A Machine Learning-Driven Virtual Biopsy System For Kidney Transplant Patients.

In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.

Antifungal prophylaxis with nebulized amphotericin-B in solid-organ transplant recipients with severe COVID-19: a retrospective observational study.

COVID-19-associated pulmonary aspergillosis (CAPA) has emerged as a frequent complication in the intensive care unit (ICU). However, little is known about this life-threatening fungal superinfection in solid organ transplant recipients (SOTRs), including whether targeted anti-mold prophylaxis might be justified in this immunosuppressed population. We performed a multicentric observational retrospective study of all consecutive ICU-admitted COVID-19 SOTRs between August 1, 2020 and December 31, 2021. SOTRs receiving antifungal prophylaxis with nebulized amphotericin-B were compared with those without prophylaxis. CAPA was defined according the ECMM/ISHAM criteria. Sixty-four SOTRs were admitted to ICU for COVID-19 during the study period. One patient received antifungal prophylaxis with isavuconazole and was excluded from the analysis. Of the remaining 63 SOTRs, nineteen (30.2%) received anti-mold prophylaxis with nebulized amphotericin-B. Ten SOTRs who did not receive prophylaxis developed pulmonary mold infections (nine CAPA and one mucormycosis) compared with one who received nebulized amphotericin-B (22.7% vs 5.3%; risk ratio 0.23; 95%CI 0.032-1.68), but with no differences in survival. No severe adverse events related to nebulized amphotericin-B were recorded. SOTRs admitted to ICU with COVID-19 are at high risk for CAPA. However, nebulized amphotericin-B is safe and might reduce the incidence of CAPA in this high-risk population. A randomized clinical trial to confirm these findings is warranted.

Recommendations for living donor kidney transplantation.

This Guide for Living Donor Kidney Transplantation (LDKT) has been prepared with the sponsorship of the Spanish Society of Nephrology (SEN), the Spanish Transplant Society (SET), and the Spanish National Transplant Organization (ONT). It updates evidence to offer the best chronic renal failure treatment when a potential living donor is available. The core aim of this Guide is to supply clinicians who evaluate living donors and transplant recipients with the best decision-making tools, to optimise their outcomes. Moreover, the role of living donors in the current KT context should recover the level of importance it had until recently. To this end the new forms of incompatible HLA and/or ABO donation, as well as the paired donation which is possible in several hospitals with experience in LDKT, offer additional ways to treat renal patients with an incompatible donor. Good results in terms of patient and graft survival have expanded the range of circumstances under which living renal donors are accepted. Older donors are now accepted, as are others with factors that affect the decision, such as a borderline clinical history or alterations, which when evaluated may lead to an additional number of transplantations. This Guide does not forget that LDKT may lead to risk for the donor. Pre-donation evaluation has to centre on the problems which may arise over the short or long-term, and these have to be described to the potential donor so that they are able take them into account. Experience over recent years has led to progress in risk analysis, to protect donors' health. This aspect always has to be taken into account by LDKT programmes when evaluating potential donors. Finally, this Guide has been designed to aid decision-making, with recommendations and suggestions when uncertainties arise in pre-donation studies. Its overarching aim is to ensure that informed consent is based on high quality studies and information supplied to donors and recipients, offering the strongest possible guarantees.

Overcoming limits: First ABO incompatible living donor paired kidney transplant in an hypersensitized pediatric recipient in Spain.

INTRODUCTION: HLA sensitization is a growing problem in children awaiting kidney transplantation. In some cases, finding an immunologically compatible donor entails contemplating the option of an ABO incompatible transplant or paired transplant. METHODS: Patient with genetic nephrotic syndrome and progressive chronic kidney disease, with a previous thrombosis of a first kidney transplant, resulting hypersensitized and remaining for a long-time on hemodialysis. Despite a desensitization strategy, family members were incompatible and deceased donation options must be ruled out due to the presentation of donor-specific antibodies (DSA). After 4 years, the possibility arises to perform a kidney paired transplant with a 62-year-old woman with an incompatible blood group. Although the current cytotoxicity- and cell-based crossmatches were negative, history of DSA were recorded. RESULTS: An intensive ABO and HLA desensitization protocol was performed in order to combat the isohemagglutinin antibodies and on the memory-HLA, based on rituximab, apheresis sessions, and immunoglobulins. Despite the donor being older in terms of pediatric transplantation, the donor-recipient weight difference, and immunological risk, the transplant was completed successfully. Maintenance of titration of up to 1/2 was confirmed after 3 weeks post-transplant (IgM and IgG). Kidney biopsy at 2 weeks and 6 months without signs of rejection. The patient is currently 12 months post-transplant and has not presented any signs of transplant rejection and has proper renal function. CONCLUSIONS: Kidney paired transplantation is an excellent solution for hypersensitized children, and ABO incompatibility can be considered to increase their options to find a good donor, without thereby obtaining worse results.

Breakthrough Infections Following mRNA SARS-CoV-2 Vaccination in Kidney Transplant Recipients.

BACKGROUND: The clinical effectiveness of coronavirus disease 2019 (COVID-19) vaccination in kidney transplant (KT) recipients is lower than in the general population. METHODS: From April to October 2021, 481 KT recipients with COVID-19, included in the Spanish Society of Nephrology COVID-19 Registry, were analyzed. Data regarding vaccination status and vaccine type were collected, and outcomes of unvaccinated or partially vaccinated patients (n = 130) were compared with fully vaccinated patients (n = 351). RESULTS: Clinical picture was similar and survival analysis showed no differences between groups: 21.7% of fully vaccinated patients and 20.8% of unvaccinated or partially vaccinated died (P = 0.776). In multivariable analysis, age and pneumonia were independent risk factors for death, whereas vaccination status was not related to mortality. These results remained similar when we excluded patients with partial vaccination, as well as when we analyzed exclusively hospitalized patients. Patients vaccinated with mRNA-1273 (n = 213) showed a significantly lower mortality than those who received the BNT162b2 vaccine (n = 121) (hazard ratio: 0.52; 95% confidence interval, 0.31-0.85; P = 0.010). CONCLUSIONS: COVID-19 severity in KT patients has remained high and has not improved despite receiving 2 doses of the mRNA vaccine. The mRNA-1273 vaccine shows higher clinical effectiveness than BNT162b2 in KT recipients with breakthrough infections. Confirmation of these data will require further research taking into account the new variants and the administration of successive vaccine doses.

Outcomes after 20 years of experience in minimally invasive living-donor nephrectomy.

INTRODUCTION: The transperitoneal laparoscopic approach is considered the gold standard technique for living kidney donation. Other accepted laparoscopic techniques include the retroperitoneal approach, natural orifice transluminal endoscopic surgery (NOTES)-assisted, laparo-endoscopic single-site surgery (LESS), with excellent results in the donor and graft. Many studies have compared these techniques with open ones. Our objective is to describe our experience and results in minimally invasive living-donor nephrectomies (MILDN): laparoscopic, NOTES-assisted, and LESS since their introduction in March 2002. MATERIALS AND METHODS: We conducted a retrospective observational study of donors undergoing MILDN between March 2002 and March 2020. RESULTS: A total of 714 MILDNs were performed at our centre. All were completed, except for one, because of recipient death. The conventional laparoscopic approach was used in 541 cases (75.88%), NOTES in 116 (16.9%), LESS in 55 (7.7%), and one mini open (0.14%). Two-thirds of the donors were females (478 cases). The mean donor age was 52.87 years (SD 10.93). Six donors (0.8%) were diagnosed beforehand with a small renal mass, which was removed before transplantation in bench surgery. The right kidney was removed in 17.8% of cases. Warm ischaemia time was higher in the NOTES and LESS groups. We had eight conversions. The global intraoperative and postoperative complication rates were 6.8% and 4.9%, respectively. None of the donors developed renal disease during follow-up (mean 3.68 years). Five-year recipient and graft survival rates were 98.8% and 96.8%, respectively. CONCLUSIONS: MILDN techniques are safe for donors and grafts, with low complication.

Outcomes in older kidney recipients from older donors: A propensity score analysis.

Background: The age of patients referred for kidney transplantation has increased progressively. However, the precise influence of age on transplant outcomes is controversial. Methods: Etrospective study in which graft and recipient survival were assessed in a cohort of ≥75 years old kidney recipients and compared with a contemporary younger one aged 60-65 years through a propensity score analysis. Results: We included 106 recipients between 60-65 and 57 patients of ≥75 years old with a median follow-up of 31 [13-54] months. Unadjusted one- and five-year recipient survival did not significantly differ between the older (91% and 74%) and the younger group (95% and 82%, P=0.06). In the IPTW weighted Cox regression analysis, recipient age was not associated with an increased risk of death (HR 1.88 95%CI [0.81-4.37], P=0.14). Unadjusted one- and five-year death-censored graft survival did not significantly differ between both groups (96% and 83% for the older and 99% and 89% for the younger group, respectively, P=0.08). After IPTW weighted Cox Regression analysis, recipient age ≥75 years was no associated with an increased risk of graft loss (HR 1.95, 95%CI [0.65-5.82], P=0.23). Conclusions: These results suggest that recipient age should not be considered itself as an absolute contraindication for kidney transplant.

Influence of Persistent Inflammation in Follow-Up Biopsies After Antibody-Mediated Rejection in Kidney Transplantation.

Background: Despite recent advances in immunosuppression treatment, antibody-mediated rejection (ABMR) remains the leading cause of kidney graft loss. Information about prognostic markers and the efficacy of treatment is scarce. Methods: Retrospective study with kidney recipients diagnosed an active ABMR from January 1, 2004 to December 31, 2019 to explore the influence of persistent inflammation in follow-up biopsies on graft survival after ABMR treatment. Results: About 116 patients were included. Active ABMR were treated with a combination of plasma exchange (PE), intravenous immunoglobulin (IVIg), rituximab, and steroids. At 6 months of treatment, 63 (54.3%) patients presented a stabilization or improvement in kidney-graft function. The effectiveness varied depending on the timepoint of the presentation between transplantation and rejection, which is lower for those with late ABMR (63 vs. 21% for early vs. late ABMR, respectively). Ninety patients (77%) underwent a control biopsy after ABMR treatment, from which 46 (51%) responded to the treatment. Microvascular inflammation (MVI) persisted in 64 (71%) biopsies, whereas tubulitis persisted in 17 (19%) biopsies. Death-censored graft survival at 1 year was significantly lower in patients with persistent MVI (86% vs. 95% without persistent MVI, P = 0.002), or with persistent tubulitis (44% vs. 66% without tubulitis, P = 0.02). In the Cox Regression analysis, the persistence of MVI [hazard ratio (HR), 4.50 (95%CI, 1.35-14.96), P = 0.01] and tubulitis [HR 2.88 95%CI (1.24-6.69), P = 0.01) in follow-up biopsies significantly increased the risk of graft failure. Conclusion: Persistent inflammation in follow-up biopsies after ABMR treatment was associated with an increased risk of graft loss, even without meeting Banff rejection criteria. Study Registration: Agencia Española de Medicamentos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTRINM-2017-01.

[Orthotopic renal allograft transplant. State of the art.] / Trasplante renal ortotópico. Estado actual.

Kidney transplantation is the treatment of choice for patients with end-stage renal disease (ESRD)as it has shown a better quality of life and longer survival compared to dialysis. Patients with ESRD have associated vascular pathology in a significant percentage, with abundant calcifications at the level of the aorto-iliac axis.The survival of transplanted patients has also increased so an important number of patients have multiple transplants,patients with an indication for a third, fourth and even fifth transplant.In these cases, in which the iliac fossa is no longer practicable(atheromatosis, vascular abnormalities, occupied iliac fossae for previous kidney transplant…), orthotopic kidney transplantation offers a viable option with good results.

El trasplante renal es el tratamiento de elección para pacientes con insuficiencia renal crónica terminal (IRCT) ya que ha demostrado una mejor calidadd e vida y mayor supervivencia en comparación ala diálisis. Los pacientes con IRCT tienen asociada patología vascular en un importante porcentaje, con abundantes calcificaciones a nivel del eje aorto-ilíaco. La supervivencia de los pacientes trasplantados también se ha incrementado por lo que cada vez más nos encontramos con pluritrasplantados, pacientes con indicación de tercer, cuarto e incluso quinto trasplante.En estos casos en los que la fosa ilíaca ya no es practicable (ateromatosis, malformaciones vasculares, ocupación de fosas ilíacas por trasplantes renales previos…),el trasplante renal ortotópico ofrece una opción viable con buenos resultados.

Trasplante renal ortotópico. Estado actual / Trapianto renale ortotopico. Stato attuale

El trasplante renal es el tratamiento deelección para pacientes con insuficiencia renal crónicaterminal (IRCT) ya que ha demostrado una mejor calidad de vida y mayor supervivencia en comparación ala diálisis. Los pacientes con IRCT tienen asociada patología vascular en un importante porcentaje, con abundantes calcificaciones a nivel del eje aorto-ilíaco. Lasupervivencia de los pacientes trasplantados también seha incrementado por lo que cada vez más nos encontramos con pluritrasplantados, pacientes con indicaciónde tercer, cuarto e incluso quinto trasplante.En estos casos en los que la fosa ilíaca ya no es practicable (ateromatosis, malformaciones vasculares, ocupación de fosas ilíacas por trasplantes renales previos...),el trasplante renal ortotópico ofrece una opción viablecon buenos resultados.(AU)

Kidney transplantation is the treatment ofchoice for patients with end-stage renal disease (ESRD)as it has shown a better quality of life and longer survivalcompared to dialysis. Patients with ESRD have associated vascular pathology in a significant percentage, withabundant calcifications at the level of the aorto-iliac axis.The survival of transplanted patients has also increasedso an important number of patients have multiple transplants, patients with an indication for a third, fourth andeven fifth transplant.In these cases, in which the iliac fossa is no longer practicable (atheromatosis, vascular abnormalities, occupiediliac fossae for previous kidney transplant...) , orthotopickidney transplantation offers a viable option with goodresults.(AU)

Application of the iBox prognostication system as a surrogate endpoint in the TRANSFORM randomised controlled trial: proof-of-concept study.

OBJECTIVES: Development of pharmaceutical agents in transplantation is currently limited by long waits for hard endpoints. We applied a validated integrative risk-prognostication system integrative Box (iBox) as a surrogate endpoint to the TRANSFORM Study, a large randomised controlled trial, to project individual patient long-term kidney allograft survival from 1 year to 11 years after randomisation. DESIGN: Post-hoc analysis of a randomised open-label controlled trial. SETTING: Multicentre study including 186 centres in 42 countries worldwide. PARTICIPANTS: 2037 de novo kidney transplant recipients. INTERVENTION: Participants were randomised (1:1) to receive everolimus with reduced-exposure calcineurin inhibitor (EVR+rCNI) or mycophenolic acid with standard-exposure CNI (MPA+sCNI). PRIMARY OUTCOME MEASURE: The iBox scores were computed for each participant at 1 year after randomisation using functional, immunological and histological parameters. Individual long-term death-censored allograft survival over 4, 6 and 11 years after randomisation was projected with the iBox risk-prognostication system. RESULTS: Overall, 940 patients receiving EVR+rCNI and 932 receiving MPA+sCNI completed the 1-year visit. iBox scores generated at 1 year yielded graft survival prediction rates of 90.9% vs 92.1%, 87.9% vs 89.5%, and 80.0% vs 82.4% in the EVR+rCNI versus MPA+sCNI arms at 4, 6, and 11 years post-randomisation, respectively (all differences below the 10% non-inferiority margin defined by study protocol). Inclusion of immunological and histological Banff diagnoses parameters in iBox scores resulted in comparable and non-inferior predicted graft survival for both treatments. CONCLUSIONS: This proof-of-concept study provides the first application of a validated prognostication system as a surrogate endpoint in the field of transplantation. The iBox system, by projecting kidney allograft survival up to 11 years post-randomisation, confirms the non-inferiority of EVR+rCNI versus MPA+sCNI regimen. Given the current process engaged for surrogate endpoints qualification, this study illustrates the potential to fast track development of pharmaceutical agents. TRIAL REGISTRATION NUMBER: TRANSFORM trial: NCT01950819.iBox prognostication system: NCT03474003.

A hybrid data envelopment analysis-artificial neural network prediction model for COVID-19 severity in transplant recipients.

In an overwhelming demand scenario, such as the SARS-CoV-2 pandemic, pressure over health systems may outburst their predicted capacity to deal with such extreme situations. Therefore, in order to successfully face a health emergency, scientific evidence and validated models are needed to provide real-time information that could be applied by any health center, especially for high-risk populations, such as transplant recipients. We have developed a hybrid prediction model whose accuracy relative to several alternative configurations has been validated through a battery of clustering techniques. Using hospital admission data from a cohort of hospitalized transplant patients, our hybrid Data Envelopment Analysis (DEA)-Artificial Neural Network (ANN) model extrapolates the progression towards severe COVID-19 disease with an accuracy of 96.3%, outperforming any competing model, such as logistic regression (65.5%) and random forest (44.8%). In this regard, DEA-ANN allows us to categorize the evolution of patients through the values of the analyses performed at hospital admission. Our prediction model may help guiding COVID-19 management through the identification of key predictors that permit a sustainable management of resources in a patient-centered model. Supplementary Information: The online version contains supplementary material available at 10.1007/s10462-021-10008-0.

Modeling patients as decision making units: evaluating the efficiency of kidney transplantation through data envelopment analysis.

The main applications of Data Envelopment Analysis (DEA) to medicine focus on evaluating the efficiency of different health structures, hospitals and departments within them. The evolution of patients after undergoing a medical procedure or their response to a given treatment are not generally studied through this programming technique. In addition to the difficulty inherent to the collection of this type of data, the use of a technique that is mainly applied to evaluate the efficiency of decision making units representing industrial and production structures to analyze the evolution of human patients may seem inappropriate. In the current paper, we illustrate how this is not actually the case and implement a decision engineering approach to model kidney transplantation patients as decision making units. As such, patients undergo three different phases, each composed by specific as well as interrelated variables, determining the potential success of the transplantation process. DEA is applied to a set of 12 input and 6 output variables - retrieved over a 10-year period - describing the evolution of 485 patients undergoing kidney transplantation from living donors. The resulting analysis allows us to classify the set of patients in terms of the efficiency of the transplantation process and identify the specific characteristics across which potential improvements could be defined on a per patient basis.

Outcomes From Brain Death Donors With Previous Cardiac Arrest Accepted for Pancreas Transplantation: A Single-center Retrospective Analysis.

OBJECTIVE: The aim of the study was to evaluate the effect of cardiac arrest time (CAT) in donors after brain death (DBD) donors on pancreas transplant outcome. SUMMARY OF BACKGROUND DATA: Results from donors after circulatory death report good outcomes despite warm ischemia times up to 57 minutes. Previous cardiac arrest in DBD has been addressed as a potential risk factor, but duration of the CAT has never been evaluated. METHODS: We conducted a retrospective analysis including 342 pancreas transplants performed at our center from 2000 to 2016, and evaluated the effect of previous cardiac arrest in DBD (caDBD) on pancreas transplant outcomes. RESULTS: A total of 49 (14.3%) caDBD were accepted for transplantation [median CAT of 5.0 min (IQR 2.5-15.0)]. Anoxic encephalopathy was most frequent and P-PASS higher (16.9 vs 15.6) in caDBD group when compared with other DBD. No differences were found in all other characteristics evaluated.Graft survival was similar between both groups, as was the incidence of early graft failure (EGF). CAT increased the risk for EGF [OR 1.09 (95% CI, 1.01-1.17)], and the duration of CPR discriminated for EGF [AUC of 0.86 (95% CI, 0.74-0.98)], with a sensitivity and specificity of 100% and 75% at a cutoff of 15 minutes. When evaluated separately, caDBD >15 min increased over 5 times the risk for EGF [HR 5.80 (95% CI, 1.82-18.56); P = 0.003], and these presented fewer days on the ICU (1.0 vs 3.0 d). CONCLUSION: CaDBD donors are suitable for routine pancreas transplantation without increasing EGF risk, and in those with longer CAT it may be prudent to postpone donation a few days to allow a thorough evaluation of organ damage following cardiac arrest.

B Cell-Derived Extracellular Vesicles Reveal Residual B Cell Activity in Kidney Graft Recipients Undergoing Pre-Transplant Desensitization.

Background: Living-donor kidney transplant (LDKT) recipients undergoing desensitization for Human Leukocyte Antigen (HLA)-incompatibility have a high risk of developing antibody-mediated rejection (ABMR). The purpose of the study is to evaluate if residual B cell activity after desensitization could be estimated by the presence of circulating B cell-derived extracellular vesicles (BEVs). Methods: BEVs were isolated by Sepharose-based size exclusion chromatography and defined as CD19+ and HLA-II+ extracellular vesicles. We analyzed stored serum samples from positive crossmatch LDKT recipients before and after desensitization at first post-transplant biopsy and at 12-month protocol biopsy (n = 11). Control groups were formed by hypersensitized patients who were not submitted to desensitization (n = 10) and by low-risk recipients (n = 9). A prospective validation cohort of 11 patients also included the analysis of B cells subpopulations in recipients' blood and lymph nodes recovered upon graft implantation, along with BEVs analysis before and after desensitization. Results: We found out that CD19+ and HLA-II+BEVs dropped significantly after desensitization and relapse in patients who later developed ABMR was evident. We validated these findings in a proof-of-concept prospective cohort of 6 patients who received the same desensitization protocol and also in a control group of 5 LDKT recipients. In these patients, B cell subpopulations were also studied in recipients' blood and lymph nodes that were recovered before the graft implantation. We confirmed the significant drop in BEVs after desensitization and that this paralleled the reduction in CD19+cells in lymph nodes, while in peripheral blood B cells, this change was almost undetectable. Conclusions: BEVs reflected B cell residual activity after desensitization and this could be a valid surrogate of humoral alloreactivity in this setting.

COVID-19 in transplant recipients: The Spanish experience.

We report the nationwide experience with solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients diagnosed with coronavirus disease 2019 (COVID-19) in Spain until 13 July 2020. We compiled information for 778 (423 kidney, 113 HSCT, 110 liver, 69 heart, 54 lung, 8 pancreas, 1 multivisceral) recipients. Median age at diagnosis was 61 years (interquartile range [IQR]: 52-70), and 66% were male. The incidence of COVID-19 in SOT recipients was two-fold higher compared to the Spanish general population. The median interval from transplantation was 59 months (IQR: 18-131). Infection was hospital-acquired in 13% of cases. No donor-derived COVID-19 was suspected. Most patients (89%) were admitted to the hospital. Therapies included hydroxychloroquine (84%), azithromycin (53%), protease inhibitors (37%), and interferon-ß (5%), whereas immunomodulation was based on corticosteroids (41%) and tocilizumab (21%). Adjustment of immunosuppression was performed in 85% of patients. At the time of analysis, complete follow-up was available from 652 patients. Acute respiratory distress syndrome occurred in 35% of patients. Ultimately, 174 (27%) patients died. In univariate analysis, risk factors for death were lung transplantation (odds ratio [OR]: 2.5; 95% CI: 1.4-4.6), age >60 years (OR: 3.7; 95% CI: 2.5-5.5), and hospital-acquired COVID-19 (OR: 3.0; 95% CI: 1.9-4.9).