Chronic Allograft Dysfunction Research Articles

Relationship of hemoglobin levels with outcomes in deceased donor kidney transplant: a retrospective cohort study.

Anemia is frequent in patients undergoing replacement therapy for kidney failure. Anemia in the pre- and post-transplantation period might be related to kidney transplant outcomes. The current study therefore sought to assess the relationship between anemia, delayed allograft function (DGF), chronic kidney allograft dysfunction (CAD), and death from any cause following kidney transplantation from a deceased donor. This was a retrospective study with 206 kidney transplant patients of deceased donors. We analyzed deceased donors' and kidney transplant patients' demographic data. Moreover, we compared biochemical parameters, anemia status, and medicines between DGF and non-DGF groups. Afterward, we performed a multivariate analysis. We also evaluated outcomes, such as CAD within one year and death in ten years. We observed a lower frequency of pre-transplant hemoglobin concentration (Hb) but higher frequency of donor-serum creatinine and red blood transfusion within one week after transplantation in the group with DGF. In addition, there was an independent association between Hb concentration before transplantation and DGF [OR 0.252, 95%CI: 0.159-0.401; p < 0.001]. There was also an association between Hb concentration after six months of kidney transplantation and both CAD [OR 0.798, 95% CI: 0.687-0.926; p = 0.003] and death from any cause. An association was found between pre-transplantation anemia and DGF and between anemia six months after transplantation and both CAD and death by any cause. Thus, anemia before or after transplantation affects the outcomes for patients who have undergone kidney transplantation from a deceased donor.

#1572 Recurrent parvovirus B19 infection-associated pure red cell aplasia in kidney transplantation

Abstract Background and Aims Anemia is frequent in kidney transplant (KT) recipients, with multiple potential causes. Parvovirus B19 (PVB19) infection-associated pure red cell aplasia (PRCA) becomes an important diagnosis in KT recipients experiencing persistent anemia, in whom other etiologies have been excluded. PVB19-associated PRCA is described in up to 27% of KT recipients with anemia and recurrent disease in up to 33% of cases. The authors describe a case of a recurrent PVB19-associated PRCA in a KT recipient. Method - Results A 42-year-old male with chronic kidney disease of unknown etiology underwent KT from a deceased donor after circulatory death in January 2021. He received induction immunosuppression (IS) with thymoglobulin and maintenance IS with prednisolone, tacrolimus, and mycophenolate mofetil (MMF). Three months after KT, the patient complained of progressive asthenia, and normocytic normochromic (NN) anemia was detected. A thorough investigation revealed normal leucocyte and platelet counts, low reticulocyte count, and no signs of bacterial infection, iron deficiency, or hemolysis; thyroid function, erythropoietin, folate, and vitamin B12 levels were normal, direct Coombs test was negative and no monoclonal spike was detected on protein electrophoresis. Endoscopic studies and cervico-thoraco-abdomino-pelvic computer tomography were unremarkable. Serum PCR of PVB19 was positive and confirmed the diagnosis of PVB19-associated PRCA. MMF was discontinued but anemia continued aggravating (nadir hemoglobin [Hg] level of 6.6 g/dL) with a sustained PVB19 load. He was admitted to the hospital, received blood transfusions, and was started on intravenous immunoglobulin (IVIG) 2 g/kg. A bone marrow aspirate was performed and was compatible with recovery after erythroid aplasia. The patient was discharged with Hg 8 g/dL and reduced PVB19 load. Although MMF remained suspended, and close monitoring of Hg and PVB19 load was performed, four months later he developed recurrent PVB19-associated PRCA, which motivated another hospital admission for IVIG with excellent response. In addition, he presented kidney dysfunction, and a kidney biopsy revealed borderline acute T-cell mediated rejection. In this setting, IS was altered to TRANSFORM SCHEEME. Four months later, he presented a second recurrence of PVB19-associated PRCA, requiring new hospitalization and treatment with IVIG. Considering the recurrent PVB19-associated PRCA, in a patient with chronic allograft dysfunction, high immunologic risk, and the foscarnet's probable nephrotoxicity, preventive therapy with IVIG (0.4 mg/kg) every 4 weeks was started. After 7 months of preventive IVIG infusion, no relapse was identified, the Hg is 11.5 g/dL (and increasing, without erythropoiesis stimulants) and the PVB19 load remains low. Conclusion PVB19-associated PRCA is characterized by persistent NN anemia with low reticulocyte counts, which is unresponsive to erythropoietin. One significant risk factor is induction IS, particularly thymoglobulin. In the setting of solid organ transplants, the absence of PVB19 antibodies does not exclude this diagnosis and viral detection should be performed. The initial therapeutic approach involves reducing IS. However, the risk of allograft rejection must be acknowledged. If this approach proves insufficient, IVIG treatment is usually successful. In our patient, considering the facts that allograft rejection limits the reduction of IS, the need for blood transfusions, and the inherent immunization, in a young patient that will possibly require a second KT, the undesirable nephrotoxicity of foscarnet, the successful response to IVIG, and patient's quality of life, chronic IVIG therapy was thought to be the best choice and proved efficacious in preventing relapses. Despite the absence of precise guidelines for chronic PVB19 infection management, maintenance therapy with prolonged IVIG infusions may be a therapeutic option for recurrent PRCA, but more studies are necessary to define the appropriate duration of treatment.

Febrile Immunocompromised Renal Transplant Recipient with Allograft Dysfunction: Detection of an Undiagnosed Prostate Abscess by [18F]FDG-PET/CT along with Treatment Response Monitoring

AbstractThe purpose of this report is to provide a comprehensive description of a post-transplant febrile patient's clinical course, complications, surgical procedure, and long-term management including evaluation by 18F-fluorodeoxyglucose [(18F)FDG] positron-emission tomography combined with computed tomography (PET/CT). A 35-year-old male, a postrenal transplant patient, developed chronic allograft dysfunction and presented with fever with chills, with suspicion of acute-on-chronic graft dysfunction, but no infective focus localization on chest X-ray, ultrasonography (USG) whole abdomen, or blood culture. Urine microscopy showed 8 to 10 pus cells/high-power field (hpf) and culture showed Klebsiella pneumoniae and Pseudomonas aeruginosa with low colony count. Culture-sensitive antibiotics were prescribed for 2 weeks, and after 3 weeks febrile episodes relapsed, symptoms progressed, and required emergency hospitalization due to acute painful urinary retention. Proteinuria and no growth were noted in urine analysis, serum creatinine was 5.36 mg/dL, and C-reactive protein was 15.7mg/dL, and remaining parameters were unremarkable. [18F]FDG-PET/CT was considered in order to resolve diagnosis, which revealed abnormal heterogeneous tracer uptake in the enlarged prostate with hypodense areas within, suggesting prostatitis with abscess formation and pyelonephritis in the upper pole of the transplant kidney. USG kidney urinary bladder (KUB) correlation confirmed prostatic abscess and transurethral drainage done, and pus culture revealed Burkholderia pseudomallei. Culture-sensitive intravenous meropenem treatment was given for 3 weeks. At 5 weeks, follow-up [18F]FDG-PET/CT showed low metabolic residual prostate uptake, suggesting a good response with residual infection. Thus, intravenous antibiotics was changed to oral antibiotics for another 6 weeks. His symptoms completely resolved at the end of treatment; however, his graft function worsened, with serum creatinine reaching 6 to 7 mg/dL, and eventually, after 8 months he became dialysis dependent.

Rictor/mTORC2 signalling contributes to renal vascular endothelial-to-mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3-mediated mitophagy.

Renal allograft interstitial fibrosis/tubular atrophy (IF/TA) constitutes the principal histopathological characteristic of chronic allograft dysfunction (CAD) in kidney-transplanted patients. While renal vascular endothelial-mesenchymal transition (EndMT) has been verified as an important contributing factor to IF/TA in CAD patients, its underlying mechanisms remain obscure. Through single-cell transcriptomic analysis, we identified Rictor as a potential pivotal mediator for EndMT. This investigation sought to elucidate the role of Rictor/mTORC2 signalling in the pathogenesis of renal allograft interstitial fibrosis and the associated mechanisms. The influence of the Rictor/mTOR2 pathway on renal vascular EndMT and renal allograft fibrosis was investigated by cell experiments and Rictor depletion in renal allogeneic transplantation mice models. Subsequently, a series of assays were conducted to explore the underlying mechanisms of the enhanced mitophagy and the ameliorated EndMT resulting from Rictor knockout. Our findings revealed a significant activation of the Rictor/mTORC2 signalling in CAD patients and allogeneic kidney transplanted mice. The suppression of Rictor/mTORC2 signalling alleviated TNFα-induced EndMT in HUVECs. Moreover, Rictor knockout in endothelial cells remarkably ameliorated renal vascular EndMT and allograft interstitial fibrosis in allogeneic kidney transplanted mice. Mechanistically, Rictor knockout resulted in an augmented BNIP3-mediated mitophagy in endothelial cells. Furthermore, Rictor/mTORC2 facilitated the MARCH5-mediated degradation of BNIP3 at the K130 site through K48-linked ubiquitination, thereby regulating mitophagy activity. Subsequent experiments also demonstrated that BNIP3 knockdown nearly reversed the enhanced mitophagy and mitigated EndMT and allograft interstitial fibrosis induced by Rictor knockout. Consequently, our study underscores Rictor/mTORC2 signalling as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis progression, exerting its impact through regulating BNIP3-mediated mitophagy. This insight unveils a potential therapeutic target for mitigating renal allograft interstitial fibrosis.

Transplantation and Pregnancy

Transplantation is becoming increasingly widespread worldwide as a life-saving treatment for patients with end-stage organ failure. While the woman's quality of life improves rapidly after transplantation, the improvement of the endocrine system helps to regain fertility. The success of conception and successful pregnancy rates are quite low compared to the general population. Particular attention should be paid to obstetric complications such as hypertension, preeclampsia, fetal growth restriction, and preterm delivery during pregnancy. Ideally, preconception counseling should begin in the period before transplantation. Initiating contraception immediately after transplantation is ideal and long-acting reversible methods such as intrauterine devices and subcutaneous implants may be preferable. Factors that influence pregnancy outcomes in women undergoing organ transplantation include good general health within two years of transplantation, no evidence of organ rejection in the last year, stable graft conditions, absence of acute infections affecting the fetus, and adequate doses of immunosuppression drugs. However, factors that may adversely affect pregnancy include the etiology of the disease requiring transplantation, chronic allograft dysfunction, renal failure, cardiopulmonary diseases, hypertension, diabetes, obesity, and infections such as hepatitis B, hepatitis C, and Cytomegalovirus (CMV). Postponing pregnancy for at least 1 year after transplantation is very important to optimize pregnancy outcomes. Pregnancy in the early post-transplant period increases the risk of acute rejection, infection risk, and graft-related problems. In general, transplanted women can have successful pregnancies and live birth rates are above 70% on average. Although perinatal morbidity and mortality rates are high, most newborns are healthy and develop normally. Specific criteria such as pre-pregnancy serum creatinine levels and blood pressure control, as well as adherence to immunosuppressive therapy, significantly influence pregnancy success in transplant patients. In this review, optimizing pregnancy outcomes often involves addressing maternal and fetal risks, regular graft monitoring to detect potential complications such as organ rejection, and regulation of transplant medications to ensure safety and efficacy during pregnancy. Successful management relies on a multidisciplinary approach with contributions from obstetricians, neonatologists, nephrologists, hepatologists, and transplant surgeons.

Performance status at the time of lung retransplant predicts long-term function.

Lung retransplantation is offered to select patients with chronic allograft dysfunction. Given the increased risk of morbidity and mortality conferred by retransplantation, post-transplant function should be considered in the decision of who and when to list. The aim of this study is to identify predictors of post-operative disability in patients undergoing lung retransplantation. Data were collected from the UNOS national dataset and included all patients who underwent lung retransplant from May 2005-March 2023. Pre- and post-operative function was reported by the Karnofsky Performance Status (KPS) and patients were stratified based on their needs. Cumulative link mixed effects models identified associations between pre-transplant variables and post-transplant function. A total of 1275 lung retransplant patients were included. After adjusting for between-group differences, pre-operative functional status was predictive of post-transplant function; patients requiring Total Assistance ( n=740) were 74% more likely than No/Some Assistance patients (n=535) to require more assistance in follow-up (OR 1.74, 95% CI 1.13-2.68, p=.012). Estimated one year survival of Total Assistance patients is lower than No/Some Assistance Recipients (72%vs. 82%, CI 69%-75%; 79%-86%) but similar to overall re-transplant survival (76%, CI 74%-79%). Both survival and regain of function in patients requiring Total Assistance prior to retransplant may be higher than previously reported. Pre-operative functional status is predictive of post-operative function and should weigh in the selection, timing and post-operative care of patients considered for lung retransplantation.

An update of palliative care in lung transplantation with a focus on symptoms, quality of life and functional outcomes.

Palliative care (PC) in lung transplantation is increasingly acknowledged for its important role in addressing symptoms, enhancing functionality, and facilitating advance care planning for patients, families, and caregivers. The present review provides an update in PC management in lung transplantation. Research confirms the effectiveness of PC for patients with advanced lung disease who are undergoing transplantation, showing improvements in symptoms and reduced healthcare utilization. Assessment tools and patient-reported outcome measures for PC are commonly used in lung transplant candidates, revealing discrepancies between symptom severity and objective measures such as exercise capacity. The use of opioids to manage dyspnea and cough in the pretransplant period is deemed safe and does not heighten risks posttransplantation. However, the integration of PC support in managing symptoms and chronic allograft dysfunction in the posttransplant period has not been as well described. Palliative care support should be provided in the pretransplant and select peri-operative and posttransplant periods to help support patient quality of life, symptoms, communication and daily function.

Comparison of resistive index and shear-wave elastography in the evaluation of chronic kidney allograft dysfunction.

Detection of early chronic changes in the kidney allograft is important for timely intervention and long-term survival. Conventional and novel ultrasound-based investigations are being increasingly used for this purpose with variable results. To compare the diagnostic performance of resistive index (RI) and shear wave elastography (SWE) in the diagnosis of chronic fibrosing changes of kidney allograft with histopathological results. This is a cross-sectional and comparative study. A total of 154 kidney transplant recipients were included in this study, which was conducted at the Departments of Transplantation and Radiology, Sindh Institute of Urology and Transplan tation, Karachi, Pakistan, from August 2022 to February 2023. All consecutive patients with increased serum creatinine levels and reduced glomerular filtration rate (GFR) after three months of transplantation were enrolled in this study. SWE and RI were performed and the findings of these were evaluated against the kidney allograft biopsy results to determine their diagnostic utility. The mean age of all patients was 35.32 ± 11.08 years. Among these, 126 (81.8%) were males and 28 (18.2%) were females. The mean serum creatinine in all patients was 2.86 ± 1.68 mg/dL and the mean estimated GFR was 35.38 ± 17.27 mL/min/1.73 m2. Kidney allograft biopsy results showed chronic changes in 55 (37.66%) biopsies. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of SWE for the detection of chronic allograft damage were 93.10%, 96.87%%, 94.73%, and 95.87%, respectively, and the diagnostic accuracy was 95.45%. For RI, the sensitivity, specificity, PPV, and NPV were 76.92%, 83.33%, 70.17%, and 87.62%, respectively, and the diagnostic accuracy was 81.16%. The results from this study show that SWE is more sensitive and specific as compared to RI in the evaluation of chronic allograft damage. It can be of great help during the routine follow-up of kidney transplant recipients for screening and early detection of chronic changes and selecting patients for allograft biopsy.

Chronic Lung Allograft Dysfunction, a Review in 2023

Chronic allograft dysfunction (CLAD) is one of the leading causes of death after lung transplantation [1]. CLAD is a progressive and irreversible decline in lung function after transplant, manifested as an obstructive, restrictive, or mixed ventilatory impairment without any identifiable etiology as infection or acute rejection. Multiple risk factors have been associated with this condition. Despite its significant effect on the mortality of transplanted patients, there is still a lack of powerfully effective therapies for patients with CLAD. Avoiding and correcting risk factors and close patient monitoring is critical in preventing disease progression. This article will discuss CLAD, the risk factors for developing the umbrella of syndromes under this term, and the current treatment alternatives and management available up to 2023.

Long-term outcomes of lung transplantation with ex vivo lung perfusion technique

Ex vivo lung perfusion (EVLP) has demonstrated encouraging short- and medium-term outcomes with limited data available on its long-term outcomes. This study assesses (1) EVLP long-term outcomes and (2) EVLP era-based sub-analysis in addition to secondary outcomes of recipients with EVLP-treated donor lungs compared with recipients of conventionally preserved donor lungs in unmatched and propensity score-matched cohorts. Double lung transplants performed between 1st January 2012 and 31st December 2021 were included. A total of 57 recipients received EVLP-treated lungs compared to 202 unmatched and 57 matched recipients who were subjected to non-EVLP-treated lungs. The EVLP group had a significantly lower mean PaO2/FiO2 ratio and significantly higher mean BMI than the non-EVLP group in the unmatched and matched cohorts. The proportion of smoking history in the unmatched cohort was significantly higher in the EVLP group, while a similar smoking history was demonstrated in the matched cohorts. No difference was demonstrated in overall freedom from death and retransplantation between the groups in the unmatched and matched cohorts (unmatched: hazard ratio (HR) 1.28, 95% confidence interval (CI) 0.79–2.07, P = 0.32; matched: HR 1.06, 95% CI 0.59–1.89). P = 0.89). In the unmatched cohort, overall freedom from chronic allograft dysfunction (CLAD) was significantly different between the groups (HR 1.64, 95% CI 1.07–2.52, P = 0.02); however, the cumulative CLAD incidence was similar (HR 0.72, 95% CI 0.48–1.1, P = 0.13). In the matched cohort, the overall freedom from CLAD (HR 1.69, 95% CI 0.97–2.95, P = 0.06) and cumulative CLAD incidence (HR 0.91, 95% CI 0.37–2.215, P = 0.83) were similar between the groups. The EVLP era sub-analysis of the unmatched cohort in 2012–2014 had a significantly higher cumulative CLAD incidence in the EVLP group; however, this was not demonstrated in the matched cohort. All secondary outcomes were similar between the groups in the unmatched and matched cohorts. In conclusion, transplantation of marginal donor lungs after EVLP evaluation is non-detrimental compared to conventionally preserved donor lungs in terms of mortality, retransplantation, cumulative CLAD incidence, and secondary outcomes. Although the unmatched EVLP era of 2012–2014 had a significantly higher cumulative CLAD incidence, no such finding was demonstrated in the matched cohort of the same era.

NSD2 modulates Drp1-mediated mitochondrial fission in chronic renal allograft interstitial fibrosis by methylating STAT1

Renal interstitial fibrosis/tubular atrophy (IF/TA) is a prominent pathological feature of chronic allograft dysfunction (CAD). Our previous study has demonstrated that epithelial-mesenchymal transition (EMT) plays a significant role in shaping the development of IF/TA. Nuclear SET domain (NSD2), a histone methyltransferase catalyzing methylation at lysine 36 of histone 3, is crucially involved in the development and progression of solid tumors. But its role in the development of renal allograft interstitial fibrosis has yet to be elucidated. Here, we characterize NSD2 as a crucial mediator in the mouse renal transplantation model in vivo and a model of tumor necrosis factor-α (TNF-α) stimulated-human renal tubular epithelial cells (HK-2) in vitro. Functionally, NSD2 knockdown inhibits EMT, dynamin-related protein 1 (Drp1)-mediated mitochondrial fission in mice. Conversely, NSD2 overexpression exacerbates fibrosis-associated phenotypes and mitochondrial fission in tubular cells. Mechanistically, tubular NSD2 aggravated the Drp-1 mediated mitochondrial fission via STAT1/ERK/PI3K/Akt signaling pathway in TNF-α-induced epithelial cell models. Momentously, mass spectrometry (MS) Analysis and site-directed mutagenesis assays revealed that NSD2 interacted with and induced Mono-methylation of STAT1 on K173, leading to its phosphorylation, IMB1-dependent nuclear translocation and subsequent influence on TNF-α-induced EMT and mitochondrial fission in NSD2-dependent manner. Collectively, these findings shed light on the mechanisms and suggest that targeting NSD2 could be a promising therapeutic approach to enhance tubular cell survival and alleviate interstitial fibrosis in renal allografts during CAD.

The association between activation of the ERK1/2-NF-κB signaling pathway by TIMP2 expression and chronic renal allograft dysfunction in the CRAD rat model

PurposeThe tissue inhibitor of metalloproteinase 2 (TIMP2), a natural inhibitor of matrix metalloproteinase (MMP), regulates inflammation, fibrosis, and cell proliferation. Chronic renal allograft dysfunction (CRAD) is a primary factor affecting the long-term survival of renal allografts. We assessed whether up-regulation of TIMP2 expression may affect the ERK1/2-NF-κB signaling pathway and CRAD development. MethodsLewis rats received orthotopic F344 kidney allografts to establish the classical CRAD model. The treatment group was injected with a lentivirus encoding a TIMP2-targeting small hairpin (sh)RNA (LTS) at 5 × 108 TU/ml monthly after kidney transplantation. A second CRAD group was injected with a lentivirus TIMP2-control vector (LTC). After 12 weeks, blood, urine, and kidney tissue were harvested to evaluate renal function and pathological examinations. Hematoxylin and eosin staining, Masson staining, and Periodic acid–Schiff staining were performed for renal histopathological evaluation according to the Banff criteria. TIMP2, phospho (p)-ERK1/2, p-p65 (NF-κB) expression levels were measured via immunohistochemical and Western blot analyses. ResultsCompared to the F344 and Lewis control groups, the expression of TIMP2, p-ERK1/2, and p-p65 were significantly higher in the CRAD and CRAD+LTC renal tissues (p < 0.05). There were also increased levels of serum creatinine, nitrogen, and 24 h urinary protein in these two groups (p < 0.05). Typical histopathological changes of CRAD were observed in the CRAD and CRAD+LTC groups. Administration of LTS effectively decreased the expression of TIMP2, p-ERK1/2, and p-P65, and reduced interstitial fibrosis and macrophage infiltration in the treatment group (p < 0.05). Additionally, MCP1 and ICAM-1, which are downstream cytokines of the NF-κB pathway, were also inhibited in the renal rat kidney from the LTS group (p < 0.05). Furthermore, renal function was well preserved in the LTS group compared to the CRAD group and CRAD+LTC group. ConclusionA decrease of TIMP2 can alleviate the progression of inflammation in CRAD via inhibition of the ERK1/2-NF-κB signaling pathway.

Immune landscape of the kidney allograft in response to rejection.

Preventing kidney graft dysfunction and rejection is a critical step in addressing the nationwide organ shortage and improving patient outcomes. While kidney transplants (KT) are performed more frequently, the overall number of patients on the waitlist consistently exceeds organ availability. Despite improved short-term outcomes in KT, comparable progress in long-term allograft survival has not been achieved. Major cause of graft loss at 5 years post-KT is chronic allograft dysfunction (CAD) characterized by interstitial fibrosis and tubular atrophy (IFTA). Accordingly, proactive prevention of CAD requires a comprehensive understanding of the immune mechanisms associated with either further dysfunction or impaired repair. Allograft rejection is primed by innate immune cells and carried out by adaptive immune cells. The rejection process is primarily facilitated by antibody-mediated rejection (ABMR) and T cell-mediated rejection (TCMR). It is essential to better elucidate the actions of individual immune cell subclasses (e.g. B memory, Tregs, Macrophage type 1 and 2) throughout the rejection process, rather than limiting our understanding to broad classes of immune cells. Embracing multi-omic approaches may be the solution in acknowledging these intricacies and decoding these enigmatic pathways. A transition alongside advancing technology will better allow organ biology to find its place in this era of precision and personalized medicine.

Antisense Oligonucleotide-Mediated Terminal Intron Retention of Endoglin to Reduce Extracellular Matrix Production in Chronic Allograft Dysfunction

Antisense Oligonucleotide-Mediated Terminal Intron Retention of Endoglin to Reduce Extracellular Matrix Production in Chronic Allograft Dysfunction

An Immune Atlas of T Cells in Transplant Rejection: Pathways and Therapeutic Opportunities.

Short-term outcomes in allotransplantation are excellent due to technical and pharmacological advances however, improvement in long-term outcomes has been limited. Recurrent episodes of acute cellular rejection, a primarily T cell-mediated response to transplanted tissue, have been implicated in the development of chronic allograft dysfunction and loss. Although it is well established that acute cellular rejection is primarily a CD4+ and CD8+ T cell mediated response, significant heterogeneity exists within these cell compartments. During immune responses, naïve (orthography) (orthography) CD4+ T cells are activated and subsequently differentiate into specific T helper subsets under the influence of the local cytokine milieu. These subsets have distinct phenotypic and functional characteristics, with reported differences in their contribution to rejection responses specifically. Of particular relevance are the regulatory subsets and their potential to promote tolerance of allografts. Unraveling the specific contributions of these cell subsets in the context of transplantation is complex, but may reveal new avenues of therapeutic intervention for the prevention of rejection.

Living-donor lobar lung transplantation

Living-donor lobar lung transplantation (LDLLT) is indicated for critically ill patients who would not survive the waiting period in the case of severe brain-dead donor shortage. It is essential to confirm that potential donors are willing to donate without applying psychological pressure from others. In standard LDLLT, the right and left lower lobes donated by 2 healthy donors are implanted into the recipient under cardiopulmonary support. LDLLT can be applied to various lung diseases including restrictive, obstructive, infectious, and vascular lung diseases in both adult and pediatric patients if size matching is acceptable. Functional size matching by measuring donor pulmonary function and anatomical size matching by 3-dimensional computed tomography volumetry are very useful. When 2 donors with ideal size matching are not available, various transplant procedures, such as single lobe, segmental, recipient lobe-sparing, and inverted lobar transplants are valuable options. There seems to be immunological advantages in LDLLT as compared to cadaveric lung transplantation (CLT). Unilateral chronic allograft dysfunction is a unique manifestation after bilateral LDLLT, which may contribute to better prognosis. The growth of adult lung graft implanted into growing pediatric recipients is suggested by radiologic evaluation. Although only 2 lobes are implanted, postoperative pulmonary function is equivalent between LDLLT and CLT. The long-term outcome after LDLLT is similar to or better than that after CLT. The author has performed 164 LDLLTs resulting in 71.6% survival rate at 10years. All living-donors returned to their previous life styles. Because of possible serious morbidity in donors, LDLLT should be applied only for critically ill patients.

Disruption of RCAN1.4 expression mediated by YY1/HDAC2 modulates chronic renal allograft interstitial fibrosis

Chronic allograft dysfunction (CAD) is a major factor that hinders kidney transplant survival in the long run. Epithelial–mesenchymal transition (EMT) has been confirmed to significantly contribute to interstitial fibrosis/tubular atrophy (IF/TA), which is the main histopathological feature of CAD. Aberrant expression of the regulator of calcineurin 1 (RCAN1), recognized as an endogenous inhibitor of the calcineurin phosphatase, has been shown to be extensively involved in various kidney diseases. However, it remains unclear how RCAN1.4 regulates IF/TA formation in CAD patients. Herein, an in vivo mouse renal transplantation model and an in vitro model of human renal tubular epithelial cells (HK-2) treated with tumor necrosis factor-α (TNF-α) were employed. Our results proved that RCAN1.4 expression was decreased in vivo and in vitro, in addition to the up-regulation of Yin Yang 1 (YY1), a transcription factor that has been reported to convey multiple functions in chronic kidney disease (CKD). Knocking in of RCAN1.4 efficiently attenuated chronic renal allograft interstitial fibrosis in vivo and inhibited TNF-α-induced EMT in vitro through regulating anti-oxidative stress and the calcineurin/nuclear factor of activated T cells cytoplasmic 1 (NFATc1) signaling pathway. In addition, suppression of YY1 mediated by shRNA or siRNA alleviated TNF-α-induced EMT through abolishing reactive species partly in an RCAN1.4-dependent manner. Notably, we confirmed that YY1 negatively regulated RCAN1.4 transcription by directly interacting with the RCAN1.4 promoter. In addition, histone deacetylase 2 (HDAC2) interacted with YY1 to form a multi-molecular complex, which was involved in TNF-α-induced RCAN1.4 transcriptional repression. Therefore, RCAN1.4 is suggested to be modulated by the YY1/HDAC2 transcription repressor complex in an epigenetic manner, which is a mediated nephroprotective effect partly through modulating O2⋅− generation and the calcineurin/NFATc1 signaling pathway. Thus, the YY1–RCAN1.4 axis constitutes an innovative target for IF/TA treatment in CAD patients.

Impact of statin treatment and exposure on the risk of chronic allograft dysfunction in Chinese lung transplant recipients

PurposeChronic lung allograft dysfunction (CLAD) was a common complication following lung transplantation that contributed to long-term morbidity and mortality. Statin therapy had been suggested to attenuate recipient inflammation and immune response, potentially reducing the risk and severity of CLAD. This study aimed to evaluate the impact of statin use and in vivo exposure on the incidence of CLAD in lung transplant recipients (LTRs), as well as their effects on immune cells and inflammatory factors. MethodsA retrospective cohort study was conducted on patients who underwent lung transplantation between January 2017 and December 2020. The incidence of CLAD, as per the 2019 ISHLT criteria, was assessed as the clinical outcome. The plasma concentrations of statin were measured using a validated UPLC-MS/MS method, while inflammation marker levels were determined using ELISA kits. ResultsThe statin group exhibited a significantly lower rate of CLAD (P = 0.002). Patients receiving statin therapy showed lower CD4+ T-cell counts, total T-lymphocyte counts, and IL-6 levels (P = 0.017, P = 0.048, and P = 0.038, respectively). Among the CLAD groups, the atorvastatin level (2.51 ± 1.31 ng/ml) was significantly lower than that in the non-CLAD group (OR = 1.438, 95%CI (1.007–2.053), P = 0.046). ConclusionStatin therapy significantly reduced the incidence of CLAD, as well as immune cell counts and inflammatory cytokine levels in LTRs. Although the statin exposure was significantly lower in CLAD patients, it was not associated with the incidence of CLAD.

Laparoscopic Toupet fundoplication: a safe and effective anti-reflux option in lung transplant recipients.

Fundoplication is known to improve allograft outcomes in lung transplant recipients by reducing retrograde aspiration secondary to gastroesophageal reflux disease, a modifiable risk factor for chronic allograft dysfunction. Laparoscopic Nissen fundoplication has historically been the anti-reflux procedure of choice, but the procedure is associated with discernable rates of postoperative dysphagia and gas-bloat syndrome. Laparoscopic Toupet fundoplication, an alternate anti-reflux surgery with lower rates of foregut complications in the general population, is the procedure of choice on our institution's lung transplant protocol. In this work, we evaluated the efficacy and safety of laparoscopic Toupet fundoplication in our lung transplant recipients. A prospective case series of 44 lung transplant recipients who underwent laparoscopic Toupet fundoplication by a single surgeon between September 2018 and November 2020 was performed. Preoperative and postoperative results from 24-h pH, esophageal manometry, gastric emptying, and pulmonary function studies were collected alongside severity of gastroesophageal reflux disease and other gastrointestinal symptoms. Median DeMeester score decreased from 25.9 to 5.4 after fundoplication (p < 0.0001), while percentage of time pH < 4 decreased from 7 to 1.1% (p < 0.0001). The severity of heartburn and regurgitation were also reduced (p < 0.0001 and p = 0.0029 respectively). Overall, pulmonary function, esophageal motility, gastric emptying, severity of bloating, and dysphagia were not significantly different post-fundoplication than pre-fundoplication. Patients with decreasing rates of FEV1 pre-fundoplication saw improvement in their rate of change of FEV1 post-fundoplication (p = 0.011). Median follow-up was 32.2months post-fundoplication. Laparoscopic Toupet fundoplication provides objective pathologic acid reflux control and symptomatic gastroesophageal reflux improvement in lung transplant recipients while preserving lung function and foregut motility. Thus, laparoscopic Toupet fundoplication is a safe and effective antireflux surgery alternative in lung transplant recipients.

Live Related Kidney Transplantation: Experience of 360 Patients in a Tertiary Care Hospital of Bangladesh

Background: Live related kidney transplantation is the most preferred form of renal replacement therapy worldwide including Bangladesh. However, it is challenging and also rewarding both for patients and treating physicians. BSMMU hospital has given maximum effort for its greater success. The aim of this study was to share our ten years’ experience regarding some aspects of live related renal transplantation. Methods: This retrospective study was conducted in nephrology department of BSMMU hospital from January 2002 to December 2015. Data were collected from hospital records and some previously conducted study on these transplant recipients. Results: A total of 360 live related kidney transplant recipients were evaluated during this period. Recipients Male: Female ratio was 1.57:1. Mean age of recipients were 39.58 ± 10.46 years. The causes of ESRD were chronic glomerulonephritis 220(61.60 %), diabetic nephropathy 58(16.24%), hypertensive nephrosclerosis 22 (6.16 %), chronic interstitial nephritis 11 (3.08 %), SLE 10(2.8%), ADPKD 6(1.68 %), unknown 19(5.32 %). Most of the donors were mother (21.84% %) followed by spouse mostly wife (20.44%) and sister (18.76 %). Almost all recipients were on MHD 352(97.78%), 2 were on CAPD and 06 were pre-emptive transplantation. Triple immunosuppressive protocol Cyclosporine or Tacrolimus, MPA or Azathioprine and Prednisolone were used in each patient. Recipients with poor HLA matching received Baciliximab in standard dose. CMV prophylaxis was given in selected patients and each patient received pneumocystis jirovecii prophylaxis. Common complications during post-operative period were ATN 41(11.48%), DGF 23(6.44%), Acute rejection 50(14%) and infection mainly urinary tract infection 46(12.88%) and RTI 14(3.92) followed by wound infection and other surgical complication. Presence of BK virus infection was studied in 29 transplant recipient and it was found to be positive in 6(20.7%) cases. Protocol biopsy was done in 37 transplant recipient in the 2008-2009 on day 14, and day 90 to see subclinical rejection and early graft dysfunction. On day 14th biopsy report showed 21(56.7%) normal histology, 5(13.5%) had subclinical rejection, 5(13.5%) had clinical rejection, 4(10.8 %) developed ATN, 2(5.2 % ) cyclosporine toxicity, and report at 3 month showed normal histology 18(48.60%), subclinical rejection 7(18.90%), clinical rejection 5(10.80%). Leading cause of chronic allograft dysfunction was chronic allograft nephropathy (CAN) 60(19.80%) followed by chronic cyclosporine toxicity 37(12.21%) and de-novo or recurrent glomerulonephritis. Mean post-transplant hospital stay was 18.46 ± 5.56 days. Mean duration of normalization of serum creatinine after surgery was 7.38 ± 3.88 days. At discharge 74.40% patients had normal renal function with mean serum creatinine 1.10 ± 0.26 mg/dl and 21.34% patients showed gradual improvement of renal function with mean serum creatinine 2.12 ± 0.97 mg/dl. In our study 1 year and 5 years’ graft survival was 93.88% and 75.16% respectively and 1 year and 5 years’ patient’s survival was 346(96.08%) and 290(81.2%). Conclusion: Our report shows that short and long term graft and patient survival is encouraging and comparable to other centers of both developing and some developed countries with limited resources and facilities.