Young Kidney Transplant Recipients Research Articles

Older age is associated with a distinct and marked reduction of functionality of both alloreactive CD4+ and CD8+ T cells

IntroductionOlder recipient age is associated with a significant decreased risk for rejection after kidney transplantation which is incompletely understood.MethodsIn a longitudinal study, circulating alloreactive T cells were assessed of young (≤45 years) and older (≥55 years) stable kidney transplant recipients. Alloreactive T-cells were identified by CD137-expression and phenotype, cytokine producing and proliferative capacity, were evaluated using multiparameter flowcytometry. ResultsThe results show that before transplantation frequencies of alloreactive CD4+ and CD8+ T-cells in older KT-recipients are significantly higher and shifted towards an effector memory-phenotype. However, the frequency of polyfunctional (≥2 pro-inflammatory cytokines) CD4+ T-cells was significantly lower and less IL2 was produced. The frequency of polyfunctional alloreactive CD4+ T-cells and proliferation of alloreactive T-cells donor-specifically declined after transplantation reaching a nadir at 12 months after transplantation, irrespective of age. A striking difference was observed for the proliferative response of alloreactive CD8+ T-cells. This was not only lower in older compared to younger recipients but could also not be restored by exogenous IL2 or IL15 in the majority of older recipients while the response to polyclonal stimulation was unaffected. ConclusionIn conclusion, older age is associated with a distinct and marked reduction of functionality of both alloreactive CD4+ and CD8+ T-cells.

Older age is associated with a distinct and marked reduction of functionality of both alloreactive CD4+ and CD8+ T cells

IntroductionOlder recipient age is associated with a significant decreased risk for rejection after kidney transplantation which is incompletely understood.MethodsIn a longitudinal study, circulating alloreactive T cells were assessed of young (≤45 years) and older (≥55 years) stable kidney transplant recipients. Alloreactive T-cells were identified by CD137-expression and phenotype, cytokine producing and proliferative capacity, were evaluated using multiparameter flowcytometry. ResultsThe results show that before transplantation frequencies of alloreactive CD4+ and CD8+ T-cells in older KT-recipients are significantly higher and shifted towards an effector memory-phenotype. However, the frequency of polyfunctional (≥2 pro-inflammatory cytokines) CD4+ T-cells was significantly lower and less IL2 was produced. The frequency of polyfunctional alloreactive CD4+ T-cells and proliferation of alloreactive T-cells donor-specifically declined after transplantation reaching a nadir at 12 months after transplantation, irrespective of age. A striking difference was observed for the proliferative response of alloreactive CD8+ T-cells. This was not only lower in older compared to younger recipients but could also not be restored by exogenous IL2 or IL15 in the majority of older recipients while the response to polyclonal stimulation was unaffected. ConclusionIn conclusion, older age is associated with a distinct and marked reduction of functionality of both alloreactive CD4+ and CD8+ T-cells.

#614 Identifying distinct patient phenotypes in patients with chronic kidney disease

Abstract Background and Aims Patients with chronic kidney disease (CKD) are heterogeneous in terms of age, causes of CKD, and comorbidities. Although individual risk factors greatly influence patients’ risk of clinical outcomes, this heterogeneity is rarely used to guide clinical decision-making. In this study we aimed to derive phenotypes in patients with CKD based on characteristics commonly available in routine clinical practice and evaluated whether these phenotypes were associated with clinical outcomes. Method Patients from the Utrecht Patient Oriented Database (UPOD) who were 18 years or older with CKD (defined as an eGFR <60 ml/min/1.73 m2 or an UACR > 3 mg/mmol present for >3 months) and visited one of the cardiovascular outpatient clinics of the University Medical Center Utrecht between 2012 and 2019 were included. Patient phenotypes were derived with latent class analyses based on age, sex, CKD stage, cause of kidney disease, and (cardiovascular) comorbidities. The incidence rate/100 person years (IR/100PY) for all-cause mortality and kidney failure (defined as initiation of kidney replacement therapy or a sustained eGFR <15) and 95% confidence interval (95% CI) was calculated for each phenotype. Results Overall 9005 patients were included (mean age 65 ± 14 years, 42% women, mean estimated glomerular filtration rate (eGFR) 49 ± 17 ml/min/1.73 m2). The median follow-up was 3.8 years [interquartile range 1.8–6.4]. Latent class analysis identified 7 phenotypes with the following characteristics: phenotype 1 were young patients with primary kidney disease (10%); phenotype 2 were patients with diabetes and a preserved eGFR (9%); phenotype 3 were patients with low comorbidity and inflammation (28%); phenotype 4 were older patients with a history of cardiovascular disease (27%); phenotype 5 were older patients with a history of cardiovascular disease and severe CKD (16%); phenotype 6 were younger patients with a kidney transplant and low comorbidity (6%); and phenotype 7 were older patients with a kidney transplant and cardiovascular disease (6%). The risk of all-cause mortality and kidney failure differed significantly between the identified phenotypes. The phenotypes of younger kidney transplant recipients, younger patients with primary kidney disease, and diabetes with preserved eGFR had the lowest risk for all-cause mortality (for all, IR/100 PY <5) (Fig. 1). The phenotypes with an intermediate incidence rate for all-cause mortality were the low comorbidity and inflammation phenotype (IR/100PY 7.4, 95% CI 6.9–8.0), the phenotype of older patients with cardiovascular disease (IR/100PY 7.2, 95% CI 6.7–7.8), and the phenotype of older patients with a kidney transplant and cardiovascular disease (IR/100PY 6.5, 95% CI 5.5–7.6). The phenotypes with highest incidence rate for all-cause mortality was the phenotype of older patients with cardiovascular disease and severe CKD (IR/100PY 12.5, 95% CI11.5–13.4). The phenotypes with the lowest risk for kidney failure were the diabetes phenotype, the low comorbidity and inflammation phenotype, and the phenotype of older patients with cardiovascular disease (all IR/100 PY <1). The phenotype of older patients with cardiovascular disease and severe CKD also had the highest risk to develop kidney failure (IR/100PY 5.8, 95% CI 5.1–6.6), followed by the phenotype of patients with primary kidney disease (IR/100PY 4.4, 95% CI 3.7 −5.5). Conclusion We identified 7 different phenotypes of patients with CKD including 2 phenotypes of patients with a kidney transplant with different clinical characteristics and prognosis. The differences in risk of all-cause mortality and kidney failure warrants a different monitoring and follow-up across the different phenotypes within the setting of CKD. Future studies should invest In evaluating the implementation of our identified phenotypes in routine clinical practice or clinical trial design with respect to differences in treatments.

Widespread form of Majocchi's granuloma in a kidney transplant recipient.

Kidney transplantation is the encouraged kidney replacement therapy due to providing more prolonged survival with a better quality of life. Unfortunately, kidney transplant recipients are susceptible to infections because of long-term utilization of immunosuppression. Despite dermatophyte infections are generally not life-threatening, the clinical significance has been recently enhanced by an increasing number of immunocompromised patients. We have presented a rare dermatophytosis course, Majocchi's granuloma, that spreads to all extremities during the early post-transplant period. A young kidney transplant recipient was exposed to intensive immunosuppression therapy due to acute rejection in the early period of post-transplantation. After four months, numerous nodular skin lesions were raised on various body parts. An invasive fungal infection was identified in the skin biopsy. Also, Trichophyton rubrum was isolated in the tissue cultures. Consequently, the patient was diagnosed with Majocchi's granuloma. An effectual treatment was attained with an oral terbinafine tablet. Majocchi's granuloma is a distinct form of dermatophytosis characterized by the spreading of infection into the dermis. In this unexpected case, we alerted physicians to opportunistic infections in the kidney transplant recipient.

Impact of hyperparathyroidism on allograft histology and function after kidney transplantation: Rethinking its causal role in graft dysfunction.

The causal relationship between hyperparathyroidism and kidney graft dysfunction remains inconclusive. Applying Bradford-Hill's temporality and consistency causation principles, we assessed the effect of parathyroid hormone (iPTH) on graft histology and eGFR trajectory on kidney transplant recipients (KTRs) with normal time-zero graft biopsies. Retrospective cohort study evaluating the effect of hyperparathyroidism on interstitial fibrosis and tubular atrophy (IF/TA) development in 1232 graft biopsies. Pre-transplant hyperparathyroidism was categorized by KDIGO or KDOQI criteria, and post-transplant hyperparathyroidism by iPTH>1× and>2× the URL 1 year after transplantation. We included 325 KTRs (56% female, age 38±13 years, follow-up 4.2 years [IQR: 2.7-5.8]). Based on pre-transplant iPTH levels, 26% and 66% exceeded the KDIGO and KDOQI targets, respectively. There were no significant differences in the development of>25% IF/TA between KTRs with pre-transplant iPTH levels above and within target range according to KDIGO (53%vs. 62%, P=.16, HR.94 [95% CI:.67-1.32]) and KDOQI (60%vs. 60%, P=1.0, HR 1.19 [95% CI:.88-1.60]) criteria. Similarly, there were no differences when using 1 year post-transplant iPTH cut-offs>88 pg/mL (58%vs. 64%, P=.33) and>176 pg/mL (55%vs. 62%, P=.19). After adjusting for confounders, no significant differences were observed in eGFR trajectories among the iPTH strata. In young KTRs who received a healthy graft, no association was found between increased pre- and post-transplant iPTH levels and graft dysfunction, as assessed histologically and through eGFR trajectory. The concept of hyperparathyroidism as a risk factor for graft dysfunction in recipients at low risk requires reevaluation.

Immunosuppression and cancer risk in kidney transplant recipients: A retrospective cohort study.

We assessed whether contemporary immunosuppression agents were associated with cancer among kidney transplant recipients (KTR), and if this association varied by age and sex. We studied a retrospective province-wide cohort of primary KTR (1997-2016). Employing multivariable Cox models, we estimated associations of cumulative doses of prednisone, mycophenolate and tacrolimus administered over the past 10 years, lagged by 2 years, with the incidence of primary malignant neoplasms (PMN). We assessed interactions with age and sex. To assess the impact of exposure recency, we used weighted cumulative exposure (WCE) modeling. Among 1064 KTR, 108 (10.2%) developed PMN over median follow-up of 73 months (interquartile range: 32-120). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 0.96 (0.64-1.43), 1.34 (0.96-1.86), and 1.06 (0.88-1.29) were estimated for cumulative daily doses of prednisone (5 mg), mycophenolate (1000 mg), and tacrolimus (2 mg) administered continuously over the past 10 years, respectively. PMN risk associated with cumulative tacrolimus exposure was modified by age (interaction p = .035) and was more pronounced in 15-year and 30-year-old KTR (aHRs of 1.57 [1.08-2.28] and 1.31 [1.03-1.66], respectively) in comparison to older KTR. PMN risk increase associated with higher cumulative mycophenolate dose was more pronounced in females (aHR = 1.86 [1.15-3.00]) than in males (aHR = 1.16 [0.74-1.81]; interaction p = .131). WCE analyses suggested increased PMN risk the higher the mycophenolate doses taken 5-10 years ago. A trend toward increased PMN risk with long-term mycophenolate exposure, particularly in females, and more pronounced risk with long-term tacrolimus exposure in younger KTR, identify opportunities for tailored immunosuppression to mitigate cancer risk.

The combinatorial effect of age and biological sex on alloimmunity and transplantation outcome.

Both age and biological sex affect transplantation outcomes. We have recently shown in a large volume clinical analysis utilizing the SRTR data that graft survival is inferior in young female kidney transplant recipients. In this multi-factorial analysis, older female recipients presented with a trend towards improved transplant outcomes compared to both young female recipients and male recipients of any age. Those data supported by reports of those of others suggest that sex and age impact alloimmune responses both, individually and synergistically. Biological sex and hormone levels change throughout a lifetime with recognized effects on longevity in addition to an impact on the development and course of several disease preconditions. Detailed mechanisms of those sex and age-specific aspects have thus far been studied outside of transplantation. Effects on alloimmunity are largely unknown. Moreover, the combinatorial impact that both, biological sex and age have on transplant outcomes is not understood. Here, we summarize available data that analyze how age in combination with biological sex may shape alloimmune responses and affect transplant outcomes.

Evolving Trends in Kidney Transplant Outcomes Among Older Adults: A Comparative Analysis Before and During the COVID-19 Pandemic.

Advancements in medical technology, healthcare delivery, and organ allocation resulted in improved patient/graft survival for older (age ≥65) kidney transplant (KT) recipients. However, the recent trends in these post-KT outcomes are uncertain in light of the mounting burden of cardiovascular disease, changing kidney allocation policies, heterogeneity in candidates' risk profile, and the coronavirus disease 2019 pandemic. Thus, we examined secular trends in post-KT outcomes among older and younger KT recipients over the last 3 decades. We identified 73 078 older and 378 800 younger adult (aged 18-64) recipients using Scientific Registry of Transplant Recipients (1990-2022). KTs were grouped into 6 prepandemic eras and 1 postpandemic-onset era. Kaplan-Meier and Cox proportional hazards models were used to examine temporal trends in post-KT mortality and death-censored graft failure. From 1990 to 2022, a 19-fold increase in the proportion of older KT recipients was observed compared to a 2-fold increase in younger adults despite a slight decline in the absolute number of older recipients in 2020. The mortality risk for older recipients between 2015 and March 14, 2020, was 39% (adjusted hazard ratio [aHR] = 0.61, 95% confidence interval [CI], 0.50-0.75) lower compared to 1990-1994, whereas that for younger adults was 47% lower (aHR = 0.53, 95% CI, 0.48-0.59). However, mortality risk during the pandemic was 25% lower (aHR = 0.75, 95% CI, 0.61-0.93) in older adults and 37% lower in younger adults (aHR = 0.63, 95% CI, 0.56-0.70) relative to 1990-1994. For both populations, the risk of graft failure declined over time and was unaffected during the pandemic relative to the preceding period. The steady improvements in 5-y mortality and graft survival were disrupted during the pandemic, particularly among older adults. Specifically, mortality among older adults reflected rates seen 20 y prior.

Social support mediates the relationship between illness perception and psychosocial adaptation among young and middle-aged kidney transplant recipients in China.

No research has yet been done on social support's influence on the association between illness perception and psychosocial adaptation among young and middle-aged kidney transplant recipients in China. Accordingly, it remains unclear how medical personnel can assist patients in successfully adjusting to the early postoperative period and improving their health. This study sought to explore the influence of illness perception and social support on the psychosocial adaptation of young and middle-aged recipients of kidney transplants in China during the early postoperative period. This study adopted a cross-sectional design. The study included 236 young and middle-aged kidney transplant recipients from a tertiary hospital in China. Demographic and disease-related data were collected. Additionally, the Psychosocial Adjustment to Illness Scale-Self-Report, the Brief Illness Perception Questionnaire, and the Multidimensional Scale of Perceived Social Support were used to assess participants' psychosocial adaptation, illness perception, and social support, respectively. The model was examined using descriptive analysis, Pearson's correlation analysis, hierarchical multiple regression analysis, and the PROCESS Macro in SPSS 26.0. A total of 176 (74.56%) participants reported an average psychosocial adaptation score >50, which is relatively negative. Marital status, education level, residence, per capita monthly income (in Chinese yuan), medical insurance, work status, post-transplant time, body mass index, creatinine status, and complications were all related to psychosocial adaptation (p < 0.05). The more negative their illness perception and the worse their social support, the worse the psychosocial adaptation of young and middle-aged kidney transplant recipients. Further, the effect of illness perception on psychosocial adaptation was partially mediated by social support (36.56%). In general, the psychosocial adaption level of young and middle-aged kidney transplant recipients was negative during the early postoperative period. Healthcare teams should assist patients in building a positive illness perception shortly following kidney transplantation, while also providing psychological care and support to help them cope with the onset of psychosocial issues.

Differences in medication adherence between preemptive and post-dialysis young kidney transplant recipients.

The mechanisms underlying the superior graft survival associated with preemptive kidney transplantation, compared with transplantation following a period of dialysis, are unknown. We aimed to compare medication adherence between preemptively transplanted young kidney transplant recipients and those who received a transplant after an interval of dialysis. This was a secondary analysis of the Teen Adherence in Kidney transplant Effectiveness of Intervention Trial (TAKE-IT), in which adherence was assessed with electronic monitoring over 15months among 11-24-year-old transplant recipients. Adherence scores were calculated for each day as 0%, 50%, or 100% (intake of none, half, or all prescribed doses). We used ordinal logistic regression, with generalized estimating equations to account for repeated measures within each participant, to estimate the association between preemptive transplantation and adherence. The model was adjusted for sex, age at transplant, time since transplant, primary kidney disease, race, donor source, medication insurer, household income, and adherence intervention. There were 43 preemptive transplant recipients and 103 who had been treated with dialysis. The median adherence score was 85.1% (IQR 81.3-88.9) for those preemptively transplanted, and 80.0% (IQR 76.7-83.4) for those transplanted after dialysis. Preemptively transplanted recipients had significantly higher odds of adherence than those dialyzed before transplantation (adjusted OR 1.76 95% CI 1.21-2.55; p = 0.003). Preemptively transplanted patients showed significantly better adherence than those treated with dialysis before transplantation. This suggests that the superior outcomes observed among preemptive kidney transplant recipients may reflect selection of patients more likely to adhere to therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.

210.14: Humoral Response to COVID-19 mRNA Vaccines in a Cohort of Young Kidney Transplant Recipients From a Single Center in Northern Italy

Objectives: To investigate immune-response to COVID-19 vaccines in young kidney transplant (KT) recipients from Northern Italy. Methods: We prospectively studied KT patients aged 12-25 years, managed in our Center on maintenance IS therapy (corticosteroids, CNI and anti-proliferative agents), eligible for antiSARS-Cov2 vaccination according to the schedule of the Italian Medicines Agency for immunosuppressed patients (two doses plus additional dose one month later). From 1st July 2021 to 28th February 2022 we evaluated antiSpike-protein antibody response at T0 (before vaccine), T1, T2 and T3 (14±3 days after 2nd and 3rd dose and 90±7 days after 3rd dose, respectively) to BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna). AntiSpike total Ig titer cut-off was 0.8 U/ml (Roche® Elecsys Anti-SARS-CoV-2-S). Exclusion criteria: KT or additional IS within 6 months, relapse of primary disease, vaccine before KT, ongoing COVID-19, patients resident outside the Region. Results: Eighty-seven patients were eligible; 68 patients were enrolled. Median age: 19.5 (IQR:16.3-21.9) years; median time from KT: 61.4 (IQR: 36.7-111.7) months. Five patients dropped out of study after enrollment. Anti-SARS-Cov2 Spike Antibodies response to mRNA vaccines is shown in Figure 1; 90% of non-responders at T1 (20 patients) seroconverted at T3. We didn’t find correlation between time from KT (the shorter time, the most intensive immunosuppression) and Ig-titer. Twelve out of 58 pts developed COVID19 after the third additional vaccine dose; in this population AntiSpike Ig titer at T2 was lower compared to the value of non infected patients, even if not statistically significant: 144 U/ml (IQR:9.4-3683) vs. 4771 U/ml (IQR:79.1-13000) respectively. None patient had side effects, including acute rejection episodes or de novo DSA development. Conclusion: KT pediatric recipients exhibit a satisfactory response after 2 doses of vaccine, that become comparable to that of immunocompetent population after the third. Furthermore, the response after two doses is better if compared with adult KT population (63.6% vs 4-48%).

213.9: Differences in Medication Adherence Between Preemptive and Post-dialysis Young Kidney Transplant Recipients

Introduction: The mechanisms underlying the superior graft survival associated with pre-emptive kidney transplantation, compared with transplantation following a period of dialysis, are unknown. Selection for pre-emptive transplantation of a group biased to better treatment adherence is possible. We aimed to compare medication adherence between pre-emptively transplanted young kidney transplant recipients and those who received a transplant after an interval of dialysis. Methods: This was a secondary analysis of the Teen Adherence in Kidney transplant Effectiveness of Intervention Trial (TAKE-IT), in which adherence was assessed with electronic monitors over a 15-month period among 11–24 year-old kidney transplant recipients. Adherence scores of 0%, 50%, or 100% were calculated for each day, depending on whether the patient took none, half, or all prescribed doses. We used ordinal logistic regression to estimate the association between pre-emptive transplantation and adherence, with generalized estimating equations to account for repeated measures within each participant. The model was adjusted for sex, age at transplant, time since transplant, primary kidney disease, race, donor source, medication insurer, household income, and adherence intervention (time-varying). Results: There were 43 pre-emptive transplant recipients (median age 15.8 [IQR 13.7-17.6]; 60.5% male) and 103 who has been treated with dialysis (median age 15.7 [IQR 13.3-17.4]; 60.2% male). The mean adherence score was 85.1% (IQR 81.3-88.9) for those pre-emptively transplanted, and 80.0% (IQR 76.7-83.4) for those transplanted after dialysis. Table 1 shows the results adjusted logistic regression model. Preemptively transplanted recipients had significantly higher odds of adherence than those dialyzed before transplantation (OR 1.76 95%CI 1.21-2.55; p=0.003). Conclusions: Pre-emptively transplanted patients showed significantly better adherence than those treated with dialysis before transplantation. This suggests that the superior outcomes observed among preemptive kidney transplant recipients likely reflect selection of patients more likely to adhere to therapy.

Investigation of Weight Gain and Affecting Factors in Kidney Transplant Recipients in the First 2 Years After Transplant.

It is necessary to examine weight gain and affecting factors after kidney transplant. This study was performed to examine weight gain and affecting factors in kidney transplant recipients in the first 2 years after transplant. This descriptive cross-sectional study included 139 kidney transplant recipients who were regularly followed by 2 university hospitals in the first 2 years after transplant. Data were collected with the use of a sociodemographic and clinical features' form and the General Self-Efficacy Scale. Weight and body mass index at 3, 6, 12, and 24 months after transplant were evaluated. Differences between weight (in kilograms) and body mass index (in kilograms divided by height in meters squared) at the first outpatient clinic visit and weight and body mass index at 24 months after transplant were calculated. The mean age of patients was 46.32 ± 12.39 years. Differences in mean weight and body mass index between the first posttransplant outpatient clinic visit and at month 24 posttransplant were 7.07 ± 7.57 and 2.6 ± 2.37, respectively. Statistically significant differences were found in weight and body mass index at 2 years posttransplant. As age increased, weight gain decreased. Differences in weight gain and body mass index were not significantly associated with sex, presence of chronic diseases, donor type, steroid dose, and self-efficacy. Kidney transplant recipients in our study population had increased weight and body mass index at 2 years after transplant. Younger kidney transplant recipients had higher weight gains. Therefore, kidney transplant recipients, especially younger ones, should be closely followed in terms of weight gain after transplant.

Safety and Tolerability of mRNA COVID-19 Vaccines in Kidney Transplant Recipients

BackgroundCOVID-19 mRNA vaccines have demonstrated excellent short-term safety in phase 3 trials. However, no kidney transplant recipients (KTR) were included. The aim of the study was to assess the safety and tolerability of COVID-19 mRNA vaccines in KTR.Materials and MethodsA longitudinal controlled study was conducted in 300 KTR and 143 control patients (CRL) without chronic kidney disease who had received 2-dose vaccinations with the mRNA vaccine. Solicited local and systemic reactogenicity and unsolicited adverse events were assessed with a standardized questionnaire. The toxicity grading scales were derived from the FDA guidelines.ResultsKTR (62.7% men) with a median (interquartile range) age of 53 (41-63) and transplant vintage of 7.25 (3-13) years did not differ with respect to age and sex distribution from CRL. One hundred percent CRL and 83.3% KTR were vaccinated with BNT162b2 (BionTech/Pfizer); 16.7% KTR received mRNA-1273 (Moderna) vaccine. Any local reactions were present in 84.7% (first dose) and 65.3% (second dose) KTR vs 67.1% and 60.1% CRL within 7 days after the vaccination. Any systemic reactions were reported by 26.7% (first dose) and 20.9% (second dose) KTR vs 24.7 and 35.7% CRL. The most common systemic reactions in KTR were fatigue, headache and myalgia. No serious adverse events were observed. Many systemic reactions were observed less frequently in KTR than CRL. Younger KTR (<54 years) reported any local and any systemic reactions significantly more frequently than older patients.ConclusionmRNA COVID-19 vaccines are safe and well-tolerated by KTR. The results may resolve patients' doubts and reduce their vaccine hesitancy.

T cell senescence and impaired CMV-specific response are associated with infection risk in kidney transplant recipients

Older kidney transplant recipients demonstrate increased rates of infection, and lower rates of rejection, compared with younger kidney transplant recipients. However, the mechanism behind this observation remains unknown. To develop a multifaceted view of age-associated immune dysfunction, we determined the function and phenotype of T cells predisposing to vulnerability to infection on a molecular level.Overlapping peptide pools representing the dominant CMV antigens were used to stimulate PBMC collected from 51 kidney transplant recipients, using cytokine secretion to determine specificity and intensity of response. Staphylococcal endotoxin B (SEB) was analyzed in parallel. To define immune cell subsets, we used single cell RNA sequencing (scRNAseq) to evaluate cellular surface markers and gene expression.We found increased frequency of SEB- and CMV-specific T cells was associated with freedom from infection, especially in older patients. Spatialized t-SNE analysis revealed decreased frequency of naïve T cells, increased frequency of TEMRA cells, and decreased frequency of IFNγ secreting T cells in patients with infection. Application of scRNAseq analysis revealed increased frequency of terminally differentiated T cells expressing NK-associated receptors and inhibitory markers.These findings offer unique insight into the mechanism behind vulnerability to infection in the kidney transplant recipient, revealing a specific T cell subtype of impaired antigen response and terminal effector phenotype as markers of T cell senescence.

Persistent headache in a young kidney transplant recipient caused by tacrolimus associated pseudotumor cerebri - A case report

Pseudotumor cerebri (PC) is characterized by chronic elevation of intracranial pressure with normal cerebrospinal fluid (CSF) examination and normal neuro-imaging. We report a case of a 22-year-old female with renal allograft and for the past 4 years on immunosuppressant including prednisolone, tacrolimus, and mycophenolate mofetil. The patient presented with persistent headache for 2 months along with nausea and vomiting. Fundoscopic examination revealed bilateral papilledema. Magnetic resonance imaging-brain with venogram was normal and cytochemical examination of CSF was also normal. Ocular coherence tomography revealed increased retinal nerve fiber layer thickness. A diagnosis of PC was made based on an elevated CSF pressure (35 cm H20). We reduced the dose of tacrolimus and added acetazolamide but the dose of prednisolone and mycophenolate mofetil was not modified. There was the gradual improvement of symptoms. On follow-up visits, papilledema disappeared and the patient is now asymptomatic with normal allograft function.

Early outcomes and long-term survival after kidney transplantation in elderly versus younger recipients from the same donor in a matched-pairs analysis.

The elderly are the fastest-growing population on waiting lists for kidney transplantation (KTx). Recognized barriers to KTx in the elderly is early post-transplant mortality and morbidity. To analyze the outcomes of KTx in recipients older than 60 years and, simultaneously, in their younger paired recipients, receiving a graft from the same donor.We included 328 kidney transplant recipients in the study. The elderly kidney transplant recipients (EKT) group included 164 patients aged 65 standard deviation (SD4) years. They were paired with younger kidney transplant recipients (YKT) aged 45 (SD12) years.The studied groups (EKT vs YKT) did not differ from the graft function estimated 1 year after the transplantation (50.7 mL/min vs 54.0 mL/min), while the estimated glomerular filtration rate decline was significantly faster in the YKT group. One-year patient survival (93.9% vs 97.0%), 1-year graft survival (90.4% vs 82.3%), and incidences of delayed graft function and acute rejection did not differ between the EKT and YKT groups. Significantly more cardiovascular complications and post-transplant diabetes mellitus were noticed in the EKT group. The long-term patient and graft survivals were poorer in the EKT group versus the YKT group, but death-censored graft survivals were the same. After having excluded donor-derived graft factors, there were no differences in the first-year outcome of KTx between recipients younger and older than 60 years. As life expectancy is lower in the EKT group, the probability of patient and graft survival was also significantly lower in this group. However, death-censored graft survival was not different in the EKT and YKT groups.

Rare and Unusual Follow-up Sequelae of Coronavirus Disease 2019: Splenic Mucormycosis in a Renal Transplant Recipient

BackgroundCoronavirus disease 2019 (COVID-19) is associated with adverse outcomes in transplantation communities. Mucormycosis, although a rare infection, has been classically linked to organ transplantation and is associated with exceptionally high morbidity and mortality rates. In this pandemic era, the double infection of mucormycosis and COVID-19 is a lethal combination but is rarely described in the literature on organ transplantation.Case presentationThis article presents the case of a young kidney transplant recipient with diabetes who acquired severe COVID-19, followed by disseminated mucormycosis. The patient was a health care worker who developed severe COVID-19, for which he received remdesivir, anticoagulation, and dexamethasone. No immunomodulatory therapy was used. His maximum oxygen support was bilevel positive airway pressure ventilation. His sugar levels were frequently deranged during the stay. He developed secondary sepsis with Klebsiella, followed by nonhealing lung consolidation. He later developed pleural effusion and splenic abscess, which was detected incidentally. He underwent an emergency splenectomy, the culture of which yielded mucormycosis. Liposomal amphotericin B 5 mg/kg was administered. The patient deteriorated, and a repeat laparotomy yielded gastric perforation, with pus culture showing mucormycosis. The patient died after a long hospital stay.ConclusionsThe diagnosis and management of this dual infection during the pandemic is extremely challenging. In this case, the unusual location of mucormycosis complicating COVID-19 calls for a meticulous approach to opportunistic fungal infections in organ transplant recipients who are positive for COVID-19, especially in those patients with diabetes.

Immunoreactivity of CD3+CD4+ in Stable Young, Middle Aged, and Elderly Kidney Transplant Recipients Receiving Maintenance Tacrolimus and Mycophenolic Acid Immunosuppression

Immunoreactivity of CD3+CD4+ in Stable Young, Middle Aged, and Elderly Kidney Transplant Recipients Receiving Maintenance Tacrolimus and Mycophenolic Acid Immunosuppression

Expression of Senescence Marker TIGIT Identifies Polyfunctional Donor-Reactive CD4+ T Cells Preferentially Lost After Kidney Transplantation.

Development of T-cell hyporesponsiveness to donor antigen may explain the substantial decreased risk for acute rejection in the years following kidney transplantation. The underlying mechanisms of donor-specific hyporesponsiveness (DSH) are largely unknown but may allow for lowering of immunosuppressive medication. Due to the onset of DSH being more rapid and pronounced in older recipients (+55 years), we hypothesized that immunosenescence/exhaustion of T lymphocytes would be a contributing factor. This study tested whether donor-reactive recipient T cells become hyporesponsive due to exhaustion from continuous stimulation by donor antigen. Circulating donor-reactive T cells of both young and elderly stable kidney transplant recipients (N=17) before and 3-5 years after transplantation were analyzed at the single cell level for expression of exhaustion markers by multi-parameter flow cytometry followed by unsupervised and unbiased clustering. Clusters containing cells of a particular expression profile with significant differential abundance after transplantation were identified and further analyzed. Unexpectedly, our results do not demonstrate an increase in exhausted donor antigen-reactive T cells post transplantation. Instead, we demonstrate a significant decrease in donor antigen-reactive CD4+ T cells expressing T cell immunoglobulin and ITIM domain (TIGIT) long after transplantation. Further analysis at earlier timepoints indicated that this decrease is already present at six months post transplantation. Characterization of these CD4+ T donor-reactive cells expressing TIGIT revealed them to have a predominantly central and effector memory T cell phenotype and a highly poly-functional cytokine expression profile. This study has therefore identified TIGIT as a marker for a previously undescribed polyfunctional donor-reactive CD4+ T cell population whose decline following kidney transplantation may explain development of DSH.