Phase Angle as Surrogate Marker of Muscle Weakness in Kidney Transplant Candidates Referred to Prehabilitation.

Phase angle (PhA), a marker of nutritional status obtained by bioelectrical impedance analysis (BIA), is associated with the integrity of cell membranes. Damage to muscle fiber membranes can impact muscle strength, which is related to adverse outcomes in adults with advanced chronic kidney disease (CKD). The main objective of this study was to determine the usefulness of the PhA in identifying muscle weakness in candidates for kidney transplants (KTs). Secondly, it aimed to examine the associations of PhA with other parameters of body composition, exercise performance, and muscle structure. Sensitivity, specificity, and area under the receiver operating characteristics curve were used to evaluate the PhA (index test) as a biomarker of muscle weakness. Muscle strength was estimated with maximal voluntary isometric contraction of the quadriceps (MVCI-Q) of the dominant side. Muscle weakness was defined as MVIC-Q < 40% of body weight. A total of 119 patients were evaluated (mean age 63.7 years, 75.6% men). A phase angle cut-off of 5.1° was identified to classify men with a higher likelihood of having low muscle strength in upper limbs (MVIC-Q 40% of their body weight). Male KT candidates with PhA < 5.1° had poorer exercise capacity, lower muscle strength, less muscle mass, and smaller muscle size. A PhA < 5.1° was significantly associated with an eight-fold higher muscle weakness risk (OR = 8.2, 95%CI 2.3-29.2) in a binary regression model adjusted by age, frailty, and hydration status. Remarkably, PhA is an easily obtainable objective parameter in CKD patients, requiring no volitional effort from the individual. The associations of PhA with aerobic capacity, physical activity, muscle mass, and muscle size underscore its clinical relevance and potential utility in the comprehensive evaluation of these patients.

Clinical and molecular spectrum of v-lesion.

Isolated v-lesion presents diagnostic stratification and clinical challenges. We characterized allograft outcomes for this entity based on post-transplant time (early: ≤1 month vs. late: >1 month) and compared its molecular phenotype with other v+ rejection forms. Using the NanoString® B-HOT panel, we analyzed 92 archival FFPE kidney biopsies from three centers: isolated v-lesion (n=23), ABMR v+ (n=26), TCMR v+ (n=10), mixed rejection v+ (n=23), and normal tissue (n=10). Six gene sets (ABMR, DSAST, ENDAT, TCMR, early/acute injury, late injury) were assessed. Early isolated v-lesions had the poorest one-year death-censored graft survival compared to late isolated v-lesions or other rejections (p=0.034). Gene set analysis showed lower TCMR-related gene expression in isolated v+ groups than TCMR and mixed rejection (p<0.001). Both early and late isolated v-lesions had lower ABMR-related gene expression than ABMR, mixed rejection, and TCMR (p≤0.022). Late isolated v-lesions showed reduced DSAST and ENDAT gene expression versus ABMR (p≤0.046); and decreased early/acute injury gene expression than early isolated v+, ABMR, TCMR, and mixed rejection (p≤0.026). In conclusion, isolated v-lesions exhibit distinct gene expression patterns versus other rejection v+ forms. Early isolated v+ is associated with poorer prognosis and increased early/acute injury gene expression than late isolated v+, suggesting distinct etiologies.

Screening for tropical and imported infections in migrant kidney transplant candidates from the kidney transplant access consultation.

BACKGROUND AND OBJECTIVE: Kidney transplantation (KT) should be postponed in those people with active bacterial, fungal, viral and parasitic processes, since these must be treated and resolved previously. The objective of this study is to present the screening circuit implemented by the Nephrology clinic and describe the prevalence of tropical and imported infections in KT candidates born or coming from endemic areas. MATERIALS AND METHODS: Descriptive cross-sectional study, carried out in 2021. Sociodemographic and clinical variables, serological data of general infections and specific tests of tropical infectious diseases were collected. A descriptive analysis of the data was carried out. RESULTS: 67 TR candidates from Latin America (32.8%), North Africa (22.4%), Sub-Saharan Africa (14.9%) and Asia (29.9%) were included. 68.7% were men and the mean age was 48.9 ±â€¯13.5 years. After the general and specific studies, 42 (62.7%) patients were referred to the Infectious Diseases Service to complete this study or indicate treatment. 35.8% of the patients had eosinophilia, and in one case parasites were detected in feces at the time of the study. Serology for strongyloidiasis was positive in 18 (26.9%) cases, while positive serology for other tropical infections was hardly detected. 34.3% of patients had latent tuberculosis infection. CONCLUSIONS: The prevalence of tropical and imported infections in migrant candidates for RT was low, except for strongyloidiasis and latent tuberculosis infection. Its detection and treatment are essential to avoid serious complications in post-TR. To this end, the implementation of an interdisciplinary screening program from the KT access consultation is feasible, necessary and useful.

Unmet Questions About Frailty in Kidney Transplant Candidates.

Frailty occurs frequently among patients with advanced chronic kidney disease, especially among women. Assessing frailty in kidney transplant (KT) candidates is crucial for informing them about associated risks. However, there is poor agreement between frailty scales and research on their correlation with transplant outcomes. Being prefrail significantly impacts both graft and patient survival, often beginning with just 1 Fried criterion. Rather than viewing frailty as a categorical state, it should be regarded as a spectrum ranging from 1 to 5 criteria, with the risk of adverse outcomes escalating as frailty worsens. Frailty status fluctuates during the waiting period for KT; hence, a 1-time frailty evaluation is insufficient to determine risks and implement strategies for improving functional status. Further research should investigate the components of frailty that most frequently change during this waiting period and establish strategies to prevent or reverse frailty. Although careful evaluation of frail KT candidates is necessary to prevent early complications and mortality, exclusion based solely on a frailty score is unwarranted. Instead, efforts should focus on timely interventions to enhance their condition before transplantation. Although evidence is limited, exercise programs appear feasible and yield positive results. A pretransplant clinical framework encompassing multimodal prehabilitation-comprising physical therapy, nutritional measures, and psychological support-during the waiting list period may help alleviate the effects of frailty and poor fitness after KT, ultimately improving key outcomes. Despite logistical challenges, there is a pressing need for interventional trials in this area.

Complex management and descriptive cost analysis of kidney transplant candidates: a descriptive cross-sectional study.

BACKGROUND: The organisational care needs involved in accessing kidney transplant have not been described in the literature and therefore a detailed analysis thereof could help to establish a framework (including appropriate timing, investment, and costs) for the management of this population. The main objective of this study is to analyse the profile and care needs of kidney transplant candidates in a tertiary hospital and the direct costs of studying them. METHODS: A descriptive, cross-sectional study was conducted using data on a range of variables (sociodemographic and clinical characteristics, study duration, and investment in visits and supplementary tests) from 489 kidney transplant candidates evaluated in 2020. RESULTS: The comorbidity index was high (> 4 in 64.3%), with a mean of 5.6 ± 2.4. Part of the study population had certain characteristics that could hinder their access a kidney transplant: physical dependence (9.4%), emotional distress (33.5%), non-adherent behaviours (25.2%), or language barriers (9.4%). The median study duration was 6.6[3.4;14] months. The ratio of required visits to patients was 5.97:1, meaning an investment of €237.10 per patient, and the ratio of supplementary tests to patients was 3.5:1, meaning an investment of €402.96 per patient. CONCLUSIONS: The study population can be characterised as complex due to their profile and their investment in terms of time, visits, supplementary tests, and direct costs. Management based on our results involves designing work-adaptation strategies to the needs of the study population, which can lead to increased patient satisfaction, shorter waiting times, and reduced costs.

Recurrence of membranous nephropathy after kidney transplantation: A multicenter retrospective cohort study.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

High exposure to tacrolimus is associated with spontaneous remission of recurrent membranous nephropathy after kidney transplantation.

Introduction: We aimed to characterize the incidence and clinical presentation of membranous nephropathy (MN) after kidney transplantation (KT), and to assess allograft outcomes according to proteinuria rates and immunosuppression management. Methods: Multicenter retrospective cohort study including patients from six Spanish centers who received a KT between 1991-2019. Demographic, clinical, and histological data were collected from recipients with biopsy-proven MN as primary kidney disease (n = 71) or MN diagnosed de novo after KT (n = 4). Results: Up to 25.4% of patients with biopsy-proven MN as primary kidney disease recurred after a median time of 18.1 months posttransplant, without a clear impact on graft survival. Proteinuria at 3-months post-KT was a predictor for MN recurrence (rMN, HR 4.28; P = 0.008). Patients who lost their grafts had higher proteinuria during follow-up [1.0 (0.5-2.5) vs 0.3 (0.1-0.5) g/24 h], but only eGFR after recurrence treatment predicted poorer graft survival (eGFR < 30 ml/min: RR = 6.8). We did not observe an association between maintenance immunosuppression and recurrence diagnosis. Spontaneous remission after rMN was associated with a higher exposure to tacrolimus before recurrence (trough concentration/dose ratio: 2.86 vs 1.18; P = 0.028). Up to 94.4% of KT recipients received one or several treatments after recurrence onset: 22.2% rituximab, 38.9% increased corticosteroid dose, and 66.7% ACEi/ARBs. Only 21 patients had proper antiPLA2R immunological monitoring. Conclusions: One-fourth of patients with biopsy-proven MN as primary kidney disease recurred after KT, without a clear impact on graft survival. Spontaneous remission after rMN was associated with a higher exposure to tacrolimus before recurrence.

Immunosuppression of HLA identical living-donor kidney transplant recipients: A systematic review.

BACKGROUND: Kidney transplant (KT) recipients of HLA identical siblings (HLAid) have lower immunological risk, but there are no specific recommendations for immunosuppression. Our aim was to analyze evidence about results from HLAid living-donor recipients under different immunosuppression in the current era of immunological risk assessment. METHODS: Systematic review of studies describing associations between outcomes of HLAid living-donor KT recipients according to their immunological risk and applied immunosuppression. RESULTS: From 1351 studies, 16 (5636 KT recipients) were included in the analysis. All studies were retrospective, ten comparing immunosuppression strategies, and six immunological risk strata. Of those ten, six studies were published in 1990 or earlier and only three included tacrolimus. The evidence is poor, and the inclusion of calcineurin inhibitors does not demonstrate better results. Furthermore, only few studies describe different immunosuppression regimens according to the patient immunological risk and, in general, they do not include the assessment with new solid phase assays. CONCLUSIONS: There are no studies analyzing the association of outcomes of HLAid KT recipients with current immunological risk tools. In the absence of evidence, no decision or proposal of immunosuppression adapted to modern immunological risk assessment can be made currently by the Descartes Working Group.

European Society of Organ Transplantation (ESOT) Consensus Statement on Prehabilitation for Solid Organ Transplantation Candidates.

There is increasingly growing evidence and awareness that prehabilitation in waitlisted solid organ transplant candidates may benefit clinical transplant outcomes and improve the patient's overall health and quality of life. Lifestyle changes, consisting of physical training, dietary management, and psychosocial interventions, aim to optimize the patient's physical and mental health before undergoing surgery, so as to enhance their ability to overcome procedure-associated stress, reduce complications, and accelerate post-operative recovery. Clinical data are promising but few, and evidence-based recommendations are scarce. To address the need for clinical guidelines, The European Society of Organ Transplantation (ESOT) convened a dedicated Working Group "Prehabilitation in Solid Organ Transplant Candidates," comprising experts in physical exercise, nutrition and psychosocial interventions, to review the literature on prehabilitation in this population, and develop recommendations. These were discussed and voted upon during the Consensus Conference in Prague, 13-15 November 2022. A high degree of consensus existed amongst all stakeholders including transplant recipients and their representatives. Ten recommendations were formulated that are a balanced representation of current published evidence and real-world practice. The findings and recommendations of the Working Group on Prehabilitation for solid organ transplant candidates are presented in this article.

New perspectives on frailty in light of the Global Leadership Initiative on Malnutrition, the Global Leadership Initiative on Sarcopenia, and the WHO's concept of intrinsic capacity: A narrative review.

This review gathered the evidence on the epidemiology of frailty, as well as on screening and diagnostic tools, and new perspectives, in light of the latest global frameworks in malnutrition, sarcopenia, and the World Health Organization's concept of intrinsic capacity. Frailty is a worldwide health challenge and highly prevalent in older adults and the population with chronic diseases independent of age. Regardless of the particular concept of frailty, many screening and diagnostic tools are able to identify frailty in older people, but none of them has shown superiority in every population and healthcare setting. Physical, cognitive, and social components are part of the larger context of frailty. The latest evidence-based initiatives on frailty recommend the use of validated tools to identify frailty's different components, tailored to the needs of specific populations and healthcare systems. Unintentional weight loss is a shared criterion between physical frailty and malnutrition according to the Global Leadership Initiative on Malnutrition criteria. A new definition of sarcopenia by the Global Leadership Initiative on Sarcopenia is awaited, but at present physical frailty shares with sarcopenia the criteria of low muscle function and physical performance (severity grading) according to the revised consensus of the European Working Group on Sarcopenia in Older People (EWGSOP2). The EWGSOP2 includes both muscle mass and function, with most scientific groups agreeing that function is a key hallmark of sarcopenia. The concept of intrinsic capacity features the reserves and positive aspects of aging, and responds to ageism by addressing the deficit model approach. Intrinsic capacity is an emerging, person-centered and public health indicator, aimed at preserving health at mid-life and beyond, to move towards a better aging process in the Decade of Healthy Aging 2020-2030.

Evolution of kidney allograft loss causes over 40 years (1979-2019).

INTRODUCTION: The improvement of kidney allograft recipient and graft survival showed a decrease over the last 40 years. Long-term graft loss rate remained stable during a 25-year time span. Knowing the changing causes and the risk factors associated with graft loss requires special attention. The present study aimed to assess the causes of graft loss and kidney allograft recipient death. Also, we aimed to compare two different periods (1979-1999 and 2000-2019) to identify changes in the characteristics of the failed allografts and recipient and donors profile. METHODS AND PATIENTS: We performed a single-center cohort study. We included all the kidney transplant recipients at the Hospital del Mar (Barcelona) between May 1979 and December 2019. Graft loss was defined as recipient death with functioning graft and as loss of graft function (return to dialysis or retransplantation). We assessed the causes of graft loss using clinical and histological information. We also analyzed the results of the two different transplant periods (1979-1999 and 2000-2019). RESULTS: Between 1979 and 2019, 1522 transplants were performed. The median follow-up time was 56 (IQR 8-123) months. During follow-up, 722 (47.5%) grafts were lost: 483 (66.9%) due to graft failure and 239 (33.1%) due to death with functioning graft. The main causes of death were cardiovascular (25.1%), neoplasms (25.1%), and infectious diseases (21.8%). These causes were stable between the two periods of time. Only the unknown cause of death has decreased in the last period. The main cause of graft failure (loss of graft function) was the allograft chronic dysfunction (75%). When histologic information was available, antibody-mediated rejection (ABMR) and interstitial fibrosis/tubular atrophy (IF/TA) were the most frequent specific causes (15.9% and 12.6%). Of the graft failures, 213 (29.5%) were early (<1 year of transplantation). Vascular thrombosis was the main cause of early graft failure in the second period (2000-2019) (46.7%) and T-cell-mediated rejection (TCMR) was the main cause (31.3%) in the first period (1979-1999). The causes of late graft loss were similar between the two periods. CONCLUSIONS: The causes of kidney allograft recipient death are still due to cardiovascular and malignant diseases. Vascular thrombosis has emerged as a frequent cause of early graft loss in the most recent years. The evaluation of the causes of graft loss is necessary to improve kidney transplantation outcomes.

Association between GLIM-defined malnutrition and hospitalizations in kidney transplant candidates: A post hoc analysis of a cohort study.

BACKGROUND: Malnutrition is frequent in patients with chronic kidney disease (CKD) and has a negative impact on morbidity, mortality, and quality of life. The objective of this study was to assess the value of the Global Leadership Initiative for Malnutrition (GLIM) criteria to predict hospitalizations and mortality in candidates to kidney transplant during their first year on the waiting list. METHODS: This was a post hoc analysis of 368 patients with advanced CKD. The main study variables were malnutrition, according to the GLIM criteria; number of hospital admissions during the first year on the waiting list; and mortality at the end of follow-up. Kaplan-Meier survival curves and binary logistic regression were performed, adjusting for age, frailty status, handgrip strength, and Charlson Index as potential confounders. RESULTS: The prevalence of malnutrition was 32.6%. Malnutrition was associated with increased risk of hospitalizations during the first year on the waiting list (odds ratio [OR] = 3.33 [95% CI = 1.34-8.26]), which persisted after adjustment for age and frailty status (adjusted OR = 3.61 [95% CI = 1.38-10.7]), age and handgrip strength (adjusted OR = 3.39 [95% CI = 1.3-8.85]), and age and Charlson Index (adjusted OR = 3.25 [95% CI = 1.29-8.13]). CONCLUSION: Malnutrition according to the GLIM criteria was highly prevalent in patients with CKD and was associated with a threefold increased risk of hospitalizations during the first year on the waiting list; these associations remained significant after adjusting for age, frailty status, handgrip strength, and comorbidities.

Evolución de las causas de pérdida del injerto en trasplante renal durante 40 años (1979-2019) / Evolution of kidney allograft loss causes over 40 years (1979-2019)

Introducción: La mejoría en la supervivencia del receptor y del injerto renal sufre un proceso de deceleración. La tasa de pérdida del injerto a medio y largo plazo permanece estable desde hace 25 años. Es fundamental conocer las causas de pérdida del injerto y los factores relacionados, así como identificar si se han producido cambios en las causas de pérdida del injerto en los últimos años. El objetivo del presente estudio fue evaluar las causas de pérdida del injerto según fallecimiento del receptor o pérdida del injerto con vuelta a diálisis/retrasplante, y analizar las causas específicas de pérdida del injerto en 2 épocas (1979-1999 y 2000-2019) para identificar cambios en el perfil de los injertos perdidos. Pacientes y métodos: Estudio retrospectivo de todos los trasplantes renales (TR) realizados en el Hospital del Mar (Barcelona) entre mayo-1979 y diciembre-2019. Consideramos pérdida del injerto el fallecimiento del paciente con injerto funcionante o el re-inicio de diálisis o retrasplante. Revisamos las causas de pérdida mediante información clínica e histológica, y analizamos los resultados en 2 periodos (1979-1999 y 2000-2019). (AU)

Introduction: The improvement of kidney allograft recipient and graft survival showed a decrease over the last 40 years. Long-term graft loss rate remained stable during a 25-year time span. Knowing the changing causes and the risk factors associated with graft loss requires special attention. The present study aimed to assess the causes of graft loss and kidney allograft recipient death. Also, we aimed to compare two different periods (1979-1999 and 2000-2019) to identify changes in the characteristics of the failed allografts and recipient and donors profile. Methods and patients: We performed a single-center cohort study. We included all the kidney transplant recipients at the Hospital del Mar (Barcelona) between May 1979 and December 2019. Graft loss was defined as recipient death with functioning graft and as loss of graft function (return to dialysis or retransplantation). We assessed the causes of graft loss using clinical and histological information. We also analyzed the results of the two different transplant periods (1979-1999 and 2000-2019). (AU)

Low Phase Angle Values Are Associated with Malnutrition according to the Global Leadership Initiative on Malnutrition Criteria in Kidney Transplant Candidates: Preliminary Assessment of Diagnostic Accuracy in the FRAILMar Study.

Malnutrition has a negative impact on patients with chronic diseases and its early identification is a priority. The primary objective of this diagnostic accuracy study was to assess the performance of the phase angle (PhA), a bioimpedance analysis (BIA)-derived parameter, for malnutrition screening using the Global Leadership Initiative for Malnutrition (GLIM) criteria as the reference standard in patients with advanced chronic kidney disease (CKD) waiting for kidney transplantation (KT); criteria associated with low PhA in this population were also analyzed. Sensitivity, specificity, accuracy, positive and negative likelihood ratios, predictive values, and area under the receiver operating characteristic curve were calculated for PhA (index test) and compared with GLIM criteria (reference standard). Of 63 patients (62.9 years old; 76.2% men), 22 (34.9%) had malnutrition. The PhA threshold with the highest accuracy was ≤4.85° (sensitivity 72.7%, specificity 65.9%, and positive and negative likelihood ratios 2.13 and 0.41, respectively). A PhA ≤ 4.85° was associated with a 3.5-fold higher malnutrition risk (OR = 3.53 (CI95% 1.0-12.1)). Considering the GLIM criteria as the reference standard, a PhA ≤ 4.85° showed only fair validity for detecting malnutrition, and thus cannot be recommended as a stand-alone screening tool in this population.

The role of Advanced Practice Nurses in creating the Kidney Transplant candidate care map (APN-preKT): a convergent-parallel mixed methods research protocol.

BACKGROUND: Waiting time for kidney transplants (KT) is an important health determinant for patients with chronic kidney disease (CKD). During this time, ongoing evaluation and participation is necessary in order to guarantee the quality and suitability of the proposed treatment. There is no existing literature on the potential impact of inclusion of an Advanced Practice Nurse (APN) role in the hospital setting on care for CKD patients who are candidates for KT. The main objectives of this protocol are: to analyse outpatient nursing activity in the care of individuals with KT in Spain; to identify the needs of individuals who are KT candidates; and to measure the impact of the APN role through patient outcomes and experiences. These objectives are fulfilled through 5 specific related substudies. METHODS: A convergent parallel mixed methods approach will be conducted between July 2021 and April 2024. Quantitative and qualitative data will be collected and analysed separately to ascertain whether the findings confirm or contradict one another. Each of the 5 substudies of the project require a specific design, sampling method, and data collection procedure in order to meet the overall objectives for the project. DISCUSSION: The results of the project are expected to inform the design of future nursing roles and contribute to future improvements in the quality of care provided. The data that may be obtained from this protocol are limited to the specific context of the study facility and may be extrapolated but not compared to other settings due to the variability of care pathways for KT candidates internationally. TRIAL REGISTRATION: This project was approved by the Clinical Research Ethics Committee (no.2020/9418/I). The study was supported by the "Strategic Plan for Health Research and Innovation" from the Generalitat de Catalunya, registration number SLT017/20/000001, with a contribution of 57,239 euros.

THSD7A-positive membranous nephropathy after kidney transplantation: A case report.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome after kidney transplantation (KT); however, scarce is known regarding post-KT thrombospondin type-1 domain-containing 7A (THSD7A)-positive MN. Herein, we report on a 72-year-old woman with end-stage kidney disease due to chronic interstitial nephritis (1996). In February 2020, she received a second deceased-donor KT, achieving optimal kidney function but presenting early post-KT proteinuria, reaching up to 1800mg/24h six months after transplantation, controlled with renin-angiotensin-aldosterone system (RAAS) blockade. In July 2021, a kidney allograft biopsy revealed features consistent with MN. Immunohistochemical stains showed diffuse and granular THSD7A and C4d deposition in glomerular capillary walls and negative PLA2R and IgG4 staining. No anti-THSD7A antibodies were detected in the serum. The pre-implantation biopsy showed no MN-associated lesions and negative THSD7A staining. Secondary triggers such as malignancy were discarded. The present report illustrates a THSD7A-positive MN in a KT recipient. Despite lacking native kidney biopsy and early presentation, a recurrent MN seemed unprovable due to documented native kidney disease and a long time span between native kidney disease and MN diagnosis. We, therefore, presumed primary de novo disease. Two years after KT, kidney function remains stable, and the patient has reached complete remission of proteinuria.

Microvascular inflammation in the absence of human leukocyte antigen-donor-specific antibody and C4d: An orphan category in Banff classification with cytotoxic T and natural killer cell infiltration.

Isolated microvascular inflammation (iMVI) without HLA donor-specific antibodies or C4d deposition in peritubular capillaries remains an enigmatic phenotype that cannot be categorized as antibody-mediated rejection (ABMR) in recent Banff classifications. We included 221 kidney transplant recipients with biopsies with ABMR (n = 73), iMVI (n = 32), and normal (n = 116) diagnoses. We compared peripheral blood leukocyte distribution by flow cytometry and inflammatory infiltrates in kidney transplant biopsies among groups. Flow cytometry showed fewer lymphocytes and total, CD4+, and CD8+ peripheral T cells in iMVI compared with ABMR and normal cases. ABMR and iMVI had fewer total natural Killer (NK) cells but more NKG2A+ NK cells. Immunohistochemistry indicated that ABMR and iMVI had greater CD3+ and CD68+ glomerular infiltration than normal biopsies, whereas CD8+ and TIA1+ cells showed only increased iMVI, suggesting they are cytotoxic T cells. Peritubular capillaries displayed more CD3+, CD56+, TIA1+, and CD68+ cells in both ABMR and iMVI. In contrast, iMVI had less plasma cell infiltration in peritubular capillaries and interstitial aggregates than ABMR. iMVI displayed decreased circulating T and NK cells mirrored by T cell and NK cell infiltration in the renal allograft, similar to ABMR. However, the lesser plasma cell infiltration in iMVI may suggest an antibody-independent underlying stimulus.

Dynamics of Humoral and Cellular Responses in Renal Transplant Recipients Receiving 3 Doses of SARS-CoV-2 mRNA Vaccine.

BACKGROUND: The original SARS-CoV-2 vaccination regimen (2 doses) induces insufficient short-term response in kidney transplant (KT) recipients. This study assessed the response to a third dose and the long-term immunogenicity after 2 doses in KT. METHODS: We analyzed the dynamics of the humoral and cellular response by monitoring SARS-CoV-2 IgG antibodies against the Spike-protein (IgG-Spike) and QuantiFERON SARS-CoV-2 IFN-γ release assay 6 mo after the second dose (T2) and 28 d after the third dose of mRNA vaccines (T3) to KT and controls (dialysis patients and healthy individuals). RESULTS: At T2, the percentage of IgG-Spike+ KT and dialysis patients decreased (KT 65.8%-52.6%, hemodialysis 92.6-81.5%, and peritoneal dialysis 100%-90%), whereas 100% of healthy controls remained positive. About the cellular response, the percentage of responders decreased in all groups, especially in KT (22.4%-9.2%, P = 0.081). At T3, 92% of KT, 94%-98% of dialysis patients, and 100% of healthy controls were IgG-Spike+. In terms of antibody titers, patients and controls showed a reduction between T2 and T3 and about 80% of dialysis patients and 100% of controls achieved high titers after the third dose (>1479.5 Binding Antibody Units/mL), whereas this percentage was only 50% in KT. With respect to the cellular response, only KT displayed a significant rise after the third dose. CONCLUSIONS: The third dose of mRNA vaccine improves both humoral and cellular responses, but less effectively in KT compared with dialysis patients and healthy controls.