) in 36% of patients (95% CI 20.8-51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L (P=0.008) and mean HbA(1c) decreased from 6.4 to 6.0% (P=0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L (P<0.001). These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required.

Treatment of First Acute Rejection Episode: Systematic Review of Level I Evidence

The primary objective of this review was to clarify the efficacy of commercially available and tested agents for the treatment of first acute rejection episode (ARE) and particularly a steroid-resistant rejection (SRR) seeking to provide generalizable level I evidence for clinical practice. The inclusion criteria were restricted to prospective randomized trials (PRT) that (1) reported outcomes of first, biopsy-proven ARE based on Banff 97 diagnostic criteria; (2) excluded borderline changes that were not considered to be acute rejection; (3) included protocol biopsies confirming reversal or recurrence of rejection; (4) utilized calcineurin inhibitor-based double or triple baseline immunosuppression prior to and after the reversal of ARE and possessed Jadad scores at least 3 upon final assessment by both reviewers. Two PRTs compared rabbit-anti-thymocyte globulin (ATG) to low-dose corticosteroids or OKT3, following a first rejection episode in renal transplantation patients. The analysis of pooled data revealed 25% and 31% absolute risk reduction (ARR), in regard to initial treatment failure and recurrence of ARE, respectively, in favor of ATG treatment. Treatment morbidity showed similar long-term graft and patient survival rates in both arms. Three optimal trials compared the efficacy of various polyclonal or polyclonal versus monoclonal (OKT3) antibodies for the treatment of SRR. The estimated efficacy potential of rabbit-ATG appeared to be 11,4% greater than horse-ATG with particularly Banff grade II but also grade III patients demonstrating the greatest benefit. Among two PRTs comparing ATG to OKT3, ATG tended to show better graft function, fewer recurrent rejections (9% ARR), fewer graft losses due to immunologic failure (7% ARR), and better tolerance. The incidence of malignant tumors was similar in both treatment arms. In conclusion, thymoglobulins, especially those of rabbit origin, displayed greater efficacy for the treatment of ARE and SRR. Application of CD3 monitoring using flow-cytometry provided a reliable guid to prevented excessive immunosuppressive administration.