Therapy In Renal Transplant Recipients Research Articles

Impact of an ultrasensitive Cytomegalovirus quantitative nucleic acid test on Cytomegalovirus detection and therapy in renal transplant recipients.

Cytomegalovirus (CMV) infection has broad implications for morbidity and mortality in renal transplant recipients (RTR). Routine surveillance for CMV replication with PCR-based quantitative nucleic acid testing (qNAT) assays is standard practice in most transplant centers, but the impact of assay sensitivity on antiviral decision-making and virologic outcomes has not been studied. We investigated the effects of an ultrasensitive CMV qNAT assay on multiple clinical outcomes, including time to detection and duration of CMV DNAemia. We conducted a single-center cohort study contrasting RTRs monitored with a qNAT with a higher lower limit of quantification (LLOQ >300IU/mL) with those monitored with a more sensitive qNAT (LLOQ >35IU/mL). Patients were stratified by donor (D)/recipient (R) CMV serostatus (D+/R-: high risk; any R+: moderate risk). CMV viral load monitoring was performed monthly post transplantation, with the primary outcomes being time to CMV DNAemia and its duration. Total 1382 patients were analyzed from 2014 to 2016 and 2019 to 2021. Moderate-risk RTRs monitored with the more sensitive assay experienced a greater hazard for the development of a first episode of CMV DNAemia (aHR: 1.95, 95% confidence interval [CI]: 1.55-2.46) and an average of 24 (95% CI: 16.40-31.98) additional days of DNAemia. There was no difference in CMV end-organ disease or 1-year all-cause mortality between moderate-risk RTRs. The more sensitive assay was associated with earlier detection and extended durations of CMV DNAemia in moderate-risk RTRs, without altering clinical outcomes. These findings inform optimal use of these assays and antiviral stewardship in RTRs. The use of ultrasensitive CMV qNAT assays in moderate-risk CMV renal transplant recipients is associated with earlier detection and longer durations of CMV DNAemia without impacting CMV end-organ disease or 1-year mortality.

Determinants of immunosuppressive therapy in renal transplant recipients: an Italian observational study (the CESIT project)

BackgroundVery scanty evidence is available on factors influencing the choice of immunosuppressive drug therapy after kidney transplantation.MethodsAn Italian multiregional real-world study was conducted integrating national transplant information system and claims data. All patients undergoing kidney transplantation for the first time during 2009–2019 (incident patients) were considered. Multilevel logistic models were used to estimate Odds Ratio (OR) and corresponding 95% Confidence intervals. Factors with statistically significance were identified as characteristics associated with treatment regimens: cyclosporin-CsA vs tacrolimus-Tac and, within the latter group, mTOR inhibitors vs mycophenolate-MMF.ResultsWe identified 3,622 kidney patients undergoing transplantation in 17 hospitals located in 4 Italian regions, 78.3% was treated with TAC-based therapy, of which 78% and 22% in combination with MMF and mTOR, respectively. For both comparison groups, the choice of immunosuppressive regimens was mostly guided by standard hospital practices. Only few recipient and donor characteristics were found associated with specific regimen (donor/receipt age, immunological risk and diabetes).ConclusionsThe choice of post-renal transplant immunosuppressive therapy seems to be mostly driven by standard Centre practices, while only partially based on patient’s characteristics and recognized international guidelines.

Dynamic Monitoring of Intracellular Tacrolimus and Mycophenolic Acid Therapy in Renal Transplant Recipients Using Magnetic Bead Extraction Combined with LC-MS/MS.

Tacrolimus (TAC) and mycophenolic acid (MPA) are commonly used immunosuppressive therapies after renal transplant. Our objective was to quantify TAC and MPA concentrations in peripheral blood mononuclear cells (PBMCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) and to evaluate and validate the performance of the methodology. A prospective follow-up cohort study was conducted to determine whether intracellular concentrations were associated with adverse outcomes in renal transplants. PBMCs were prepared using the Ficoll separation technique and purified with erythrocyte lysis. The cells were counted using Sysmex XN-3100 and then packaged and frozen according to a 50 µL volume containing 1.0 × 106 cells. TAC and MPA were extracted using MagnaBeads and quantified using an LC-MS/MS platform. The chromatography was run on a reversed-phase Waters Acquity UPLC BEH C18 column (1.7 µm, 50 mm × 2.1 mm) for gradient elution separation with a total run time of 4.5 min and a flow rate of 0.3 mL/min. Mobile phases A and B were water and methanol, respectively, each containing 2 mM ammonium acetate and 0.1% formic acid. Renal transplant recipients receiving TAC and MPA in combination were selected for clinical validation and divided into two groups: a stable group and an adverse outcome group. The concentrations were dynamically monitored at 5, 7, 14, and 21 days (D5, D7, D14, and D21) and 1, 2, 3, and 6 months (M1, M2, M3, and M6) after operation. Method performance validation was performed according to Food and Drug Administration guidelines, showing high specificity and sensitivity. The TAC and MPA calibration curves were linear (r2 = 0.9988 and r2 = 0.9990, respectively). Both intra-day and inter-day imprecision and inaccuracy were less than 15%. Matrix effects and recoveries were satisfactory. The TAC and MPA concentrations in 304 "real" PBMC samples from 47 renal transplant recipients were within the calibration curve range (0.12 to 16.40 ng/mL and 0.20 to 4.72 ng/mL, respectively). There was a weak correlation between PBMC-C0TAC and WB-C0TAC (p < 0.05), but no correlation was found for MPA. The level of immunosuppressive intra-patient variation (IPV) was higher in PBMC at 77.47% (55.06, 97.76%) than in WB at 34.61% (21.90, 49.85%). During the dynamic change in C0TAC, PBMC-C0TAC was in a fluctuating state, and no stable period was found. PBMC-C0TAC did not show a significant difference between the stable and adverse outcome group, but the level of the adverse outcome group was generally higher than that of the stable group. Compared with conventional therapeutic drug monitoring, the proposed rapid and sensitive method can provide more clinically reliable information on drug concentration at an active site, which has the potential to be applied to the clinical monitoring of intracellular immunosuppressive concentration in organ transplantation. However, the application of PBMC-C0TAC in adverse outcomes of renal transplant should be studied further.

#4610 LACK OF EFFICACY AND SAFETY OF ECULIZUMAB FOR TREATMENT OF ANTIBODY-MEDIATED REJECTION FOLLOWING RENAL TRANSPLANTATION

Abstract Background and Aims We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis and intravenous immunoglobulin therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). Method This was a multicenter, open-label, prospective, randomized analysis. The patients were randomized by therapy type (eg, eculizumab infusions or standard of care [SOC]: plasmapheresis/intravenous immunoglobulin). The patients (ie, eculizumab arm: 7 patients, SOC arm: 4 patients) were evaluated for the continued presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histologic evidence, using repeat renal biopsy after treatment. Results The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Cases of AMR were diagnosed in the early post-transplantation period in 2 patients (eculizumab arm: 1 patient, SOC arm: 1 patient) and in the late period in 9 patients. Most of the reports show that eculizumab, in combination with other therapeutic measures such as PP and/or IVIG, effectively reversed rejection. However, eculizumab alone could not treat AMR effectively. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. After AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Conclusion Eculizumab alone cannot treat AMR effectively and does not prevent acute AMR from progressing to chronic AMR or transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

Lack of Efficacy and Safety of Eculizumab for Treatment of Antibody-Mediated Rejection Following Renal Transplantation

We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis and intravenous immunoglobulin therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). This was a multicenter, open-label, prospective, randomized analysis. The patients were randomized by therapy type (eg, eculizumab infusions or standard of care [SOC]: plasmapheresis/intravenous immunoglobulin). The patients (ie, eculizumab arm: 7 patients, SOC arm: 4 patients) were evaluated for the continued presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histologic evidence, using repeat renal biopsy after treatment. The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. After AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Eculizumab alone cannot treat AMR effectively and does not prevent acute AMR from progressing to chronic AMR or transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

P1755EFFICACY AND SAFETY ECULIZUMAB FOR THE TREATMENT OF ANTIBODY MEDIATED REJECTION FOLLOWING RENAL TRANSPLANTATION

Abstract Background and Aims : We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis (PP) and intravenous immunoglobulin (IVIG) therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). Methods This was a multi-center, open-label, prospective, randomized analysis. The patients were randomized as to therapy type (eculizumab infusions or standard of care, SOC: PP/IVIG). The patients (eculizumab arm: 7 patients, SOC arm: 4 patient) were evaluated for the continuing presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histological evidence, using repeat renal biopsies after treatment. Results The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. Following AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Conclusion Eculizumab alone is not sufficient to treat AMR and does not prevent acute AMR from progressing to chronic AMR or to transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

Chemoprevention of keratinocyte carcinoma and actinic keratosis in solid-organ transplant recipients: Systematic review and meta-analyses

To the Editor: Skin cancers account for 40% of malignancies in solid-organ transplant recipients (SOTRs), who have an 80-fold increased risk of squamous cell carcinoma (SCC) and a 16-fold increased risk of basal cell carcinoma (BCC). Systemic chemoprevention is one method to mitigate this amplified risk. Acitretin, for instance, has been used to prevent keratinocyte carcinomas (KC) and actinic keratoses (AK) in SOTRs since 1995,1Bavinck J.N. Tieben L.M. Van der Woude F.J. et al.Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study.J Clin Oncol. 1995; 13: 1933-1938Crossref PubMed Google Scholar but its adverse effects include mucositis, liver and lipid abnormalities, and teratogenicity.2George R. Weightman W. Russ G.R. et al.Acitretin for chemoprevention of non-melanoma skin cancers in renal transplant recipients.Australas J Dermatol. 2002; 43: 269-273Crossref PubMed Scopus (130) Google Scholar Nicotinamide, an amide form of vitamin B3, is a newer chemoprophylaxis with fewer adverse effects.3Chen A.C. Martin A.J. Dalziell R.A. et al.A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients.Br J Dermatol. 2016; 175: 1073-1075Crossref PubMed Scopus (61) Google Scholar Here we report results of a pairwise and network meta-analyses to summarize the current evidence regarding chemoprevention. We selected studies that analyzed the efficacy of systemic chemoprevention to prevent KC/AK in patients who are SOTRs or have a history of 2 or more KCs, or both. We limited our search to placebo-controlled, randomized control trials (RCTs) that reported the number of new KC/AK in both arms. Two authors (L.Y.T., S.Y.C.T.) independently conducted the literature search, screened titles and abstracts for eligibility, and extracted data. Statistical synthesis was performed with RevMan 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). After the literature search, 6 RCTs with 734 patients were included in the quantitative synthesis (Appendix A, available via Mendeley at https://doi.org/10.17632/m6z2fzkkxn.2). Of the 6 RCTs, 3 studies with 580 patients (range, 17-192 patients) compared nicotinamide to placebo, and 3 studies with 154 patients (range, 19-35 patients) compared acitretin to placebo. Pairwise meta-analysis of all 6 RCTs using a random-effects model demonstrated a significant risk reduction with chemoprevention (Fig 1). The overall mean difference was 0.855 (95% confidence interval, 0.365-1.345; P < .001). In addition, acitretin and nicotinamide were both efficacious, with a combined mean difference of 0.792 (95% confidence interval, 0.298-1.286; P = .00168) for acitretin and a combined mean difference of 4.239 (95% confidence interval, 0.611-7.866; P = .0220) for nicotinamide. A network meta-analysis comparing nicotinamide and acitretin found no significant difference between the 2 treatments (Fig 2, Appendix B).Fig 1Forest plot of the pairwise meta-analysis of randomized controlled trials. The squares indicate the mean difference and are proportional to the weights used in the meta-analysis. The horizontal lines represent the 95% confidence interval (CI). The diamond indicates the weighted mean difference, and the lateral tips of the diamond indicate the associated 95% CI.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 2Network graph and league table of the network meta-analysis. Mean differences and 95% confidence intervals are calculated using a random-effects model. A mean difference >1 means the top-left treatment is better.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This meta-analysis does not address the optimal dosages of the drugs or the frequency of adverse effects. In addition, owing to the limited numbers of eligible RCTs, we are unable to investigate how chemoprevention is influenced by the duration or type of transplantation, duration of systemic chemoprevention, or existing immunosuppressive regimens. Moving forward, topical chemoprevention may be a suitable alternative to systemic chemoprophylaxis in SOTRs. Notably, large RCTs have evaluated topical chemoprevention for actinic keratosis. For instance, the Veterans Affairs Keratinocyte Carcinoma Chemoprevention trial found that topical 5% 5-fluorouracil cream resulted in a 49% relative risk reduction in the number of AK after 6 months and reduced the risk of SCC requiring surgery by 75% after 1 year but did not lower the risk of BCC.4Hyemin P. Hogan D. Eilers D. et al.Long-term efficacy of topical fluorouracil cream 5% for treating actinic keratosis: a randomized clinical trial.JAMA Dermatol. 2015; 151: 952-960Crossref PubMed Scopus (69) Google Scholar,5Weinstock M.A. Thwin S.S. Siegel J.A. et al.Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: a randomized clinical trial.JAMA Dermatol. 2018; 154: 167-174Crossref PubMed Scopus (54) Google Scholar To our knowledge, this is the first meta-analysis that statistically integrates the current evidence regarding chemoprevention of KC/AK. This study demonstrates that systemic chemoprevention with nicotinamide or acitretin is effective in lowering the risk of KC/AK. Yet, even with the advent of better chemoprevention, regular physician surveillance and sun protection are still key basic strategies that should be practiced by all SOTRs.

Direct-Acting Antiretroviral Therapy in Renal Transplant Recipients With Human Immunodeficiency Virus–Hepatitis C Virus Coinfection: Report of Our Experience and Literature Review

A minor graft and patient survival are described in renal transplant recipients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection than in recipients infected with only HIV. The high efficacy of direct-acting antivirals could improve the results. The experience reported in renal transplant recipients with coinfection is very limited. Material and MethodsWe analyzed the evolution of renal recipients with HIV-HCV coinfection treated with direct-acting antivirals in our center. Clinical, analytical, and microbiological variables were collected before and after treatment. ResultsFrom 2001 to 2018 we performed 11 renal transplants in patients with HIV infection, and 6 (54.5%) had HIV-HCV coinfection. One patient lost the graft before the development of direct-acting antivirals. Another patient with functioning graft has refused to receive any treatment.Four patients have been treated with direct-acting antivirals. One was treated 18 months before the transplant; 3 received treatment after transplant. All received sofosbuvir-based therapies. All had a sustained virologic response after 12 weeks and an improvement of liver function.In the patients treated after renal transplant, time post transplant at the beginning of treatment was 99.6 (SD, 22.8) months, and follow-up after treatment in all patients was 40.2 (SD, 8.16) months. To modify immunosuppressive regimen was not necessary, although 2 patients required an increase of tacrolimus doses. We do not observe deterioration of renal function. All have maintained a good immunologic and microbiological control without requiring changes in antiretrovirals. We do not observe complications associated with treatment. ConclusionsDirect-acting antivirals therapy is safe and effective and may offer new possibilities to patients with HIV-HCV coinfection.

Coronavirus disease in a renal allograft recipient: A case report

Coronavirus disease-19 (COVID-19) affected everyone on the globe, including renal transplant recipients who are at increased risk of infection. The clinical manifestations, immunosuppressive modifications, and treatment protocol are not well defined. We are reporting a case of renal transplant recipient and reviewed all case reports and series (a total of 100 patients) published to date to comprehend the clinical manifestations, immunosuppression modifications, treatment given, and outcomes of the patients. A 57-year-old male kidney transplant recipient had a fever, headache, weakness, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. He became asymptomatic with the treatment of hydroxychloroquine, azithromycin, and oseltamivir. However, he remained persistently positive by reverse transcriptase-polymerase chain reaction for SARS-CoV-2 for 4 weeks and became negative only after Ivermectin therapy, a safer medicine than antivirals/antiretrovirals used for COVID therapy in renal transplant recipients. Of the 100 patients review of case series, fever was noted in 85%, cough 71%, diarrhea 10%, and radiographic abnormalities in 75% of cases. Only in 3% of cases, steroid was stopped, and in the rest of the cases, 63% either continued in the same doses or changed to methylprednisolone in 34%. Calcineurin inhibitors were temporarily stopped in 42% of cases, reduced in 9% of cases, and continued in the same doses in 49% of cases. The anti-metabolites were discontinued in 83%, reduced in 9% of cases, and not changed in 8% of cases. SARI was observed in 18% and acute kidney injury (AKI) in 26% of cases. Of all the AKI, 11% required renal replacement therapy. Mortality was observed in 21% of cases. COVID in renal transplant recipients may show an unusually longer positivity. Ivermectin may be used in the absence of any conclusive SARS-CoV-2 antivirals. Mortality is high in renal transplant recipients.

Bone biomarkers in de novo renal transplant recipients

Successful kidney transplantation (partly) corrects the physiologic and metabolic abnormalities driving chronic kidney disease – mineral and bone disorders. At the same time, renal transplant recipients are exposed to immunosuppressive agents that may affect bone metabolism. Bone biomarkers have been suggested as surrogates of or adjuncts to bone biopsy and imaging techniques to assess bone health and to classify risk of bone loss and fractures. Bone biomarkers may be classified as circulating factors that affect bone metabolism (commonly referred to as bone metabolism markers) or that reflect bone cell number and/or activity (commonly referred to as bone turnover markers). A growing body of evidence shows that successful renal transplantation has a major impact on both bone metabolism and bone turnover. Analytical issues, including the cross-reactivity with fragments, complicate the interpretation of bone biomarkers, especially in the setting of a rapid changing kidney function, as is the case after successful renal transplantation. Overall, bone turnover seems to decline following renal transplantation, but inter-individual variability is substantial. Preliminary evidence indicates that bone biomarkers may be useful in guiding mineral and bone therapy in renal transplant recipients.

Mobile medication manager application to improve adherence with immunosuppressive therapy in renal transplant recipients: A randomized controlled trial.

BackgroundNonadherence to immunosuppressive therapy after renal transplantation is associated with poor graft outcomes. We aimed to evaluate whether the use of the Adhere4U mobile medication manager application could improve adherence among renal transplant recipients ≥1 year posttransplantation. Adhere4U can provide medication reminders, monitor medication use, and provide information on immunosuppressants.MethodsWe conducted a prospective randomized controlled study to compare the rate of nonadherence to index immunosuppressant (tacrolimus or cyclosporine) in a group using the Adhere4U app (mobile group) and in another group receiving conventional care (control group). The primary outcome was the nonadherence rate, which was evaluated using an electronic medication event monitoring system during the 6-month intervention period. Our secondary outcome included self-reported adherence using the Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS) and the visual analog scale (VAS) based on a 4-week recall on days 28, 90, and 180. Longitudinal data of repeated measures of self-rated adherence were analyzed using generalized estimating equations (GEE) to compare the between-group difference in adherence change over time.ResultsBetween November 2013 and May 2015, 138 renal transplant recipients were randomly allocated to the control (n = 67) or the mobile group (n = 71). The overall nonadherence rate over the 6-month study period by electronic monitoring was 63.6%, with no between-group difference [mobile group, 65.0% (n = 39/60); control group, 62.1% (n = 36/58); odds ratio 1.14; 95% confidence interval 0.53–2.40; p = 0.89]. Self-rated nonadherence assessed using the BAASIS and VAS at baseline was 53.7% and 51.5%, respectively. Although the self-rated nonadherence by BAASIS of the mobile group was lower than the control group throughout the study period, there was no between-group difference in the change of nonadherence over time (χ2 = 2.82, df = 3, p = 0.42 by logistic GEE). There also was no significant between-group difference in the nonadherence by VAS (χ2 = 1.71, df = 3, p = 0.63 by logistic GEE) over time. The main limitation of this study was the low rate of patient engagement with the app among the mobile group. The rate of app use was 47.6% (31/65) at 28 days, 33.9% (19/56) at 90 days, and 11.5% (6/52) at 180 days.ConclusionsThe Adhere4U application did not improve adherence to immunosuppressive therapy. Our evidence is limited by the high rate of attrition. Further studies on strategies to facilitate patient engagement with mobile interventions are warranted.

MTOR Inhibitor Everolimus in Regulatory T Cell Expansion for Clinical Application in Transplantation.

Experimental and preclinical evidence suggest that adoptive transfer of regulatory T (Treg) cells could be an appropriate therapeutic strategy to induce tolerance and improve graft survival in transplanted patients. The University of Kentucky Transplant Service Line is developing a novel phase I/II clinical trial with ex vivo expanded autologous Treg cells as an adoptive cellular therapy in renal transplant recipients who are using everolimus (EVR)-based immunosuppressive regimen. The aim of this study was to determine the mechanisms of action and efficacy of EVR for the development of functionally competent Treg cell-based adoptive immunotherapy in transplantation to integrate a common EVR-based regimen in vivo (in the patient) and ex vivo (in the expansion of autologous Treg cells). CD25 Treg cells were selected from leukapheresis product with a GMP-compliant cell separation system and placed in 5-day (short) or 21-day (long) culture with EVR or rapamycin (RAPA). Multi-parametric flow cytometry analyses were used to monitor the expansion rates, phenotype, autophagic flux, and suppressor function of the cells. phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway profiles of treated cells were analyzed by Western blot and cell bioenergetic parameters by extracellular flux analysis. EVR-treated cells showed temporary slower growth, lower metabolic rates, and reduced phosphorylation of protein kinase B compared with RAPA-treated cells. In spite of these differences, the expansion rates, phenotype, and suppressor function of long-term Treg cells in culture with EVR were similar to those with RAPA. Our results support the feasibility of EVR to expand functionally competent Treg cells for their clinical use.

Post-Renal Transplant Metabolic Acidosis: A Neglected Entity.

Metabolic acidosis is a prevalent yet overlooked entity among renal transplant recipients (RTRs) and incurs adverse effects on graft function. Although graft dysfunction and calcineurin inhibitor usage have been linked with renal tubular acidosis (RTA), there is no Indian data on prevalence or risk factors of post-transplant acidosis. A cross-sectional study was conducted on 106 adult RTRs, with a transplant duration of >6 months and an estimated glomerular filtration rate (GFR) >40 ml/min/1.73 m2. Acidosis was diagnosed on basis of plasma bicarbonate and arterial pH. Serum and urine electrolytes with anion gap were determined to diagnose and type RTA. Acidosis was diagnosed in 44 of 106 patients (41.5%) with 23 (52.27%) having severe acidosis. Type I RTA was the most common subtype (52.5%) followed by type IV (30.9%) and type II RTA (7.5%). The correlation between estimated glomerular filtration rate and acidosis was minimally linear (r = 0.1088), with multivariate analysis revealing previous acute rejection episodes, current serum tacrolimus levels, cotrimoxazole usage and intake of animal proteins to be independent risk factors. The serum albumin levels were low in the acidosis group and showed linear correlation with bicarbonate levels (r = 0.298). There is a high prevalence of metabolic acidosis in RTRs with type I RTA being most common subtype. Screening of RTRs on a regular basis is a feasible approach for early diagnosis and intervention. However, prospective studies are needed to demonstrate the effect of acidosis on graft survival and benefit of bicarbonate therapy in RTRs.

Dermatosis en pacientes trasplantados renales

IntroductionThe chronic use of immunosuppressive therapy in renal transplant recipients (RTRs) favors the appearance of cutaneous lesions. Members of the multidisciplinary team should have knowledge of these diseases in order for them to be able to provide timely treatment. ObjectiveTo determine the prevalence of cutaneous diseases among adult RTRs seen in the outpatient clinic of Hospital de San José de Bogotá, Colombia, between July 2015 and July 2016. Materials and methodsA descriptive cross-sectional study including 33 adult RTRs. ResultsThe mean age was 49.7 years (SD 11.6), 23 were females (69.7%), with a 4-year median time after transplant (IQR p:25:2 years - p:75:7years). All patients were receiving maintenance immunosuppressive therapy. The prevalence of skin lesions was 81.8% (n=27); the most prevalent were inflammatory and other type disorders (51.5%), followed by infections (33.3%). Three suspicious malignancy lesions were identified (9.0%). Biopsies demonstrated two basal-cell carcinomas (n=2) and one infiltrating squamous cell carcinoma (n=1). ConclusionThe frequency of cutaneous lesions is high in RTRs. This study design does not allow establishing a cause-effect relationship between the type of immunosuppressive regimen received and the appearance of skin lesions. The importance of periodic dermatologic examinations of RTRs to detect skin and mucosal membrane disorders affecting the quality of life is emphasized.

Percutaneous coronary interventions and antiplatelet therapy in renal transplant recipients.

Cardiovascular disease is the leading cause of mortality and morbidity following renal transplantation (RT), accounting for 40-50% of all deaths. After renal transplantation, an adverse cardiovascular event occurs in nearly 40% of patients; given the dialysis vintage and the average wait time, the likelihood of receiving coronary revascularization is very high. There is a significant gap in the literature in terms of the outcomes of prophylactic coronary revascularization in renal transplantation candidates. Current guidelines on myocardial revascularization stipulate that renal transplant patients with significant coronary artery disease (CAD) should not be excluded from the potential benefit of revascularization. Compared with percutaneous coronary intervention (PCI), however, coronary artery bypass grafting is associated with higher early and 30-day mortality. About one-third of renal transplant patients with CAD have to be treated invasively and so PCI is currently the most popular mode of revascularization in these fragile and compromised patients. A newer generation drug-eluting stent (DES) should be preferred over a bare metal stent (BMS) because of its lower risk of restenosis and improved safety concerns (stent thrombosis) compared with first generation DES and BMS. Among DES, despite no significant differences being reported in terms of efficacy, the newer everolimus and zotarolimus eluting stents should be preferred given the possibility of discontinuing, if necessary, dual antiplatelet therapy before 12 months. Since there is a lack of randomized controlled trials, the current guidelines are inadequate to provide a specifically tailored antiplatelet therapeutic approach for renal transplant patients. At present, clopidogrel is the most used agent, confirming its central role in the therapeutic management of renal transplant patients undergoing PCI. While progress in malignancy-related mortality seems a more distant target, a slow but steady reduction in cardiovascular deaths, improving pharmacological and interventional therapy, is nowadays an achievable medium-term target in renal transplant patients.

Does African American Race Impact Statin Efficacy in Renal Transplant Outcomes?

There is a lack of studies assessing if race impacts the efficacy of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitor (“statin”) therapy on renal transplantation (RTx) outcomes. We examined the association between statin therapy and RTx outcomes, while concurrently quantifying the effect modification African American (AA) race has on statin efficacy.This was a retrospective longitudinal cohort study of solitary adult RTx (n = 1176) between June 2005 and May 2013. The Cox proportional hazard model was used to examine the impact of statin therapy on graft loss, death, and acute rejection and determine if significant interactions exist between statin therapy and race. Models were adjusted for demographics, socioeconomic status, cardiovascular history, medication use, and transplant characteristics.AAs (n = 624) and non-African Americans (n = 552) were equally likely to receive statin therapy (P = 0.922). Mean LDL and TGs in AA were 94 mg/dL and 133 mg/dL compared to 90 mg/dL and 163 mg/dL in non-AA, respectively. After adjusting for confounders, high statin users had 52% lower risk of developing graft loss (HR 0.48, 95% CI 0.29–0.80) and a nonstatistically significant reduction in death (HR 0.50, 95% CI 0.23–1.06) compared to low statin users. Acute rejection was not significantly influenced by statin use (HR 0.77 95% CI 0.46–1.27). There was a significant interaction between race and statin therapy for death (P = 0.007), but not for graft loss (P = 0.121) or rejection (P = 0.605). After stratifying by race, high statin use reduced the risk of death in AAs (HR 0.43, 95% CI 0.20–0.94), but not in non-AAs (HR 1.09, 95% CI 0.49–2.44).High statin use reduces the risk of graft loss in RTx, with a mortality benefit in AAs compared to non-AA, despite similar LDL levels. These results suggest a compelling reason to optimize statin therapy in renal transplant recipients (RTR), especially in AAs.

Safety and Efficacy Endpoints for Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients.

Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejection rates declined, alternative surrogate markers such as renal function, histological findings, and immunological markers are used to measure efficacy and to provide mechanistic insight. In this review, we will discuss the current status of MSCs in renal transplantation with a focus on the endpoints used in the different experimental and clinical studies.

Changes in the T and B- Cell Subsets Following Treatment with a CD25-Antibody in Patients with Steroid Refractory GvHD

Allogeneic stem cell transplantation is the therapeutic option for a variety of malignant and non-malignant haematological diseases. Graft versus Host Disease (GvHD) is a common post transplant complication. In 40% of these patients, GvHD is steroid refractory and associated with a mortality of around 60%. Basiliximab is a chimeric murine –human antibody also selective for interleukin -2 receptor (IL-2R) with a half life of 7 days. It is routinely used as part of the induction therapy in renal transplant recipients to prevent acute rejection following successful phase III studies. Phase 2 studies have demonstrated its superior efficacy in treating patients with steroid refractory GvHD (1). We administered Basiliximab in 14 patients with steroid refractory GvHD with a median age of 41 (range 20-69). M: F 7:7. All patients but one 13/14 received PBSC from unrelated donors and 6/13 had mismatched unrelated donors. Overall response was in the order of 12/14 (85%). One patient could not be assessed. 7/14 (50%) achieved a complete response to treatment. We aimed to study the in vivo T- and B-cell changes following Basiliximab administration as this would be an ideal platform to monitor the alterations in the regulatory T and B-cell compartment.PBMCs were obtained from all donors after informed consent, Immucan (Nr 11-116) approved by our local ethics committee, prior to and after weekly administration of Basiliximab 40mg for 4 weeks. Control samples were obtained from patients with steroid responsive acute GvHD.The total number of CD3+ as well as CD4+ and CD8+ T-cells remained constant during treatment and no change was observed on comparison with the controls. Gagliani et al (2) demonstrated that regulatory type 1 T-cells can be identified by the co-expression of CD49b and Lag3. No difference was observed between the % CD49d+, Lag3+ T-cells in the control cohort and the treatment cohort prior to therapy, ie day 0. The % CD49d+, Lag3+ T-cells decreased during the treatment period (statistically significant) in comparison to the control cohort. Despite the use of the CD25-antibody, a small population of CD25+, CD127+ cells could be detected and this population correlated to the % CD49d+, Lag3+ T-cells. [Display omitted] [Display omitted] The % CD19+, CD20+ B-cells were similar prior to treatment in the treatment group and control. Following the first administration a rise was observed followed by a decline over the next 3 weeks. No changes were seen in the activated (CD20+, CD86+) and anergic B-cell subsets (CD20+, CD21-) during the observation period. The % of CD24high, CD27+ regulatory B-cells were found to be twice that seen in the controls. With treatment a decrease was seen in this population. The CD24high, CD38high transitional B-cells were also found to be higher than that seen in the controls. No change was observed in this subset with treatment. [Display omitted] This is the first attempt to study the in-vivo changes induced by a CD25 antibody in patients with steroid refractory GvHD. We conclude that this antibody not only depletes the alloreactive CD25+ T and B-cell population but also alters the regulatory T and B-cell subsets in comparison to patients with steroid responsive GvHD. Our clinical data supports the efficacy of this drug in patients with steroid refractory GvHD. Contrary to the current knowledge that regulatory T-cells are required for GvHD suppression our data suggests that Basiliximab facilitates regulatory T-cell depletion. The reduction of the regulatory T-cell subset observed in patients responding to anti CD25 treatment suggests a complex regulation and potential dichotomous role of these cells in acute GvHD. 1.Schmidt-Hieber M, Fietz T, Knauf W, Uharek L, Hopfenmuller W, Thiel E, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol. 2005 Aug;130(4):568-74.2.Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, et al.Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013 Jun;19(6):739-46 DisclosuresNo relevant conflicts of interest to declare.

Cost utility analysis of immunosuppressive regimens in adult renal transplant recipients in England and Wales.

BackgroundEnd-stage renal disease is the irreversible final stage of chronic kidney disease and is fatal when not managed by either transplantation or dialysis. Transplantation is generally preferred over dialysis. However, to prevent graft rejection or loss, lifelong immunosuppression is required. Tacrolimus is currently the cornerstone of post-transplantation immunosuppression. The study aim was to carry out an economic evaluation of immunosuppression, including more recent agents such as a once-daily prolonged-release formulation of tacrolimus (Advagraf™) and belatacept, relative to a twice-daily immediate-release formulation of tacrolimus (Prograf™).MethodsA model was constructed comprising six states: onset of biopsy-confirmed acute rejection, functioning graft with or without a biopsy-confirmed acute rejection, non-functioning graft (dialysis), re-transplantation, and death. Data on clinical effectiveness were derived from a systematic literature review and the model captured the effects of patient adherence to immunosuppressant therapy on graft survival using relative risk of graft survival and published data on adherence in patients using Advagraf and Prograf. In the base case, the time horizon was 25 years and one-way and probabilistic sensitivity analyses were conducted.ResultsThe analysis demonstrated that Prograf was cost-effective when compared with cyclosporin and belatacept and was more effective than sirolimus, but would not be considered cost-effective against sirolimus. The modeled improvement in the adherence profile of patients using Advagraf relative to Prograf resulted in both improved clinical outcomes and reduced costs.ConclusionPrograf was more clinically effective than cyclosporin, belatacept, and sirolimus, supporting its current positioning as the mainstay of immunosuppressive therapy in renal transplant recipients. Based on improved patient adherence with Advagraf, the model projected that Advagraf would be both more effective and less costly than Prograf. Replacing Prograf with Advagraf as the standard of care for post-transplant immunosuppression could likely result in both cost savings and improved clinical outcomes.

Induction Therapy in Renal Transplant Recipients: A Review

Transplant science has improved significantly over the last decade. Influenced by novel advancements, rejection rates and short-term graft losses diminished substantially. Induction therapy was shown to reduce rejection rates and improve short-term graft survival. In this article, we discuss the most commonly used induction agents and the choice of induction therapy in different renal transplant recipient subgroups. The medical literature as well as our own experience was used to prepare this review. At this time, induction therapy is commonly used in upwards of 80%, of renal transplant recipients. Depleting agents are the most frequently used agents and they account for more than 75% of all induction therapies in the United States. Currently, there is no consensus regarding the choice of induction therapy. The type of induction therapy is generally selected based on a comprehensive evaluation of the recipient and the donor’s immunological risks, the risk of developing opportunistic infection and malignancy, recipient comorbidities, financial burden and the choice of maintenance immunosuppressive regimen.