Immunosuppressant drugs and quality-of-life outcomes in kidney transplant recipients: An international cohort study (EU-TRAIN)

Immunosuppressant; Quality of life; TransplantationImmunosupressor; Qualitat de vida; TrasplantamentInmunosupresor; Calidad de vida; TrasplanteIntroduction: Patient-Reported Outcomes (PRO) integrate a wide range of holistic dimensions that arenot captured within clinical outcomes. Particularly, from induction treatment to maintenance therapy, patient quality-of-life (QoL) of kidney transplant recipients have been sparsely investigated in international settings. Methods: In a prospective, multi-centric cohort study, including nine transplant centers in four countries, we explored the QoL during the year following transplantation using validated elicitation instruments (EQ-5D-3L index with VAS) in a population of kidney transplant patients receiving immunosuppressive therapies. Calcineurin inhibitors (tacrolimus and ciclosporin), IMPD inhibitor (mycophenolate mofetil), and mTOR inhibitors (everolimus and sirolimus) were the standard-of-care (SOC) medications, together with tapering glucocorticoid therapy. We used EQ-5D and VAS data as QoL measures alongside descriptive statistics at inclusion, per country and hospital center. We computed the proportions of patients with different immunosuppressive therapy patterns, and using bivariate and multivariate analyses, assessed the variations of EQ-5D and VAS between baseline (i.e., inclusion Month 0) and follow up visits (Month 12). Results: Among 542 kidney transplant patients included and followed from November 2018 to June 2021, 491 filled at least one QoL questionnaire at least at baseline (Month 0). The majority of patients in all countries received tacrolimus and mycophenolate mofetil, ranging from 90.0% in Switzerland and Spain to 95.8% in Germany. At M12, a significant proportion of patients switched immunosuppressive drugs, with proportion varying from 20% in Germany to 40% in Spain and Switzerland. At visit M12, patients who kept SOC therapy had higher EQ-5D (by 8 percentage points, p < 0.05) and VAS (by 4 percentage points, p < 0.1) scores than switchers. VAS scores were generally lower than EQ-5D (mean 0.68 [0.5–0.8] vs. 0.85 [0.8–1]). Discussion: Although overall a positive trend in QoL was observed, the formal analyses did not show any significant improvements in EQ-5D scores or VAS. Only when the effect of a therapy use was separated from the effect of switching, the VAS score was significantly worse for switchers during the follow up period, irrespective of the therapy type. If adjusted for patient characteristics and medical history (e.g., gender, BMI, eGRF, history of diabetes), VAS and EQ-5D delivered sound PRO measures for QoL assessments during the year following renal transplantation.The project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 754995. Open access funding by University of Lausanne

Influence of lipid profile and statin administration on arterial stiffness in renal transplant recipients

Background: Hyperlipidemia is one of the major risk factors for developing a cardiovascular disease (CVD) and it is a frequent post-transplant complication, occurring in up to 60% of the renal transplant recipients (RTRs). Lipid lowering therapy with HMG-CoA reductase inhibitors (statins) is generally recommended and may reduce the overall cardiovascular risk. The aim of this study was to evaluate the lipid profile, statin administration and their relationship with arterial stiffness parameters in renal transplant recipients. Methods: Three hundred and forty-four stable RTRs (62.5% male) transplanted between 1994 and 2018 were randomly enrolled to the study. The following parameters of arterial stiffness was measured in each patient: carotid femoral pulse wave velocity (baPWV left and right, cfPWV) and pulse pressure (PP right and left). The study group was divided based on the use statins: 143 (41.6%) and 201 (58.4%). RTRs were qualified to the statin (+) and the statin (–) group, respectively. Results: In the statin (+) as compared to statin (–) group there were more patients with a CVD (32.9% vs. 14.9%) and diabetes (25.2% vs. 14.4%). In the whole study group, CVD was associated with a significant increase of both baPWV and cfPWV as well as PP (8.5 mmHg). There were significant differences in arterial stiffness parameters (baPWV, cfPWV, PP) between the statin (+) and the statin (–) group. Conclusions: Arterial stiffness was increased in RTRs with CVD and hyperlipidemia. The control of hyperlipidemia was poor in RTRs

Predictors of graft survival at diagnosis of antibody‐mediated renal allograft rejection: a retrospective single‐center cohort study

Antibody-mediated rejection (ABMR) is a major cause of graft loss in renal transplantation. We assessed the predictive value of clinical, pathological, and immunological parameters at diagnosis for graft survival. We investigated 54 consecutive patients with biopsy-proven ABMR. Patients were treated according to our current standard regimen followed by triple maintenance immunosuppression. Patient characteristics, renal function, and HLA antibody status at diagnosis, baseline biopsy results, and immunosuppressive treatment were recorded. The risk of graft loss at 24 months after diagnosis and the eGFR slope were assessed. Multivariate analysis showed that eGFR at diagnosis and chronic glomerulopathy independently predict graft loss (HR 0.94; P = 0.018 and HR 1.57; P = 0.045) and eGFR slope (beta 0.46; P < 0.001). Cyclophosphamide treatment (6x 15 mg/m²) plus high-dose intravenous immunoglobulins (IVIG) (1.5 g/kg) was superior compared with single-dose rituximab (1x 500 mg) plus low-dose IVIG (30 g) (HR 0.10; P = 0.008 and beta 10.70; P = 0.017) and one cycle of bortezomib (4x 1.3 mg/m(2)) plus low-dose IVIG (HR 0.16; P = 0.049 and beta 11.21; P = 0.010) regarding the risk of graft loss and the eGFR slope. In conclusion, renal function at diagnosis and histopathological signs of chronic ABMR seem to predict graft survival independent of the applied treatment regimen. Stepwise modifications of the treatment regimen may help to improve outcome

Cardiac and renal function in a large cohort of amateur marathon runners

Background Participation of amateur runners in endurance races continues to increase. Previous studies of marathon runners have raised concerns about exercise-induced myocardial and renal dysfunction and damage. In our pooled analysis, we aimed to characterize changes of cardiac and renal function after marathon running in a large cohort of mostly elderly amateur marathon runners. Methods A total of 167 participants of the BERLIN-MARATHON (female n = 89, male n = 78; age = 50.3 ± 11.4 years) were included and cardiac and renal function was analyzed prior to, immediately after and 2 weeks following the race by echocardiography and blood tests (including cardiac troponin T, NT- proBNP and cystatin C). Results Among the runners, 58% exhibited a significant increase in cardiac biomarkers after completion of the marathon. Overall, the changes in echocardiographic parameters for systolic or diastolic left and right ventricular function did not indicate relevant myocardial dysfunction. Notably, 30% of all participants showed >25% decrease in cystatin C-estimated glomerular filtration rate (GFR) from baseline directly after the marathon; in 8%, we observed a decline of more than 50%. All cardiac and renal parameters returned to baseline ranges within 2 weeks after the marathon. Conclusions The increase in cardiac biomarkers after completing a marathon was not accompanied by relevant cardiac dysfunction as assessed by echocardiography. After the race, a high proportion of runners experienced a decrease in cystatin C-estimated GFR, which is suggestive of transient, exercise-related alteration of renal function. However, we did not observe persistent detrimental effects on renal function

De-novo malignancies after kidney transplantation: A long-term observational study

Background: De-novo malignancies after kidney transplantation represent one major cause for mortality after transplantation. However, most of the studies are limited due to small sample size, short follow-up or lack of information about cancer specific mortality. Methods: This long-term retrospective analysis included all adult patients with complete follow-up that underwent kidney transplantation between 1995 and 2016 at our centre. All patients with diagnosis of malignancy excluding non-melanoma skin cancer (NMSC) were identified and a matched control group was assigned to the kidney transplant recipients with post-transplant malignancies. Results: 1417 patients matched the inclusion criteria. 179 malignancies posttransplant were diagnosed in 154 patients (n = 21 with two, n = 2 patients with three different malignancies). Mean age at cancer diagnosis was 60.3±13.3 years. Overall incidence of de-novo malignancies except NMSC was 1% per year posttransplant. Renal cell carcinoma was the most common entity (n = 49, incidence 4.20 per 1000 patient years; cancer specific mortality 12%), followed by cancer of the gastro-intestinal tract (n = 30, 2.57; 50%), urinary system (n = 24, 2.06; 13%), respiratory system (n = 18, 1.54; 89%), female reproductive system (n = 15, 1.29; 13%), posttransplant lymphoproliferative disorders and haematological tumours (n = 14, 1.20; 21%), cancers of unknown primary (n = 7, 0.60 100%) and others (n = 22, 1.89; 27%). Male sex, re-transplantation and time on dialysis were associated with de-novo malignancies after transplantation. Conclusion: De-novo malignancies continue to be a serious problem after kidney transplantation. To improve long-term outcome after Kidney transplantation, prevention and cancer screening should be more tailored and intensified

Mucosal associated invariant T cells are differentially impaired in tolerant and immunosuppressed liver transplant recipients

Mucosal associated invariant T (MAIT-) cells represent a semi-invariant T cell population responsive to microbial vitamin B metabolite and innate cytokine stimulation, executing border tissue protection and particularly contributing to human liver immunity. The impact of immunosuppressants on MAIT cell biology alone and in context with solid organ transplantation has not been thoroughly examined. Here, we demonstrate that in vitro cytokine activation of peripheral MAIT cells from healthy individuals was impaired by glucocorticoids, whereas antigen-specific stimulation was additionally sensitive to calcineurin inhibitors. In liver transplant (LTx) recipients, significant depletion of peripheral MAIT cells was observed that was largely independent of the type and dosage of immunosuppression, equally applied to tolerant patients, and was reproducible in kidney transplant recipients. However, MAIT cells from tolerant LTx patients exhibited a markedly diminished ex vivo activation signature, associated with individual regain of functional competence toward antigenic and cytokine stimulation. Still, MAIT cells from tolerant and treated liver recipients exhibited high levels of PD1, accompanied by functional impairment particularly toward bacterial stimulation that also affected polyfunctionality. Our data suggest interlinked effects of primary liver pathology and immunosuppressive treatment on overall MAIT cell fitness after transplantation and propose their monitoring in context with tolerance induction protocols

eHealth in transplantation

eHealth ("electronic" Health) is a new field in medicine that has the potential to change medical care, increase efficiency, and reduce costs. In this review, we analyzed the current status of eHealth in transplantation by performing a PubMed search over the last 5 years with a focus on clinical studies for post-transplant care. We retrieved 463 manuscripts, of which 52 clinical reports and eight randomized controlled trials were identified. Most studies were on kidney (n = 19), followed by liver (n = 10), solid organ (n = 7), bone-marrow (n = 6), and lung transplantation (n = 6). Eleven articles included adolescents/children. Investigated eHealth features covered the whole spectrum with mobile applications for patients (n = 24) and video consultations (n = 18) being most frequent. Prominent topics for patient apps were self-management (n = 16), adherence (n = 14), symptom-reporting (11), remote monitoring of vital signs (n = 8), educational (n = 7), and drug reminder (n = 7). In this review, we discuss opportunities and strengths of such new eHealth solutions, the implications for successful implementation into the healthcare process, the human factor, data protection, and finally, the need for better evidence from prospective clinical trials in order to confirm the claims on better patient care, potential efficiency gains and cost savings

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation

Purpose: Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder. Methods: In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders. Results: In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected. Conclusion: Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD