IL-23 plasma level is strongly associated with CMV status and reactivation of CMV in renal transplant recipients.

BACKGROUND: Cytomegalovirus seropositivity is an independent risk factor for atherosclerosis in patients with ESRD. Donor CMV seropositivity is associated with higher graft loss. Dendritic cells, macrophages and Th17 lymphocytes are defined as producers of IL-23. IL-23 is thought to be involved in the promotion of Th17 cell polarization. Latent CMV-induced Th17 might be involved in the pathogenesis of CMV infection in patients with ESRD. We aimed to evaluate associations of Th17-dependent cytokines with ESRD, CMV status and post-transplant outcome in kidney transplantation. RESULTS: IL-21 plasma levels were similar in patients and healthy controls (p = 0.47), whereas IL-9 (p = 0.02) and IL-23 (p < 0.0001) levels were significantly higher in ESRD patients. CMV-seronegative (p = 0.002) and -seropositive (p < 0.001) patients had significantly higher IL-23 plasma levels than controls. CMV-seropositive patients showed excessively higher IL-23 (p < 0.001) plasma levels than CMV-seronegative patients. Patients with post-transplant CMV reactivation had higher IL-23 plasma levels than patients without CMV reactivation (p = 0.025). CONCLUSIONS: Our results indicate that latent CMV induces IL-23. IL-23 might be an inflammatory mediator of latent CMV infection in patients with ESRD and predisposes patients for post-transplant CMV reactivation.

Early pregnancy serum neopterin concentrations predict spontaneous preterm birth in asymptomatic pregnant women.

OBJECTIVE: To investigate if early pregnancy serum neopterin concentrations (EPSN) could predict spontaneous preterm birth (SPB). METHODS: EPSN was measured in 92 sera collected from 46 pregnant women with birth at term and 40 sera from 20 pregnant women with preterm birth. Two sera were collected for each case: in the first and early second trimester. RESULTS: EPSN concentrations correlate with gestational age (ρ=0.275, P=0.001), a correlation which was present in both groups: term and preterm birth. EPSN were higher in pregnancies with SPB compared with normal pregnancies (6.27±1.03 vs. 6.04±0.15, P=0.039). Patients with SPB showed a considerable increase of EPSN in the second trimester compared with patients with birth at term (7.30±1.53 vs. 6.16±0.23, P=0.043). A sharper increase was found in the group with SPB before 32 weeks of pregnancy (wp) (9.83±4.36 vs. 6.16±0.23, P=0.016). Pregnant women with an early second trimester serum neopterin value of above 8 nmol/L are associated with a risk of SPB before 32 wp (odds ratio=14.4, P=0.01) and of SPB before 34 wp (odds ratio=3.6, P=0.05), respectively. CONCLUSIONS: EPSN increases with the gestational age and predicts SPB in asymptomatic pregnant women.

Association of low serum TGF-ß level in hantavirus infected patients with severe disease.

BACKGROUND: Hantaviruses are emerging zoonotic pathogens which cause hemorrhagic fever with renal syndrome, an immune-mediated pathogenesis is discussed. The aim of the present study was to investigate the role of TGF-ß expression in acute hantavirus infection. RESULTS: We retrospectively studied 77 patients hospitalised with acute Puumala infection during a hantavirus epidemic in Germany in 2012. Hantavirus infection was confirmed by positive anti-Puumala hantavirus IgG and IgM. Plasma levels of transforming growth factor (TGF)-ß1 and TGF-ß2 were analysed. Based on glomerular filtration rate on admission, patients were divided in mild and severe course of disease. Puumala virus RNA was detected by PCR amplification of the viral L segment gene. Out of 77 Puumala virus infected patients, 52 (68%) were male. A seasonal distribution was detected in our cohort with a peak in summer 2012, the highest incidence was observed in the age group of 30-39 years. Puumala virus RNA was detectable in 4/77 cases. Patients with severe disease had a significant longer hospital stay than patients with mild disease (6.2 vs 3.6 days). Thrombocyte count (186 vs 225 per nl), serum TGF-ß1 (74 vs 118 ng/l) and TGF-ß2 (479 vs 586 pg/l) were significantly lower in severe compared to mild disease. However, C-reactive protein (CRP) was significantly higher in patients with severe disease (62 vs 40 mg/l). TGF-ß1/Cr was the most sensitive and specific marker associated with renal dysfunction. CONCLUSION: High serum CRP and low serum TGF-ß in the early phase of hantavirus infection is associated with a severe course of disease. Our results support the hypothesis of an immune-mediated pathogenesis in hantavirus infection.

Correction: Oweira et al. Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells. J. Clin. Med. 2022, 11, 4794.

There was an error in the original publication [...].

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepG2 Tumor Cells.

There are two main enzymes that convert tryptophan (Trp) to kynurenine (Kyn): tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Kyn accumulation can promote immunosuppression in certain cancers. In this study, we investigated Trp degradation to Kyn by IDO and TDO in primary human hepatocytes (PHH) and tumoral HepG2 cells. To quantify Trp-degradation and Kyn-accumulation, using reversed-phase high-pressure liquid chromatography, the levels of Trp and Kyn were determined in the culture media of PHH and HepG2 cells. The role of IDO in Trp metabolism was investigated by activating IDO with IFN-γ and inhibiting IDO with 1-methyl-tryptophan (1-DL-MT). The role of TDO was investigated using one of two TDO inhibitors: 680C91 or LM10. Real-time PCR was used to measure TDO and IDO expression. Trp was degraded in both PHH and HepG2 cells, but degradation was higher in PHH cells. However, Kyn accumulation was higher in the supernatants of HepG2 cells. Stimulating IDO with IFN-γ did not significantly affect Trp degradation and Kyn accumulation, even though it strongly upregulated IDO expression. Inhibiting IDO with 1-DL-MT also had no effect on Trp degradation. In contrast, inhibiting TDO with 680C91 or LM10 significantly reduced Trp degradation. The expression of TDO but not of IDO correlated positively with Kyn accumulation in the HepG2 cell culture media. Furthermore, TDO degraded L-Trp but not D-Trp in HepG2 cells. Kyn is the main metabolite of Trp degradation by TDO in HepG2 cells. The accumulation of Kyn in HepG2 cells could be a key mechanism for tumor immune resistance. Two TDO inhibitors, 680C91 and LM10, could be useful in immunotherapy for liver cancers.

Mitomycin C-treated dendritic cells inactivate autoreactive T cells: toward the development of a tolerogenic vaccine in autoimmune diseases.

Treatment of autoimmune diseases remains a challenge for immunological research. An ideal therapy should inhibit the immune reaction against the diseased organ and leave the rest of the immune response intact. Our previous studies showed that donor-derived dendritic cells (DCs) treated in vitro with mitomycin C (MMC) suppress rat heart allograft rejection if injected into recipients before transplantation. Here we analyze their efficacy in controlling autoimmunity. MMC-DCs loaded with myelin-basic-protein (MBP) inhibited specific T cells derived from multiple sclerosis patients in vitro. If coincubated with MMC-DCs, T cells were arrested in the G(0)/G(1) cell cycle phase. Microarray gene scan showed that MMC influences the expression of 116 genes in DCs, one main cluster comprising apoptotic and the second cluster immunosuppressive genes. Apparently, the combination of apoptosis with expression of tolerogenic molecules renders MMC-DCs suppressive. MBP-loaded MMC-DCs also inhibited mouse T cells in vitro and, in contrast to MBP-loaded naïve DCs, did not induce experimental autoimmune encephalitis. Most importantly, mice vaccinated with inhibitory DCs became resistant to the disease. Whereas this is not the first report on generation of suppressive DCs, it delineates a method using a clinically approved drug at nontoxic concentrations, which yields irreversibly changed DCs, effective across species in vitro and in vivo.

Function of the tryptophan metabolite, L-kynurenine, in human corneal endothelial cells.

PURPOSE: Penetrating keratoplasty has been the mainstay for the treatment of blindness and is the most common form of tissue transplantation worldwide. Due to significant rates of rejection, treatment of immunological transplant reactions is of wide interest. Recently in a mouse model, the overexpression of indoeleamine 2,3 dioxigenase (IDO) was led to an extension in corneal allograft survival. L-kynurenine is a tryptophan metabolite, which may render activated T-cells apoptotic and therefore might modulate an allogenous transplant reaction. The function of L-kynurenine in the human cornea remains unclear. We analyzed the expression levels of IDO in human corneal endothelial cells (HCECs) and downstream tryptophan/kynurenine mechanisms in cell culture. METHODS: An immunological activation profile was determined in proliferation assays of monocytes from healthy donors. Reversed-phase high pressure liquid chromatography (HPLC), western blot, real time polymerase chain reaction (PCR), and microarray analyses were used. The expression of IDO and immunological infiltration of rejected human corneal allografts (n=12) were analyzed by immunohistochemistry. RESULTS: We found IDO and an associated tryptophan/kynurenine transporter protein exchange mechanism upregulated by inflammatory cytokines in HCECs. The inhibition of T-cell proliferation might depend on rapid delivery of the tryptophan metabolite, L-kynurenine, to the local corneal environment. Microarray analysis gives evidence that the large amino acid transporter 1 (LAT1) transporter protein is responsible for this mechanism. CONCLUSIONS: Our data support that adequate levels of functional L-kynurenine might contribute to the maintenance of a relative immune privilege in the ocular anterior chamber, thereby contributing to the preservation of corneal allogeneic cells.

Association of Graft Effluent Parameters with Donor Body Mass Index, Graft Quality, and Post-Transplant Events.

BACKGROUND We evaluated whether effluent parameters prior to reperfusion correlate with post-transplant outcomes in liver transplant recipients. MATERIAL AND METHODS Concentrations of high mobility group box 1 protein (HMGB1), uncleaved cytokeratin-18 (M65), caspase-cleaved cytokeratin 18 fragment (M30), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP) were measured in effluent samples from 53 adult liver recipients (42 survived for 1 year and 11 did not survive). RESULTS Effluent concentrations of ALP (p=0.006), AST (p=0.050), and Ca++ (p=0.003) were higher in patients with bacteriemia in the first post-transplant year and ALP (p=0.015) was higher in patients with early graft dysfunction (EAD). Multivariate analysis of effluent parameters showed that Ca++ >0.30 mmol/l (p=0.012, odds ratio [OR]=7.12, confidence interval [CI]=1.56-32.58), and ALP ≥27 IU/l (p=0.033, OR=5.31, CI=1.14-27.74) were significantly associated with 1-year post-transplant bacteriemia, whereas ALP ≥27 IU/l (p=0.020, OR=5.56, CI=1.32-23.46) was significantly associated with EAD. HMGB1 >54 pg/ml (p=0.008, OR=6.05, CI=1.59-23.00) was significantly associated with the donor body mass index (p=0.008, OR=6.05, CI=1.59-23.00) and fatty liver (p=0.005, OR=11.68, CI=2.10-64.01). CONCLUSIONS Effluent parameters are indicators of liver quality and predict the outcome of liver transplantation. High effluent Ca++ and ALP are risk factors of post-transplant bacteriemia. In addition, high ALP is a risk factor of EAD, and high HMGB1 is an indicator of liver quality.

Serum Caspase-Cleaved Cytokeratin (M30) Indicates Severity of Liver Dysfunction and Predicts Liver Outcome.

BACKGROUND The Model for End-Stage Liver Disease (MELD) score is a well-established tool for assessing hepatic failure. The present retrospective study investigated whether serum keratin 18 (M65) and caspase-cleaved cytokeratin (M30) were associated with liver dysfunction and post-transplant graft failure. MATERIAL AND METHODS A total of 147 patients with liver cirrhosis were categorized into 2 groups according to their baseline MELD score (group I: MELD score <20, n=87, and group II: MELD score ≥20, n=60). Serum M65 and M30 levels were measured by ELISA. RESULTS Cirrhotic patients had significantly higher serum M65 and M30 levels than healthy controls (p<0.0001). Serum M65 was correlated with the MELD score and serum bilirubin (p≤0.007) and serum M30 was correlated with the MELD score, international normalized ratio, and serum bilirubin (p≤0.001). Group II had significantly higher serum M65 and M30 levels than group I (M65, p=0.025 and M30, p<0.001). Patients who lost the allograft during the first post-transplant year had significantly higher serum M30 levels than patients with a graft survival of >1 year (p=0.004). In the regression analysis, serum M30 was associated with the MELD score (odds ratio [OR]=2.545, p=0.005), serum bilirubin (OR=2.605, p=0.005) and 1-year graft loss (OR=3.61, p=0.006). CONCLUSIONS Our data indicate that serum M30 levels reflect the degree of liver dysfunction and can predict 1-year graft loss.

Early post-operative acute phase response in patients with early graft dysfunction is predictive of 6-month and 12-month mortality in liver transplant recipients.

UNLABELLED: Early allograft dysfunction (EAD) after liver transplantation is mostly a reversible event caused by factors related to ischemia/reperfusion (I/R) injury. EAD represents a hepatic injury associated with pre- and early post-transplant inflammatory cytokine responses. Aim of the present study was to evaluate the prognostic and diagnostic value of CRP in liver transplant recipients with EAD. MATERIALS AND METHODS: Forty-seven patients with EAD were compared with 115 non-EAD patients. Pre- and post-transplant parameters were analyzed. EAD was defined based on postoperative liver function tests such as INR, bilirubin and liver enzymes. Statistical analysis was performed using SPSS version 18.0. RESULTS: Pre-transplant liver enzyme were not significantly different in the two groups. At day 3, 5 and 10 post-transplant CRP was significantly higher in patients with EAD than in non-EAD patients (p⩽0.001 for all investigations) and remained consistently high in patients with EAD and low in non-EAD patients. EAD patients with high CRP at post-transplant days 3 and 5 showed lower survival at 6-month and 12-month post-transplant than patients with low CRP. CONCLUSION: Our results indicate a prognostic and diagnostic value of CRP in patients with early graft dysfunction and predict 6-month and 12-month mortality in liver transplant recipients.

Early post-transplant neopterin associated with one year survival and bacteremia in liver transplant recipients.

Bacterial infections are the most common complications, and the major cause of mortality after liver transplantation (Tx). Neopterin, a marker of immune activation, is produced in monocyte/macrophages in response to inflammation. The aim of our study was to investigate whether early post-operation serum levels of neopterin were associated with post-transplant bacteremia and mortality in liver transplant recipients. We studied 162 of 262 liver Tx patients between January 2008 and February 2011 of whom pre- and early post-Tx sera samples were available. Pre- and early post-operative risk factors of infection and mortality were evaluated in 45 bacteremic patients and 117 non-bacteremic patients. During one-year follow-up, 28 of 262 patients died because of graft failure, septicemia and other diseases. Post-Tx serum neopterin on day 10 (p<0.001) were significantly higher in bacteriemic patients than in patients without bacteremia. Logistic regression analyses showed that day 10 post-Tx neopterin serum level ⩾40 nmol/l has a predictive value (OR=6.86: p<0.001) for bacteremia and mortality (OR=3.47: p=0.021). Our results suggest that early post-Tx neopterin serum levels are very sensitive predictive markers of one-year post-Tx bacteremia and mortality in liver Tx recipients.

Role of human corneal endothelial cells in T-cell-mediated alloimmune attack in vitro.

PURPOSE: Human corneal endothelial cells (HCEC) are a potential target of immune attack after corneal transplantation. The aim of this in vitro study was to investigate the role of HCEC during the alloimmune response of T-cells by examining cytokine profiles, function of the immunosuppressive enzyme indoleamine 2,3-dioxigenase (IDO), major histocompatibility complex (MHC-I/-II), T-cell proliferation, and the induction of cell death. METHODS: Real-time PCR and RP-HPLC were used to determine IDO expression and activity. Multiplex assay was performed for quantification of cytokine levels. T-cell proliferation was assessed by thymidine incorporation, and HCEC cell death was measured by flow cytometry. RESULTS: Human corneal endothelial cells induce strong proliferation of allogeneic T-cells and an increase of proinflammatory cytokines such as interleukin-1α (IL-1α), IL-1ß, IL-6, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). Tumor necrosis factor-alpha (and to a lesser extent IFN-γ) induces apoptosis. Moreover, IFN-γ strongly upregulates MHC-II molecules and IDO activity in HCEC as reflected by high kynurenine (Kyn) concentrations. Interestingly, the T-cell response was not affected by increased IDO activity, since blocking of IDO did not affect the proliferation rate. Indoleamine 2,3-dioxigenase-induced Kyn levels did not exceed concentrations of 175 ± 20 µM. Concentrations of ≥400 µM Kyn were required to suppress T-cell proliferation. CONCLUSIONS: Our data show that T-cell attack on HCEC leads to increased concentrations of proinflammatory cytokines. Inflammatory cytokines induce apoptosis and upregulate MHC-II molecules and IDO in HCEC. Although increased IDO activity does not influence the T-cell response, it constitutes an inflammatory marker of the alloimmune response toward HCEC.

Plasmapheresis adjusts inflammatory responses in potential kidney transplant recipients.

BACKGROUND: Plasmapheresis (PP) has been used in the treatment of various immunologic disorders, and its efficacy has mainly been attributed to the removal of humoral factors and autoantibodies. Besides these effects, PP may induce modifications of the cellular immunologic status, contributing to the restoration of impaired immunologic function. The effect of PP on lymphocyte subpopulations, plasma neopterin, and cytokines in renal transplant recipients was investigated in this study. METHODS: We compared pre-PP and post-PP lymphocyte subpopulations and plasma neopterin in 37, and cytokine plasma levels in 30, potential renal transplant recipients. Plasma neopterin and cytokines were measured by enzyme-linked immunosorbent assay kits, lymphocyte subsets were determined using four-color fluorescence flow cytometry. RESULTS: Lymphocyte subpopulation counts and ratios including CD45:µL (P=0.005), CD3:µL (P=0.02), CD4DR:µL (P=0.002), CD8:µL (P=0.01), and CD8DR:µL (P=0.005) T cells; CD4DR:CD4 (P=0.009) and CD8DR:CD8 (P=0.0004) ratios; DR cells:µL (P=0.003); CD19 B lymphocytes:µL (P=0.001); and plasma levels of neopterin (P<;0.0001), soluble interleukin-1 receptor antagonist (P<;0.0001), IL-8 (P=0.0001), and tumor necrosis factor-α (P=0.008) were significantly decreased after PP as compared with before PP. The results indicate a decrease of activated DR, CD4, and CD8 T lymphocytes and B lymphocytes, and a decrease of monocyte and macrophage activation as a result of PP. CONCLUSION: Based on these results, we conclude that PP not only removes antibodies from the plasma but, in addition, modulates T-lymphocyte activation and the inflammatory response by decreasing plasma proinflammatory cytokines.

Increased serum levels of quinolinic acid indicate enhanced severity of hepatic dysfunction in patients with liver cirrhosis.

BACKGROUND: The Model for End-Stage Liver Disease (MELD) score is a tool for assessment of the degree of hepatic insufficiency/failure. Quinolinic acid (QuinA) is a tryptophan metabolite produced by activated macrophages. Here we investigate whether the degree of systemic inflammation (QuinA, neopterin, CRP and IL-6) correlates with clinical liver dysfunction according to the MELD Score. METHOD: Ninety-four patients with liver cirrhosis were categorized into 2 groups according to baseline MELD score (group I, MELD <20, n = 61, and group II, MELD ≥20, n = 33). RESULTS: Serum levels of QuinA, neopterin, CRP, and IL-6 significantly correlated with MELD score (r = 0.77, 0.75, 0.57, and 0.50; p < 0.0001, respectively). Patients of group II had significantly higher serum levels of QuinA, neopterin, CRP, and IL-6 than group I (p0.0001). ROC curve analysis showed that QuinA and neopterin are more sensitive markers for severity of liver disease than established markers of inflammation such as CRP and IL-6 (sensitivity = 86% and 79%, respectively) (AUC=0.89 and 0.89, respectively). QuinA provided the most sensitive index with regard to the identification of patients with hepatic encephalopathy. CONCLUSION: Serum levels of QuinA reflect the degree of liver dysfunction. Moreover, high levels of QuinA may serve as a sensitive indicator of hepatic encephalopathy.

Strong association of phenylalanine and tryptophan metabolites with activated cytomegalovirus infection in kidney transplant recipients.

Infection-induced inflammation triggers catabolism of proteins and amino acids. Phenylalanine and tryptophan are 2 amino acids related to infections that regulate immune responses. Polyomavirus BK (BKV) and cytomegalovirus (CMV) are important pathogens after kidney transplantation. We investigated the clinical relevance of phenylalanine, tryptophan, and tryptophan metabolites (kynurenine and quinolinic acid) plasma levels in kidney transplant recipients with active CMV (BKV(-)CMV(+), n = 12) or BK virus infection (BKV(+)CMV(-), n = 37). Recipients without active viral infections (CMV(-)BKV(-), n = 28) and CMV(-)BKV(-) healthy individuals (HCs, n = 50) served as controls. In contrast to BKV infection, activated CMV infection is tightly linked to increased phenylalanine and tryptophan metabolite plasma levels (p ≤ 0.002). The association of phenylalanine (cutoff 50 µmol/L) with CMV infection demonstrates high sensitivity (100%) and specificity (94%). By contrast, kynurenine (p = 0.029) and quinolinic acid (p = 0.003) values reflect the severity of CMV infection. In this early proof-of-concept trial, evidence indicates that activated CMV infection is strongly associated with increased phenylalanine as well as kynurenine and quinolinic acid plasma levels. Moreover, tryptophan metabolite levels correlate with disease severity. Measurement of these amino acids is an inexpensive and fast method expected to complete conventional diagnostic assays.

Increased pretransplantation plasma kynurenine levels do not protect from but predict acute kidney allograft rejection.

Indoleamine 2,3-dioxygenase (IDO), an enzyme expressed in many cell types, catalyses degradation of tryptophan (Trp) to kynurenine (Kyn) and may exert immunosuppressive functions, mediated mainly by kynurenines. Therefore, increased Kyn concentrations would be expected to protect allografts from rejection. We conducted this study to examine whether Kyn has predictive value for kidney graft outcome. End-stage renal disease patients (n = 210) demonstrated an increased Kyn/Trp ratio compared with healthy controls (n = 30). Both Kyn and Trp levels were significantly higher in patients who subsequently developed acute rejection than in patients who did not (p < 0.001 and p < 0.001, respectively). Furthermore, pretransplantation Kyn and Trp plasma concentrations were significantly different in patients who went on to develop acute rejection (high values) or acute tubular necrosis (low values) (p = 0.007 and p = 0.021, respectively). After transplantation Kyn levels decreased. Approximately 3 days before biopsy-confirmed rejection, Kyn was significantly increased in patients with rejection compared with those without rejection (p < 0.001). Contrary to expectation, high Kyn plasma levels before transplantation were not predictive of low rejection risk. Although informative in overall terms, at the present stage, Kyn levels do not allow the concise risk differentiation of individual patients.

Urinary proinflammatory cytokine response in renal transplant recipients with polyomavirus BK viruria.

BACKGROUND: Polyomavirus BK (BKV) has emerged as an important complication after kidney transplantation. BKV-associated nephropathy develops in approximately 5% to 8% of renal transplant recipients, and its prognosis is poor. The relationship between urine cytokines and BK viruria in kidney recipients has not been defined. PATIENTS AND METHODS: We compared posttransplant urine cytokine levels of 65 renal transplant outpatients with (BK-positive) or without BK viruria (BK-negative, n=33), low- (n=16) or high-level (n=16) BK viral load (VL), and 24 healthy controls (HCs). Soluble interleukin-1 receptor antagonist (sIL-1RA), interleukin (IL)-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, IL-17, transforming growth factor-beta2, interferon-gamma, and tumor necrosis factor-alpha levels were determined using commercially available ELISA kits. RESULTS: BK-positive patients showed higher urine IL-3 (P=0.006), sIL-6R (P=0.010), IL-6 (P=0.020), and sIL-1RA (P=0.050) than BK-negative patients. Compared with HCs, BK-negative patients had lower urine sIL-1RA (P=0.003), sIL-6R (P=0.001), and IL-17 (P<0.001), whereas BK-positive patients had higher urine IL-3 (P=0.004) and IL-6 (P=0.001) and lower IL-17 (P<0.001), suggesting cytokine suppression by immunosuppression and upregulation by BK-infection. Urine sIL-6R (P=0.003) and IL-6 (P=0.010) were higher in patients with high VL than in patients with low VL. Additionally, patients with high VL showed higher urine IL-6 (P=0.001), sIL-6R (P=0.001), sIL-1RA (P=0.016), and IL-3 (P=0.047) than BK-negative patients, and higher urine IL-6 (P<0.001) and lower IL-17 (P<0.001) than HCs. CONCLUSION: BK-positive renal transplant recipients, especially those with high VL, showed strong inflammatory cytokine responses with increases of urine sIL-1RA, IL-3, IL-6, and sIL-6R. Our data suggest that monocyte- and Th-2-induced cytokines are involved in the pathogenesis of BKV-associated nephropathy.

Association of pretransplant soluble glycoprotein 130 (sgp130) plasma levels and posttransplant acute tubular necrosis in renal transplant recipients.

OBJECTIVE: Previously, we reported that high pretransplant sIL-6R plasma levels are associated with posttransplant acute tubular necrosis (ATN). In this study, we examined associations of pretransplant plasma levels of sgp130 with ATN. PATIENTS AND METHODS: Pretransplant serum creatinine (Cr), plasma neopterin, and sgp130 levels were studied in 105 first renal transplant recipients who received grafts from deceased donors. Although 57 patients had immediate and sustained graft function, ATN was diagnosed in 30 patients within the first 11.3+/-7.8 posttransplant days and acute rejection in 18 patients during the first 27.1+/-27.6 days. RESULTS: Pretransplant serum Cr and plasma neopterin were similar in the three patient groups. Pretransplant sgp130 plasma levels, however, were significantly lower in patients with ATN than in patients with immediate graft function (P=0.004) or acute rejection (P=0.009). Multivariable logistic regression analysis for ATN showed an odds ratio of 4.3 of patients with pretransplant sgp130 less than or equal to 250 pg/mL with posttransplant ATN (P=0.006). CONCLUSION: Patients at risk of ATN showed immediately before transplantation low anti-inflammatory sgp130, suggesting a contribution of the IL-6 cytokine family to the development of ATN. It might be useful to measure IL-6 family plasma levels pretransplant to identify patients who are at an increased risk of developing ATN.