Analysis of T-cell alloantigen response via a direct pathway in kidney transplant recipients with donor-specific antibodies

Donor-specific antibodies (DSAs) are the main cause of graft loss over time. The direct pathway of alloantigen recognition is important in the pathogenesis of acute rejection. Recent studies have suggested that the direct pathway also contributes to the pathogenesis of chronic injury. Nevertheless, there are no reports on T-cell alloantigen response via the direct pathway in kidney recipients with DSAs. We analyzed the T-cell alloantigen response via the direct pathway in kidney recipients with DSAs (DSA+) or without DSAs (DSA−). A mixed lymphocyte reaction assay was implemented to assess the direct pathway response. DSA+ patients showed significantly higher CD8+ and CD4+ T cell responses to donor cells than DSA− patients. Furthermore, proliferating CD4+ T cells showed a marked increase in Th1 and Th17 responses in DSA+ patients than in DSA− patients. In a comparison between anti-donor and third-party responses, the anti-donor CD8+ and CD4+ T cell response was significantly lower than the anti-third-party response. In contrast, the donor-specific hyporesponsiveness was absent in DSA+ patients. Our study demonstrated that DSA+ recipients have a greater potential for developing immune responses against the donor tissues via the direct alloantigen recognition pathway. These data contribute to an understanding of DSAs pathogenicity during kidney transplantation

Characterization of the DIMS system based on astronomical meteor techniques for macroscopic dark matter search

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Laminins affect T cell trafficking and allograft fate

Lymph nodes (LNs) are integral sites for the generation of immune tolerance, migration of CD4+ T cells, and induction of Tregs. Despite the importance of LNs in regulation of inflammatory responses, the LN-specific factors that regulate T cell migration and the precise LN structural domains in which differentiation occurs remain undefined. Using intravital and fluorescent microscopy, we found that alloreactive T cells traffic distinctly into the tolerant LN and colocalize in exclusive regions with alloantigen-presenting cells, a process required for Treg induction. Extracellular matrix proteins, including those of the laminin family, formed regions within the LN that were permissive for colocalization of alloantigen-presenting cells, alloreactive T cells, and Tregs. We identified unique expression patterns of laminin proteins in high endothelial venule basement membranes and the cortical ridge that correlated with alloantigen-specific immunity or immune tolerance. The ratio of laminin α4 to laminin α5 was greater in domains within tolerant LNs, compared with immune LNs, and blocking laminin α4 function or inducing laminin α5 overexpression disrupted T cell and DC localization and transmigration through tolerant LNs. Furthermore, reducing α4 laminin circumvented tolerance induction and induced cardiac allograft inflammation and rejection in murine models. This work identifies laminins as potential targets for immune modulation

Administration of donor splenocytes via the respiratory tract generates CD8α+ regulatory dendritic cells and induces hyporesponsiveness to fully allogeneic cardiac grafts

Background: We previously showed that pretreatment with intratracheal delivery (ITD) of alloantigen induced prolonged cardiac allograft survival and generated regulatory T cells (Tregs) in mice. In this study, we examined the role of splenic dendritic cells (DCs) in the ITD model. Methods: CBA mice were treated with ITD from C57BL/10 splenocytes and 7 days later received transplantation of C57BL/10 hearts. In adoptive transfer studies, splenic DCs from ITD-treated mice were transferred into naive CBA recipients that received C57BL/10 hearts immediately after the transfer. In addition, to determine the role of splenic DCs isolated from ITD-treated mice, the cells were incubated under stimulation with lipopolysaccharide (LPS). Results: ITD-treated CBA recipients had markedly prolonged allograft survival (median survival time [MST], 67 days) while naive recipients rejected allografts acutely (MST, 8 days). In adoptive transfer studies, CBA recipients of the transfer of splenic DCs from ITD-treated mice had prolonged allograft survival (MST, 85 days), while CBA recipients of the transfer of splenic DCs from naive mice did not have prolonged allograft survival (MST, 8 days). In another transfer study, CBA recipients of the transfer of splenic CD8α+ DCs from ITD-treated mice had prolonged allograft survival (MST, 79 days), while those receiving splenic CD8α- DCs from ITD-treated mice did not have prolonged allograft survival (MST, 8 days). In vitro studies showed that ITD-treated splenic DCs produced more IL-10 and less IL-12 than naive splenic DCs under stimulation with LPS. Conclusions: ITD pretreatment induces regulatory DCs, which produce high amounts of IL-10 resulting in the prolongation of graft survival in our model

Long-Term Outcome of Single Institutional Experience with Conservative and Surgical Management for Renal Artery Aneurysm

Background: Spontaneous rupture risk in renal artery aneurysm (RAA) is extremely low. Indication criteria for surgical repair of RAA remain uncertain. Objective: Long-term outcomes of conservative therapy and surgical repair were evaluated. Patients: The study included fifty-eight patients (17 male, 41 female) diagnosed with RAA during the last 21 years. Median age at the time of diagnosis was 62 (19-85) years old, and the median follow-up period was 69 (3-216) months. Methods: The patients were divided into two groups; conservative group (n = 30) who had been followed up with blood pressure control, and treatment group (n = 29), who underwent intervention. Results: Multiple efferent aneurysmal branches were found in seven conservative cases and 16 treatment cases (P = 0.002). The median maximum diameter of aneurysm was lower in conservative group than in the treatment group (15 versus 25 mm, P = 0.005). Two cases in conservative group showed increase in aneurysm size during follow-up. Hypertensive state had been essentially no change in both groups during follow-up. Renal function decreased with age similarly both in conservative and treatment groups. Conclusions: Our conservative management criteria for RAA are justifiable and even too strict. More loose criteria will be pursued in conservative group selection

Regional secondary focal segmental glomerulosclerosis in a transplanted kidney : resolution with treatment of a segmental renal artery stenosis

Background: Conditions associated with high intraglomerular filtration pressure can cause secondary focal segmental glomerulosclerosis (FSGS). Unilateral renal artery stenosis (RAS) or its occlusion results in FSGS-like changes and the nephrotic syndrome in the contralateral kidney due to hyperfiltration. However, it has been rarely reported that stenosis of a renal arterial branch can result in FSGS-like changes in a different portion in the same kidney allograft. Case presentation: A 60-year-old male kidney recipient developed allograft dysfunction after angiotensin II receptor blockade for hypertension 4 months after transplantation. It was proven that one of two arterial branches of the graft was markedly stenotic. Graft dysfunction improved after percutaneous transluminal arterioplasty (PTA), however; the stenosis recurred and massive proteinuria developed 5 months later. Graft biopsy showed ischemic changes in the region fed by the stenotic artery branch and in contrast FSGS-like changes in the region fed by the other branch. His clinicopathological manifestation including massive proteinuria almost normalized after the repeat PTA. Conclusion: Here we report a case of secondary FSGS of a kidney allograft due to severe RAS of a branch of the same kidney, in which clinical and pathological improvement were confirmed after radiological intervention. When moderate to severe proteinuria appear, secondarily developed FSGS as well as primary (recurrent or de novo) FSGS should be taken into account in kidney transplant recipients

Orthotopic kidney transplantation from a living renal donor after interventional therapy for bilateral arteriosclerosis obliterans of the iliac arteries: A case report and literature review

Introduction Orthotopic kidney transplantation is an option when heterotopic kidney transplantation into the iliac fossa is inappropriate. We report a case of orthotopic kidney transplantation following stenting of both external iliac arteries to treat arteriosclerosis obliterans. Case presentation A 56‐year‐old woman on hemodialysis for end‐stage kidney disease underwent living‐donor kidney transplantation. Desensitization therapy was administered because of her history of sensitization by pregnancy. Stents had been placed previously in both external iliac arteries. The left kidney was removed via an oblique lumbar incision. The two graft arteries were conjoined and anastomosed to the native renal artery end‐to‐end. The urinary tract was reconstructed by uretero‐ureterostomy with ureteral stent placement. Renal function improved promptly after surgery. Conclusion Preoperative imaging of vascular anatomy is important for successful orthotopic kidney transplantation in patients who have previously undergone stenting of both external iliac arteries for arteriosclerosis obliterans

Risk Factors for Lower Urinary Tract Dysfunction and Symptoms After Successful Renal Transplantation

BACKGROUND: We investigated risk factors for lower urinary tract (LUT) dysfunction and LUT symptoms in patients who successfully underwent renal transplantation (RTX). MATERIAL AND METHODS: Ninety-five patients (54 males and 41 females) undergoing RTX (median age: 45 years old) at Hokkaido University Hospital were included in this study. Uroflowmetry (UFM), postvoid residual urine volume (PVR), and 24-h bladder diaries were performed. We analyzed risk factors for voiding dysfunction, urinary frequency, polyuria, nocturia, and nocturnal polyuria after RTX using logistic regression analysis. RESULTS: End-stage renal disease arose from diabetes mellitus in 18 patients (19%). Pre-transplant dialysis had been carried out in 74 patients. Voiding dysfunction as assessed by UFM and PVR was observed in 24 patients (27%). Based on the 24-h bladder diaries, we identified frequent micturition in 29 patients (35%), polyuria in 44 (54%), nocturia in 30 (37%), and nocturnal polyuria in 46 (56%). A multivariable logistic regression analysis revealed that diabetes mellitus, which may cause autonomic disorders, was a risk factor for voiding dysfunction and nocturnal polyuria. A risk factor for frequent micturition and nocturia was older age at RTX. Being female was a risk factor for polyuria, which suggested that fluid intake in relation to body weight was higher in females. CONCLUSIONS: LUT dysfunction and LUT symptoms were not uncommon in patients who successfully underwent RTX. LUT dysfunction and LUT symptoms need to be considered in patients with risk factors such as diabetes mellitus, older age at RTX, and being female, even after successful RTX

Successful Kidney Transplantation Ameliorates Arterial Stiffness in End-Stage Renal Disease Patients

Purpose: Successful kidney transplantation (KTx) can ameliorate bodily damage caused by end-stage renal disease (ESRD). Arterial stiffness (AS) is one of the critical factors, that shorten the survival of patients due to cardiovascular events. KTx may reduce AS as well; however, this has not been investigated well. We therefore conducted a retrospective study using non-invasive pulse wave velocity (PWV), which is a useful index of aortic damage. Patients and methods: Fifty-eight consecutive kidney recipients (34 men, 24 women) were enrolled in this study. Mean age at transplantation was 40.5±12.3 years and the dialysis period was 73.1±95.8 months. The brachial-ankle PWV was measured preoperatively and six months postoperatively. First, we investigated the relationship between the PWV and the other parameters related to AS. Second, we studied the pre- to post-transplant change in PWV to evaluate the amelioration of AS after successful kidney transplantation. Results: PWV showed significant positive correlations with age, systolic blood pressure (BP), diastolic BP and abdominal aortic calcification index. After successful KTx, PWV significantly decreased. (P < 0.01) In addition, systolic and diastolic BP significantly decreased. (P < 0.01 and P < 0.05, respectively) Conclusion: Successful KTx ameliorates AS in ESRD patients. This might explain the improved cardiovascular prognosis of ESRD patients who undergo kidney transplantation

Development of a Formula to Correct Particle-Enhanced Turbidimetric Inhibition Immunoassay Values so That it More Precisely Reflects High-Performance Liquid Chromatography Values for Mycophenolic Acid

Background: Mycophenolic acid (MPA) concentration measured by homogeneous particle-enhanced turbidimetric inhibition immunoassay (PETINA) may be overestimated due to its cross-reactivity with pharmacologically inactive MPA glucuronide (MPAG), as well as other minor metabolites, accumulated with renal function impairment or co-administered cyclosporine A. In contrast, high-performance liquid chromatography (HPLC) is precise because it can exclude the cross-reactivity. In this study, we assumed HPLC values for MPA (HPLC-MPA) as a reference and aimed to develop a formula correcting PETINA values for MPA (PETINA-MPA) to more precisely reflect HPLC-MPA. Methods: MPA trough concentrations were measured both by HPLC-UV and PETINA in 39 samples issued from 39 solid-organ transplant recipients. MPAG concentrations were also measured using HPLC UV assay. We determined the impacts of renal function and coadministered calcineurin inhibitor on concentrations of MPA and MPAG measured by HPLC. Then, we evaluated the difference between PETINA-MPA and HPLC-MPA. Finally, we develop a formula to reflect HPLC-MPA by using multilinear regression analysis. Results: MPAG concentration was negatively correlated with estimated glomerular filtration rate (eGFR) (R2 = 0.376, P < 0.001), although MPA was not correlated with eGFR. There were no significant differences in MPA or MPAG concentrations per dose between the patients who were co-administered tacrolimus versus cyclosporine A. Finally, we developed the formulas to reflect HPLC-MPA: Formula 1: Estimated MPA concentration = 0.048 + 0.798 × PETINA‐MPA Formula 2: Estimated MPA concentration = - 0.059 + 0.800 × PETINA‐MPA + 0.002 × eGFR However, there was no significant improvement in the coefficient of determination with addition of eGFR in the formula, suggesting that HPLC-MPA can be well predicted by only 1 variable, PETINA-MPA.Conclusions: This study developed a formula so that PETINA-MPA can be corrected to more precisely reflect HPLC-MPA