Strong Absorption of Hadrons with Hidden and Open Strangeness in Nuclear Matter.

We present the first observation of K^{-} and ϕ absorption within nuclear matter by means of π^{-}-induced reactions on C and W targets at an incident beam momentum of 1.7 GeV/c studied with HADES at SIS18/GSI. The double ratio (K^{-}/K^{+})_{W}/(K^{-}/K^{+})_{C} is found to be 0.319±0.009(stat)_{-0.012}^{+0.014}(syst) indicating a larger absorption of K^{-} in heavier targets as compared to lighter ones. The measured ϕ/K^{-} ratios in π^{-}+C and π^{-}+W reactions within the HADES acceptance are found to be equal to 0.55±0.04(stat)_{-0.07}^{+0.06}(syst) and to 0.63±0.06(stat)_{-0.11}^{+0.11}(syst), respectively. The similar ratios measured in the two different reactions demonstrate for the first time experimentally that the dynamics of the ϕ meson in nuclear medium is strongly coupled to the K^{-} dynamics. The large difference in the ϕ production off C and W nuclei is discussed in terms of a strong ϕN in-medium coupling. These results are relevant for the description of heavy-ion collisions and the structure of neutron stars.

Pretransplant Immune Interplay Between Donor and Recipient Influences Posttransplant Kidney Allograft Function.

BACKGROUND: Renal transplant candidates present immune dysregulation caused by chronic uremia, and deceased kidney donors present immune activation induced by brain death. Pretransplant donor and recipient immune-related gene expression were examined in the search for novel predictive biomarkers crosslinking recipient and donor pretransplant immune status with transplant outcome. MATERIALS AND METHODS: This study included 33 low-risk consecutive renal transplant recipients and matched deceased donors. The expression of 29 genes linked to tissue injury, T-cell activation, cell migration, and apoptosis were assessed in postreperfusion kidney biopsies, as well as 14 genes in pretransplant peripheral blood of the kidney recipients. Gene expression was analyzed with real-time polymerase chain reaction on custom-designed low-density arrays. RESULTS: Donor MMP9 expression was related to delayed graft function occurrence (P = .036) and short term kidney allograft function (14th day rs = -0.44, P = .012; 1st month rs = -0.46, P = .013). Donor TGFB1 expression was associated with short- and long-term graft function (14th day rs = -0.47, P = .007; 3rd month rs = -0.63, P = .001; 6th month rs = -0.52, P = .010; 12th month rs = -0.45, P = .028; 24th month rs = -0.64, P = .003). Donor TGFB1 expression was not related to donor age (rs = 0.32, P = .081), which was also an independent factor influencing the outcome. Recipient gene expression was not related to graft function but determined the acute rejection risk. Recipient IFNG and, to a lesser extent, IL18 expression were protective against acute rejection (area under the curve [AUC] 0.84, P < .001, and AUC 0.79, P < .001, respectively). CONCLUSION: Kidney transplant outcome depends on the interplay between donor-related immune factors, which mostly affect allograft function and recipient immune milieu, influencing an alloreactive response.

Functional Activity of the Complement System in Deceased Donors in Relation to Kidney Allograft Outcome.

Complement activation is considered one of the mediators of renal ischemia-reperfusion injury. Elevated levels of C5b-9, C3a, and C5a are detected in sera of deceased kidney donors. The goal of the study was to characterize the functional activity of complement pathways in donor sera and to assess their influence on transplant outcome. MATERIALS AND METHODS: Sixty-four deceased kidney donors (age 45 ± 16 years; 28 female, 36 male) and 27 healthy controls (age 42 ± 12 years; 14 female, 13 male) were enrolled in the study. The results of transplantation for the respective 122 kidney recipients were included in the analysis. The functional activities of classical (CP), lectin (LP), and alternative (AP) pathways were measured using Wielisa-kit (reference normal level = 100%). In most cases, decreased functional activity reflects the activation status of the pathway. RESULTS: The median (interquartile range) functional activities of the pathways in donor sera were CP 118 (89-150)%, LP 80 (20-127)%, and AP 74 (50-89)%, and did not differ from the control values CP 110 (102-115)%, LP 81 (26-106)%, AP 76 (61-88)%. The frequency of pathway activation observed in controls was CP 0%, LP 11%, and AP 0%. Deceased donors did not differ in activation of classical (11%) and lectin (13%) pathways, but presented a higher rate of alternative pathway activation (19%, P = .03). No significant influence of any pathway functional activity or its activation was proved to influence the transplant outcome. CONCLUSION: Complement activation via alternative pathway was observed in diseased donor sera. No predictive potential of donor complement functional activity on the transplant outcome could be proved.

Kidney Transplantation From Old Deceased Donors: Impact of Uric Acid Level-A Quarter-Century of Experience in One Transplant Center.

BACKGROUND: The long-term burden of higher donor age on graft function and survival after kidney transplantation remains uncertain. Because both recipient and donor characteristics have evolved and the general population age is on the increase, we looked at the causes of kidney graft outcome. AIM: The aim of this study was to evaluate the impact of different clinical parameters on long-term outcome of older-donor kidney transplantation. This retrospective study included 345 adult patients (58 patients received kidney from donors at least 55 years old) transplanted between January 1993 and December 2005 and were followed in one center throughout the post-transplant course (median, 9.4 years). Data included recipient and donor age, cold ischemia time, delayed graft function, panel reactive antibodies, HLA mismatch, time on dialysis, graft function at different time points, uric acid level, proteinuria, immunosuppression, and biopsy-proven rejection. RESULTS: Improvement of estimated glomerular filtration rate at 36 months after transplantation was a good prognostic factor for long-term kidney function. Higher donor age decreased the chance for improvement of kidney function by 2.8% per year of life (P = .0244). Hyperuricemia was found in 46% of the study population; estimated glomerular filtration rate less than 50 mL/min/1.72 m2 was associated with hyperuricaemia. A higher uric acid level was associated with inferior kidney function in recipient of older kidneys. Graft failure occurred late (median, 6.3 years post-transplantation) in 26 (44.8%) of older-donor recipients and in 87 (30.3%) of the remaining patients. CONCLUSIONS: Our results suggest an important association between older donor age and decreased allograft function in kidney recipients with elevated uric acid level. Recipients of older kidneys with normal uric acid level presented satisfactory outcomes.

Endothelin A Receptors Expressed in Renal Blood Vessels of Renal Transplant Patients Are Connected With Acute Tubular Necrosis or Antibody-Mediated Rejection.

BACKGROUND: The role of non-HLA antibodies named antiendothelin A receptor antibodies is potentially significant but not established. The significance of the endothelin A receptor (ETAR) and its expression in renal biopsy has not been defined. We decided to evaluate the presence and relevance of ETARs in renal transplant biopsy for cause. The aim of our study was to evaluate the immunoreactivity of the ETAR and its significance in patients who had a renal transplant biopsy due to deterioration of transplant function (biopsy for cause) with detailed characterization of staining in small and intermediate arteries of renal transplant biopsies. METHODS: Immunohistochemical expression of ETARs was analyzed in 162 renal transplant biopsies. Microscopic evaluation of ETAR expression (polyclonal antibody) was performed on paraffin sections. ETAR expression was analyzed in renal blood vessels (small and intermediate arteries) based on three-step scale. RESULTS: We analyzed 154 patients who had renal allograft biopsy between 6 days and 24 years (median 597 days) after transplantation. Positive staining of ETAR in small and intermediate arteries was noticed in 9 patients. Among these patients, 4 had early biopsies (<3 months after transplantation), all developed acute tubular necrosis, and 1 developed additionally acute humoral rejection. Further, 4 patients had late biopsy (1-8 years after transplantation) and all developed characteristics of antibody mediated rejection. Lastly, 1 patient had no characteristic changes in the biopsy 4 months after transplantation. Graft loss 1 year after biopsy was higher in patients who were ETAR-positive but statistical significance was not achieved. CONCLUSIONS: The expression of endothelin receptors in renal blood vessels (small and intermediate arteries) seems to be important in diagnosis of damage during acute tubular necrosis and antibody-mediated rejection.

Histopathological Relevance of Angiotensin II Type 1 Receptor in Renal Transplant Biopsy.

The occurrence of anti-angiotensin II type 1 receptor (AT1R) antibodies is thought to be a risk factor for transplant injury, but the relationship of AT1R to graft loss in renal transplantation has not been assessed. The aim of our study was to evaluate the expression of AT1R and its relationship with graft loss in patients who had a renal transplant biopsy for cause. METHODS: AT1R immunoreactivity was analyzed in 170 renal transplant biopsies. Immunohistochemical evaluation of AT1R expression was performed on 4 µm-thick paraffin sections mounted on silanized slides. AT1R expression was analyzed in 5 compartments: 1. glomeruli, 2. renal blood vessels (small and intermediate arteries), 3. peritubular capillaries, 4. tubular epithelium, and 5. interstitium based on a 3-step scale. RESULTS: Initially we checked 170 consecutive samples of biopsies for the immunoreactivity of the AT1R. The study finally included 118 renal transplant patients in 1-year observation after the biopsy. The renal allograft biopsy was performed between 6 days and 24 years after transplantation and the diagnosis was based on Banff criteria. We observed positive immunostaining of AT1R in tubular epithelium in 26.3% (42/118) of patients. A total of 7 patients had staining assessed as 2 and 35 as 1. One year post-biopsy graft loss in the AT1R (+) patients was 35.7 % (15/42) compared to 14.5% (11/76) in the AT1R (-) group (P = .008). CONCLUSIONS: The expression of AT1R in tubular epithelium of the biopsy for cause was associated with significantly higher graft loss. The relevance of AT1R should be considered for better transplant immunological risk assessment.

Issues of Immunological and Hemodynamic Monitoring Before and During Kidney Transplantation in Sensitized Heart Transplant Recipient.

Previously transplanted highly sensitized patients experience problems with subsequent transplantation. It is also difficult to provide optimal hemodynamic conditions during successive kidney transplantation in heart transplant recipients. PATIENT AND METHODS: We present a case of a 56-year old patient with end-stage renal failure after heart transplantation performed 21 years ago and hemodialyzed using arteriovenous fistula. The patient had 69% panel-reactive antibodies, had been on the active waiting list since 2013, and presented 335 positive crossmatches with deceased donors. He also positively crossmatched with a potential living donor. Detailed examination of anti-HLA antibodies revealed the absence of IgG donor-specific antibodies and negative crossmatch with dithiothreitol-treated serum. The transplantation from his wife was performed with positive crossmatch after 4 plasma exchanges and thymoglobulin induction. Because sympathetic and parasympathetic denervation of the transplanted heart and the presence of arteriovenous fistula induced volume overload of the right heart, we used central venous pressure (CVP) and the PiCCO2 for postsurgical assessment of cardiac output. RESULTS: Monitoring, like CVP and other static exponents of preload obtained by PICCO (extravascular lung water, global end-diastolic volume index) as well as the dynamic parameters obtained by PiCCO2 (pulse pressure variation, stroke volume variation), was not sensitive enough to describe recipient volume status. The immediate graft function was observed, and after 11 months satisfactory estimated glomerular filtration rate is noted with the absence of donor-specific antibodies. CONCLUSION: The history of heart transplantation with existing arteriovenous fistula makes clinical tools such as continuous cardiac output monitoring and CVP parameter inadequate for describing the hemodynamic situation. The high level of panel-reactive antibodies and positive crossmatch possibly caused by IgM antibodies do not have to withdraw the recipient from kidney transplantation.

Increased plasma matrix metalloproteinase-2 (MMP-2), tissue inhibitor of proteinase-1 (TIMP-1), TIMP-2, and urine MMP-2 concentrations correlate with proteinuria in renal transplant recipients.

BACKGROUND: The most frequent cause of kidney allograft loss is chronic allograft injury, often with proteinuria as the clinical feature. Occurrence of proteinuria late after kidney transplantation is associated with worse graft function and patient survival. AIM: The aim of the study was to assess plasma and urine matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in proteinuric renal transplant recipients (RTRs). The factors were determined by enzyme-linked immunosorbent assay in 150 RTRs (51 women and 99 men), aged 49.2 ± 11.5 years, at mean 73.4 ± 41.2 months after kidney transplantation (range: 12 to 240 months). RESULTS: Proteinuric RTRs compared with non-proteinuric RTRs had higher median plasma MMP-2 (P = .012), TIMP-1 (P = .0003), and TIMP-2 (P = .0021) concentrations, as well as higher urine MMP-2 (P < .0001) excretion. The presence of proteinuria had no impact on plasma MMP-9 and urine MMP-9, TIMP-1, and TIMP-2. Proteinuria and estimated daily proteinuria (uPr:uCr) correlated positively with plasma MMP-2 (rs = 0.226, P = .0054 and rs = 0.241, P = .003), TIMP-1 (rs = 0.305, P = .00015 and rs = 0.323, P = .000055), TIMP-2 (rs = 0.273, P = .0007 and rs = 0.269, P = .001) and urine MMP-2 (rs = 0.464, P < .0001 and rs = 0.487, P < .0001), respectively. Proteinuric RTRs had impaired graft function with higher median serum creatinine concentrations (1.91 [1.60-2.43] mg/dL versus 1.41 [1.20-1.65] mg/dL, P < .00001) and lower estimated glomerular filtration rate (36 [28-45] mL/min/1.73 m(2) versus 53 [43-61] mL/min/1.73 m(2), P < .00001) than RTRs without proteinuria. CONCLUSIONS: Our research revealed that in RTRs, proteinuria was significantly associated with increased concentrations of enzymes involved in extracellular matrix (ECM) degradation: plasma MMP-2, TIMP-1, TIMP-2, and urine MMP-2. Findings strongly emphasize increased plasma TIMPs in proteinuric RTRs that inhibit degradation of ECM by MMPs and favor excessive deposition of ECM proteins.

Advanced age of renal transplant recipients correlates with increased plasma concentrations of interleukin-6, chemokine ligand 2 (CCL2), and matrix metalloproteinase 2, and urine concentrations of CCL2 and tissue inhibitor of metalloproteinase 1.

BACKGROUND: Advanced age of renal transplant recipients (RTRs) has a negative impact on kidney allograft survival through impaired extracellular matrix degradation by the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) system. Moreover, older RTRs are at risk of smoldering inflammation, known as inflammaging. AIM: The aim of the study was to assess the impact of a RTR's age on plasma and urine concentrations of interleukin 6 (IL-6), chemokine ligand 2 (CCL2), and the MMPs/TIMPs system. MATERIAL AND METHODS: One hundred fifty adult RTRs (8.7% ≥ 65 years) and 37 adult healthy volunteers (10.8% ≥ 65 years) were enrolled in the study. The studied factors (IL-6, CCL2, MMP-2, MMP-9, TIMP-1 and TIMP-2) were quantified in plasma and urine with enzyme-linked immunosorbent assay. The Mann-Whitney U test and Spearman's (rs) rank correlation were applied, and differences with a P < .05 were considered statistically significant. RESULTS: There was a weak but significant positive correlation between increasing RTR's age and plasma IL-6 (rs = 0.18, P = .028), CCL2 (rs = 0.27, P = .001), and MMP-2 (rs = 0.20, P = .017), as well as urine CCL2 (rs = 0.16, P = 0.050) and TIMP-1 (rs = 0.20, P = .014) concentrations. CONCLUSIONS: Advancing age of RTRs correlates with increasing plasma IL-6 and CCL2 concentrations, reflecting smoldering inflammation (known as inflammaging) and alterations in MMPs/TIMPs profiles, especially with increased plasma MMP-2 and urine TIMP-1 concentrations.

Impaired kidney allograft: how long can it function? A single-center study of the transplantation population.

Impaired renal graft function is a matter of particular concern during post-transplantation care because low estimated glomerular filtration rate (eGFR) is a risk factor for graft loss. The aim of the study was to assess risk factors for inferior outcomes of kidney transplantations with low eGFRs. We identified 72 patients who underwent transplantation between 1999 and 2005 who had chronic renal graft dysfunction after 6 months post-transplantation (eGFR < 40 mL/min/1.73 m(2)), received a kidney transplant between 1999 and 2005, and were treated in one center through the entire post-transplantation course. Three patients who were lost for follow up after 6.4, 6.7, and 8.5 years are not included in this analysis. A group of 23 patients (33%) had chronic kidney disease stage 4 (eGFR < 30 mL/min/1.73 m(2)) at 6 months. In 39 patients (56%), delayed graft function was diagnosed. Forty-eight patients (70%) had at least one episode of acute graft rejection. Results were confirmed using biopsy in 39 patients. Eight patients (12%) died and 35 patients (51%) lost their grafts between 1.6 and 14 years (median, 6.3 years). The remaining 26 (38%) patients have still functioning allografts 11 years after transplantation (median). The initial immunosuppression included calcineurin inhibitor (CNI) in all cases. At the end of study, 6 (8.3%) patients received mammalian target of rapamycin inhibitor plus steroids, whereas the remaining were treated with CNIs. Improvement of kidney function by 15% was observed in 23% of the studied population between 6 and 24 months. This satisfactory outcome was a result of the careful follow-up examinations and comprehensive medical care provided by our dedicated staff of nurses and physicians. Improvement of kidney function may reflect a state of immune quiescence in some patients which allows them to sustain a functioning kidney despite injury.

The impact of de novo donor-specific anti-human leukocyte antigen antibodies on 5-year renal transplant outcome.

Numerous studies have shown that circulating donor-specific antibodies targeting human leukocyte antigen (HLA) are associated with accelerated renal transplant failure, but many patients with these antibodies have good graft function. The aim of our study was to investigate the long-term graft function and survival in patients with de novo post-transplant donor-specific anti-HLA antibodies (DSA). Our prospective study included 78 consecutive recipients with a negative crossmatch before transplantation. Recipient serum samples were assayed for DSA in week 2 and 1, 3, 6, 9, 12 months after transplantation using a complement-dependent lymphocytotoxic technique with donor lymphocytes. Additionally, patients with DSA and stable renal function in the first year were tested with a more sensitive flow-panel-reactive antibody. DSA were present in 34 (44%) of our patients during the first 12 months after transplantation. Biopsy-proved acute rejection occurred in 11 DSA-positive and 10 DSA-negative patients. Seven DSA-positive patients had antibody-mediated rejection and no DSA-negative ones developed humoral rejection. The serum creatinine level in DSA-positive patients was significantly higher (2.48 vs 1.43 mg/dL) in year 5. The 13 (38%) DSA-positive patients with good graft function in month 12 were stable during a 5-year follow-up: their serum creatinine was 1.46 ± 0.4 in year 1 and 1.56 ± 0.4 mg/dL in year 5 and nobody lost their allograft. One- and 5- year graft survivals were appropriately 85% and 59% in DSA-positive patients compared to 93% and 93% in DSA-negative patients. To sum up, post-transplant DSA had a significant influence on kidney function and graft survival but in 38% of patients the presence of DSA did not decrease a 5-year renal function. A good renal allograft function in the presence of DSA in the first year after transplantation and cessation of their production in the subsequent years may be a good prognostic marker for a long-term allograft function and survival.

Increased plasma tissue inhibitors of metalloproteinase concentrations as negative predictors associated with deterioration of kidney allograft function upon long-term observation.

Chronic allograft injury (CAI) is the most frequent cause of progressive kidney allograft impairment and eventual loss, which is due to interstitial fibrosis and tubular atrophy (IF/TA). Mechanisms of CAI are not fully understood. Chemokines, cytokines, metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) play roles in fibrosis development. The aims of this study were to evaluate plasma and urine TIMPs (TIMP-1 and TIMP-2), MMPs (MMP-2 and MMP-9), proinflammatory interleukin-6 (IL-6), chemokine (C-C motif) ligand 2 (CCL2 chemokines previously known as monocyte chemoattractant protein-1 [MCP-1]) among 150 recipients beyond 1 year post-renal transplantations and to explore the usefulness of these potential biomarkers of ongoing allograft injury. Renal transplant recipients compared with healthy volunteers (control group) showed significantly increased plasma and urine IL-6, MMP-9, TIMP-1, and TIMP-2, as well as lower plasma MMP-2 and urine CCL2 concentrations. Compared with recipients showing good function those with impairments displayed higher plasma TIMP-1 (P < .001) and TIMP-2 (P = .003) concentrations. The recipient estimated glomerular filtration rate (eGFR) values negatively correlated with plasma TIMP-1 and TIMP-2 levels (r = -0.43; P < .0001 and rs = -0.42; P < .0001, respectively) and with urine IL-6 excretion (rs = -0.33; P < .0001). Multivariate and receiver operating characteristic (ROC) analyses showed TIMP-1 plasma level assessments to be useful estimates of allograft injury.

Duration of brain death and cold ischemia time, but not warm ischemia time, increases expression of genes associated with apoptosis in transplanted kidneys from deceased donors.

Apoptosis is one of the most important mechanisms leading to kidney graft injury during transplantation. The aim of this study was to assess the expression of genes involved in apoptosis in transplanted kidneys derived from deceased donors (DD) at various stages of the transplant procedure, seventy eight transplanted kidneys procured from 43 DD were included in this study. As a baseline control for gene expressions we used six kidney allografts obtained from living donors (LD). Three core biopsies were performed: biopsy 1--5 minutes before organ perfusion in the donor; biopsy 2--at the end of cold ischemia before kidney implantation; and biopsy 3--30 minutes after reperfusion. Tumor protein p53 (TP53), caspase-3 (CASP3), B-cell lymphoma 2 protein (Bcl2), and heme oxygenase 1 (HO-1) gene expression levels were determined using custom-designed low-density arrays (TaqMan assay). Comparison of gene expression between DD and LD kidneys revealed greater expression of all genes in kidneys from DD in all biopsies; however, only CASP3 expression in biopsy 1 and TP53 expression in biopsy 3 were statistically significant. Prolongation duration of brain death beyond 10 hours in DD resulted in a significantly decreased CASP3 expression in biopsy 1. When the cold ischemia time (CIT) was longer than 24 hours, the expressions of Bcl2, TP53, and CASP3 were significantly higher compared to kidneys with ClT<24 hours. There was no correlation between warm ischemia time and gene expression in biopsy 3. CASP3 and TP53 expression only in biopsy 1 were significantly higher among kidney allografts with delayed (DGF) compared with immediate graft function. In conclusion expression of genes involved in apoptosis was more pronounced in kidney allografts from deceased donors. A prolonged donor brain-death period beyond 10 hours resulted in decreased CASP3 expression. CIT longer than 24 hours was associated with increased expressions of Bcl2, TP53, and CASP3. CASP3 and TP53 expressions were significantly higher among kidneys allografts displaying DGF.

Kidney ischemic injury genes expressed after donor brain death are predictive for the outcome of kidney transplantation.

The results of deceased donor kidney transplantation largely depend on the extent of organ injury induced by brain death and the transplantation procedure. In this study, we analyzed the preprocurement intragraft expression of 29 genes involved in apoptosis, tissue injury, immune cell migration, and activation. We also assessed their influence on allograft function. Before flushing with cold solution we obtained 50 kidney core biopsies of deceased donor kidneys immediately after organ retrieval. The control group included 18 biopsies obtained from living donors. Gene expression was analyzed with low-density arrays (Taqman). LCN2/lipocalin-2 is considered a biomarker of kidney epithelial ischemic injury with a renoprotective function. HAVCR1/KIM-1 is associated with acute tubular injury. Comparison of deceased donor kidneys to control organs revealed a significantly higher expression of LCN2 (8.0-fold P=.0006) and HAVCR1 (4.7-fold, P<.0001). Their expressions positively correlated with serum creatinine concentrations after 6 months after transplantation: LCN2 (r=.65, P<.0001), HAVCR1 (r=.44, P=.006). Kidneys displaying delayed graft function and/or an acute rejection episode in the first 6 months after showed higher LCN2 expression compared to event-free ones (1.7-fold, P=.027). A significantly higher increase in expression of TLR2 (5.2-fold), Interleukin (IL) 18 (4.6-fold), HMGB1 (4.1-fold), GUSB (2.4-fold), CASP3 (2.0-fold) FAS (1.8-fold), and TP53 (1.6-fold) was observed among deceased donor kidneys compared with the control group. Their expression levels were not related to clinical outcomes: however, they showed significant correlations with one another (r>.6, P<.0001). We also observed a slightly reduced expression of IL10 (0.6-fold, P=.004). Our data suggested that increased LCN2 and HAVCR1 expression observed in the kidneys after donor brain death were hallmarks of the organ injury process. LCN2 expression level in retrieved kidneys can predict kidney transplantation outcomes.

Extracorporeal photopheresis as an antirejection prophylaxis in kidney transplant recipients: preliminary results.

Extracorporeal photopheresis (ECP) is considered a promising immunomodulatory therapy of acute allograft rejection in organ transplantation and graft-versus-host disease. Our aim was to investigate the biological responses of 10 patients who underwent kidney transplantation with ECP as prophylactic treatment. They received conventional immunosuppressive therapy plus ECP immediately after transplantation: 12 to 16 applications over the course of 2.5 months. ECP procedures were performed using an automated system for leukocyte separation and photoactivation with methoxsalen. All recipients were followed by estimated glomerular filtration rate (eGFR) and peripheral T, B, natural killer, T-regulatory (Treg) and dendritic cells (DC) counts and phenotypes. An acute rejection episode appeared in one control group recipient. The ECP group showed a positive trend to an higher GFR at months 3 (53±11 vs 47.1±9; P=.17) and 6 (67.5±10 vs 53.6±3; P=.03, Wilcoxon test). An increased percentage of Treg (CD3+ CD4+ CD25+) among the total CD3 cell count (4.9%±1% to 9.4%±15%) as well as inducible Treg (CD3+ CD8+ CD28-) was observed among CD3 cells (3.3%±3% to 11.8%±8%, P=.025) within 3 months of ECP treatment. A significant difference in the percentage of Treg was noted at month 3 (completed ECP) between the ECP and the control groups (9.4%±15% vs 3%±1%; P=.01). Addition of ECP to standard immunosuppression was associated with a significantly higher GFR at 6 months and with a significant increase in natural Treg among CD3 cells.

Imbalance of metallaproteinase/tissue inhibitors of metalloproteinase system in renal transplant recipients with chronic allograft injury.

INTRODUCTION: Nowadays, renal allografts continue to be lost at the rate of 2% to 4% per year beyond the first year after transplantation due to chronic allograft injury. Excessive accumulation of extracellular matrix results from overproduction and/or defective degradation by proteolytic enzymes, among which metalloproteinases (MMPs) play a major role. The aim of this study was to assess the role of MMPs in renal transplant recipients (RTR) in the context of allograft injury or proteinuria. MATERIALS AND METHODS: Plasma and urine MMP-2 and MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) were assessed by enzyme-linked immunoassay in 150 RTR including 66% males with an overall mean age of 49.2±11.5 years. The subjects were examined at a mean of 73.4±41.2 months (range=12-240) after kidney transplantation. Thirty-seven healthy volunteers including 54% male with an overall mean age of 48.4±14.1 years served as a control group. RESULTS: Renal transplant recipients displayed significantly decreased plasma MMP-2 activity compared with healthy controls (P<.000) probably due to increased inhibitory plasma (p) TIMP-2 activity (P=.0029), and lower plasma MMP-2:TIMP-2 index (P<.0001). Plasma MMP-9 and pTIMP-1 activities were twofold increased in RTR compared with controls (P=.0015 and P<.000) but with a nearly stable plasma MMP-9:TIMP-1 index (P=NS). There was no difference between RTR and controls according to urine (u) MMP-2 activity, but uMMP-9 was increased in RTR compared with healthy controls (P=.0032). Urine MMP-9 potential was probably diminished by increased uTIMPs (uTIMP-2, P=.017; uTIMP-1, P=.000), which contributed to graft impairment or proteinuria. CONCLUSION: Our study revealed profibrotic MMP/TIMP constellations in RTR that show an imbalance in plasma MMP-2 and MMP-9 with increased plasma and urinary TIMPs. The net proteolytic potential of increased plasma and urinary MMP-9 may be diminished significantly by enhanced plasma and urine TIMP activities.

Pretransplantation cellular alloreactivity is predictive of acute graft rejection and 1-year graft function in kidney transplant recipients.

OBJECTIVE: To study cellular alloimmunity in kidney allograft recipients using an interferon-gamma enzyme-linked immunosorbent spot assay (ELISPOT). MATERIAL AND METHODS: Donor splenocyte peripheral blood mononuclear cells were obtained during kidney recovery in 53 kidney recipients including 11 with positive panel-reactive antibodies pretransplantation. For ELISPOT data analysis, the spot number, size, and intensity were calculated, reflecting the volume of cytokine secretion at the single-cell level. Results were recalculated as the ratio of the values observed for donor-stimulated to unstimulated recipient cells corrected for residual donor activity. RESULTS: Significantly greater pretransplantation donor-stimulated activity was observed in recipients who experienced an acute rejection episode (ARE) within 1 year (P < .05). Mean change in spot number, size, and intensity in patients without or with AREs was 0.99 vs 3.33, 1.60 vs 6.05, and 1.40 vs 6.31, respectively. The assessed parameters were prognostic of high risk of ARE: 1.5-fold increase in spot number (ARE incidence, 52% vs 9%), 2.5-fold increase in spot size (ARE incidence, 53% vs 13%), and 2.7-fold increase in spot intensity (ARE incidence, 52% vs 9%). The 3 parameters correlated with 1-year serum creatinine concentration (P < .05). In 14 recipients, AREs could have been predicted in 11 using pretransplantation ELISPOT results, and in only 2 on the basis of panel-reactive antibodies. CONCLUSION: The ELISPOT-determined capacity of donor-induced reactivity observed in recipient cells obtained just before transplantation is predictive of risk of graft rejection and 1-year allograft function.

Estimated glomerular filtration rate evolution between 6 and 24 months predicts long-term kidney transplant survival among patients with inferior graft function.

UNLABELLED: One-year serum creatinine and other clinical and immunologic factors remain uncertain predictors of long-term kidney allograft outcomes. The aim of our retrospective study was to evaluate the prognostic significance of the estimated glomerular filtration rate (eGFR) monitoring of patients with suboptimal kidney allograft function. The analysis included 332 patients (median age, 43 years), who received deceased donor kidney transplantations between 1995 and 2007 with graft function for at least 1.5 years (median follow-up, 7 years). We examined the eGFR (the 4-variable Modification of Diets in Renal Disease [MDRD] equation) at 6 month posttranspant and every 6 months thereafter. Based on eGFR stratification (>60, 50-60, 40-49, and <40 mL/min per 1.73 m(2)) at 6 months we divided the patients into 4 groups. We identified patients with eGFR improvement (as judged by >20% increment between 6 and 24 months), versus stable or declining eGFR courses. RESULTS: Among the groups, the eGFR improved among 47% of patients. Demographic characteristics including time on dialysis, human leukocyte antigen matching, cold ischemia times were similar across groups. A greater incidence of disadvantageous characteristics was observed among the deteriorating groups: older donor, higher delayed graft function incidence, as well as more frequent and severe acute rejection episodes. Excellent and comparable 5-year graft survivals were noticed among patients with improved eGFR between 6 and 24 months (97%, 100%, 100%, 94%). CONCLUSION: Assessment of eGFR was a valuable biomarker for long-term kidney transplant outcomes among patients with inferior renal transplant function. A tendency to improve eGFR between 6 and 24 months posttransplant was advantageous for graft survival, possibly indicating state of immunologic quiescence.

Favorable resolution of hepatic infarctions in transplanted liver after portal vein thrombosis treated by surgical thrombectomy: a case report.

Portal vein thrombosis (PVT) after orthotopic liver transplantation (OLT) is a life-threatening complication associated with a high rate of graft loss and patient death, with reported incidence of 1% to 2% in adults. We report a case of an early PVT after OLT complicated by hepatic infarctions in the liver graft. After surgical thrombectomy and restoration of the portal inflow, hepatic infarctions resolved spontaneously within 6 months, which was confirmed by computed tomography.