Cohort Of Kidney Transplant Recipients Research Articles

Detection of Ganciclovir-Resistant Cytomegalovirus in a Prospective Cohort of Kidney Transplant Recipients Receiving Subtherapeutic Valganciclovir Prophylaxis.

ABSTRACTCytomegalovirus infection during antiviral prophylaxis occurs in transplant recipients despite individualized regimens based on renal function. Fifty kidney transplant recipients were assessed between 2016 and 2019 for valganciclovir dosing, ganciclovir exposure, cytomegalovirus infection, and genotypic resistance markers during the first year posttransplant. Ganciclovir plasma concentrations were measured using mass spectrometry. Population pharmacokinetics was used to determine individual ganciclovir exposure and to evaluate the ability of manufacturer dosing guidelines to meet therapeutic target daily area under the curve (AUC24) of 40 to 50 μg·h/mL. Full-length UL54 and UL97 were assessed using high-throughput sequencing in cytomegalovirus DNA-positive patient specimens. Valganciclovir doses administered to recipients with creatinine clearance of <40 mL/min were higher than specified by guidelines, and they were lower for recipients with creatinine clearance of ≥40 mL/min. The mean ganciclovir AUC24 was 33 ± 13 μg·h/mL, and 82% of subjects did not attain the therapeutic target. Pharmacokinetic simulations showed that the guidelines similarly could not attain the therapeutic target in 79% of individuals. Cytomegalovirus breakthrough occurred in 6% (3/50) of recipients, while 12% (6/50) developed late-onset infection. The mean AUC24s of recipients with (n = 3) and without (n = 47) infection were not significantly different (P = 0.528). However, one recipient with an AUC24 of 20 μg·h/mL acquired two UL97 ganciclovir resistance mutations. Current prophylaxis guidelines resulted in subtherapeutic ganciclovir exposure in several study recipients, including the emergence of resistance genotypes.IMPORTANCE This study examined the pharmacokinetics and viral genomic data from a prospective cohort of kidney transplant recipients undergoing valganciclovir prophylaxis for cytomegalovirus (CMV) prevention. We showed for the first time using high-throughput sequencing the detection of ganciclovir resistance mutations in breakthrough CMV infection during subtherapeutic plasma ganciclovir as indicated by the pharmacokinetic parameter daily area under the curve (AUC24). In addition, we found that current valganciclovir dosing guidelines for CMV prophylaxis are predicted to attain therapeutic targets in only 21% of recipients, which is consistent with previous pharmacokinetic studies. The novel findings of resistance mutations during subtherapeutic ganciclovir exposure presented here can inform future studies investigating the dynamics of drug selection pressure and the emergence of resistance mutations in vivo.

MO975: Immunogenicity to A Third Dose of the Mrna-1273 Vaccine in Kidney Transplant Recipients

BACKGROUNDHumoral response after two doses of mRNA-based SARS-CoV-2 vaccines is weak in kidney transplant recipients (KTRs) [1]. Of concern, even a third dose of the mRNA-1273 vaccine induced a suboptimal humoral response in a cohort of KTRs who did not respond after two doses [2]. However, the assessment also of the T-cell immune response of mRNA vaccines in KTRs is limited in the literature [3]. Herein, we report the evaluation of humoral response induced after a third dose of the mRNA-1273 vaccine in a cohort of KTRs and T-cell immune responses in not responders to the third dose.METHODSObservational cohort data were collected from KTRs actively followed up in our outpatient clinic, with no history of COVID-19 infection, who received a third mRNA-1273 vaccine dose, 6 months after the second dose, as per suggested local policy.The primary endpoint was the humoral response provided at least 4 weeks after the third dose compared with the humoral response after the second dose.Anti-S1-RBD IgG antibodies were determined using a fluoroimmunoenzymatic method (Thermo Fisher Scientific), and the quantitative result expressed in BAU/mL (reference interval: <28 Negative; 28–40 Borderline; >40 Positive; linear range between 0.7 and >1632 according to the manufacturer). In seronegative and borderline KTRs after the third dose, an INFγ-release assay (IGRA) [Euroimmun, Lubeck, Germany] was used to detect T-cell immune responses. A patient result was considered negative, borderline and positive when IFNγ values were respectively <100, 100–200 and >200 mIU/mL.RESULTSSixty KTRs received a third dose of the mRNA-1273 vaccine. Overall, we obtained the antibody titre in 57 KTRs at a median of 23 days (IQR: 22–31) after the second dose and 23 days (IQR: 21–26) after the third dose.After the second dose, positive antibody titres were detectable in 28 KTRs (49%), and 2 KTRs (4%) had a borderline positivity. While after third dose, positive and borderline antibody responses were observed in 40 (70%) and 4 (7%) KTRs, respectively.Among all 57 KTRs, the median anti-S1-RBD IgG titre significantly increased after the third dose ( 448 versus 39 BAU/mL; P = 0.0018; Mann–Whitney test). While in 28 KTRs already seropositive after the second dose, the median antibody titre increased from 556 to >1632 BAU/mL (P = 0.0285; Mann–Whitney test). Figure 1 shows the kinetics of anti-S1-RBD IgG titres after the second and the third dose for all the 57 KTRs.Among 17 KTRs with negative and borderline humoral responses after the third dose, IFNγ values were positive and borderline in only 1 (6%) and 1 (6%) KTRs, respectively. The median IFNγ value was 22 mIU/mL (IQR: 0–1014).The 34 KTRs receiving mycophenolate mofetil (MMF) were less likely to develop adequate immune responses than the 23 KTRs not receiving MMF; 12 KTRs (35%) receiving MMF had no antibody and IFNγ positive response after the third dose in comparison to 4 KTRs (17%) not receiving MMF, and the median anti-S1-RBD IgG titre beyond the two groups after the third dose was statistically different (205 versus > 1632; P = 0.0046; Mann–Whitney test).CONCLUSIONSIn this study, the third dose of the mRNA-1273 vaccine increases the rate of positive antibody responses in non-responders KTRs after the second dose, and improves the magnitude of these responses in already seropositive KTRs. However, a fraction of KTRs still lacks protective antibody titres and T-cell responses after a third dose, with mycophenolate mofetil to be associated with poor immune responses. Alternative vaccination protocols are needed to protect this high-risk group.

MO987: Risk Predictors and Impact of Post-Transplant Cardiovascular Disease in A 20-Year Cohort of Kidney Transplant Recipients

Abstract BACKGROUND AND AIMS Although improvement in histocompatibility matching, immunosuppressive therapy and antimicrobial treatment have led to improved long-term allograft survival, cardiovascular diseases (CVD) remain the major cause of morbidity and mortality in kidney transplant recipients (KTR). In addition to the accumulated risks due to chronic kidney disease and dialysis, kidney transplantation conveys its own unique risk factors for CVD. These include the metabolic effects of immunosuppressive treatments such as post-transplant hyperglycaemia, dyslipidaemia and hypertension as well as the effects of suboptimal kidney function including volume overload, anaemia, mineral bone disease and left ventricular hypertrophy. The predictors of cardiovascular diseases in KTR, however, have not been clearly defined. This study aimed to first ascertain the incidence of post-transplant CVD in those KTR without a prior confirmed history of CVD, then identify the predictors of CVD transplant associated CVD risk factors and finally evaluate the impact of CVD on graft and patient survival in this era of modern immunosuppressive medications. METHOD We evaluated 962 KTR transplanted between 2000 and 2020 and followed in a single centre. About 328 KTR with a history of pre transplant CVD were excluded. CVD was defined as a composite of Ischaemic heart disease, myocardial infarction, heart failure, stroke or peripheral vascular disease. Logistic regression analyses were performed to identify the risk predictors of post-transplant CVD. Kaplan–Meier plots and multivariate Cox proportional hazards regression analysis were used to identify and characterize predictors of dialysis free survival. RESULTS Among 634 KTR included in the analysis (mean age: 45 ± 15 years), CVD was reported in 101 KTR (16%) during a median follow-up of 95.9 months. About 274(43%) were females, 531(84%) were Caucasians. KTR with post-transplant CVD were likely to be older (50 ± 13 versus 44 ± 15 years; P &amp;lt; 0.001), had spent more time on dialysis [median (IQR) 21 (1–51) versus 11 (0–3) months; P = 0.004] and received cyclosporin maintenance (18% versus 7%; P = 0.01). Incidence of post-transplant CVD was independently predicted by older age [OR: 1.40 (1.15–1.70: P = 0.001)], tacrolimus therapy [OR: 0.81 (0.71–0.93), P = 0.002], mean haemoglobin concentration [OR: 0.86 (0.75–1.00), P = 0.049] and average C-reactive protein (CRP) level [OR: 1.13 (1.02–1.25), P = 0.02] (Figure 1). The median dialysis free survival was significantly lower in KTR who developed post-transplant CVD (14.7 versus 20 years, P = 0.009). In the multivariate Cox regression analysis, the factors associated with worse dialysis free survival in our cohort (survival with a functioning graft) were older age at transplantation [hazard ratio (HR): 1.03; P &amp;lt; 0.001), a history of post-transplant CVD (HR: 1.68; P = 0.006), higher post-transplant parathormone levels (HR: 1.02; P &amp;lt; 0.001), higher mean urine protein creatinine ratio (uPCR) (HR: 1.003: P &amp;lt; 0.001), a greater annual rise in uPCR (HR: 1.002; P &amp;lt; 0.001) and a history of acute rejection (HR: 1.56; P = 0.03). Statin treatment was associated with better dialysis free survival outcome (HR: 0.60; P = 0.01). CONCLUSION The incidence of post-transplant CVD in KTR with no history of pre-transplant CVD was 16%. Age at transplantation and average CRP were independent predictors of post-transplant CVD whereas treatment with Tacrolimus was associated with a lower risk of CVD. Statin therapy was associated with better dialysis free survival whereas a higher PTH was linked to poor survival. It was interesting to note that diabetes was not independently associated with the risk and outcome of post-transplant CVD in our cohort.

MO946: Factors Associated With Changes in Health-Related Quality of Life (Hrqol) in A Greek Cohort of Kidney Transplant Recipients: A Prospective Study

Abstract BACKGROUND AND AIMS Kidney transplantation is recognized as the treatment of choice for patients with End Stage Kidney Disease (ESKD). Improvement in short term patient and graft survival of kidney transplant recipients (KTRs), has shifted interest to the long-term outcomes and Health-Related Quality of Life (HRQoL) estimation is closely related. Thus, reliable evaluation of HRQoL with disease-specific questionnaires is of great importance. The aim of our study was to assess prospectively possible changes in HRQoL during follow up period and to identify associated factors that might affect these changes. METHOD We used the Greek version of the translated and adapted by our team disease-specific instrument Kidney Transplant Questionnaire 25 (KTQ-25) and the Greek SF-36 were administered in a cohort of KTRs during their routine visit in the transplant outpatient clinic twice, at study entry and after one year. Sociodemographic and medical information were also collected at both time points. Inclusion criteria were, aged ≥18-year-old, time since transplant ≥1 year, functioning transplant. All participants provided written informed consent. RESULTS A total of 84 KTRs (59 males; mean age 53.5 ± 10.7; mean e-GFR 47.7 ± 15.1 mL/min/1.73 m2; average time since transplantation 55.7 ± 48.3 months) included in the study at the first time point, while 74 KTRs (88.1%) remained for the second assessment (3 died, 4 denied and 4 changed transplant unit). The majority of KTRs were married (73.8%), with children (77.4%), non-smokers (81.6%) and retired (60.7%). The 45.8% had family monthly income ≤ 1000€. In 62%, hemodialysis was the modality before transplantation and 59.52% had received graft from deceased donor. Immunosuppressive treatment was 84.34% corticosteroids, 54.22% Tacrolimus, 40.96% Cyclosporine, 91.75% MMF and 3.61% Azathioprine. The observed SF-36 scores in all dimensions both time-points were similar without significant changes. Also, no significant changes found between the two time-points at all 5 dimensions and total score of the KTQ-25. A multivariate regression analysis for the 5 dimensions of the KTQ-25 at the second time-point was done. Showed that variables significantly associated with Physical Symptoms dimension was age (P = 0.021) directly and Osteoporosis (P = 0.025) inversely. In regression analysis of Fatigue dimension, variables that remained significant were female sex (P = 0.046) and higher serum cholesterols’ levels (P = 0.012). Uncertainty/Fear dimension was significantly worse in KTRs with history of cardiovascular disease (P = 0.032). Appearance dimension was significantly and positively correlated with female sex and negative with age and history of cardiovascular disease (P = 0.018, P = 0.043 and P = 0.041, respectively). No significantly correlation found for Emotions dimension. Total KTQ-25 score was significantly correlated with female sex (P = 0.024), while history of cardiovascular disease had a negative impact on the score (P = 0.013). CONCLUSION In this one-year prospective study of the HRQoL of KTRs, no statistically significant changes were found in the scores of KTQ-25 and SF-36 instruments. Age, sex, osteoporosis, serum cholesterols’ levels and history of cardiovascular disease are some of the factors that might affect prospectively HRQoL of KTRs.

FC 114: Monoclonal Gammopathy in Kidney Transplanted Patients: Novel Insights into Long-Term Outcomes

Abstract BACKGROUND AND AIMS As in the general population the prevalence of monoclonal gammopathies (MG) in kidney transplant (KT) candidates increases with age. Little is known about the epidemiology and long-term consequences of MG on overall survival, graft outcomes and infectious and neoplastic complications in patients undergoing KT. METHOD We retrospectively identified patients with MG at the time of transplant (KTMG) or appearing de novo after the KT (DNMG) in 3059 patients who underwent a KT from January 2007 to June 2019 at Necker Hospital Paris (N = 1978) and from January 1998 to December 2017 at CHU Poitiers, France (N = 1081). Using a propensity score, we established a control cohort of KTMG from Necker Hospital, matched on the main covariates influencing post KT outcomes. RESULTS We identified 70 (2.3%) KTMG and 114 (3.7%) DNMG patients, presenting with identical demographic characteristics except for an older age in KTMG (62 versus 57 years; P = 0.03). MG isotypes among the 184 KT recipients with MGUS were IgG (n = 117, 64%), IgA (n = 16, 9%) or IgM (n = 16, 9%). Interestingly, DNMG patients presented more frequently with bi- or triclonal MG than KTMG patients (n = 28, 25% versus n = 7, 10%, respectively; P = 0.02). At the time of KT, among 62 patients with available sFLC measurement in KTMG, 11 (17%) had an abnormal kappa/lambda ratio. Because of systematic evaluation of SPEP during follow-up, we observed that MG disappeared during follow up more frequently in DNMG compared to KTMG (n = 51, 45% versus n = 17, 24%, respectively; P = 0.007). Figure 1 represents the results of SPEP during follow-up. FIGURE 1: Monoclonal gammopathy timescale. Serum protein electrophoresis follow-up from KT;each patient is represented by one line. Blueand green lines represent negative SPEP, performed before and after the detection of MG, and red lines represent positive SPEP with MG identification. Clinical last follow-up is represented by dots: red dot for death, blue dot for graft loss and green dot for last follow-up alive with functional graft. Overall survival was poorer in KTMG than in DNMG (87 versus 176 months; P &amp;lt; 0.001). Cox model including age, sex, rank of transplantation and KTMG or DNMG revealed that age, rank of transplantation and KTMG were independent risk factors for death. Graft survival, occurrence of rejection and haematological complications were comparable between the two groups. To better evaluate the effect of MGUS at the time of KT, KTMG patients from Necker Hospital were compared with matched KT recipients. There was no difference between KTMG and controls regarding the main baseline predictors of post-KT outcomes except for lower level of residual gammaglobulins [7.5 g/L (IQR 6–9.9)] in KTMG versus 10.7 g/l (IQR 8.9–13.1) in controls (P &amp;lt; 0.0001). KTMG patients developed more frequently solid cancers (15% versus 5%; P = 0.04) and bacterial infections (63% versus 48%; P = 0.08). There was no significant difference regarding survival, frequency of rejection or haematological complications. However, KTMG patients with an abnormal kappa/lambda ratio at the time of KT tended to have poorer overall survival than those with normal kappa/lambda ratio and controls (respective medians 72, 87 and 103 months; P = 0.08) (Figure 2). CONCLUSION We report here the largest cohort of KT recipients who underwent systematic SPEP screening at the time of KT and yearly during post-transplant follow-up. We observed that MGUS prevalence in KT candidates is close to that reported in the general population. We confirm that outcomes of patients harboring MGUS at the time of KT are similar to those of matched controls without MGUS, supporting that MGUS should not be a contraindication for KT. Nevertheless, we observed that KTMG patients developed more frequently and earlier solid cancers and infections, suggesting that MGUS is associated with a relative immunodeficiency in these patients. We also showed that patients with abnormal sFLC kappa/lambda ratio experienced poor outcomes, claiming for systematic measurement of sFLC in the pre-KT workup. Clinical last follow-up is represented by dots: red dot for death, blue dot for graft loss and green dot for last follow-up alive with functional graft.

MO637: Effectiveness and Safety of Glucagon-Like Peptide-1 Receptor Agonist in a Cohort of Kidney Transplant Recipients

Abstract BACKGROUND AND AIMS Diabetes mellitus (DM) is a complication in kidney transplant (KT). Therapies such as glucagon-like peptide-1 receptor agonist analogs (GLP-1RA) have been incorporated that could have benefits in KT, although experience is limited [1, 2]. The objective of our study is to describe the effectiveness and safety of GLP-1RA in KT patients. METHOD Retrospective cohort study of KT with DM who started GLP-1RA between February 2016 and December 2021. Clinical and demographic variables were analyzed. We collected GLP-1RA type and dose. Glomerular filtration rate (eGFR), proteinuria and weight were collected at the start of treatment and after 6 and 12 months. We analyze glycemic control, blood pressure and lipid profile. Acute rejections (AR), de novo donor-specific antibodies (DSA) and adverse effects were documented. A descriptive analysis was performed and the variables described before and after the start of treatment were compared. Parametric and non-parametric tests were performed according to the normality of the sample. RESULTS In this period, 50 KT with DM treated with GLP-1RA in our center from 1 March 2016 to 15 December 2021. Sixteen patients (32%) had developed post-transplant diabetes mellitus (PTDM). The mean age was 62.8 years and 52.5% were men. Mean baseline estimated glomerular filtration rate (eGFR) was 46.1 mL/min/1.73 m2 and the time post-KT was 38 months. The GLP-1RA mostly prescribed was semaglutide (47.5%), followed by liraglutide (32.5%) and dulaglutide (20%). Twenty-nine patients (58%) reached the maximum recommended dose of the drug. All patients received steroids, tacrolimus and mycophenolate. Forty KT recipients had a minimum follow-up of 6 months and 26 were followed for 12 months. Values of variables compared during the follow-up are shown in Table 1. We observed an improvement in eGFR (+3.5 mL/min/1.73 m2 at 12 months, P = 0.030) and a reduction in proteinuria (−59.1 mg/g at 6 months, P = 0.009 and −48.5 mg/g at 12 months, P = 0.021) during all the follow-up. Additionally, we found a significant reduction in systolic blood pressure (−9.2 mmHg at 12 months, P = 0.022) despite the number of patients receiving angiotensin receptor blockers, angiotensin-converting enzyme and other antihypertensive therapies as well as their doses that did not change during the period of the study. In our cohort, body weight significantly reduced (−2.4 Kg at 6 months, P = 0.006 and −3 Kg at 12 months, P = 0.041). Furthermore, HbA1c decreased (−9 mmol/mol at 6 months, P &amp;lt;0.001 and −5 mmol/mol at 12 months, P = 0.018). Notably, insulin dose was also reduced (−4 UI/day at 6 months, P = 0.003 and −4 UI/day at 12 months, P = 0.036) and the rest of antidiabetic treatment did not significantly change. Finally, we observed a reduction in total cholesterol (−14 mg/dL at 6 months, P = 0.015 and −6.3 mg/dL at 12 months, P = 0.344) and LDL-c (−8.8 mg/dL at 6 months, P = 0.49 and −4.9 mg/dL at 12 months, P = 0.384) during the follow-up. Twelve patients (24%) suffered from side effects, mainly nausea and vomiting, and only two patients (4%) discontinued the treatment. One patient discontinued the treatment due to the diagnosis of pancreatic cancer 8 months after starting the drug. We did not find differences in the levels or in the dose of tacrolimus. Neither AR episodes nor de novo DSAs’ development was notified. CONCLUSION In conclusion, this is one of the largest series reporting the effectiveness and safety of GLP-1RA in a cohort of KT. Our results support that it can be an option for the management of DM in these patients. Its use is safe and it does not seem to alter tacrolimus trough levels, to induce AR episodes or de novo DSAs development.

MO941: Novel Peripheral Molecular Markers Predict Premature Graft Loss: Lessons Learned from Operational Tolerance Assessment

Abstract BACKGROUND AND AIMS TOMOGRAM, a European multicenter study, recently identified a new cohort of kidney transplant recipients (KTR) with operational tolerance (OT) with the aim to identify new transcriptomic signatures of OT. METHOD RNA sequencing of peripheral blood was evaluated in 15 OT KTR identified by TOMOGRAM, 23 stable KTR (≥15 years, STA), 14 KTR with transplant glomerulopathy (≥1 year, CR), 14 CyA-treated primary GN patients and 14 healthy controls (HC). The ability to discriminate OT from others was analyzed using three classifiers (GLMNET, voomNSC and SVM-RFE) with 10-fold cross-validation and visualized by principal component analysis (PCA) of molecular archetypes. RESULTS Peripheral blood transcriptome of OT patients is similar to the STA group (AUC &amp;lt; 0.6) and different from the CR group (AUC &amp;gt; 0.8). Also, in PCA of molecular archetypes, direction of correlation suggested similarity between STA and OT and their anti-correlation to CR (Figure 1). Top 10 transcripts differentiated OT from CR were assessed in prospective independent cohort (n = 396) to predict premature graft loss. Multivariable Cox regression model based on the expression of 5 of those transcripts at 3 time-points was associated with graft loss at 3 years with an AUC = 0.815. CONCLUSION Identification of the OT peripheral molecular signature among stable KTR is not feasible. Instead, novel peripheral molecular markers associated with premature graft loss were identified.

MO955: Serum Cystatin C in Renal Transplantation: Beyond GFR Estimation, A Prognosis Marker?

Abstract BACKGROUND AND AIMS In renal transplantation, death with a functioning graft remains one of the main causes of graft loss. In the general population, renal function impairment is strongly associated with cardiovascular and all-cause mortality. Whether this association holds true for kidney transplant recipients (KTR) is unclear. This uncertainty is likely to be due, in part, to the fact that glomerular filtration rate (GFR) estimation based on serum creatinine (SCr) does not always provide an accurate evaluation of the graft function in KTR. As compared to SCr, we have previously shown in a large cohort of KTR that serum cystatin C (SCysC) is a much better marker of GFR. Herein, we sought to study the ability of the 1-year-post-transplant renal function to predict all-cause mortality according to the methods used to assess GFR. METHOD Four hundred and ten consecutive KTR for whom a measurement of GFR by inulin clearance was available at 1 year post-transplant were included. SCr and ScysC were measured with standardized methods. The association of the 1-year inulin clearance value the 1-year MDRD Study equation value and the 1-year CKD-EPI ScysC equation value with all-cause mortality was studied by ROC analysis and Cox model. RESULTS During a median follow-up of 17 years, 131 KTR died. Mean (±SD) inulin clearance at 1-year-post-transplant was 47 (±13) mL/min/1.73 m2. Areas under the ROC curves were similar for inulin and CKD-EPI ScysC equation values (0.62 for both), and were both significantly superior to that of the MDRD equation (0.54, P &amp;lt; 0.01). In Cox analysis, while all types of GFR evaluations were significantly associated to graft loss, only an inulin and a CKD-EPI ScysC equation values below 45 mL/min/1.73 m2 were associated with an excess risk of mortality (HR of 1.55, 1.45 and 1.01 for inulin, CKD-EPI ScysC and MDRD, respectively). CONCLUSION We conclude that ScysC-based GFR estimation might better predict KTR outcome as compared with a traditional SCr-based estimation. The one year-post transplant GFR value given by the CKD-EPI ScysC equation should be further evaluated as a potential surrogate marker for both graft and patient survival.

Pathways from Diagnosis to Death from Keratinocyte Cancer in Kidney Transplant Recipients

Background: Kidney transplant recipients are at increased risk of developing and dying from keratinocyte cancer. We aimed to describe the clinical course of keratinocyte cancer-related deaths in a cohort of kidney transplant recipients. Methods: In kidney transplant recipients transplanted between 1995 and 2014 in Queensland, Australia, we ascertained keratinocyte cancer deaths by searching national transplant and state death registries to March 2020. Deceased transplant recipients’ medical records were reviewed to assess features of the primary lesion of the fatal keratinocyte cancer, metastases, and clinical information before death. Results: Of 658 kidney transplant recipient deaths, 49 (7%) were due to keratinocyte cancer, and medical records were available for 36 (73%). One death was due to basal cell carcinoma, and 35 were from squamous cell carcinoma (SCC), primarily from the head and neck (24; 69%). The most common site of metastasis was the lungs (21; 58%). Median time (minimum, maximum) from the diagnosis of primary SCC to metastasis was 5 months (0, 29). After this, the median time to death was 9 months (1, 50). Conclusion: Fatal keratinocyte cancers overwhelmingly arise on the head and neck, with lungs the most common metastasis site. The short time from diagnosis of primary to death indicates the aggressive nature of these keratinocyte cancers.

Radiofrequency Echographic Multi-Spectrometry (REMS) technology and DXA for BMD assessment in kidney transplant recipients

Radiofrequency Echographic Multi-Spectrometry (REMS) is a novel ultrasound-based technique that has shown good reliability in the assessment of BMD in women affected by post-menopausal osteoporosis. Data on special populations with secondary osteoporosis are needed. The aim of this study was to compare the performance of the REMS BMD assessment with DXA in a cohort of kidney transplant recipients (KTR). Consecutive patients referring to our KTR clinic were enrolled. All subjects fulfilled the following inclusion criteria: Caucasian population, both genders, age between 40 and 80 years, BMI < 40kg/m2. The enrolled patients underwent a lumbar spine (LS) and femoral neck (FN) examination with DXA and REMS. Differences in DXA vs REMS T-scores were analyzed through Student's t test for independent samples, correlations were tested though Pearson's correlation. Differences in prevalence were tested trough Chi-squared test. Written informed consent was obtained from all participants (protocol 1483CESC). 40 patients were enrolled (table 1). At the LS, BMD was significantly lower when assessed through REMS. The correlation between the T-scores obtained with DXA and REMS are depicted in figure 1. When adopting the worst site, the prevalence of subjects with T-score <-2.5 was 40.5% with DXA and 37.8% with REMS (p=NS) and of subjects with T-score <-1 was 89% with DXA and 97.5% with REMS (p=0.003). These results showed a good reliability of the REMS technology with respect to DXA in the classification of KTR patients as having low bone mass and/or osteoporosis. Furthermore, REMS might be more sensitive than DXA in the detection of early bone impairment and in the classification of KTR patients with low bone mass. Uploaded File(s)

De Novo Membranous Nephropathy Associated With Antibody-Mediated Rejection in Kidney Transplant Recipients

Membranous nephropathy (MN) is a rare autoimmune disease that can develop a persistent nephrotic syndrome and end-stage kidney disease, with a recurrence rate of 30% to 40% after kidney transplant. Retrospective case series of membranous nephropathy observed in a cohort of kidney transplant recipients with donor-specific anti-human leukocyte antigen antibodies and biopsy-proven antibody-mediated rejection (AMR). We report 4 cases of membranous nephropathy associated with AMR. MN was diagnosed 10 to 92 months posttransplant, associated with de novo donor-specific antibodies, specific to class I in 2 cases, and class II in another 2. All cases presented typical morphology of membranous nephropathy, with subepithelial deposits with spikes at electron microscopy. Immunostaining for immunoglobulin G4 was negative in all cases, and podocyte-expressed M-type phospholipase A2 receptor was detected in glomerular basement membrane of 3 cases. Biopsy specimens from patients with longer follow-up showed more intense microvascular inflammation and chronic injury markers, possibly because of subclinical immunologic injury. AMR therapy included immunoglobulin 2g/kg in 3 patients, isolated or associated with plasmapheresis. One patient was not treated because of an active disseminated infection. Two patients remain with functioning grafts and under antiproteinuric therapy. Two grafts were lost, 1 because of chronic failure and the other because of death secondary to infection. Despite treatment, donor-specific antibodies remain detectable in a 6-month follow-up. De novo MN is a rare manifestation associated with AMR in kidney transplant recipients. The occurrence of podocyte-expressed M-type phospholipase A2 receptor in de novo MN suggests antibody-mediated activation, despite the use of maintenance immunosuppression.

Pregnancy Outcomes After Kidney Transplantation and Long-Term Evolution of Children: A Single Center Experience

Pregnancies in women who underwent kidney transplants are at high risk compared with the general population. In this study, we aimed to retrospectively assess the obstetrical complications, delivery outcomes, and impact of pregnancy on kidney allograft function in a single-center cohort of kidney transplant recipients (KTRs). We provide data regarding the long-term evolution of children. Thirty-two KTRs underwent a total of 57 pregnancies between 1994 and 2010. Fourteen pregnancies (24 %) did not survive caused by miscarriages (n=9), stillborn (n=1), ectopic pregnancies (n=2), and medical abortion (n=2). Live birth occurred in 76% of pregnancies. Delivery was by cesarean in 66%. The mean gestational age was 30.45 ± 11.3 weeks and 65% of newborns were premature. A low birth weight <2500g was noted in 46%. Obstetric complications were de novo hypertension in 4%, pre-eclampsia in 9%, and gestational diabetes in 2%. The 5- and 10-year post-delivery death-censored graft loss rates were 3.1% and 12.5%, respectively. Data on 21 children were collected via a self-questionnaire. After a median follow-up time of 17 years, they appeared in good medical and psychological health. None of them suffered from chronic disease (especially uronephrological condition) or was taking chronic medication. Long-term evolution of children born to women who underwent kidney transplants seems favorable. Pregnancies in KTRs are successful in two-thirds of cases but are at increased risk of prematurity, delivery by cesarean, and low birth weight.

SARS-CoV-2 antibody dynamics among kidney transplant recipients 3 months after BNT162b2 vaccination: a prospective cohort study.

ABSTRACTData regarding immunogenicity of mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among kidney transplant recipients in the months following vaccination are lacking. We aimed to investigate humoral immune response at 3–4 months post-vaccination among a cohort of kidney transplant recipients, compared with a control group of dialysis patients. Anti-spike antibodies were tested at 1 and 3–4 months after vaccination. Of 259 kidney transplant recipients tested at a median time of 110 days from second vaccine dose, 99 (38%) were seropositive, compared with 83% (101/122) of control patients. Younger age, better renal function and lower immunosuppression levels were associated with seropositivity. A total of 14% (13/94) of participants seropositive at 1 month became seronegative at follow-up and 11% (18/165) became seropositive. The latter were mainly individuals with higher antibody levels at 1 month. Antibody levels at 3–4 months were significantly reduced in both study groups, although the decline was more pronounced in the control group. Kidney transplant recipients present poor antibody response to mRNA SARS-CoV-2 vaccination, with only 38% seropositive at 3–4 months. Nevertheless, the decay in antibody response over time is modest, and some patients may present delayed response, reaching adequate antibody levels at 3–4 months. Low seropositivity rates in this group call for investigating other immunization strategies.

An Antibody-Aptamer-Hybrid Lateral Flow Assay for Detection of CXCL9 in Antibody-Mediated Rejection after Kidney Transplantation.

Chronic antibody-mediated rejection (AMR) is a key limiting factor for the clinical outcome of a kidney transplantation (Ktx), where early diagnosis and therapeutic intervention is needed. This study describes the identification of the biomarker CXC-motif chemokine ligand (CXCL) 9 as an indicator for AMR and presents a new aptamer-antibody-hybrid lateral flow assay (hybrid-LFA) for detection in urine. Biomarker evaluation included two independent cohorts of kidney transplant recipients (KTRs) from a protocol biopsy program and used subgroup comparisons according to BANFF-classifications. Plasma, urine and biopsy lysate samples were analyzed with a Luminex-based multiplex assay. The CXCL9-specific hybrid-LFA was developed based upon a specific rat antibody immobilized on a nitrocellulose-membrane and the coupling of a CXCL9-binding aptamer to gold nanoparticles. LFA performance was assessed according to receiver operating characteristic (ROC) analysis. Among 15 high-scored biomarkers according to a neural network analysis, significantly higher levels of CXCL9 were found in plasma and urine and biopsy lysates of KTRs with biopsy-proven AMR. The newly developed hybrid-LFA reached a sensitivity and specificity of 71% and an AUC of 0.79 for CXCL9. This point-of-care-test (POCT) improves early diagnosis-making in AMR after Ktx, especially in KTRs with undetermined status of donor-specific HLA-antibodies.

Humoral and T-cell response to SARS-CoV-2 mRNA BNT162b2 vaccination in a cohort of kidney transplant recipients and their cohabitant living kidney donor partners.

Humoral and T-cell response to SARS-CoV-2 mRNA BNT162b2 vaccination in a cohort of kidney transplant recipients and their cohabitant living kidney donor partners.

SARS-CoV-2 infection in kidney transplant recipients: clinical impact and outcomes - a single center experience.

ABSTRACTIntroduction:Kidney transplant recipients are a subgroup of patients at higher risk of critical forms of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection and poor outcomes due to immunosuppression treatment. Herein, we present data from a single center cohort of kidney transplant recipients with SARS-CoV-2 infection.Methods:In a prospective study, baseline characteristics, clinical features, antiviral and immunosuppression management were compared between outpatients and hospitalized patients, during a one-year period.Results:Seventy-seven kidney transplant recipients were analyzed, including outpatients and hospitalized patients, with a median age of 57.7 (IQR 49.7-64.9) years. Twenty-eight (36.4%) were managed as outpatients, while 49 (63.6%) patients required hospital admission. Among hospitalized patients, 18.4% were admitted in ICU, 49% had AKI, and 20.4% died. Immunosuppression adjustments were performed in 95.9% of hospitalized patients, with dose of anti-metabolites adjusted in 83.7%, mTOR inhibitors in 14.3%, calcineurin inhibitors in 12.2%, and corticosteroid therapy in 81.6%.Conclusion:Among hospitalized patients, immunosuppression management included reduction or withdrawal of anti-metabolite and increase of corticosteroid dose. AKI occurred in almost half of patients and mortality in hospitalized patients reached 20%, reflecting greater disease severity than the general population.

Effect of pulmonary hypertension on 5-year outcome of kidney transplantation.

Pulmonary hypertension affects about one in four patients with advanced chronic kidney disease and significantly increases the risk of death. Kidney transplantation is the recommended management option for patients with progressive or end‐stage kidney disease. However, the resource‐limited nature of kidney transplantation and its intensive peri‐operative and posttransplantation management motivates careful consideration of potential candidates’ medical conditions to optimally utilize available graft organs. Since pulmonary hypertension is known to increase peri‐operative morbidity and mortality among patients living with chronic kidney disease, we performed a retrospective cohort study to assess the impact of pretransplantation pulmonary hypertension on posttransplantation outcome. All patients who underwent single‐organ kidney transplantation at our center in calendar years 2010 and 2011 were identified and the presence of pulmonary hypertension was determined from pretransplantation echocardiography. Outcome was assessed at 5 years following kidney transplantation. Of 350 patients who were included, 117 (33%) had evidence of pulmonary hypertension. The risk of death, graft dysfunction, or graft failure at 5 years after kidney transplantation was higher among those with pulmonary hypertension, primarily owing to an increased risk of graft dysfunction. Importantly, in this institutional cohort of kidney transplant recipients, pretransplant pulmonary hypertension was not associated with a difference in posttransplant survival at 5 years. While institutional and regional differences in outcome can be expected, this report suggests that carefully selected patients with pulmonary hypertension receive similar long‐term benefits from kidney transplantation.

Association of endothelial dysfunction with sarcopenia and muscle function in a relatively young cohort of kidney transplant recipients.

BackgroundSarcopenia and endothelial dysfunction are both common among kidney transplant (KT) recipients. We aimed to evaluate the association between endothelial dysfunction and sarcopenia, as well as its individual components.MethodsVascular reactivity index (VRI), skeletal muscle index (SMI = skeletal muscle mass/height2), handgrip strength (HGS), and 6-meter usual gait speed (GS) were measured in 95 KT recipients. Low SMI was defined as SMI less than 10% of the sex-specific reference values from Chinese adults; low HGS as HGS < 28 kg for men and < 18 kg for women; slow GS as GS below 1.0 m/s. Sarcopenia was diagnosed based on the presence of low SMI as an essential criterion, accompanied by either low HGS or slow GS. Vascular reactivity was classified as being indicative of poor (VRI < 1.0), intermediate (1.0 ≤ VRI < 2.0), or good (VRI ≥ 2.0) vascular reactivity.ResultsOf the 95 patients, aged 45.2 ± 10.9 years, 11.6% had sarcopenia and 13.7% had poor vascular reactivity. Patients with sarcopenia were lower in body mass index (p = 0.001) and VRI (p = 0.041), and have a higher proportion of low muscle mass (p < 0.001), low HGS (p < 0.001), and slow GS (p = 0.001). Patients with poor vascular reactivity have a higher proportion of sarcopenia (p = 0.005), low HGS (p = 0.006), and slow GS (p = 0.029). Multivariate logistic regression analysis showed that patients in the poor VRI group were significantly associated with sarcopenia (odds ratio, OR = 6.17; 95% confidence interval [1.06–36.04]; p = 0.043), comparing to those with good VRI. We further analysed the effects of VRI on individual components of sarcopenia and found that VRI predicted slow GS significantly (OR = 0.41; 95% CI = [0.21–0.79]; p = 0.007), but not low SMI (OR = 1.15; 95% CI [0.53–2.49]; p = 0.718) and HGS (OR = 0.59; 95% CI [0.31–1.16]; p = 0.125).ConclusionsWe concluded that endothelial dysfunction is a key determinant of sarcopenia in KT recipients. Furthermore, endothelial dysfunction is more closely related to gait speed than muscle mass and strength.

Maternal, Decidual, and Neonatal Lymphocyte Composition Is Affected in Pregnant Kidney Transplant Recipients.

Pregnancy after renal transplantation is associated with an increased risk of complications. While a delicately balanced uterine immune system is essential for a successful pregnancy, little is known about the uterine immune environment of pregnant kidney transplant recipients. Moreover, children born to kidney transplant recipients are exposed in utero to immunosuppressive drugs, with possible consequences for neonatal outcomes. Here, we defined the effects of kidney transplantation on the immune cell composition during pregnancy with a cohort of kidney transplant recipients as well as healthy controls with uncomplicated pregnancies. Maternal immune cells from peripheral blood were collected during pregnancy as well as from decidua and cord blood obtained after delivery. Multiparameter flow cytometry was used to identify and characterize populations of cells. While systemic immune cell frequencies were altered in kidney transplant patients, immune cell dynamics over the course of pregnancy were largely similar to healthy women. In the decidua of women with a kidney transplant, we observed a decreased frequency of HLA-DR+ Treg, particularly in those treated with tacrolimus versus those that were treated with azathioprine next to tacrolimus, or with azathioprine alone. In addition, both the innate and adaptive neonatal immune system of children born to kidney transplant recipients was significantly altered compared to neonates born from uncomplicated pregnancies. Overall, our findings indicate a significant and distinct impact on the maternal systemic, uterine, and neonatal immune cell composition in pregnant kidney transplant recipients, which could have important consequences for the incidence of pregnancy complications, treatment decisions, and the offspring’s health.

Longitudinal Assessment of Electrolyte Disorders in a Cohort of Chronic Stable Kidney Transplant Recipients

Kidney transplantation is complicated by various electrolyte disturbances with variable reported prevalence and incidence and of multifactorial pathogenesis. The aim of our study was the retrospective longitudinal assessment of the serum electrolytes in a cohort of stable kidney transplant recipients (KTRs) and the possible associated parameters, including graft function and medications. We included 93 stable KTRs under follow-up in our hospital's kidney transplant unit. Serum magnesium, calcium, phosphorus, potassium, sodium, and urine sodium levels were recorded retrospectively during 3 consecutive years. In addition, comorbidities, biochemical parameters, medications, and graft function (estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation and 24-hour urinary protein [uTpr]) were recorded. Mean age at baseline was 51 ± 11 years; 64 KTRs were men (68.8%), 17 (18.3%) had diabetes, 79 (85%) had hypertension, and 11 (11.8%) had cardiovascular disease. Mean eGFR and uTpr (mg/24 h) at study initiation were 47.1 ± 13.5 mL/min/1.73 m2 and 369.4 ± 404.2 mg/24 h, respectively. Hypomagnesemia was the most common disturbance observed in 21.7% of KTRs. Patients with hypomagnesemia displayed higher parathyroid hormone levels and more frequently had diabetes. Hypophosphatemia was recorded in 9.7% of KTRs during the first year. Hyperkalemia, hypokalemia, and hypercalcemia were rare (<5%). Mean serum and urine sodium concentration remained stable during the study, whereas urinary sodium levels showed a positive correlation with uTpr (P < .05). In our cohort of KTRs, there were no significant electrolyte disorders, either in terms of frequency or severity, with hypomagnesemia being the most prevalent disturbance. The identification of potential associated risk factors and clinical data correlations are pivotal for the development of individualized and evidence-based therapeutic approach and decisions.