Normal Graft Research Articles

Tacrolimus intrapatient variability in BK virus nephropathy and chronic calcineurin toxicity in kidney transplantation.

Intrapatient variability (IPV) in tacrolimus has been increasingly acknowledged as a risk factor for poor graft survival after kidney transplantation. Although past studies have mainly accounted for IPV in acute or chronic rejection states as due to underimmunosuppression, this is not yet clear. So far, tacrolimus IPV for BK virus-associated nephropathy (BKVN) and chronic calcineurin inhibitor toxicity (CNIT) has not been investigated. Here, we evaluated IPV in tacrolimus for BKVN and chronic CNIT, which are mainly considered as overimmunosuppression states. In this case-control study, kidney allograft biopsies conducted between 1998 and 2018 were included, with patients grouped by biopsy results as BKVN alone group, CNIT alone group, and normal graft function (control group). IPV was estimated as mean absolute deviation. Our study groups included 25 kidney transplant recipients with BKVN alone, 91 patients with CNIT alone, and 60 patients with normal 5-year graft survival (control group). In analyses of IPV in tacrolimus six months before graft biopsy, IPV was highest in the BKVN group (P = 0.001). The BKVN group also had the highest IPV in tacrolimus at 12 months after biopsy (P = 0.001), with all pairwise comparisons statistically different between groups. At 12 months after biopsy, five patients (20%) in the BKVN group and 10 patients (10.9%) in the CNIT group had graft loss. Among other risk factors, BKVN and chronic CNIT are consequences related to high IPV. Quantification of IVP for tacrolimus in clinical practice would help to optimize kidney transplant outcomes.

Hypothermic Oxygenated Machine Perfusion of Liver Grafts: Preliminary Experience in a Single Center.

Background: The need to maximize the use of donor organs and the issue of ischemia-reperfusion injury led to the use of thermoregulated oxygenated machine perfusion that improves the function of liver graft prior to transplantation. Among these methods, the HOPE (hypothermic oxygenated perfusion) protocol shows significant benefits. The aim of the paper is to analyze the early experience in using such procedure in a high-volume liver transplantation center. Methods: Normal liver grafts with cold ischemia time â?¥6 hours, marginal grafts and discarded (beyond ECD criteria) grafts were perfused using HOPE. Our selection criteria for dual HOPE (hepatic artery and portal perfusion) were steatosis, at least 3 associated ECD criteria, and discarded grafts. The main criteria to establish graft improvement were the progressive increase of arterial and portal flows, with lactate under 3 mmol/L or, even if over this value, with a decreasing trend during perfusion. Results: Whole liver grafts harvested from 28 donors between February 2016 and June 2021 benefitted from HOPE: 9 otherwise discarded grafts were assessed and considered not fit for transplantation, while the other 19 were ECD or standard grafts that were subsequently transplanted. Dual HOPE was used in 8 out of the 19 procedures (42.1%). We obtained a significant increase of arterial and portal flow (p=0.005 and p=0.001, respectively). In recipients, significant improvement of AST, ALT, INR and lactate values were recorded (p 0.001, p 0.001, p 0.001, and p=0.05, respectively). The rate of major postoperative complications (Dindo-Clavien grade 3) after LT was 26.3%, while the rate of early graft dysfunction was 15.8%. No PRS or acute rejection was recorded. The postoperative mortality rate was 15.8%. After a median follow-up of 9.3 months (range 2-44), the late major complication rate was 15.8%, without mortality. Conclusion: Machine perfusion is nowadays part of current clinical practice. This way, marginal liver grafts (DCD, ECD-DBD) may be safely used for transplantation improving the outcome, thus effectively enhance the use of a persistent scarce pool of donors. For best results, we believe that both techniques of HOPE (mono and dual HOPE) should be used based on specific selection criteria.

Live-related renal transplant with bench repair of saccular aneurysm of graft renal artery - A case report

Renal artery aneurysm is a rare entity with an incidence of about 1%. The preoperative evaluation of a voluntary kidney donor incidentally revealed a saccular aneurysm of the right renal artery on a computed tomography angiogram. Laparoscopic right donor nephrectomy was performed with Bench repair of the aneurysm and transplantation of this kidney to the recipient in the right iliac fossa. Transplant kidney had good perfusion on revascularization with normal postoperative graft function. Transplanting kidneys with renal artery aneurysm can be safely performed with a win-win situation for both donor and recipient.

Renal transplantation in a patient with polyarteritis nodosa - A case report

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis, predominantly affecting medium-sized arteries, and usually involving the kidneys, heart, gastrointestinal tract, and nervous system. The common clinical presentation is renovascular hypertension due to renal artery stenosis. We report a 38-year-old man, who presented with secondary hypertension and progressive renal failure leading on to end-stage renal disease (ESRD). He had renal artery stenosis on evaluation which caused ischemic damage to the kidneys resulting in ESRD. He also had multivessel coronary artery disease requiring percutaneous transluminal angioplasty. Coronary angiogram and renal angiogram showed areas of ectatic segments and aneurysms along with stenotic segments, which was consistent with medium-vessel vasculitis. We had challenges in considering him for kidney transplantation due to significant coronary artery disease, and he required coronary angioplasty on two occasions 6 months apart. He underwent bilateral nephrectomy prior to the transplantation as he had refractory hypertension requiring five antihypertensive medications. Histology of the nephrectomy specimen confirmed the diagnosis of PAN. Our patient did not show evidence of hepatitis B infection which is commonly associated with PAN. Renal failure and progression to ESRD are rare in PAN and are due to ischemic damage to the kidneys. He underwent kidney transplantation and had a smooth perioperative period and normal graft functions 6 months after the transplant surgery. To the best of our knowledge, this is the second reported case of PAN, who underwent successful kidney transplantation. Significant coronary artery disease is a rare manifestation in PAN.

T cell receptor repertoires within liver allografts are different to those in the peripheral blood

T cells are the main mediators of allogeneic immune responses. Specific T cell clones can be tracked by their unique T cell receptor (TCR), but specificity and function remain elusive and have not been investigated in human liver biopsies thus far. TCR repertoire analysis of CD4+, CD8+, and regulatory T cells of the peripheral blood and liver graft was performed in 7 liver transplant recipients with either stable course (non-rejector, NR), subclinical cellular rejection (SCR), or acute cellular rejection (ACR) during an observation period from pre-transplant to 6 years post-transplant. Furthermore, donor-reactive T cells, identified by their expression of CD154 and glycoprotein A repetitions predominant (GARP) after allogeneic activation, were tracked longitudinally in peripheral blood and within the liver allograft. Although overall clonality of the TCR repertoire did not increase in peripheral blood after liver transplantation, clonality of donor-reactive CD4+ and regulatory T cells increased and these clones accumulated within the liver graft. Surprisingly, the TCR repertoires between the liver graft and the periphery were distinct and showed only limited overlap. Notably, during ACR, TCR repertoires aligned suggesting either graft-specific homing or release of activated T cells from the graft. This is the first study comparing TCR repertoires between liver grafts and blood in patients with NR, SCR, and ACR. Moreover, we attribute specificity and function to a subgroup of intragraft T cell populations. Given the limited overlap between peripheral blood and intragraft repertoires, future studies investigating function and specificities of T cells after liver transplantation should focus on the intragraft immune response. In solid organ transplantation, T cells are key mediators of the recipient's immune response directed at the transplanted organ. In our study, we characterised the T cell repertoire in a cohort of 7 liver transplant recipients. We demonstrate that donor-specific T cells expand clonally and accumulate in the transplanted liver. Moreover, we show that the composition of T cells in peripheral blood differs from the T cells in the liver allograft, only aligning in the context of acute cellular rejection but not in normal graft or subclinical cellular rejection. This indicates that the intragraft immune response is not mirrored in the peripheral blood. Our findings clarify the importance of protocol liver biopsies in identifying intragraft immune responses for future investigations of allo-directed immune responses.

Case report: Transcatheter valve repair with Cardioband: a new treatment option for secondary tricuspid regurgitation in cardiac transplant patients.

BackgroundTricuspid regurgitation (TR) is the most frequent valvular complication after cardiac transplantation. As in native hearts, the role of surgical therapy particularly in secondary TR is unclear due to high procedural risk and unsatisfying results. Currently, percutaneous techniques are under development for TR repair with less procedural risk and promising preliminary results.Case summaryWe present a 67-year-old man who underwent heart transplantation (biatrial anastomosis) because of ischaemic heart disease 15 years ago and aortic valve replacement in 2010. Because of progressive severe dyspnoea (New York Heart Association Class III) in 2018 and signs of right heart failure with ascites he underwent transthoracic echocardiography which showed normal graft function, but massive TR of functional aetiology. The heart team decision was an interventional approach using the Cardioband System (Edwards Lifesciences) to treat TR based on the high risk associated with a third cardiac surgery and impaired right ventricular function. The procedure was performed in general anaesthesia with transoesophageal echocardiography and fluoroscopic guidance. Tricuspid regurgitation improved from massive to mild with a mean pressure gradient of 2.9 mmHg.DiscussionThis is the first case report of Cardioband implantation in tricuspid position in a heart transplant patient with the good technical and clinical result, suggesting that this technique might offer a treatment option to highly selected post-transplant patients with secondary severe TR and high surgical risk.

Development and Validation of a Comprehensive Model to Estimate Early Allograft Failure Among Patients Requiring Early Liver Retransplant

Expansion of donor acceptance criteria for liver transplant increased the risk for early allograft failure (EAF), and although EAF prediction is pivotal to optimize transplant outcomes, there is no consensus on specific EAF indicators or timing to evaluate EAF. Recently, the Liver Graft Assessment Following Transplantation (L-GrAFT) algorithm, based on aspartate transaminase, bilirubin, platelet, and international normalized ratio kinetics, was developed from a single-center database gathered from 2002 to 2015. To develop and validate a simplified comprehensive model estimating at day 10 after liver transplant the EAF risk at day 90 (the Early Allograft Failure Simplified Estimation [EASE] score) and, secondarily, to identify early those patients with unsustainable EAF risk who are suitable for retransplant. This multicenter cohort study was designed to develop a score capturing a continuum from normal graft function to nonfunction after transplant. Both parenchymal and vascular factors, which provide an indication to list for retransplant, were included among the EAF determinants. The L-GrAFT kinetic approach was adopted and modified with fewer data entries and novel variables. The population included 1609 patients in Italy for the derivation set and 538 patients in the UK for the validation set; all were patients who underwent transplant in 2016 and 2017. Early allograft failure was defined as graft failure (codified by retransplant or death) for any reason within 90 days after transplant. At day 90 after transplant, the incidence of EAF was 110 of 1609 patients (6.8%) in the derivation set and 41 of 538 patients (7.6%) in the external validation set. Median (interquartile range) ages were 57 (51-62) years in the derivation data set and 56 (49-62) years in the validation data set. The EASE score was developed through 17 entries derived from 8 variables, including the Model for End-stage Liver Disease score, blood transfusion, early thrombosis of hepatic vessels, and kinetic parameters of transaminases, platelet count, and bilirubin. Donor parameters (age, donation after cardiac death, and machine perfusion) were not associated with EAF risk. Results were adjusted for transplant center volume. In receiver operating characteristic curve analyses, the EASE score outperformed L-GrAFT, Model for Early Allograft Function, Early Allograft Dysfunction, Eurotransplant Donor Risk Index, donor age × Model for End-stage Liver Disease, and Donor Risk Index scores, estimating day 90 EAF in 87% (95% CI, 83%-91%) of cases in both the derivation data set and the internal validation data set. Patients could be stratified in 5 classes, with those in the highest class exhibiting unsustainable EAF risk. This study found that the developed EASE score reliably estimated EAF risk. Knowledge of contributing factors may help clinicians to mitigate risk factors and guide them through the challenging clinical decision to allocate patients to early liver retransplant. The EASE score may be used in translational research across transplant centers.

Renal transplantation using vascular conduit reconstruction in deceased kidneys with multiple renal arteries and short renal veins

BackgroundTransplantation of kidneys with vascular anatomical variants remains a challenge. Due to its varying success in regard to graft function after transplantation, these organs have been frequently discarded assuming in advance an unaffordable rate of vascular complications. Patients and methodsWe performed three kidney transplants using organs from deceased donors harboring vascular variants (multiple arteries and short veins), including an unsplittable horseshoe kidney. Different grafts harvested from the same donor aorta, common iliac artery, and inferior vena cava, were used to reconstruct the initial vascular configuration by creating single arterial and venous conduits aimed to simplify the vascular anastomoses in the recipient. ResultsNo post-operative complications were recorded. Warm ischemia times remained comparable to single artery renal allografts. No delayed graft function was noted in any case, and every patient regained normal renal function after transplantation. ConclusionsVascular reconstruction using arterial and venous grafts harvested from the same deceased donor may result a helpful tool to simplify vascular anastomoses during transplantation surgery, thus avoiding their discard in advance, minimizing perioperative complications, and enabling normal graft function rates in the long-term follow-up. The successful outcome obtained by using this approach would help to expand the donor criteria for the inclusion of organs containing vascular anatomical variants.

Coronary Artery Vasospasm: A Under-recognized Phenomenon in Orthotopic Heart Transplant

Introduction Cardiac allograft vasculopathy (CAV) is known as the primary cause of death in the first year after orthotopic heart transplant (OHT). Coronary artery spasm (CAS) in OHT is a rare and under-recognized phenomenon in patients undergoing surveillance. The mechanism of coronary vasospasm in OHT remain largely unknown. The presentation can vary from an incidental finding to severe episodes of symptomatic ventricular arrhythmias, high-degree atrioventricular block, syncope, cardiac arrest, or even myocardial infarction in cases of prolonged ischemia. Case Presentation 65 yo female with history of chronic kidney disease, diabetes mellitus type 2, hypertension, hyperlipidemia, and orthotopic heart transplantation with CMV mismatch in 2016 secondary to apical hypertrophic cardiomyopathy. Prior coronary angiography (CA) done at our institution had shown no evidence of vasculopathy. During one of her follow-up visits in the Clinic, she complained of increasing dyspnea on exertion, prompting urgent referral for CA, as per our surveillance protocols. Prior to the procedure, echocardiography was performed which revealed normal graft function and no valvular abnormalities. She underwent CA which showed a proximal significant diffuse luminal narrowing of the right coronary artery (RCA) (Image 1) and normal left coronary artery anatomy (Image 2). We proceed to repeat CA with intracoronary administration of nitroglycerin (ICN) and measurement of fractional flow reserve (FFR) of RCA (Image 3, 4). Angiography revealed near resolution of the RCA lesion, ultimately suggesting that transient vasospasm had been responsible for the previous angiographic appearance (Image 1). Summary CAS can present in patients with or without vasculopathy. It can produce luminal narrowing and can be difficult to distinguish angiographically from CAV. Misdiagnosis of this entity has led to the incorrect diagnosis of CAV and subsequent unnecessary stenting. ICN use can improve angiographic visualization, and prevent the adverse effects of coronary spasm. In conclusion, CAS is a rare and potential complication post OHT. It is a difficult entity to prognosticate due to scarcity of clinical evidence, as prevalence ranges from 4.9% to 12.1%. Some authors hypothesize that CAS in OHT carries a poor prognosis as it is often an early manifestation of CAV. However, this remains largely hypothetical and further studies are needed to better understand this disease.

Upside-down kidney placement: An alternative in pediatric renal transplantation

Purpose“Upside-down” kidney placement has been reported as an acceptable alternative in cases of technical difficulty in kidney transplantation but there are few reports in the pediatric population.The aim of our study is to analyze whether the placement of the upside-down kidney could affect graft outcome or produce more complications. Materials and methodsA retrospective study was conducted of pediatric kidney transplants performed in our center between 2005 and 2017 with at least 6 months' follow-up.Epidemiological and anthropometric data, type of donor (deceased/living), graft position (normal/upside-down), reason for the upside-down placement, early, medium and long-term complications and renal function were analyzed and compared with patients transplanted in the same period with a normal graft placement. ResultsFrom 181 transplants, 167 grafts were placed in a normal position (mean age: 10 y and mean weight: 30 kg) and 14 were placed upside-down (10 y, 37 kg) mainly because of vessel shortness after laparoscopic nephrectomy. Male predominance was observed in both groups.57% of grafts from the control group and 64% of those from study group came from a living donor.Four vascular and two ureteral re-anastomoses were recorded in the control group and two vascular and one ureteral re-anastomosis in the study group (p > 0.05). In the latter group, no grafts have been lost due to vascular or urological causes and no patients have required dialysis. ConclusionsWhen necessary, an upside-down placement for the renal graft is a safe alternative in the pediatric population. Level of evidenceLevel III.

A circulating exosomal microRNA panel as a novel biomarker for monitoring post-transplant renal graft function.

Accurate and effective biomarkers for continuous monitoring of graft function are needed after kidney transplantation. The aim of this study was to establish a circulating exosomal miRNA panel as non‐invasive biomarker for kidney transplant recipients. Plasma exosomes of 58 kidney transplant recipients and 27 healthy controls were extracted by gel exclusion chromatography and characterized by transmission electron microscopy, nanoparticle tracking analysis and Western blotting. Post‐transplant renal graft function was evaluated by estimated glomerular filtration rate (eGFR). Quantitative real‐time polymerase chain reaction was used to determine the expression of exosomal microRNAs (miRNAs). Exosomal miR‐21, miR‐210 and miR‐4639 showed negative correlations with eGFR in the training set and were selected for further analysis. In the validation set, miR‐21, miR‐210 and miR‐4639 showed the capability to discriminate between subjects with chronic allograft dysfunction (eGFR < 60 mL/min/1.73 m2) and those with normal graft function (eGFR > 90 mL/min/1.73 m2). Three‐miRNA panel exhibited higher accuracy compared with individual miRNAs or double indicators. One‐year follow‐up revealed a stable recovery of allograft function in subjects with low calculated score from three‐miRNA panel (below the optimal cut‐off value). In conclusion, a unique circulating exosomal miRNA panel was identified as an effective biomarker for monitoring post‐transplant renal graft function in this study.

IgE-Mediated Immune Response and Antibody-Mediated Rejection.

Active antibody-mediated rejection is the main cause of kidney transplant loss, sharing with SLE the alloimmune response and the systemic activation of the IFN-α pathway. IgE-mediated immune response plays a key role in the development of SLE nephritis and is associated with IFN-α secretion. The aim of our study was to investigate IgE-mediated immune response in antibody-mediated rejection. This was a cross-sectional study of 56 biopsy-proven antibody-mediated rejection study participants, 80 recipients with normal graft function/histology (control), 16 study participants with interstitial fibrosis/tubular atrophy, and six participants with SLE. We evaluated graft IgE deposition, tryptase (a mast cell marker), and CD203 (a specific marker of activated basophils) by immunofluorescence/confocal microscopy. In addition, we measured serum concentration of human myxovirus resistance protein 1, an IFN-α-induced protein, and anti-HLA IgE. We observed a significantly higher IgE deposition in tubules and glomeruli in antibody-mediated rejection (1766±79 pixels) and SLE (1495±43 pixels) compared with interstitial fibrosis/tubular atrophy (582±122 pixels) and control (253±50 pixels). Patients with antibody-mediated rejection, but not control patients and patients with interstitial fibrosis/tubular atrophy, presented circulating anti-HLA IgE antibodies, although with a low mean fluorescence intensity. In addition, immunofluorescence revealed the presence of both mast cells and activated basophils in antibody-mediated rejection but not in control and interstitial fibrosis/tubular atrophy. The concentration of circulating basophils was significantly higher in antibody-mediated rejection compared with control and interstitial fibrosis/tubular atrophy. MxA serum levels were significantly higher in antibody-mediated rejection compared with control and correlated with the extent of IgE deposition. Our data suggest that IgE deposition and the subsequent recruitment of basophils and mast cells within the kidney transplant might play a role in antibody-mediated rejection.

Altered Phosphorylation of Cytoskeleton Proteins in Peripheral Blood Mononuclear Cells Characterizes Chronic Antibody-Mediated Rejection in Kidney Transplantation.

Chronic antibody-mediated rejection (CAMR) is the major cause of kidney transplant failure. The molecular mechanisms underlying this event are still poorly defined and this lack of knowledge deeply influences the potential therapeutic strategies. The aim of our study was to analyze the phosphoproteome of peripheral blood mononuclear cells (PBMCs), to identify cellular signaling networks differentially activated in CAMR. Phosphoproteins isolated from PBMCs of biopsy proven CAMR, kidney transplant recipients with normal graft function and histology and healthy immunocompetent individuals, have been investigated by proteomic analysis. Phosphoproteomic results were confirmed by Western blot and PBMCs’ confocal microscopy analyses. Overall, 38 PBMCs samples were analyzed. A differential analysis of PBMCs’ phosphoproteomes revealed an increase of lactotransferrin, actin-related protein 2 (ARPC2) and calgranulin-B in antibody-mediated rejection patients, compared to controls. Increased expression of phosphorylated ARPC2 and its correlation to F-actin filaments were confirmed in CAMR patients. Our results are the first evidence of altered cytoskeleton organization in circulating immune cells of CAMR patients. The increased expression of phosphorylated ARPC2 found in the PBMCs of our patients, and its association with derangement of F-actin filaments, might suggest that proteins regulating actin dynamics in immune cells could be involved in the mechanism of CAMR of kidney grafts.

INTRA-PATIENT TACROLIMUS LEVEL VARIABILITY IN BK VIRUS ASSOCIATED NEPHROPATHY

Introduction: Tacrolimus is a potent immunosuppressive drug but has a narrow therapeutic window with considerable intra-patient variability (IPV) in its pharmacokinetics. Tacrolimus IPV is related to fluctuation of blood concentrations over a period of time and was claimed to be a predictor of inferior outcomes in kidney transplantation. But tacrolimus IPV and BK virus nephropathy (BKVN) correlation is not known. The aim in this study was to analyze whether high tacrolimus IPV (>30%) rates were also a risk factor for BKVN in kidney transplant setting. Materials and Methods: We analyzed patients on tacrolimus+mycophenolate+steroid for kidney transplantation between 2009 and 2019 retrospectively. In this case-control study 22 biopsy proven BKVN patients were compared with 60 normal graft function patients. BKVN group had graft loss during 5 year, while control group had >5year-graft survival. BKVN group patients had graft biopsy because of serum creatinine increase. Patients <18 years-old and graft loss before 5 year were excluded. IPV was calculated as mean absolute deviation (MAD %) with the formula; MAD%= 1/n x100c. 0-1 year IPV, 0-3 year IPV and 0-5 year IPV analyzed. Results: Twenty-two BKVN patients and 60 normal graft function patients were analyzed retrospectively. Mean serum creatinine level was higher in BKVN group as expected (2.24±0.52 vs 0.95±0.17, p=0.002). 0-1 year IPV (37.10±12.2 vs 28.35±11.9, p=0.012), 0-3 year IPV (41.31±16.1 vs 31.43±10.7, p=0.006) and 0-5 year IPV (42.50±14.92 vs 33.02±10.8, p=0.005) were higher in BKVN group (Figure-1). All BKVN patients were with high IPV (>30%) during 3rd and 5th year of transplantation. Conclusion: BKVN is a serious complication of kidney transplantation and high tacrolimus IPV is prominent in this condition. High IPV mainly may be related to drug/dose changes to stop over-immunosuppression. While reducing immunosuppression during BKVN, it must be in kept in mind that instable tacrolimus levels are may be related under-suppression and graft loss after BKVN.54n

Estimation of Abbreviated Mycophenolic Acid Area Under the Concentration- Time Curve during Stable Post-transplant Period by Limited Sampling Strategy.

The Area Under the Concentration-time curve (AUC) of Mycophenolic Acid (MPA), is a valid prognosticator of the risk of rejection and the gold standard in its Therapeutic Drug Monitoring (TDM), over time post-transplantation. This study aimed to investigate MPA pharmacokinetic parameters and develop a Limited Sampling Strategy (LSS) to estimate an abbreviated MPA AUC, in the stable phase post-renal transplantation. In this study, 19 patients with normal graft function (glomerular filtration rate >70 ml/min) who fulfilled the inclusion and exclusion criteria were involved. Blood samples at various times were taken in the stable phase after transplantation. MPA plasma concentration was measured by reverse-phase high-performance liquid chromatography. MPA AUC0-12h was calculated using the linear trapezoidal rule. Multiple stepwise regression analysis was used to determine the minimal time points of MPA levels that could be used to yield model equations best fitted to MPA AUC 0-12h. The findings of this study were compared with the results of our previous study, which was done similarly in the early phase post-renal transplantation. The results demonstrated that the MPA-AUC and clearance were not affected over time, but MPA-tmax was significantly lower in the stable phase in comparison with the early phase (P=0.001). The best regression equation for AUC estimation in the stable phase was AUC=9.57*C6+27.238 (r2=0.907). The validation of the method was performed using the jackknife method. The mean prediction error of these models was not different from zero (P > 0.05) and had a high root mean square prediction error (7.91). In conclusion, the pharmacokinetics of MPA could be affected by time after transplantation, making it essential to develop a limited sampling strategy as an efficacious approach for therapeutic drug monitoring during the stable post-transplant period.

Diffusion Tensor Imaging for Quantitative Assessment of Anterior Cruciate Ligament Injury Grades and Graft.

As the need for quantitative assessment of anterior cruciate ligament (ACL) injuries and ACL graft increases, diffusion tensor imaging (DTI) becomes a more valuable measuring tool. However, DTI changes in differing injury grades of ACL and longitudinal graft remain unclear. To investigate the diagnostic performance of DTI in quantitatively assessing ACL injury severity and the development of ACL grafts within 6 months of surgery. A cohort study. Thirty-five patients diagnosed with grades I-IV ACL injuries and 20 volunteers as controls were recruited. T1 -weighted, T2 -weighted, proton density (PD)-weighted, and DTI at 3.0T MRI. ACL injury grades in arthroscopic images and DTI quantitative data were evaluated from July 2016 to July 2018. Chi-square test, analysis of variance, Spearman correlation analysis, and receiver operator characteristic (ROC) curves. Both fractional anisotropy (FA) (r = -0.898, P < 0.05) and apparent diffusion coefficient (ADC) (r = 0.851, P < 0.05) were significantly correlated with the severity of ACL injuries. The area under the curve (AUC) values for differentiation between low- and high-grade ACL injuries with FA and ADC were 0.973 and 0.963, respectively. Although there were no significant differences in FA (P > 0.05) and ADC (P > 0.05) between grades I and II ACL injuries or in ADC (P > 0.05) between grades III and IV, there were significant differences in FA and ADC between two grades (P < 0.05). There were significant differences in FA (P < 0.05) and ADC (P < 0.05) between normal ACL and 3-month graft postoperation, as well as in ADC values between 3-month and 6-month graft postoperation (P < 0.05). DTI could be used to quantitatively evaluate the ACL injury grades and the development of ACL grafts. The diagnostic efficiency of FA values was higher than that of ADC values. 1 TECHNICAL EFFICACY: Stage 3.

Immune Tolerance Induction Using Cell-Based Strategies in Liver Transplantation: Clinical Perspectives.

Liver transplantation (LT) has become the best chance and a routine practice for patients with end-stage liver disease and small hepatocellular carcinoma. However, life-long immunosuppressive regimens could lead to many post-LT complications, including cancer recurrence, infections, dysmetabolic syndrome, and renal injury. Impeccable management of immunosuppressive regimens is indispensable to ensure the best long-term prognosis for LT recipients. This is challenging for these patients, who probably have a post-LT graft survival of more than 10 or even 20 years. Approximately 20% of patients after LT could develop spontaneous operational tolerance. They could maintain normal graft function and histology without any immunosuppressive regimens. Operational tolerance after transplantation has been an attractive and ultimate goal in transplant immunology. The liver, as an immunoregulatory organ, generates an immune hyporesponsive microenvironment under physiological conditions. In this regard, LT recipients may be ideal candidates for studies focusing on operative tolerance. Cell-based strategies are one of the most promising methods for immune tolerance induction, including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory T cells, regulatory dendritic cells, regulatory macrophages, regulatory B cells, and mesenchymal stromal cells. The safety and the efficacy of many cell products have been evaluated by prospective clinical trials. In this review, we will summarize the latest perspectives on the clinical application of cell-based strategies in LT and will address a number of concerns and future directions regarding these cell products.

Reduced Flow in Delayed Graft Function as Assessed by IVIM Is Associated With Time to Recovery Following Kidney Transplantation.

Delayed graft function (DGF), defined as the need for dialysis in the first week after kidney transplantation, frequently complicates posttransplantation care. The most common cause of DGF is ischemia-reperfusion injury (IRI). To date, no clinical tools can accurately estimate its severity, nor the time required for recovery of kidney function. To investigate if parameters related to directed flow and diffusion of water, as determined by intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI), could be used to differentiate DGF from normal graft function posttransplantation, predict time to recovery from DGF, and hence serve as a surrogate measure of IRI severity. Prospective, cross-sectional cohort study. Fifty consecutive kidney transplant recipients within 3-10 days posttransplantation at our hospital. 3.0T/IVIM-DWI. The following IVIM-DWI parameters were studied: flow-fraction (f), apparent diffusion coefficient (ADC), and total-ADC (ADCT ). Mean intrarenal resistive index (R.I.) from Doppler ultrasound was also included for a comparison of IVIM-DWI with the clinical standard of care. Welch's t-test, Spearman's correlation, and linear regression. f was significantly reduced in DGF compared to non-DGF patients in the cortex, medulla, and whole renal parenchyma (P < 0.05). Time to recovery with respect to MRI correlated negatively with f (P < 0.05; rho = -0.52 (cortex), and -0.65 [parenchyma]), ADC (P < 0.05; rho = -0.59 [cortex], 0.59 [medulla], and -0.59 [parenchyma]) and ADCT (P < 0.05; rho = -0.54 [cortex], and -0.52 [medulla]). Whole renal parenchymal f predicted time to recovery relative to MRI (P < 0.05, adjusted r-squared = 0.36). R.I. was significantly different between the groups but did not correlate with time to recovery with respect to MRI (rho = 0.43, P = 0.096). Quantification of renal flow using IVIM-DWI has the potential to serve as a surrogate measure of IRI severity to estimate the degree of and recovery from DGF. 2 TECHNICAL EFFICACY STAGE: 3.

Feasibility of Dual Living Donor Liver Transplantation From Donors With Complex Portal Vein Variations

Living donor liver transplantation (LDLT) from donors with complex portal vein anomalies has been considered a challenging procedure because vasculobiliary variations of the donor’s liver may lead to significant increases in donor and recipient complications. The use of donors with anatomic variations may be considered under the accurate preoperative planning if a more suitable donor is not available. We report a successful dual LDLT for 2 donors with portal vein anomaly to overcome the small-for-size graft syndrome and secure donor safety. A 62-year-old man was referred to our institution for liver transplant because of hepatitis B–related liver cirrhosis with hepatocellular carcinoma. The only available donors were his son and his daughter-in-law, one with type IV portal venous anatomic variation and the other with type III variation. Neither of the 2 available donors were suitable as a single donor because of the complexity of the portal vein reconstruction and the donor’s safety. Therefore, the decision was made to perform LDLT using dual graft, and we planned to harvest the right posterior sector graph from the first donor together with the left lobe graft of the second donor. Donor hepatectomy and recipient total hepatectomy were performed in the usual manner. He has recovered well with normal graft function, and there has been no tumor recurrence after dual LDLT. Dual graft LDLT using right posterior sector and left lobe graft could be undertaken successfully to overcome the small-for-size graft syndrome and secure the safety of donors in cases with the complex portal vein anomalies.

IL-17a exacerbates hepatic ischemia-reperfusion injury in fatty liver by promoting neutrophil infiltration and mitochondria-driven apoptosis.

Hepatic ischemia-reperfusion (IR) injury is a critical issue during liver transplantation (LT). Recent studies have demonstrated that IL-17a contributes to IR injury and steatohepatitis. However, the underlying mechanism is not understood. This study aimed to examine the role of IL-17a on hepatic IR injury in fatty liver and to investigate the underlying mechanisms. The correlation between serum IL-17a levels and liver function was analyzed in LT patients receiving fatty (n=42) and normal grafts (n=44). Rat LT model was applied to validate the clinical findings. IL-17a knockout (KO) and wild-type mice were fed with high-fat diets to induce fatty liver and subjected to hepatic IR injury with major hepatectomy. Frequency of circulating neutrophils and IL-17a expression on PBMCs were analyzed by flow cytometry. Mitochondrial outer membrane permeabilization (MOMP) was examined by a living intravital image system. Serum IL-17a was elevated after human LT, especially with fatty grafts. The aspartate aminotransferase and alanine transaminase levels were increased in recipients with fatty grafts compared with normal grafts. In rat LT model, the intragraft IL-17a expression was significantly higher in fatty grafts than normal ones post-LT. KO of IL-17a in mice notably attenuated liver damage after IR injury in fatty liver, characterized by better-preserved liver architecture, improved liver function, and reduced neutrophil infiltration. MOMP triggered cell death after hepatic IR injury in a caspase-independent way via IL-17a/NF-κB signaling pathway. KO of IL-17a protected the fatty liver against IR injury through the suppression of neutrophil infiltration and mitochondria-driven apoptosis.