The Global Longitudinal Strain in Renal Transplant Recipients and Immunosuppressive Regimen.

BACKGROUND: Echocardiographic global longitudinal strain (GLS) has recently been considered as a more effective assessment than the ejection fraction (EF) in detecting subtle changes of left ventricular (LV) systolic function. The aim of the study is to compare GLS in renal transplant recipients (RTrs) with preserved LVEF, depending on the recipient's immunosuppressive regimen. The impaired GLS was considered to be > -18%. METHODS: A total of 84 RTrs were divided into 2 groups depending on immunosuppressive regimen: group 1, which included 32 patients (aged 62.3 ± 7.5) receiving mammalian target of rapamycin inhibitors, and group 2, which included 52 patients (aged 58.9 ± 13.9 treated with calcineurin inhibitors. In all patients, echocardiography was performed, including calculation of GLS, and laboratory and clinical markers of cardiovascular risk were assessed. RESULTS: The frequency of men was significantly higher in group 1 (P = .01). There were no differences between the groups in age, body mass index, frequency of diabetes, hypertension, time of hemodialysis (HD) before kidney transplantation (KTx), time after KTx, concentration of cholesterol and creatinine, echocardiographic linear parameters, and LV mass. The estimated glomerular filtration rate and triglyceride concentration were significantly higher in group 1. The mean value of GLS was similar in both groups (-19.8 [-3.5] vs -18.9 [-3.0]; P = .22). The multivariate logistic regression analysis revealed that duration of HD > 26 months is associated with GLS ≥ -18% (odds ratio 2.95, 95% CI 1.08-7.99, P = .03) CONCLUSIONS: The frequency of impaired GLS in RTr was similar regardless of the type of the immunosuppressive regimen. The impaired GLS was associated with duration of HD before KTx.

Assessment of Global Longitudinal Strain in Patients Receiving Renal Replacement Therapy With Preserved Left Ventricular Ejection Fraction.

BACKGROUND: Patients with chronic kidney disease, including those on renal replacement therapy (RRT), have higher cardiovascular mortality. Global longitudinal strain (GLS) detects subtle changes in the left ventricle (LV) and constitutes a more sensitive predictor of cardiovascular mortality than the LV ejection fraction (LVEF). The aim of this study was to assess the prevalence of impaired GLS among patients on RRT with preserved LVEF. We also aimed to identify the possible clinical factors responsible for GLS impairment. METHODS: A total of 108 patients on RRT with preserved LVEF and no history of cardiac disease were evaluated. We assessed echocardiogram parameters with a calculation of GLS, laboratory parameters, presence of diabetes, hypertension, duration of hemodialysis (HD), and the time after kidney transplantation (KTx). An impaired GLS value was set at ≥-18%. The multivariate stepwise logistic regression analysis was used to identify the factors related to impaired GLS. RESULTS: Among 108 patients aged 58.5 ± 13.5 on RRT with preserved LVEF, 45% had GLS ≥-18% (62% on HD, 39% after KTx). The ROC analysis revealed that the cutoff point for the predicted GLS ≥-18% by HD duration was more than 28 months (0.75 [95% CI 0.66-0.84]; P < .001). In multivariate stepwise logistic regression analysis, a duration of HD longer than 28 months was associated with GLS ≥-18%. CONCLUSIONS: About 45% patients on RRT, despite preserved LVEF and no history of heart diseases, had LV systolic dysfunction defined as GLS ≥-18%. HD longer than 28 months significantly increases the risk of GLS impairment in patients on RRT.

Post-transplant lymphoproliferative disorder in adult renal transplant recipients: case series and review of literature.

Post-transplant lymphoproliferative disorder (PTLD) is serious life-threating complication of transplantation. The clinical picture differs from lymphomas observed in the general population, with different manifestation, histopathology, higher aggressiveness with involvement of sites beyond the primary lymph node, and poorer outcome. The objective of the study was to present nine cases of PTLD observed in our centre among the kidney transplant recipient population and discuss the results with up-to-date literature. We performed a retrospective single-centre assessment of PTLD incidence in the cohorts of kidney transplant recipients followed by our centre. We found nine cases of PTLD, five men and four woman, aged from 26 to 67 years at the time of diagnosis (mean [SD] 48 [5] years), transplanted between 1997 and 2013. The disease was diagnosed between 2002 and 2017, from 6 to 440 months after transplantation (mean [SD] 96 [137] months). A diffuse large B-cell lymphoma was found in seven cases early as well as late after transplantation, and two patients presented T-cell lymphoma. Five patients achieved complete remission with no relapses after 6 to 13 months of treatment. In three cases the remission was achieved by switching to mammalian target of rapamycin inhibitors (mTORi) only. Four recipients died from 2 weeks to 15 months after PTLD was diagnosed. Although the diagnostic criteria of different forms of PTLD are commonly known, rapid and correct diagnosis is not easy. PTLD is a relatively a rare disease, so there are too few studies and little consensus on the optimal treatment.

Aortic root dilation in kidney transplant recipients.

INTRODUCTION Aortic root (AoR) dilation is associated with cardiac damage and higher cardiovascular risk. Cardiovascular disease is the most common cause of death in patients after kidney transplantation (KTx ). OBJECTIVES The aim of this study was to assess the prevalence of enlarged AoR diameter in KTx recipients. Patients with bicuspid aortic valve, significant valvular disease, or evidence of connective tissue disorder were excluded. PATIENTS AND METHODS A total of 87 KTx recipients were divided into 2 groups depending on immunosuppressive regimen: 41 patients receiving mammalian target of rapamycin inhibitors (mTORi) and 46 patients treated with calcineurin inhibitors (CNIs). In all patients, echocardiography was performed, laboratory and clinical markers of cardiovascular risk were assessed, and the AoR diameter was calculated. RESULTS There were no differences between groups in age, sex, body surface area, body mass index, frequency of diabetes, hypertension, dyslipidemia, time after replacement therapy, creatinine levels, and estimated glomerular filtration rate. In the CNI group, the observed and calculated AoR diameters were similar (P = 0.8). In the mTORi group, the observed AoR diameter was higher than the calculated one (P = 0.002). The concentric and eccentric left ventricular hypertrophy was similar in both groups (P = 0.12 and P = 0.69, respectively). In the stepwise regression analysis, the AoR diameter was associated with body surface area and mTORi treatment. CONCLUSIONS KTx recipients have a high prevalence of AoR dilation. Immunosuppressive regimen based on mTORi increases the incidence of AoR enlargement.

Immunoregulatory role of B lymphocytes in alloresponse to kidney transplant.

B cells are a group of diverse phenotype and function subsets, which can both stimulate and inhibit the immune response to an allograft. They participate in the rejection process by influencing differentiation, proliferation and effector functions of T lymphocytes. B cells injure the graft via the ADCC (antibody-dependent cellular cytotoxicity) reaction and humoral rejection through plasmocyte production of donor-specific antibodies. A converse, suppressive mode of B cells can attribute to the development of tolerance and protect the graft from rejection. This function is provided by the regulatory B cells, which negatively control the immune response by producing suppressor cytokines (IL-10, IL-35, TGF-ß), natural antibodies and through cellular interactions. In effect they inhibit the development of Th1 and Th17 effector cells, and induce differentiation of regulatory T cells. Operational immune tolerance in human kidney transplant recipients was associated with increased number of naïve and transitional B cells of regulatory function, and increased gene expression for differentiation of B cells. However, in chronic alloantibody transplant rejection the distorted distribution and function of regulatory B cells was found, which implies their pivotal role in graft tolerance. Currently, the immunosuppressive regimens unselectively inhibit the activity of T and B cells, by interfering with their effector and immunoregulatory functions. They do not fully control the chronic rejection reaction, which is the major cause of graft loss. Comprehension of the mechanisms of immunologic homeostasis dependent on B cells can help develop immunosuppressive protocols targeted at tolerance.

Immune activation- and regulation-related patterns in stable hand transplant recipients.

We assessed cell subsets and expression of a set of genes related to the T-cell populations in peripheral blood mononuclear cells to elucidate whether immune status of stable hand transplant recipients (HTx) differs from stable kidney transplant recipients (KTx). The study was conducted on five HTx 4.8 ± 1.7 years after transplantation and 30 stable KTx 7.9 ± 2.4 years after transplantation as well as 18 healthy volunteers. The research involved PBMC gene expression analysis of CD4, CD8, CTLA4, GZMB, FOXP3, IL10, IL4, ILR2A, NOTCH, PDCD1, PRF1, TGF-B, and TNF-A genes on a custom-designed low-density array (TaqMan) as well as flow cytometry assessment of lymphocyte subpopulations. HTx presented significantly increased expression of immunomodulatory genes (TNF, IL10, GITR, and PDCD1) compared to KTx and controls. HTx revealed a proinflammatory molecular pattern with higher expression of NOTCH and CD8 compared to KTx and controls. KTx showed a reduced level of regulatory T cells compared to controls and HTx. Both HTx and KTx presented an increased number of CD8+ and CD8+ CD28- T cells compared to controls. Stable hand transplant recipients exhibit persistent immune activation with rejection-related gene expression pattern counterbalanced by secondary induction of regulatory mechanisms.

The influence of warm ischemia elimination on kidney injury during transplantation - clinical and molecular study.

Kidney surface cooling was used during implantation to assess the effect of warm ischemia elimination on allograft function, histological changes and immune-related gene expression. 23 recipients were randomly assigned to a group operated on with kidney surface cooling during implantation (ice bag technique, IBT group), and the other 23 recipients receiving the contralateral kidney from the same donor were operated on with a standard technique. Three consecutive kidney core biopsies were obtained during the transplantation procedure: after organ recovery, after cold ischemia and after reperfusion. Gene expression levels were determined using low-density arrays (Format 32, TaqMan). The IBT group showed a significantly lower rate of detrimental events (delayed graft function and/or acute rejection, p = 0.015) as well as higher glomerular filtration rate on day 14 (p = 0.026). A greater decrease of MMP9 and LCN2 gene expression was seen in the IBT group during total ischemia (p = 0.003 and p = 0.018). Elimination of second warm ischemia reduced the number of detrimental events after kidney transplantation, and thus had influence on the short-term but not long-term allograft function. Surface cooling of the kidney during vascular anastomosis may reduce some detrimental effects of immune activation resulting from both brain death and ischemia-reperfusion injury.

Urological complications after renal transplantation - a single centre experience.

INTRODUCTION: Urological complications after renal transplantation occur in between 2.5% and 30% of all graft recipients. The aim of the study was to present 7 years of experience in urological treatment of patients with a transplanted kidney. We aimed to identify retrospectively late urological complications in renal transplant recipients at a single center and analyze the treatment modalities and their outcome. MATERIAL AND METHODS: Between January 2008 and December 2014, a total of 58 patients after KTX were treated in the Department of Urology because of post-transplant urological complications that occurred during follow-up at the Transplant Outpatient Department. Retrieved data were analysed in retrospectively. RESULTS: In the group of 38 patients with ureteral stenosis (Clavien grade III), 29 patients underwent endoscopy, 8 open surgical procedures and one both endoscopic and open operation. Ten patients were admitted with symptomatic lymphocoele (Clavien III), of which 9 were successfully treated with drainage and one with surgical marsupialization. Because of urolithiasis in the grafted kidney (Clavien grade III), 4 patients were treated with ureterorenoscopic lithotripsy (URSL) and one only with the extracorporeal shock wave lithotripsy (ESWL) procedure. Five urethral strictures plasties and one graftectomy because of purulent pyelonephritis were also conducted. The average age in the group of recipients who experienced urologic complications was similar (46.1 vs. 47.8) to those without complications. There was no vesicoureteral reflux or ureteral necrosis requiring surgical intervention, no graft loss and death related to urological complication and treatment. CONCLUSIONS: Most complications could be successfully treated with endourological procedures. The kidney function improved in the majority of patients.

Pretransplant Immune- and Apoptosis-Related Gene Expression Is Associated with Kidney Allograft Function.

Renal transplant candidates present immune dysregulation, caused by chronic uremia. The aim of the study was to investigate whether pretransplant peripheral blood gene expression of immune factors affects clinical outcome of renal allograft recipients. Methods. In a prospective study, we analyzed pretransplant peripheral blood gene expression in87 renal transplant candidates with real-time PCR on custom-designed low density arrays (TaqMan). Results. Immediate posttransplant graft function (14-day GFR) was influenced negatively by TGFB1 (P = 0.039) and positively by IL-2 gene expression (P = 0.040). Pretransplant blood mRNA expression of apoptosis-related genes (CASP3, FAS, and IL-18) and Th1-derived cytokine gene IFNG correlated positively with short- (6-month GFR CASP3: P = 0.027, FAS: P = 0.021, and IFNG: P = 0.029) and long-term graft function (24-month GFR CASP3: P = 0.003, FAS: P = 0.033, IL-18: P = 0.044, and IFNG: P = 0.04). Conclusion. Lowered pretransplant Th1-derived cytokine and apoptosis-related gene expressions were a hallmark of subsequent worse kidney function but not of acute rejection rate. The pretransplant IFNG and CASP3 and FAS and IL-18 genes' expression in the recipients' peripheral blood is the possible candidate for novel biomarker of short- and long-term allograft function.

Beneficial effect of bilateral native nephrectomy as complete denervation on left ventricular mass and function in renal transplant recipients.

INTRODUCTION: Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular morbidity and mortality in renal transplant recipients. The development of LVH is connected with excessive activation of the sympathetic nervous system. A bilateral nephrectomy is an example of complete renal denervation. OBJECTIVES: The aim of this study was to evaluate the effect of pretransplant bilateral native nephrectomy on left ventricular mass and function during a long-term follow-up of patients after kidney transplantation. PATIENTS AND METHODS: The study group consisted of 32 renal transplant recipients who had previously undergone pretransplant bilateral native nephrectomy. The control group involved 32 recipients with preserved native kidneys, matched for age, sex, creatinine levels, estimated glomerular filtration rate, immunosuppressive treatment, and the time of renal replacement therapy. All patients were evaluated by echocardiography, and 16 patients--by cardiac magnetic resonance (CMR). In addition, all patients had their arterial blood pressure (BP) and metabolic markers measured. RESULTS: In comparison with controls, the study group had lower systolic BP (P = 0.048) and received a lower number of antihypertensive agents (P = 0.001). Lipid and hemoglobin levels were similar in both groups. The study group had a lower left ventricular mass index (LVMI; P = 0.001) and left atrial volume index (LAVI; P = 0.004). The left ventricular mass evaluated by CMR was also lower in the study group (P <0.001). Mild left ventricular diastolic dysfunction (LVDD) was more frequent in the study group compared with the control group ( P <0.001). CONCLUSIONS: In a long-term follow-up of patients after kidney transplantation, the bilateral native nephrectomy before transplantation was associated with a lower LVMI and LAVI as well as a lower grade of LVDD. These patients had lower systolic BP and used fewer antihypertensive drugs.

Transplantology: Challenges for Today.

Clinical transplantology in Poland had its 50th anniversary this year. With the early and long results comparable to the best achieved in the world leading centers, we face old and completely new challenges for this medical speciality. Main and growing challenge is insufficient number of available organs. With less than 15 donors/mln population/year Poland stay in the lower row of European countries in this measurement of transplant activity. Donation system is not efficient enough and we lose a big number of potential donors still. Living donation (with the exception for the fragments of the liver) remains low despite of different initiatives made so far on the national and local levels. Donation after cardiac death is possible from the point of Polish juridical regulations, but since last 3 years had not showed real impact on country donation rates (only three procedures done). Methods of tissue typing remain slow and cause relatively long times of cold ischemia for kidney programs. Second main challenge is chronic rejection causing loss of organs in the long-term follow-up and no efficient treatment employed. The emerging possibility of tolerance induction despite of plenty of new protocols proposition in the publications does not show up a clinical everyday practice in work. The same is with xenotransplantation promises; even we were informed recently that till 2030 such genetically modified porcine organs will be available. The next challenge is production of organs and tissues from own recipients cells installed on the different scaffolds or 3D printed. Other challenge is the personnel working in this field. We observe like in the other European countries lack of new candidates for work in this field together with serious problems of nursing staff, being a catastrophic perspective in country medical service in general, not only in transplant centers. The last but not least challenge is financial side of transplant programs.

Increased Numbers of 6-sulfo LacNAc (slan) Dendritic Cells in Hand Transplant Recipients.

BACKGROUND: Vascularized composite allotransplantation (VCA) is a modern option for the treatment of functionally significant limb and tissue defects. In our study we aimed to characterize the morphological and histological features of the hand transplant recipient skin rejection. MATERIAL AND METHODS: We clinically evaluated the skin and mucous membranes and microscopically assessed biopsies taken from the patient's own skin and from the allogenic grafted limb (n=5). We also performed immunohistochemistry for presence of T lymphocytes (CD3, CD4, and CD8), B lymphocytes (CD20), macrophages (CD68), Langerhans cells (CD1a+), plasmacytoid dendritic cells (pDCs) (CD123+) and 6-sulfo LacNAc+ dendritic cells (slanDCs) (DD2+). RESULTS: Only scattered pDCs were present in both own and skin grafts. The number of LC in the epidermis was higher in graft skin in all cases and CD1a+ cells were also present in the dermis in transplanted skin in patients with grade 1 rejection. Most interestingly, we identified far increased numbers of dermal slanDCs in the grafted skin. SlanDCs have a high capacity to produce proinflammatory cytokines and have been described as inflammatory dermal dendritic cells in psoriasis and lupus erythematosus. CONCLUSIONS: It may be hypothesized that slanDCs identified in the skin after limb transplantation may support the local inflammatory skin reaction.

Type of Renal Replacement Therapy (Hemodialysis versus Peritoneal Dialysis) Does Not Affect Cytokine Gene Expression or Clinical Parameters of Renal Transplant Candidates.

UNLABELLED: Patients with renal failure suffer from immune disturbances, caused by uremic toxins and influenced by dialysis treatment. The aim of the present study was to reveal whether type of dialysis modality (hemodialysis, HD, versus peritoneal dialysis, PD) differentially affects the immunocompetence, particularly the expression of genes involved in the immune response. MATERIAL: 87 renal transplant candidates (66 HD, 21 PD) were included in the study. METHODS: The peripheral blood RNA samples were obtained with the PAXgene Blood system just before transplantation. The gene expression of CASP3, FAS, TP53, FOXP3, IFNG, IL2, IL6, IL8, IL10, IL17, IL18, LCN2, TGFB1, and TNF was assessed with real-time PCR on custom-designed low density arrays (TaqMan). Gene expression data were analyzed in relation to pretransplant clinical parameters. RESULTS: The mean expression of examined genes showed no significant differences between PD and HD with the exception of FAS, expression of which was 30% higher in PD patients compared to the HD group. There was nonsignificantly higher expression of proinflammatory cytokines in the PD group. The clinical inflammatory parameters (CRP, albumin, cholesterol, and hemoglobin levels) did not differ between the groups. CONCLUSION: Type of renal replacement therapy exerts no differential effect on cytokine gene expression or inflammatory clinical parameters.

Assessment of vascular function of hand allografts.

BACKGROUND: Insufficiency of blood vessels supplying a limb allograft may lead to loss of the extremity. Thus, a regular evaluation of perfusion of transplants seems a reasonable approach. The purpose of the present study was assessment of allograft perfusion by means of non-invasive methods. MATERIAL/METHODS: Six hand allografts transplanted in 5 patients were included in the study group. The transplant procedure occurred on average 45 months before. The study group comprised 2 allografts at forearm level, 2 transplants of the arm, and 1 bilateral transplant of the forearm. Parameters of blood flow using Doppler ultrasonography, impedance plethysmography, Doppler measurement of segmental pressures, optical pulse oscillography (OPO), and thermography were performed in all participants. RESULTS: DUS revealed increased resistive index in ulnar arteries of transplant hands compared to native hands and an altered blood supply was confirmed by IP. Flow-mediated dilatation within the transplanted extremity was abnormal in most patients and was inversely correlated with number of episodes of acute rejection. Analysis of oscillographic spectrum revealed flattening of the dicrotic notch in transplant hands. A tendency for lower temperature of the skin of transplanted hands compared to native extremities was also observed. CONCLUSIONS: In asymptomatic patients after limb transplantation, non-invasive methods disclosed discreet abnormalities of graft perfusion. Thus, regular measurement of perfusion parameters using these methods appears to be a promising approach to detect early and potentially reversible disturbances of blood supply. Further observational studies are required to determine its clinical significance.

The influence of non-HLA antibodies directed against angiotensin II type 1 receptor (AT1R) on early renal transplant outcomes.

Non-HLA antibodies (Abs) targeting vascular receptors are thought to have an impact on renal transplant injury. Anti-angiotensin II type 1-receptor-activating antibodies (anti-AT1R) have been mentioned to stimulate a severe vascular rejection, but the pretransplant screening has not been introduced yet. The aim of our study was to assess the incidence and importance of anti-AT1R antibodies and their influence on renal transplant in the 1st year of observation. We prospectively evaluated the presence of anti-AT1R antibodies in 117 consecutive renal transplant recipients in pre- and post-transplant screening. Anti-AT1R antibodies were observed in 27/117 (23%) of the analyzed recipients already before transplantation. The function of renal transplant was considerably worse in anti-AT1R(+) group. The patients with anti-AT1R Abs >9 U/ml lost their graft more often. Biopsy-proven AR was described in 4/27 (15%) pts in the anti-AT1R(+) group and 13/90 (14.4%) in the anti-AT1R(-) group, but more severe cases of Banff IIB or antibody-mediated rejection (AMR) were more often observed in anti-AT1R (+) 4/27 (15%) vs. 1/90 (1.1%) in anti-AT1R(+) (P = 0.009). Patients with anti-AT1R Abs level >9 U/ml run a higher risk of graft failure independently of classical immunological risk factors. The recipients with anti-AT1R Abs developed more severe acute rejections described as IIB or AMR in Banff classification. More recipients among the anti-AT1R-positive ones lost the graft. Our study suggests monitoring of anti-AT1R Abs before renal transplantation for assessment of immunologic risk profiles and the identification of patients highly susceptible to immunologic events, graft failure, and graft loss.

Humoral immunity in hand transplantation: anti-HLA and non-HLA response.

UNLABELLED: Antibodies against donor's HLA antigens and B cell activity are recognized modulators of immune response to allograft. The role of both anti-HLA and non-HLA antibodies is understood in solid organ transplantation, but has not been addressed in composite tissue allografts. AIM: We decided to evaluate the presence and role of anti-HLA and non-HLA antibodies after hand transplantation. METHODS: We assayed anti-HLA and non-HLA antibodies in 5 consecutive hand transplant patients. The presence of anti-HLA antibodies was tested by flow-PRA method (One Lambda). Non-HLA antibodies were defined as anti-endothelial cell (AECA), anti-angiotensin II type 1 receptor (anti-AT1R), anti-endothelin receptor antibodies (anti-ETAR). RESULTS: Anti-HLA antibodies were present in 1 patient in class I and in another one in class II. Both patients developed one episode of acute rejection. AECA were present in only one recipient with borderline activity. Both anti-AT1R and Anti-ETAR were found strongly positive in one patient who repeatedly developed acute rejection episodes. CONCLUSION: The presence of non-HLA antibodies (anti-AT1R and anti-ETAR) and the occurrence of multiple rejection episodes found in one patient here require further investigation into a possible association and role of humoral immunity in composite tissue rejection.

Catatonic episode after kidney transplantation.

There is a growing body of case reports of catatonic symptoms after organ transplantations. A considerable number of these cases might be attributed to neurotoxicity induced by immunosuppressive medications. However, the etiology of other cases remains unclear. We present the case of a 21-year-old woman who developed catatonia after kidney transplantation from a deceased donor. In this case, nontoxic tacrolimus levels were found, and other causal factors including infections, uremia or transplant rejection were excluded. Electroconvulsive therapy followed by olanzapine proved to be effective treatment.