Impaired Graft Function Research Articles

Endothelin Inhibitors in Chronic Kidney Disease: New Treatment Prospects.

The endothelin system is reported to play a significant role in glomerular and tubulointerstitial kidney disease. In the kidney, endothelins are produced in mesangial cells and the glomerular basement membrane by the endothelium and podocytes. The endothelin system regulates glomerular function by inducing proliferation, increasing permeability and in effect proteinuria, and stimulating inflammation, tubular fibrosis, and glomerular scarring. Endothelin A receptor antagonists have been proven to delay the progression of chronic kidney disease and play a protective role in immunoglobulin A nephropathy, focal segmental glomerulosclerosis, and diabetic nephropathy. There are several ongoing research studies with ETAR antagonists in nondiabetic nephropathy, Alport disease, vasculitis and scleroderma nephropathy, which results are promising. Some reports suggest that the endothelin system might contribute to ischemia-reperfusion injury, acute graft rejection and deterioration of graft function. Endothelin inhibition in renal transplantation and its influence on graft survival is the future direction needing further research. The most frequent side effects associated with ETAR antagonists is fluid retention. Additionally, it should be considered if selective ETAR antagonists therapy needs to be co-administered with sodium-glucose co-transporter 2 inhibitors, renin-angiotensin-aldosterone inhibitors or diuretics and which patients should be recruited to such treatment to minimize the risk of adverse outcomes.

Risk of cellular or antibody-mediated rejection in pediatric kidney transplant recipients with BK polyomavirus replication-an international CERTAIN registry study.

In kidney transplant recipients (KTR), BK polyomavirus-associated nephropathy (BKPyVAN) is a major cause of graft loss. To facilitate the clearance of BKPyV-DNAemia, reduction of immunosuppression is currently the treatment of choice but may increase the risk of graft rejection. This international CERTAIN study was designed to determine the risk of alloimmune response and graft dysfunction associated with immunosuppression reduction for BKPyV treatment in 195 pediatric KTR. BKPyV-DNAemia was associated with a more than twofold increased risk of late T cell-mediated rejection (TCMR) (HR 2.22, p = 0.024), of de novo donor-specific HLA antibodies (dnDSA) and/or antibody-mediated rejection (ABMR) (HR 2.64, p = 0.002), and of graft function deterioration (HR 2.73, p = 0.001). Additional independent risk factors for dnDSA/ABMR development were a higher HLA mismatch (HR 2.72, p = 0.006) and re-transplantation (HR 6.40, p = 0.000). Other independent predictors of graft function deterioration were TCMR (HR 3.98, p = 0.003), higher donor age (HR 1.03, p = 0.020), and re-transplantation (HR 3.56, p = 0.013). These data indicate that reduction of immunosuppression for BKPyV-DNAemia management is associated with increased alloimmune response in pediatric KTR. Therefore, regular dnDSA screening and close monitoring of graft function in case of BKPyV-DNAemia followed by subsequent reduction of immunosuppressive therapy are recommended.

Impact of deceased-donor characteristics on early graft function: outcome of kidney donor pairs accepted for transplantation.

The impact of deceased donor characteristics on kidney transplant outcomes is controversial. Correspondingly, the predictive performance of deceased donor scores remains moderate, and many transplant centers lack validated criteria for graft acceptance decisions. To better dissect donor-related risk from recipient and periprocedural variables, we analyzed outcomes of kidney donor pairs transplanted in different individuals. This study explored (a)symmetry of early outcomes of 328 cadaveric kidney transplant recipients from 164 donor pairs transplanted at three Eurotransplant centers. The primary discriminatory factor was (a)symmetry of partner graft function, defined as early graft loss or impaired graft function [estimated glomerular filtration rate (eGFR) <30 mL/min] 3 months after transplantation. We reasoned that a relevant impact of donor factors would result in a high concordance rate of limited graft function or failure. The observed number of symmetric graft failure after transplantation was less than statistically expected (3 months: 1 versus 2, p = 0.89; and 12 months: 3 versus 5, p = 0.26). However, we found a trend toward an impaired 5-year graft survival of grafts with good function 3 months after transplantation but a failed or impaired partner graft compared to symmetrically well-functioning grafts (p = 0.09). Subsequently, we explored the impact of individual donor and recipient variables on early transplant outcomes. Generalized estimating equations after feature selection with LassoGEE bootstrap selected donor age, donor body mass index, and donor eGFR as the relevant risk factors. Our findings indicate that donor factors impact early outcomes in kidney transplantation but may have a limited role in long-term graft survival, once a graft has been accepted for transplantation. Utilizing donor-based clinical scores has the potential to aid clinicians in acceptance decisions, giving them an estimate of individual posttransplant outcomes. However, the ultimate decision for acceptance should rest with clinicians, who must consider the complex interplay of donor factors, as well as recipient and periprocedural characteristics.

Transcriptomic signatures during normothermic liver machine perfusion correspond with graft quality and predict the early graft function

A better understanding of the molecular events during liver normothermic machine perfusion (NMP) is warranted to develop a data-based approach for the identification of biomarkers representative of graft quality and posttransplant outcome. We analysed the dynamic transcriptional changes during NMP and linked them to clinical and biochemical parameters. 50 livers subjected to NMP for up to 24h were enrolled. Bulk RNA sequencing was performed in serial biopsies collected pre and during NMP, and after reperfusion. Perfusate was sampled to monitor liver function. qPCR and immunohistochemistry were performed to validate findings. Molecular profiles were compared between transplanted and non-transplanted livers, and livers with and without early allograft dysfunction. Pathways related to immune and cell stress responses, cell trafficking and cell regulation were activated during NMP, while cellular metabolism was downregulated over time. Anti-inflammatory responses and genes involved in tissue remodelling were induced at later time-points, suggesting a counter-response to the immediate damage. NMP strongly induced a gene signature associated with ischemia-reperfusion injury. A 7-gene signature corresponds with the benchmarking criteria for transplantation or discard at 6h NMP (area under curve 0.99). CD274 gene expression (encoding programmed cell-death ligand-1) showed the highest predictive value. LEAP2 gene expression at 6h NMP correlated with impaired graft function. Assessment of gene expression markers could serve as a reliable tool to evaluate liver quality during NMP and predicts early graft function after transplantation. The research was supported by "In Memoriam Dr. Gabriel Salzner Stiftung", Tiroler Wissenschaftsfond, Jubiläumsfonds-Österreichische Nationalbank and MUI Start grant.

Epstein-Barr Virus-Associated Smooth Muscle Tumor After Kidney Transplantation: A French Multicenter Retrospective Study.

Epstein-Barr virus (EBV) is a herpesvirus linked to nine different human tumors and lymphoproliferative disorders. Immunosuppression promotes EBV-driven malignancies. The most frequent EBV-induced malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (EBV-SMT). EBV-SMT is a rare oncological entity for which no current guideline for diagnosis or management exists. Data on posttransplant EBV-SMT (PT-SMT) are scarce in kidney transplant recipients. We conducted a national multicentric retrospective study and collected cases among transplantation centers in France. Kidney transplant recipients experiencing histologically proven PT-SMT were included. We collected data on demographic characteristics of patient, history of kidney transplantation, history of PT-SMT, evolution of graft function, and patient survival. Eight patients were included. The median age at PT-SMT diagnosis was 31 years (range 6.5-40). PT-SMT occurred after a median delay of 37.8 months after transplantation (range 6-175). PT-SMT management consisted in immunosuppressive regimen minimization in all patients. Introduction of mTOR inhibitors was performed in two patients. Four patients (50%) needed chemotherapy. Surgical resection was performed in four patients. At last follow-up after PT-SMT diagnosis (median 33 months (range 17-132)), five patients were considered in complete remission, and two patients had died. Two patients experienced graft rejection; two resumed dialysis (25%). All patients with available data presented with impaired graft function at last follow-up. PT-SMT is a subacute and progressive disease during kidney transplantation. Even if the risk of developing PT-SMT is low in kidney transplant recipients (0.07% in our cohort), PT-SMT is associated with significant graft loss, possibly due to reduced immunosuppression. Developing guidelines could help transplantation teams better manage these patients.

Thoracoscopic Decortication for Tubercular Empyema in a Lung Transplant Recipient

Tubercular empyema thoracis is a morbid postoperative complication in lung transplant recipients, which significantly impairs graft function and affects the survival rate. This report describes a case of tubercular empyema thoracis in a 42-year-old female, who underwent bilateral sequential lung transplantation for interstitial lung disease (non-specific interstitial pneumonia). She underwent video-assisted thoracoscopic surgery decortication, a preferred surgical approach due to its minimally invasive nature with excellent success rates. This report highlights the effectiveness of tailored surgical interventions and the importance of individualized post-transplant care to optimize patient recovery and graft functionality.

Immuno-protective vesicle-crosslinked hydrogel for allogenic transplantation

The longevity of grafts remains a major challenge in allogeneic transplantation due to immune rejection. Systemic immunosuppression can impair graft function and can also cause severe adverse effects. Here, we report a local immuno-protective strategy to enhance post-transplant persistence of allografts using a mesenchymal stem cell membrane-derived vesicle (MMV)-crosslinked hydrogel (MMV-Gel). MMVs are engineered to upregulate expression of Fas ligand (FasL) and programmed death ligand 1 (PD-L1). The MMVs are retained within the hydrogel by crosslinking. The immuno-protective microenvironment of the hydrogel protects allografts by presenting FasL and PD-L1. The binding of these ligands to T effector cells, the dominant contributors to graft destruction and rejection, results in apoptosis of T effector cells and generation of regulatory T cells. We demonstrate that implantation with MMV-Gel prolongs the survival and function of grafts in mouse models of allogeneic pancreatic islet cells and skin transplantation.

#1658 Association of blood dd-cfDNA levels with Banff scores and histopathological lesions in kidney allograft biopsies: results from an observational trial

Abstract Background and Aims Donor-derived cell-free DNA (dd-cfDNA) is a novel blood biomarker of kidney allograft injury. While primarily studied to discriminate rejection from no rejection, knowledge about its dynamics in other graft pathologies is scarce and merits further investigation. Previous research has highlighted its superior diagnostic performance in detecting ABMR compared to TCMR and borderline changes, however, recent studies have suggested that its increase is not limited to damage due to alloimmune injury. Therefore, we aimed to assess the association between dd-cfDNA release and diverse histopathological patterns as well as its correlation with Banff lesion scores in renal allograft biopsies. Method For this analysis, we identified all dd-cfDNA-paired allograft biopsies from a prospective observational trial of kidney transplant recipients undergoing an indication biopsy with deterioration in graft function, persistence of anti-HLA donor-specific antibodies (DSA), or proteinuria. Dd-cfDNA was collected at the time of allograft biopsy and measured using droplet-digital PCR. Both relative and absolute quantification of dd-cfDNA, with cutoffs of 0.5% and 50cp/ml, respectively, were available for clinical interpretation. All biopsy specimens were examined by a central pathologist blinded to the dd-cfDNA results. Histopathological diagnoses were assigned according to the Banff 2019 classification. Results In total, we examined 125 dd-cfDNA paired biopsies from 110 patients performed at our center between April 2020 and October 2023. Absolute levels of dd-cfDNA were significantly higher in mixed rejection (median 156 cp/mL, IQR 138-176), antibody-mediated rejection (ABMR) (median 63cp/mL, IQR 48-81), DSA-negative microvascular inflammation (DSAnegMVI) (median 74 cp/mL, IQR 35-134), and BK-virus associated nephropathy (BKVAN) (median 168cp/mL, IQR 54-311) in comparison to glomerulonephritis (median 12cp/mL, IQR 8-19; p &amp;lt; 0.001, &amp;lt;0.001, 0.02, 0.01, respectively) as well as in comparison CNI-toxicity (median 10, IQR 6-15; p &amp;lt;0.001, &amp;lt;0.001, 0.004, 0.003, respectively). Additionally, patients with mixed rejection, ABMR, and BKVAN had higher absolute dd-cfDNA levels than patients with IFTA (median 13, IQR 8-16; p 0.004, 0.004, and 0.04, respectively), as well as normal histology (median 7, IQR 7-11, p 0.004, 0.008, 0.03, respectively). Finally, absolute dd-cfDNA levels were higher in patients with mixed rejection than in those with UTI (median 14, IQR 12-16, p = 0.02) (Fig. 1). In the univariable analysis, absolute dd-cfDNA levels were significantly correlated with Banff lesion scores for glomerulitis (g), peritubular capillaritis (ptc), and tubulitis (t). In the multivariable analysis, ptc and t were independently correlated with absolute dd-cfDNA levels. Conclusion Increased donor-derived cell-free DNA is not specific for rejection, but also occurs in alternative injury patterns showing microvascular inflammation and severe tubulointerstitial inflammation, such as DSAnegMVI and BKVAN (BK-virus associated nephropathy). Interestingly, dd-cfDNA levels remain low in the setting of de novo or recurrent glomerulonephritis and CNI-toxicity, which are important differential diagnoses in patients with clinical indication biopsy.

#1692 Prevalence and risk factors for persistent hyperparathyroidism in long-term kidney transplant recipients

Abstract Background and Aims Secondary hyperparathyroidism, associated with fractures and cardiovascular mortality in end-stage kidney disease, often resolves after kidney transplantation (KT). However, limited knowledge exists regarding persistent hyperparathyroidism (persist-PTH) after long-term KT. We aimed to define the prevalence and risk factors of persist-PTH in KT recipients at ≥3 years post-KT. Method A historical cohort study was conducted in adult KT recipients at Srinagarind Hospital, Khon Kaen University, Thailand, from 2015 to 2020. Persist-PTH is defined as serum parathyroid hormone (PTH) exceeding twice the upper limit of normal (&amp;gt;130 pg/mL) after ≥3 years post-KT. Results A total of 281 patients were included, with a median age of 41.4 years (interquartile range (IQR), 32.7-49.1), and 117 patients (41.6%) were female. The median post-KT follow-up was 71 months (IQR, 54-89) with a glomerular filtration rate (GFR) of 61.8 mL/min/1.73 m² (IQR, 48.2-76.9). The respective median pre-KT and post-KT PTH were 403 pg/mL (IQR, 196.3-862) and 96.7 pg/mL (IQR, 67.3-166). Post-KT PTH levels correlated with pre-KT PTH levels (r²=0.18; P&amp;lt;0.001). Persist-PTH occurred in 100 patients, with a prevalence of 35.6% (95% confidence interval (CI), 30.2-41.4%). Multivariate analysis revealed significant associations between persist-PTH and a longer dialysis vintage (odds ratio (OR) 1.13 per 6-month increase; 95% CI, 1.06-1.20; P&amp;lt;0.001), lower GFR (OR, 0.76 per 10 mL/min/1.73 m² increase; 95% CI, 0.63-0.92; P=0.004), and higher pre-KT PTH (HR, 1.06 per 50 pg/mL increase; 95% CI, 1.02-1.10; P=0.001). Furthermore, persist-PTH with hypercalcemia (&amp;gt;10.2 mg/dL) occurred in 44 patients (15.7%; 95% CI, 11.8-20.4%), and with hypophosphatemia (&amp;lt;2.5 mg/dL) in 23 patients (8.2%; 95% CI, 5.5-12.0%). Conclusion Persist-PTH occurred in over one-third of long-term post-KT recipients, particularly in those with extended dialysis vintage, impaired graft function, and elevated pre-KT PTH levels. This underscores the need for optimal pre-KT PTH control and vigilant graft function monitoring to prevent persist-PTH.

#740 Very early BK polyomavirus viremia is associated with graft dysfunction in kidney transplant recipients

Abstract Background and Aims BK polyomavirus-associated nephropathy (BKN) is a leading cause of graft dysfunction and loss, mostly related to the lack of effective treatments. Increasing BK polyomavirus viremia (BKV) precedes BKN, and its monitoring is therefore the focus of preventive strategies; whether BKV itself and its timing of occurrence post-transplant are associated with graft dysfunction is not clearly understood. Method We designed a single-center retrospective study enrolling all patients who received a kidney transplant at our center from January 1st 2018 to June 30th 2022. The study received approval from local Ethical Committee (252/2023/OSS*/AOUMO SIRER ID 651-BKNEPHMO). We collected clinical and demographical data at baseline; donor and transplant characteristics, significant clinical parameter during follow-up. Patients were regularly screened for BK viremia (roughly, once every two weeks in the first 3 months, then monthly until 1 year, then at least every 3 months or on clinical indication). We defined sustained viremia as the presence of BK viremia confirmed in 3 different measurements; probable BKN as the presence of BKV with a viral load &amp;gt;3log10 copies/ml; presumptive BKN as BKV with a viral load &amp;gt;4log10 copies/ml. Results After exclusion of patients with less than 6 months of follow-up, we considered 138 subjects. We stratified patients in 3 groups: no viremia (group A), any BKV (after more than one month from transplant, group B) and very early BKV (within one month from transplant, group C). Clinical, demographic, transplant characteristics are reported in Fig. 1. Of note, group C had a significantly higher proportion of patients with diabetes mellitus (DM) and positive anti-HBc serology, and a lower proportion of Caucasians; there were no differences in transplant characteristics. During follow-up, patients in group C had a significantly stronger reduction in immunosuppressive treatment (especially with regards to MMF), had higher chance of receiving a graft biopsy and were more likely to develop donor-specific antibodies. While patients in group C had a higher probability of sustained BKV compared to those in group B, there were no differences in the proportion of probable, presumptive and histological BKN. With univariate logistic regression, pre-transplant DM and positive anti-HBc were significantly associated with development of very early BKV, while Caucasian ethnicity was a protective factor; only DM maintained statistical significance at multivariate analysis after adjustment for age and sex (OR 7959 with 95% CI 1593-39 771, p = 0.012). Time to eGFR &amp;lt;50% from baseline and time to graft failure were significantly shorter in group C (see Fig. 2). With univariate logistic regression, higher cold-ischemia time and positive BKV within one month from transplant were significantly associated with eGFR loss &amp;gt;50% at 12 months in our cohort; only BKV within one month maintained statistical significance at multivariate analysis after adjustment for age, sex and baseline eGFR (OR 22.17 with 95% CI 1.81-271.47, p = 0.015). Conclusion Patients who develop BKV very early after kidney transplantation are at increased risk of premature severe graft dysfunction (irrespective of the development of BKN); these patients should be offered close and intense surveillance with strategies aiming at identifying treatable causes of progressive kidney damage, and careful management of immunosuppressive treatment. Considering study design and low number of enrolled patients, further data are needed to confirm our findings, to elucidate risk factors for very early BKV and precise causes of rapid deterioration of graft function in these patients.

The Influence of Tacrolimus Exposure and Metabolism on the Outcomes of Kidney Transplants.

Tacrolimus (TAC) has a narrow therapeutic window and patient-specific pharmacokinetic variability. In our study, we analyzed the association between TAC exposure, metabolism, and kidney graft outcomes (function, rejection, and histological lesions). TAC trough (C0), coefficient of variation (TAC CV), concentration/dose ratio (C/D), and biomarkers related to kidney injury molecule-1 (KIM-1) and neutrophil gelatinase lipocalin (NGAL) were analyzed. We examined 174 patients who were subjected to a triple immunosuppressive regimen and underwent kidney transplantation between 2017 and 2022. Surveillance biopsies were performed at the time of kidney implantation and at three and twelve months after transplantation. We classified patients based on their Tac C/D ratios, classifying them as fast (C/D ratio < 1.05 ng/mL × 1/mg) or slow (C/D ratio ≥ 1.05 ng/mL × 1/mg) metabolizers. TAC exposure/metabolism did not significantly correlate with interstitial fibrosis/tubular atrophy (IF/TA) progression during the first year after kidney transplantation. TAC CV third tertile was associated with a higher chronicity score at one-year biopsy. TAC C/D ratio at three months and Tac C0 at six months were associated with rejection during the first year after transplantation. A fast TAC metabolism at six months was associated with reduced kidney graft function one year (OR: 2.141, 95% CI: 1.044-4.389, p = 0.038) and two years after transplantation (OR: 4.654, 95% CI: 1.197-18.097, p = 0.026), and TAC CV was associated with reduced eGFR at three years. uNGAL correlated with IF/TA and chronicity scores at three months and negatively correlated with TAC C0 and C/D at three months and one year. Conclusion: Calculating the C/D ratio at three and six months after transplantation may help to identify patients at risk of suffering acute rejection and deterioration of graft function.

Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson’s disease models

BackgroundClinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival.MethodsIn a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection.ResultsAt the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats.ConclusionsThe results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.

Pregnancy outcomes and complications after renal transplantation

Introduction. Chronic kidney disease (CKD) in pregnancy poses certain risks of both gestational complications and adverse perinatal outcomes, which increase with the decline of renal function.Aim to access pregnancy outcomes in patients who underwent nephrotransplantation.Materials and methods. Retrospective study of pregnant women who gave birth at Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology in the period from 2005 to 2021: 102 pregnancies in 97 patients were analyzed: five recipients had two successful pregnancies.Results. The average age of pregnant women was 31 ± 4.03 years. In equal proportions, patients underwent related or cadaveric kidney transplantation – 52% (n = 53) and 48% (n = 49) of cases, respectively. The average delivery time was 35.5 ± 2.7 weeks. The average weight of newborns was 2545 ± 655 grams. Premature birth (PB) occurred in 47.1%, the average period of birth was 33.4 ± 2.87 weeks, of which early birth (&lt;32 weeks) was 22.5%. The average period of pregnancy after transplantation was 5 ± 3.31 (1–18) years, this period was not associated with obstetric complications or deterioration of graft function. A significant increase in the following parameters was noted during pregnancy: serum creatinine level (p = 0.006), proteinuria (p = 0.003). The glomerular filtration rate also decreased significantly by the end of pregnancy (p = 0.011). Preeclampsia was the leading cause of decreased graft function during pregnancy (32.4%).Conclusions. In general, pregnancy outcomes after nephrotransplantation are favorable, but there is an increased risk of preeclampsia, preterm birth, including operative delivery, urinary tract infection and anemia.

Pregnancy in Liver and Kidney Female Recipient: A Case Report

Deterioration of kidney function after orthotopic liver transplantation is a common complication. It may occur due to perioperative acute kidney injury (AKI) and pre-existing or developing chronic kidney disease (CKD). AKI is described in early postoperative period in more than half of the recipients whereas the main cause of CKD is pharmacotherapy. When end-stage renal failure occurs, patients may be qualified for additional transplantations.A case report: We present a rare case of 27-year-old female who as teenager underwent two liver transplantations due to Wilson's disease. Operations were complicated by systemic infection and multiple organ failure. The kidneys did not regain their function, therefore, after 6 months of dialysis, the organ was transplanted. In total, three organ transplantations were performed. Due to the patient's willingness and good graft functions, patient started trying to conceive. Three months before successful conception, immunosuppressive therapy was changed to tacrolimus and azathioprine. Pregnancy was complicated by pregnancy induced hypertension and its course was closely monitored. Organs' functions and immunosuppressive therapy were regularly assessed. Due to the pre-eclampsia developed in the 35th week of gestation, a caesarean section was performed and she gave birth to daughter weighing 2350g (Apgar 7-7-8). Women decided on breastfeeding. No obstetric complications or graft function deterioration were observed in the early postpartum period. Mother and daughter left home after 7 days of hospitalization.Conclusions: The presented clinical situation proves that successful pregnancy is possible by multi-organ transplantation recipients, without impairing the graft functions. Therefore, it requires adequate preparation and increased care.

Rhabdomyolysis and Neuroleptic Malignant Syndrome in a Postrenal Transplant Patient: Is Desidustat a Culprit?

We report a case of a 46-year-old female – a postrenal transplant patient, having developed rhabdomyolysis and neuroleptic malignant syndrome (NMS), after 2.5 months of desidustat initiation – for anemia. Post renal transplant anemia (PTA) is common among renal transplant recipients. Apart from treating it with iron supplements, folic acid, andrecombinant human erythropoietin (EPO), novel agents like hypoxia-inducible factor–prolyl hydroxylase domain (HIF–PHI) are also used, with a very few studies available on its efficacy and safety in PTA patients. Anemia occurring in the first 6 months is called early PTA – occurring most commonly due to iron deficiency, while anemia occurring after 6 months is called late PTA – associated with impaired graft function. The optimal target of hemoglobin in transplant recipients is 12.5–13 gm/dl, which is higher than targets in chronic kidney disease patients. NMS is a life-threatening emergency – mainly seen in patients on antipsychotic medications. It needs to be differentiated from other closely related conditions such as central nervous system infections (meningitis and encephalitis), tetanus, heatstroke, serotonin syndrome, and thyrotoxicosis. Desidustat is an oral HIF–PHI that stimulates erythropoiesis by preventing EPO degradation. Its adverse effects include high blood pressure, myocardial infarction, heart failure, high potassium, and dizziness; however, there is only one case report of rhabdomyolysis associated with desidustat, and none of NMS. It is, therefore, important to be aware of this potential severe side effect of the drug that was not known earlier so that practicing physicians can be vigilant of the same.

Azathioprine Associated with Intrahepatic Cholestasis in a Patient with Twin Pregnancy after a Second Kidney Transplant.

Most pregnancies in women after a kidney transplant result in a live birth, but kidney functions should be stable for one year before conception. For immunosuppression modification occurring before pregnancy, azathioprine is used because it is considered safe for major congenital malformations during pregnancy. However, there may be an association between exposure to azathioprine during pregnancy and the onset of an unusual, early and severe form of intrahepatic cholestasis. A young patient with a twin pregnancy after a second kidney transplant experienced intrahepatic cholestasis. There was a wide range of differential diagnosis. A battery of tests was requested including autoimmune markers, virology, and imaging. The conclusion that azathioprine was contributing to intrahepatic cholestasis with pregnancy was reached after exclusion of all other differentials. Complications of pregnancy after a kidney transplant include hypertension, pre-eclampsia, deterioration of graft function up to rejection, but also unusual side effects of immunosuppression medication. A twin pregnancy after a second kidney transplant is rare.In addition to bone marrow suppression and elevation of liver enzymes, azathioprine can contribute to intrahepatic cholestasis of pregnancy.Complications of pregnancy after kidney transplant include hypertension, pre-eclampsia, deterioration of graft function up to rejection, but also unusual side effects of immunosuppression medication.

Routine screening for HLA Antibodies in Heart Transplant patients-Does it affect clinical decision making?

We aimed to assess outcomes in patients with and without donor specific antibodies (DSA) and to evaluate the relationship between DSA presence and graft function, cardiac allograft vasculopathy (CAV), and mortality. The study population comprises 193 consecutive long-term heart transplanted (HTx) patients who underwent DSA surveillance between 2016 and 2022. The patients were prospectively screened for CAV through serial coronary angiograms, graft function impairment through serial echocardiograms, and cardiac biomarkers. The patients were followed from the first DSA measurement until death, 5 years follow-up or right censuring on the 30th of June 2023. DSAs were detected in 50 patients using a cut-off at MFI ≥1000 and 45 patients using a cut-off at ≥2000 MFI. The median time since HTx was 9.0 years [3.0-14.4]. DSA positive patients had poorer graft function and higher values of NT-proBNP and troponin T, and more prevalent CAV than DSA negative patients. In total, 25 patients underwent endomyocardial biopsies due to DSA presence while another eight patients underwent endomyocardial biopsies for other reasons. Histological antibody mediated rejection (AMR) signs were seen in three biopsies. During a median follow-up of five years [4.7-5], a total of 41 patients died. Mortality rates did not differ between DSA positive and DSA negative patients (HR 1.2, 95% CI.6-2.4). DSA positive patients were more likely to experience CAV progression than DSA negative patients (HR 2.7, 95% CI 1.5-4.8) CONCLUSIONS: Routine screening reveals DSA in approximately 25% of long-term HTx patients but is rarely related to histopathological AMR signs. DSA presence was associated with poorer graft function and more prevalent and progressive CAV. However, DSA positive patients had similar survival rates to DSA negative patients.

Recognition of intraglomerular histological features with deep learning in protocol transplant biopsies and its association with kidney function and prognosis

Abstract Background and hypothesis The Banff classification may not adequately address protocol transplant biopsies categorized as normal in patients experiencing unexplained graft function deterioration. This study seeks to employ convolutional neural networks to automate the segmentation of glomerular cells and capillaries and assess their correlation with transplant function. Methods 215 patients were categorized into three groups. In the Training cohort, glomerular cells, and capillaries from 37 patients were manually annotated to train the networks. The Test cohort (24 patients) compared manual annotations to automated predictions, while the Application cohort (154 protocol transplant biopsies) examined predicted factors in relation to kidney function and prognosis. Results In the test cohort, the networks recognized histological structures with Precision, Recall, F-score, and Intersection Over Union exceeding 0.92, 0.85, 0.89, and 0.74, respectively. Univariate analysis revealed associations between the estimated Glomerular Filtration Rate at biopsy and relative endothelial area (r=0.19, P=.027), endothelial cell density (r=0.20, P=.017), mean parietal epithelial cell area (r=-0.38, P&amp;lt;.001), parietal epithelial cell density (r=0.29, P&amp;lt;.001), and mesangial cell density (r=0.22, P=.010). Multivariate analysis retained only endothelial cell density as associated with estimated Glomerular Filtration Rate (Beta=0.13, P=.040). Endothelial cell density (r=-0.22, P=.010) and mean podocyte area (r=0.21, P=.016) were linked to proteinuria at biopsy. Over 44±29 months, 25 patients (16%) reached the primary composite endpoint (dialysis initiation, or 30% estimated Glomerular Filtration Rate sustained decline), with relative endothelial area, mean endothelial cell area, parietal epithelial cell density below medians linked to this endpoint (Hazard Ratios respectively of 2.63, P=.048, 2.60, P=.039, and 3.23, P=.019). Conclusion This study automated the measurement of intraglomerular cells and capillaries. Our results suggest that the precise segmentation of endothelial and epithelial cells may serve as a potential future marker for the risk of graft loss.

The medical cost and outcome of desensitization protocol in kidney transplantation recipients with high immunological risks.

Kidney transplantation is a well-established alternative in renal replacement therapy. Compared with hemodialysis, low-immunological-risk kidney transplantation can reduce the medical treatment costs associated with end-stage renal disease. However, there are few reports on whether high-immunological-risk kidney transplantation reduces the financial burden on governments. We investigated the medical costs of high-immunological-risk kidney transplantation in comparison with the cost of hemodialysis in Japan. We compared the medical costs of high-immunological-risk kidney transplantation with those of hemodialysis. 15 patients who underwent crossmatch-positive and/or donor-specific antibody-positive kidney transplantations between 2020 and 2021 were enrolled in this study. The patients received intravenous immunoglobulin, plasmapheresis, and rituximab as desensitizing therapy. Acute antibody-mediated rejection was detected in nine (60%) recipients, while there were no indications of graft function deterioration during the follow-up. For each patient, the transplant hospitalization cost was 38 428 ± 8789 USD. However, the cumulative costs were 59 758 ± 10 006 USD and 79 781 ± 16 366 USD, at 12 and 24 months, respectively. Compared with hemodialysis (34 286 USD per year), high-immunological-risk kidney transplantation tends to be expensive in the first year, but the cost is likely to be lower than that of hemodialysis after 3 years. Although kidney transplantation is initially expensive compared with hemodialysis, the medical cost becomes advantageous after 3 years even in kidney transplant recipients with high immunological risk.

Beyond graft function impairment after liver transplantation: the prolonged cold ischemia time impact on recurrence of hepatocellular carcinoma after liver transplantation-a single-center retrospective study.

Hepatocellular carcinoma (HCC) is one of the malignant tumors responsible for high mortality and recurrence rates. Although liver transplantation (LT) is an effective treatment option for HCC, ischemia-reperfusion injury (IRI) is a contributor to HCC recurrence after LT. Moreover, prolonged cold ischemia time (CIT) is a risk factor for IRI during LT, and there is insufficient clinical evidence regarding the impact of CIT on HCC recurrence after LT. This retrospective study analyzed 420 patients who underwent LT for HCC between February 2015 and November 2020 at The First Affiliated Hospital, Sun Yat-sen University. The duration of CIT was defined as the time from clamping of the donor aorta until portal reperfusion. A total of 133 patients (31.7%) experienced tumor recurrence after LT, and CIT > 568 min was the independent risk factor for HCC recurrence (OR, 2.406; 95% CI [1.371-4.220]; p = 0.002). Multivariate Cox's regression analysis revealed that the recipients' gender, exceeding Milan criteria, poor differentiation, and alpha-fetoprotein (AFP) ≥400 ng/ml in CIT > 568 min group were independent risk factors for disease-free survival. The peak 7-day postoperative alanine aminotransferase (ALT) level (p<0.001), the peak 7-day postoperative aspartate aminotransferase (AST) level (p<0.001), the peak 7-day postoperative peak total bilirubin (TBIL) level (p=0.012), and the incidence of early allograft dysfunction (EAD) (p=0.006) were significantly higher in the CIT > 568 min group compared to the CIT ≤ 568 min group. Moreover, the amount of fresh frozen plasma (FFP) infusion during the operation increased (p=0.02), and the time of mechanical ventilation postoperative was longer (p=0.045). An effective strategy to improve the prognosis is to reduce CIT; this strategy lowers the recurrence of HCC in patients undergoing LT, especially those within the Milan criteria.