Immunosuppressed Renal Transplant Research Articles

Donor-Derived Cell-Free DNA for Personalized Immunosuppression in Renal Transplantation.

The long-term outcomes of solid organ transplantation remain suboptimal. Therefore, appropriate biomarkers are needed in addition to immunosuppressive drugs and other traditional approaches for graft monitoring to achieve personalized immunosuppression and reduce premature graft loss. Donor-derived cell-free DNA (dd-cfDNA) is a minimally invasive biomarker of cell death due to graft injury. It can be quantified using droplet digital polymerase chain reaction and next-generation sequencing. Fractional dd-cfDNA determination can be affected by changes in recipient cfDNA, such as those caused by leukopenia or infection, leading to false positive or negative results, respectively. Absolute quantification of dd-cfDNA helps in overcoming this limitation. Overall, there is sufficient evidence of the clinical validity of dd-cfDNA. It detects rejection episodes early at an actionable stage and reflects the severity of graft injury without being rejection-specific. Owing to its high negative predictive value, dd-cfDNA is very useful for ruling out graft injury. Dd-cfDNA complements histological findings and can help in avoiding unnecessary biopsies. It indicates a response to rejection treatment and detects under-immunosuppression. Monitoring changes in dd-cfDNA over time may be helpful in adapting immunosuppression to prevent graft rejection. Moreover, serial dd-cfDNA determination may increase the effectiveness of transplant recipient surveillance and facilitate personalized immunosuppression when combined with other relevant clinical and diagnostic findings.

A Comprehensive Review of Calcineurin Inhibitors Used for Immunosuppression in Cardiac Transplantation.

Calcineurin inhibitors (CNIs) have been the foundation of immunosuppression in solid organ transplantation since the 1980s. Cyclosporine A (CSA), the first in class, was identified as the metabolite of the soil fungus Tolypocladium inflatum Gams as part of a larger program of screening for naturally occurring fungal metabolites with biologic activity in the 1970s. Significant immunosuppressive effects were discovered and consequently CSA was trialed as an immunosuppressant in renal transplantation. This initial success led to its widespread study and adoption in solid organ transplantation. This novel agent yielded significant improvements in both 1year and longer-term allograft and patient survival. Subsequently, a similar and more potent CNI, tacrolimus was developed. Today, it is the principal CNI used for prevention of allograft rejection. Like all other immunosuppressives, the benefits of CNIs are counterbalanced by side effects and complications resulting from drug toxicity. This chapter comprehensively reviews the clinical use of CNIs in cardiac transplantation.

Exploring the safety and efficacy of adding ketoconazole to tacrolimus in pediatric renal transplant immunosuppression.

BACKGROUNDGuatemala is a developing country in Central America with limited health resources. In order to expand successful renal transplant care to children and adolescents at the lowest possible cost, our pediatric renal transplant clinic uses a post-transplant tacrolimus-sparing strategy via inhibition of CYP3A4.AIMTo study the safety, efficacy and the associated cost reduction of ketoconazole in combination with tacrolimus in this pediatric population.METHODSA retrospective chart review was carried out among the cohort of pediatric renal transplant recipients treated at the Foundation for pediatric renal patients (Fundación para el Niño Enfermo Renal - FUNDANIER), a pediatric tertiary care renal transplant center in Guatemala City, Guatemala. Patient charts were reviewed to ascertain the number of transplant recipients who were transitioned from tacrolimus based immunosuppression to combination therapy with ketoconazole and tacrolimus. Twenty-five post-transplant patients that used ketoconazole combined with tacrolimus were identified. Anthropometric, clinical and laboratory data was collected from patient charts before and after the transition. RESULTSOf the 25 patient charts reviewed 12 (48%) patients were male and the average patient age was 13 years. Twenty-four (96%) transplants were from living donors. There was a non-significant difference between the mean tacrolimus doses six months and two months prior to ketoconazole: -0.10 ± 0.04 (95%CI: 0.007, -0.029), P = 0.23. However, the difference between the mean tacrolimus doses six months prior to ketoconazole initiation and six months after ketoconazole addition was significant: 0.06 ± 0.05 (95%CI: -0.034, -0.086) P < 0.001. All tacrolimus doses were reduced by 45% after the addition of ketoconazole. Therapeutic levels of tacrolimus ranged between 6.8-8.8 ng/mL during the study period and patients demonstrated an increase in estimated glomerular filtration rate. The combination of tacrolimus and ketoconazole resulted in a 21% reduction in cost.CONCLUSIONPatients experienced an effective dose-reduction of tacrolimus with the administration of ketoconazole. There was no relevant variations in tacrolimus serum levels, number of rejections, or significant liver toxicity. The strategy allowed a cost reduction in pediatric immunosuppressive therapy.

Immunosuppression and Graft Rejection in Living-related HLA-identical Renal Transplantation: The RADOVFULL Study.

We aimed to describe the immunosuppressive regimens and graft rejection rates in living-related HLA-identical (LR HLAid) renal transplantation. We performed a retrospective multicenter analysis of the French national database for LR HLAid renal transplantations performed between 2002 and 2012. Univariate and multivariate analysis were performed to determine risk factors for graft rejection in LR HLAid recipients. A total of 27 218 renal transplantations were performed, of whom 163 had a LR HLAid donor. About immunosuppressive treatment, <60% of the cohort had induction therapy with polyclonal or monoclonal antibodies, 28% did not receive calcineurin inhibitors, and 36% did not receive steroids in maintenance. Biopsy-proven acute rejection was diagnosed in 21 patients (12.9%). Rejection occurred on an average of 24 months after transplantation, in 28.5% of the cases after minimization of immunosuppression. Factors associated with rejection were age of recipient (OR, 0.91 [0.84-0.96]; P = 0.003), the body mass index of donors (odds ratio [OR], 1.22 [1.04-1.46]; P = 0.01), and minimization of immunosuppression (OR, 26.2 [5.48-166.6]; P < 0.001). Overall and graft survival rates were not statistically different according to rejection at 1, 5, and 10 years posttransplantation. Minimization of immunosuppression should be done with caution in LR HLAid renal transplantations.

Determinants of Successful Use of Sirolimus in Renal Transplant Patients

BackgroundSirolimus is an established immunosuppressant in renal transplantation with antineoplastic and antiviral features, but side effects like proteinuria limit its use. The aim of this retrospective multicenter observational study is to define predictors for determining which patients most likely benefit from a sirolimus-based therapy. MethodsAll patients from 10 German centers that were switched to a sirolimus-containing maintenance immunosuppression in 2000 to 2008 after 3 months or later post-transplantation were enrolled (n = 726). Observation times after switching to sirolimus ranged from 4 days to 9 years (median: 24.3 months). With multinomial logistic regression, risk factors for the endpoints terminal graft failure and withdrawal of sirolimus therapy compared to successful therapy were identified. ResultsSuccessful sirolimus therapy was observed in 304 patients. Forty patients died with functioning graft. Therapy failures included graft loss (n = 106) and sirolimus-discontinuation for various reasons (n = 276). Successful sirolimus-use was predicted in 83% and graft failure in 65%, whereas prediction of deliberate sirolimus-discontinuation was poor (48%). Most favorable results for sirolimus-use were observed in patients switched in 2006 to 2008. Using ROC analysis, an estimated glomerular filtration rate (eGFR) below 32 mL/min was shown to be the cut-off in patients withdrawing from therapy as a result of renal reasons, as well as in patients with graft loss. Proteinuria above 151 mg/L was shown to be predictive for patients with graft failure. ConclusionseGFR and proteinuria are the major determinants for successful sirolimus-therapy. Our findings help stratifying patients who will benefit most from this therapy and avoid toxicities in patients without potential benefits for this therapy.

SUN-296 CYP3A5 AND ABCB1 GENETIC POLYMORPHISMS IN RENAL TRANSPLANT RECIPIENT PATIENTS AND ITS RELATION WITH TACROLIMUS DOSING AND COMPLICATIONS

Tacrolimus is the mainstay of immunosuppression in renal transplantation (RT). However, it has highly variable bioavailability and a narrow therapeutic range. Its metabolism depends upon CYP3A4 and ABCB1gene polymorphism. There is limited data regarding the influence of this polymorphisms on TAC drug level and complications from India. This is a prospective study done over a period of 2 years (2016-2018) from NIMS Hyderabad. A total of 152 patients were recruited. Frequency of CYP3AB(A6986>G) & ABCB1 (C1236>T, G2677>T and C3435>T) polymorphisms were detected by PCR followed by Sanger’s sequence-based genotype & RFLP. Accordingly patients were divided into wild variant(CYP3A5-AA) where there is full expression of the enzyme, heterozygous( CYP3A5-AG), homozygous group who were non expressors (CYP3A5-GG). Day 3, 30,60,90 tacrolimus concentrations and tacrolimus concentration/drug (C/D) ratio were measured. Tacrolimus related toxicity, infections and rejections and the serum creatinine at the time of discharge were compared among the groups Out of 152 renal transplant recipients, 120(78%) were males. 37 patients received deceased donor grafts. Immediate graft function was seen in 117(76%). Tacrolimus C/D ratio was less in wild (AA) variety compared to both AG ( 0.006) and GG ( P<o.ooo1). Tacrolimus toxicity was noted in 28(18%) patients, of which ATN 24(85%), TMA 3(11%), Pancreatitis in 1(3.5%). Most common infectious complication was UTI seen in 22(14%) patients (AA-3(10%), AG-9(14%), GG-10 (16.7%) followed by CMV disease. BPAR were seen in 5 patients. ABCB1 polymorphisms and showed no correlation with tacrolimus C/D ratio. Mean serum creatinine at the time of discharge was 1±0.2 in AA, 1.3±0.8 in AG (AA vs AG P < 0.002), 1.27±0.47 in GG(AA vs GG P <0.004). Our study shows that genetic polymorphism effects the tacrolimus dose requirement. Enzyme expressor (AA) is associated with low C/D ratio and higher risk of acute rejection. Heterozygous (AG) and non expressors (GG) are at higher risk of developing tacrolimus related nephrotoxicity and infections. ABCB1 polymorphisms has no significant impact on tacrolimus C/D ratio

Rapid reduction of high-level pre-formed donor-specific antibodies after simultaneous liver-kidney transplantation: a report of two cases

BackgroundKidney transplantation performed in the presence of high-titre donor-specific antibodies (DSA) may result in hyper-acute or accelerated antibody-mediated rejection and rapid allograft loss. Previous studies have shown that this risk may be mitigated with simultaneous liver-kidney transplantation (SLKT); however, the mechanisms are not well defined. Here we report the evolution of pre-formed, high-level DSAs in two highly sensitised SLKT recipients peri-operatively and describe a profound sustained depletion of all DSAs from the time of liver anastomosis with no extra desensitisation therapy required.Case presentationTwo patients underwent SLKT and received our centre’s standard renal transplant immunosuppression with basiliximab and methylprednisolone for induction therapy and prednisolone, mycophenolate and tacrolimus for maintenance therapy. HLA antibody samples were collected pre-operatively, and immediately post-liver and post-kidney revascularisation, and then regularly in the post-transplant period. Complement Dependant Cytotoxicity (CDC) crossmatches were also performed. Both patients were highly sensitised with a PRA over 97%. One patient had a positive B- and T-cell crossmatch pre-transplant. These positive CDC crossmatches became negative and the level of pre-formed DSAs reduced profoundly and rapidly, within 3 h post-liver revascularisation. The reduction in pre-formed DSAs, regardless of subclass, was seen immediately post-liver revascularisation, before implantation of the renal allografts. No significant reduction in non-donor specific HLA-antibodies was observed. Both patients maintained good graft function with no rejection on kidney allograft protocol biopsies performed at 10-weeks post-transplant.ConclusionsThese cases support the protective immunoregulatory role of the liver in the setting of SLKT, with no extra desensitisation treatment given pre-operatively for these highly sensitised patients.

Cilastatin protects against tacrolimus-induced nephrotoxicity via anti-oxidative and anti-apoptotic properties

BackgroundCilastatin (CL) is an inhibitor of dehydropeptidase-I, which is safely used in clinical practice to prevent nephrotoxicity of antibiotics. Tacrolimus (TAC) is the most important immunosuppressant in renal transplantation, but it causes considerable nephrotoxicity. We evaluated the protective effects of CL against chronic TAC-induced nephropathy.MethodsChronic nephropathy was induced by administering TAC (1.5 mg/kg/ day, subcutaneous injection) to rats on a low-salt diet for 4 weeks. CL (75 or 150 mg/kg/day, intraperitoneal injection) was concomitantly treated with TAC. Human proximal tubular cells were exposed to TAC (50 μg/mL) with or without CL (250 μg/mL). We investigated the effects of CL on TAC-induced injury in terms of renal function, tubulointerstitial fibrosis, and inflammation. The effects of CL on oxidative stress and apoptosis were evaluated in both in vivo and in vitro models of TAC nephrotoxicity.ResultsCL treatment improved TAC-induced renal dysfunction and decreased renal interstitial fibrosis (reduced expression of e-cadherin and TGFβ-1) and interstitial inflammation (decreased infiltration of ED-1-positive and osteopontin-positive cells). Compared to TAC treatment alone, CL co-treatment reduced oxidative stress (serum 8-OHdG level and immunoreactivity of 8-OHdG and 4-HHE in renal tissue) and increased renal expression of anti-oxidant enzyme, manganese superoxide dismutase. CL treatment decreased apoptotic cell death (decreased TUNEL-positive cells and reduced expression of active caspase-3) in TAC-treated kidney. In vitro CL treatment prevented tubular cell death from TAC treatment and decreased number of annexin V-positive cells were observed in cilastatin-cotreated cells.ConclusionCL has protective effects against chronic TAC-induced nephrotoxicity owing to its anti-oxidative and anti-apoptotic properties.

Conversion from Twice-Daily Prograf® to Once-Daily Advagraf® in Multi-ethnic Asian Adult Renal Transplant Recipients With or Without Concomitant Use of Diltiazem: Impact of CYP3A5 and MDR1 Genetic Polymorphisms on Tacrolimus Exposure

Tacrolimus is the mainstay of immunosuppression in renal transplantation. Given that once-daily administration improves patient compliance, 1:1 dose conversion from twice-daily Prograf® to once-daily Advagraf® is recommended. Although cytochrome P450 (CYP) 3A5 and multi-drug resistance 1 (MDR1) polymorphisms influence tacrolimus concentrations, it is unknown if these impact on conversion. This study investigated the change in the pharmacokinetics of tacrolimus after conversion from Prograf® to Advagraf® and examined the impact of CYP3A5 and MDR1 C3435T polymorphisms on those pharmacokinetics. A prospective open-label pharmacokinetic study of 1:1 conversion from Prograf® to Advagraf® with or without diltiazem was conducted on 26 stable renal transplant recipients. Blood samples were collected over 24h during each phase, tacrolimus concentrations were assayed, and noncompartmental pharmacokinetic analysis was performed. All participants were genotyped for CYP3A5*3 and MDR1 C3435T. After conversion, without diltiazem, the area under the concentration-time curve at steady state from 0 to 24 h after dose administration (AUCss, 0-24) was significantly reduced [median224 (range172-366) vs. 184 (104-347) ng·h/mL, p = 0.006, n = 26]. A decrease in tacrolimus exposure (median 21%) was only evident among CYP3A5 expressors [227 (172-366) vs. 180 (104-347) ng·h/mL, p = 0.014, n = 18], not among non-expressors [215 (197-290) vs. 217 (129-281) ng·h/mL, p = 0.263, n = 8]. In contrast, among CYP3A5 expressors receiving diltiazem, AUCss, 0-24 did not change significantly upon conversion [229 (170-296) vs. 221 (123-342) ng·h/mL, p = 0.575, n = 10]. An independent effect was not evident for MDR1 C3435T polymorphism. The high prevalence of CYP3A5 polymorphism among Asians may lead to a significant reduction in tacrolimus exposure with 1:1 dose conversion of Prograf® to Advagraf®. These results advocate for CYP3A5 determination prior to conversion, and suggest that 1:1.25 conversion should be used for CYP3A5 expressors and 1:1 conversion for other patients.

Lymphocyte depletion and risk of acute rejection in renal transplant recipients at increased risk for delayed graft function.

Delayed graft function (DGF) is a risk factor for acute rejection (AR) in renal transplant recipients, and KDIGO guidelines suggest use of lymphocyte-depletion induction when DGF is anticipated. We analyzed the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) database to assess the impact of induction immunosuppression on the risk of AR in deceased kidney recipients based on pretransplant risk of DGF using a validated model. Recipients were categorized into 4 groups based upon the induction immunosuppression: (1) Rabbit anti-thymocyte globulin (rATG); (2) Alemtuzumab (C1H); (3) IL2-receptor antagonists (IL2-RA; basiliximab or daclizumab), and (4) No antibody induction. The primary endpoint for analysis was a composite endpoint of treated AR or graft failure by 1-year posttransplantation. Compared to no antibody induction, rATG and C1H had consistently lower adjusted odds of the composite endpoint across all risk strata for DGF risk, whereas IL2-Ra was associated with increased adjusted odds of the composite endpoint with increasing DGF risk. When the induction agents were compared, rATG and C1H were associated with decreasing adjusted odds for the composite endpoint with increasing risk of DGF, especially at the higher risk spectrum of DGF. Consideration must be given to use of lymphocyte-depletion induction when the anticipated risk of DGF is increased.

Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial

B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients. We aimed to determine the safety and activity of an anti-BLyS antibody, belimumab, in addition to standard-of-care immunosuppression in adult kidney transplant recipients. We used an experimental medicine study design with multiple secondary and exploratory endpoints to gain further insight into the effect of belimumab on the generation of de-novo IgG and on the regulatory B-cell compartment. We undertook a double-blind, randomised, placebo-controlled phase 2 trial of belimumab, in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone) at two centres, Addenbrooke's Hospital, Cambridge, UK, and Guy's and St Thomas' Hospital, London, UK. Participants were eligible if they were aged 18-75 years and receiving a kidney transplant and were planned to receive standard-of-care immunosuppression. Participants were randomly assigned (1:1) to receive either intravenous belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions. The co-primary endpoints were safety and change in the concentration of naive B cells from baseline to week 24, both of which were analysed in all patients who received a transplant and at least one dose of drug or placebo (the modified intention-to-treat [mITT] population). This trial has been completed and is registered with ClinicalTrials.gov, NCT01536379, and EudraCT, 2011-006215-56. Between Sept 13, 2013, and Feb 8, 2015, of 303 patients assessed for eligibility, 28 kidney transplant recipients were randomly assigned to receive belimumab (n=14) or placebo (n=14). 25 patients (12 [86%] patients assigned to the belimumab group and 13 [93%] patients assigned to the placebo group) received a transplant and were included in the mITT population. We observed similar proportions of adverse events in the belimumab and placebo groups, including serious infections (one [8%] of 12 in the belimumab group and five [38%] of 13 in the placebo group during the 6-month on-treatment phase; and none in the belimumab group and two [15%] in the placebo group during the 6-month follow-up). In the on-treatment phase, one patient in the placebo group died because of fatal myocardial infarction and acute cardiac failure. The co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. Treatment with belimumab did not significantly reduce the number of naive B cells from baseline to week 24 (adjusted mean difference between the belimumab and placebo treatment groups -34·4 cells per μL, 95% CI -109·5 to 40·7). Belimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral alloimmunity. GlaxoSmithKline.

Do clinical trials reflect reality? A systematic review of inclusion/exclusion criteria in trials of renal transplant immunosuppression.

Renal transplant recipients and donors are becoming increasingly more marginal, with more expanded criteria (ECD) and donation after circulatory death (DCD) donors and older recipients. Despite this, high-risk donors and recipients are often excluded from clinical trials, leading to uncertainty about the generalizability of findings. We extracted data regarding inclusion/exclusion criteria from 174 trials of immunosuppression in renal transplant recipients published over a 5-year period and compared criteria with those specified in published trial registries. Frequently reported donor exclusion criteria were age (16.1%), donor type and cold ischaemic time (22.4%). Common recipient exclusion criteria included upper age limit (38.5%), high panel reactive antibody (PRA) (42.5%) and previous transplantation (39.7%). Inclusion/exclusion criteria recorded in trial registries matched those reported in the manuscript in only 6 (7.8%) trials. Of registered trials, 51 (66.2%) trials included additional criteria in the manuscript, 51 (66.2%) were missing criteria in the manuscript specified in the protocol, and in 19 (24.7%) key criteria changed from the protocol to the manuscript. Our findings suggest many recent immunosuppression trials have restrictive inclusion criteria which may not be reflective of current renal transplant populations. Discrepancies between trial protocols and published reports raise the possibility of selection bias.

Clinical Trials for Immunosuppression in Transplantation: The Case for Reform and Change in Direction.

Currently trials of immunosuppression in transplantation are in decline because their objectives remain focused on improving acute rejection rates and graft survival in the first 12 months. With 1 year renal graft survival rates of greater than 90% the best that can be hoped for is noninferiority trial outcomes compared with current standard of care. Current trial design is not leading to novel therapies improving long-term outcomes and safety, and hence important unmet clinical needs in transplantation remain unanswered. Issues that need to be addressed include but are not limited to: prevention of subclinical rejection in the first year, better 5- and 10-year graft outcomes, more effective treatment for high immunological risk and sensitized (including donor-specific antibody) patients, immunosuppressive combinations that are better tolerated by patients with fewer side effects and less morbidity and mortality. In September 2015, the Transplantation Society convened a group of transplant clinical trial experts to address these problems. The aims were to substantially realign the priorities of clinical trials for renal transplant immunosuppression with the current unmet needs and to propose new designs for clinical trials for transplant immunosuppression. Moving forward, the transplant community needs to provide trial data that will identify superior treatment options for patient subgroups and allow new agents to be evaluated for efficacy and safety and achieve timely regulatory approval. Trial designs for new transplant immunosuppression must be intelligently restructured to ensure that short- and long-term clinical outcomes continue to improve.

Long-term outcome after early cyclosporine withdrawal in kidney transplantation: ten years after.

Despite long-term side effects, calcineurin inhibitors (CNI) remain a cornerstone of immunosuppression in renal transplantation. Few trials assessed the long-term outcome after early CNI withdrawal. This intention-to-treat study assessed the 10-year outcome of 108 patients randomly converted from a cyclosporine (CsA)-mycophenolate mofetil (MMF)-prednisone regimen to a dual therapy (CsA-prednisone or MMF-prednisone) at 3months postgraft. At 10years, 3.7% in the CsA group and 35.2% in the MMF group remained on the protocol regimen (P<.001). eGFR was higher in the MMF group (64.4±21 vs 49.7±14.7 mL/min/1.73 m², P<.001), although acute rejection (12 vs 4 in the CsA group, P=.03) and Class II DSA incidences were increased. CNI-related toxicity (P=.019) and moderate-to-severe IF/TA (P=.004) were higher in the CsA group. Ten-year graft and patient survivals were not different. In multivariate analysis, acute rejection remained the strongest predictor of graft loss (HR=11.64, 95% CI [5.05-26.79], P<.0001). MMF withdrawal largely failed due to CNI toxicity, while CsA withdrawal led to increased graft failure due to uncontrolled acute rejection without increasing graft survival. From this study, it remains unclear which patients could benefit from limiting CNI exposure.

Quality and consistency of outcome reporting in clinical trials of immunosuppression in renal transplantation.

Interpretation, comparison, and combination of results of clinical trials are reliant on accurate and complete reporting of outcomes. This study aimed to assess the quality and variability in outcome reporting in immunosuppression trials following renal transplantation. All randomized controlled trials comparing immunosuppressive interventions in renal transplant recipients published over a 5-year period were included. Outcomes reported in these studies were extracted, along with data regarding completeness of reporting and whether a clear definition of the method used to measure the outcome was provided. A total of 4760 outcomes were identified from 182 studies. Overall, 90.3% outcomes were completely reported; the remainder had missing data that would preclude use in meta-analysis; 31.5% manuscripts did not define a primary endpoint. Efficacy outcomes were more likely to be clearly defined than safety outcomes (OR: 0.022, P<.001) or patient-reported outcome measures (PROMs) (OR: 0.014, P<.001). PROMs were reported in less than half of manuscripts, and only five reported quality-of-life data using a validated tool. There was significant variability in the way that common efficacy and safety outcomes were defined. Variability in the way that endpoints are selected and reported in trials in renal transplantation makes interpretation and comparison between studies difficult.

Renal Squamous Cell Carcinoma of a Native Kidney After Renal Transplant: A Case Report

BackgroundRenal squamous cell carcinoma is a rare primary tumor of the kidney that rapidly invades local structures and has a poor prognosis. Presentation is usually nonspecific and is associated with renal stone disease and chronic infection. Immunosuppressed renal transplant recipients are more likely to develop a malignancy than the general population. Squamous cell carcinoma of the kidney in the context of a renal transplant and long-term immunosuppression has not previously been described in the literature. Case ReportA 46-year-old white man with previous renal stones and recurrent urinary infections underwent a right nephrectomy and subsequent renal transplantation owing to failure of the remaining kidney. Five years posttransplant, an abdominal ultrasound scan was performed owing to recurrent urinary infections and ongoing pyuria. This was reported as normal, but he later developed a discharging sinus in his left flank. A computed tomography (CT) scan revealed a tracking perinephric abscess with an associated cystic lesion of the left kidney. A left nephrectomy was performed and histologic examination suggested an invasive squamous cell carcinoma of the renal pelvis. The patient later required major surgery for chronic infection, and further imaging revealed metastatic disease, resulting in the decision to manage palliatively. ConclusionGiven the nonspecific nature of the symptoms and the poor prognosis, health care professionals should have a lower threshold for diagnostic imaging in these patients. Abdominal ultrasonography was unhelpful and only a later CT scan revealed the underlying malignancy. This should be expedited if there is a persistent abnormality on urinalysis. Once diagnosed, a change in immunosuppressant regime to include sirolimus should be considered.

Outcomes of two-drug maintenance immunosuppression for pediatric renal transplantation: 10-yr follow-up in a single center.

Minimizing IS to reduce side effects without compromising long-term renal transplant survival is the goal of all IS protocols. We conducted a retrospective study of pediatric renal transplants performed August 1988 to July 2008 and treated with two-drug maintenance therapy by one of three protocols: prednisone/cyclosporine without induction (SB) or with daclizumab induction (SBI), or tacrolimus/mycophenolate with daclizumab induction (SF). Kaplan-Meier survival curves were used to determine graft and patient survival at one, three, five, and 10 yr. Associations between graft survival and patient/transplant characteristics were determined using log-rank test and CPH model adjusting for treatment group. About 208 patients were included in the analysis (96 SB, 97 SBI, 15 SF; 148 DD, 60 LD, 37 pre-emptive). Overall graft and patient survival at one, three, five, and 10 yr were similar to the previously published results of pediatric renal transplants in similar years treated predominantly with three-drug maintenance therapy (https://web.emmes.com/study/ped/annlrept/2010). Only biopsy-proven TG was significantly associated with worse graft survival (HR 11.5, 95% CI: 3.4, 38.7). Malignancy rate was low (2.4%) with little PTLD (0.5%). Few opportunistic or other infections occurred (<5% patients). Minimizing IS to a two-drug maintenance regimen had no adverse effect on long-term transplant outcome and had low malignancy and infection rates.

Anti-Erythropoietin Antibody Associated Pure Red Cell Aplasia Resolved after Liver Transplantation.

Patients undergoing antiviral therapy for chronic hepatitis C often develop anemia secondary to ribavirin and interferon. Recombinant erythropoietin has been used to improve anemia associated with antiviral therapy and to minimize dose reductions, which are associated with decreased rates of sustained virologic response. A rare potential side effect of recombinant erythropoietin is anti-erythropoietin antibody associated pure red cell aplasia. In chronic kidney disease patients with this entity, there have been good outcomes associated with renal transplant and subsequent immunosuppression. In this case, a chronic liver disease patient developed anti-erythropoietin associated pure red cell aplasia and recovered after liver transplantation and immunosuppression. It is unclear whether it is the transplanted organ, the subsequent immunosuppression, or the combination that contributed to the response. In conclusion, anti-erythropoietin associated pure red cell aplasia is a serious complication of erythropoietin therapy, but this entity should not be considered a contraindication for solid organ transplantation.

Belatacept in kidney transplantation.

Calcineurin inhibitors (CNIs) play a major role in long-term renal allograft dysfunction because of their nephrotoxic side-effects. Belatacept, a selective costimulation blockade agent, is the first biological agent approved for maintenance immunosuppression in renal transplantation. Studies have shown better preservation of glomerular filtration rate and improved metabolic end points with belatacept when compared with CNIs. More recent studies have shown that belatacept can be an effective first-line immunosuppressive agent with complete avoidance of CNIs and corticosteroids. Newer biological agents like belatacept may replace CNIs/corticosteroids in renal transplant recipients, with a benefit of better short-term and long-term renal function, better compliance, and ultimately a possible improvement in long-term renal allograft survival.

Soluble CD30 does not predict late acute rejection or safe tapering of immunosuppression in renal transplantation

BackgroundPrevious reports revealed the potential value of the soluble CD30 level (sCD30) as biomarker for the risk of acute rejection and graft failure after renal transplantation, here we examined its use for the prediction of safe tapering of calcineurin inhibitors as well as late acute rejection. MethodsIn a cohort of renal transplant patients receiving triple immunosuppressive therapy we examined whether sCD30 can be used as a marker for safe (rejection-free) discontinuation of tacrolimus at six months after transplantation (TDS cohort: 24 rejectors and 44 non-rejecting controls). Also, in a second cohort of patients (n=22, rejectors n=11 and non-rejectors n=11), participating in a clinical trial of rituximab as induction therapy after renal transplantation (RITS cohort), we examined whether sCD30 could predict the occurrence of late (>3months post-transplant) acute rejection episodes. sCD30 was measured by ELISA in serum taken before and at several time points after transplantation. ResultsOverall, in the TDS cohort sCD30 decreased after transplantation. No difference in sCD30 was observed between rejectors and non-rejecting controls at any of the time points measured. In addition, in the RITS cohort, sCD30 measured at three months after transplantation were not indicative for the occurrence of late acute rejection. ConclusionIn two prospectively followed cohorts of renal transplant patients we found no association between sCD30 and the occurrence of either late acute rejection or acute rejection after reduction of immunosuppression.