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Proteinuria is a hallmark of glomerular injury, and persistent proteinuria is associated with graft failure in kidney transplant patients. Recently, it is known that the level of circulating angiopoietin-like 4 (ANGPTL4) is elevated in the patients with human nephrotic syndrome, in which ANGPTL4 is responsible for relieving proteinuria.The purpose of this study is to determine effects of clinical factors and genetic polymorphism of ANGPTL4 on proteinuria after kidney transplantation.A total of 282 patients out of 400 renal transplant patients between 2008 and 2012 at St. Vincent Medical Center, CA were studied in a retrospective study design. The level of proteinuria was measured by random urine protein to creatinine ratio, and divided into two groups (Group 1: UPC500mg/day, Group 2: ≥500mg/day). Single nucleotide polymorphisms of ANGPTL4 genes (rs1044250, rs2278236, rs116843064, rs11672433, rs4076317) were determined by real time PCR with sequence specific primers.Among various clinical factors, only delayed graft function, mTOR inhibitor use and fish oil use were significantly associated with posttransplant proteinuria. Statistical differences were found in genetic polymorphisms of ANGPTL4 (rs1044250, rs2278236) in regards to proteinuria among tested patients. rs1044250 (C/T, T228M, missense mutation) alleles showed multiple significant differences (Group 1 vs. Group 2: C vs. T: OR=1.893, CI=1.322-2.710, p0.001). Similar trends were found in rs2278236 (A/G) alleles with statistical significances (Group 1 vs. Group 2: A vs. G: OR=0.620, CI=0.443-0.867, p=0.005). With multiple logistic regression, rs1044250 was still a significant risk factor of moderate/severe proteinuria (p=0.021).This study suggests that the presence of C allele of rs1044250 and G allele of rs2278236 in ANGPTL4 gene is associated with higher risk of moderate/severe proteinuria in renal transplant patients.

Acute Pneumonia, Emphasis, Antibiotic-Resistant, Therapeutic, Stereotypes, Vascular Membranes, Blood Pressure, Pulmonary Vessels...

BACKGROUND BK virus nephropathy (BKVN) is a major complication in kidney transplant patients. This study aimed to investigate the efficacy of intravenous immunoglobulin (IVIG) therapy against persistent BKVN and to evaluate the association between persistent BKVN and Fc gamma receptor (FcγR) single nucleotide polymorphisms (SNPs). METHODS A total of 86 patients out of 279 kidney recipients with BKVN were investigated in a single-center retrospective study. The majority of 86 patients were Hispanic and Asian (69.8% and 17.4%). Patients were treated with adjunctive IVIG or standard therapy (controls). Subgroup analysis was performed between IVIG responders and non-responders. BK virus copy number and serum creatinine (SCr) were measured to evaluate the impact of IVIG. We analyzed the association between the response to IVIG and genotype at FcγR3A (rs396991) and FcγR2A (rs1801274) SNPs. RESULTS Viral load in IVIG non-responders was significantly higher than in responders at the time of diagnosis (219 271.8 vs 29 816.3 copies/mL, P = .015) and after 6 months of IVIG use (12 789.5 vs 1369.5 copies/mL, P

Background Anemia is a very common occurrence in post-renal transplant patients. Post-transplantation anemia (PTA) is associated with significant graft loss or cardiovascular morbidity. The objective of this study is to identify clinical risk factors associated with anemia after kidney transplantation. Methods Our retrospective cohort study included a total of 570 renal transplant recipients. For the definition of anemia, we adopted “the lower limit of normal for Hgb concentration of blood” proposed by Beutler E and Waalen J [14], which has adjustments for age, gender and ethnicity. Post-transplant anemia (PTA) was defined as anemia that arose between 30 and 180 days after transplantation. Based on this definition, of the 570 renal transplant recipients, 344 patients (62.1%) experienced PTA. The patients were divided into anemic and non-anemic groups, and a total of 20 clinical factors were compared between the two groups. Results In the univariate analysis, age, race, multiple transplants, delayed graft function (DGF), and use of tacrolimus, sirolimus, thymoglobulin, ganciclovir, ACE inhibitors, and ARBs were associated with PTA. In the multivariate analysis, age (> 60 years old, OR = 2.62, p = 0.001), race (OR = 2.54, p = 0.001), and use of sirolimus (OR = 2.01, p = 0.019), antiviral agents (OR = 1.96, p = 0.015), thymoglobulin (OR = 1.86, p = 0.011), and DGF (OR = 2.78, p = 0.001) remained significant. Conclusion The current results show that undergoing a transplant at age 60 or older, use of sirolimus, antiviral agents, and thymoglobulin are independent clinical risk factors associated with PTA. In terms of ethnicity, AA, MEA, or PI is higher risk for PTA and Hispanic is significantly lower risk for PTA compared to Caucasians.

Background Hematological abnormalities after transplantation are complications that may arise after renal transplantation, of which thrombocytopenia is associated with increased risk of bleeding and other complications. The development of thrombocytopenia is affected by various clinical conditions, and the stromal-derived factor 1 (SDF1) and platelet factor 4 (PF4) genes are known to be involved in the production or destruction of platelets. The purpose of this study was to investigate the prevalence of posttransplant thrombocytopenia and its association with other clinical conditions and genetic polymorphisms of SDF1 and PF4 genes a long time after transplantation. Methods This is a retrospective study that includes a total of 305 kidney transplant (KT) recipients between 2008 and 2012 at St. Vincent Medical Center, Los Angeles, CA. In this study, posttransplant thrombocytopenia was defined as a 30% reduction in platelet count from the baseline in the first week or a decrease of Results In the first week, 65 patients had a 30% reduction in platelet count (21.3%). Gender, simultaneous kidney-pancreas transplantation, induction therapy (IT), and only alleles of rs2297630 of SDF1, among the SDF1 and PF4 genes, showed statistically significant differences. The rs2297630 alleles were consistently significant risk factors (non G vs. G: odds ratio = 0.445; 95% confidence interval, 0.224–0.884; p = .021) in the multiple logistic regression. In the 1-year study, 61 patients (20.0%) had platelet counts of Conclusions In this study, non-G group of rs2297630 in SDF1 significantly increased the risk of post-transplant thrombocytopenia in the first week of kidney transplantation.

The posttransplant development of donor specific antibodies (DSA) initiates the antibody mediated rejection (AMR), which is associated with the increased rate of graft loss. One of the characteristics of AMR is the infiltration of innate immune system including macrophages, monocytes, neutrophils or NK cells. Macrophage inhibitory factor (MIF) and B-cell activating factor (BAFF) are well known cytokines that are associated with the activation of the innate immune system which can damage kidney allograft. In this article, the association of the genetic polymorphisms of MIF and BAFF with the development of DSA including Class I and II in kidney transplant patients is investigated. A total of 231 renal transplant patients between 2008 and 2012 at St. Vincent Medical Center, CA were studied in a retrospective study design. DSA were determined by Luminex technology, and single nucleotide polymorphisms (SNP) of MIF and BAFF were determined by the real time PCR based on 5′ nuclease allelic discrimination assay. The genetic polymorphisms of MIF rs1007888 (C/T) was associated with increased risk of positive DSA detection (p = 0.04) after transplantation, and consistently significant after 1 year (p = 0.016). Furthermore, the presence of C allele were associated with the increased risk of Class I DSA detection (OR 1.816, CI 1.141–2.889, p = 0.011). Also, genetic polymorphisms of BAFF rs12583006 were associated with the increased risk of Class II DSA detection (p = 0.033). In conclusion, the genetic polymorphisms of MIF and BAFF may increase the risk of posttransplant development of DSA. This result suggests the association between the development of posttransplant DSA and the activation of innate immune system.

The association between donor specific antibodies (DSA) and renal transplant rejection has been generally established, but there are cases when a DSA is present without rejection. We examined 73 renal transplant recipients biopsied for transplant dysfunction with DSA test results available: 23 patients diffusely positive for C4d (C4d+), 25 patients focally positive for C4d, and 25 patients negative for C4d (C4d−). We performed C1q and IgG subclass testing in our DSA+ and C4d+ patient group. Graft outcomes were determined for the C4d+ group. All 23 C4d+ patients had IgG DSA with an average of 12,500 MFI (cumulative DSA MFI). The C4d− patients had average DSA less than 500 MFI. Among the patients with C4d+ biopsies, 100% had IgG DSA, 70% had C1q+ DSA, and 83% had complement fixing IgG subclass antibodies. Interestingly, IgG4 was seen in 10 of the 23 recipients’ sera, but always along with complement fixing IgG1, and we have previously seen excellent function in patients when IgG4 DSA exists alone. Cumulative DSA above 10,000 MFI were associated with C4d deposition and complement fixation. There was no significant correlation between graft loss and C1q positivity, and IgG subclass analysis seemed to be a better correlate for complement fixing antibodies in the C4d+ patient group.

Aim Differential glycosylation of Immunoglobulin G (IgG) is known to affect the functions of IgG by modulating the interactions with its binding proteins, such as C1q and Fc receptors. Our research aim was to develop an assay to analyze glycosylation of donor specific antibodies (DSA) using conventional single antigen microbead technology, and subsequently to analyze glycosylation profiles of kidney transplant patients with DSA and biopsy data for graft function assessment. Methods Conventional Class I and II LABScreen® single antigen beads were pretreated to eliminate glycans on the Class I and II antigens. Patient serum was incubated with the pretreated beads according to the standard assay. Glycans of the DSA bound to the beads were detected with biotinylated lectins known to specifically detect sialic acid, galactose, or fucose residues, along with neutravidin-PE (phycoerithrin). Data acquisition was performed using a LABScan 3D™. Results Pretreated Class I and II single antigen beads maintained DSA binding capabilities comparable to the untreated conventional beads when PAN IgG-PE was used as the detection agent. Using pretreated beads, glycans on the bound DSA were specifically detectable with lectin/neutravidin based reporters with slight modification of conventional LABScreen® single antigen protocol (Figure: Detection of Class I DSA with lectin specific to galactose vs. PAN IgG). Conclusions We have demonstrated a simple and robust assay for detection of glycans on DSA using modifications of conventional LABScreen® single antigen technology. We used lectins as specific glycan probes and neutravidin-PE as a reporter. Further research is in progress to assess the clinical validity of the assay and to assess the predictive value of glycosylation profiles of Class I and II DSA on the outcome of kidney transplant recipients. Download : Download high-res image (109KB) Download : Download full-size image

Aim The association between donor specific antibodies (DSA) and renal transplant rejection has been generally established, but there are cases when a DSA is present without rejection. The Luminex® Single Antigen (SA) assay is the current standard for identifying HLA IgG antibody specificities and determining if they are donor specific. As a means to improve the ability to discriminate between harmful and benign antibodies, the SA C1q assay was developed to detect antibodies that are capable of fixing complement. We also have adapted the standard SA IgG assay by utilizing IgG-subclass specific monoclonal antibodies. We sought to explore the detection capacity of the three SA assays and their correlation with renal transplant rejection. Methods 23 patients were selected who had received biopsies due to graft dysfunction and all had C4d deposition on the peritubular capillaries. Out of the 23 patients who presented with graft dysfunction, 5 proceeded to graft loss. Serum samples collected within a week of the biopsy were used for Luminex SA IgG, C1q and IgG subclass analysis. Results All 23 C4d+ patients had SA IgG DSAs with an average of 12,500 MFI (cumulative DSA MFI). 25 control patients with C4d− biopsies had average DSAs less than 500 MFI. The C1q assay showed 16 positive results out of the 23 DSA and C4d+ patients. The C1q assay appeared to be less sensitive particularly when multiple low level IgG DSAs occurred. There was no significant correlation to graft loss and C1q positivity. The IgG subclass assay showed complement fixing IgG1 in 20 of 23 patients. IgG2 DSAs were found in six patients and IgG3 DSAs were found in two patients, all in conjunction with IgG1 DSAs. Interestingly, IgG4 was seen in 10 of the 23 recipients’ sera, but always along with complement fixing IgG1. The detection of IgG4 subclass did not correspond to any enhanced graft survival outcome. Conclusions Cumulative DSA’s above 10,000 MFI were associated with C4d deposition and complement fixation. In this study of patients with C4d+ biopsies, 100% had IgG DSAs, 70% had C1q+ DSAs, and 83% had complement fixing IgG subclass antibodies. We could not demonstrate any enhanced benefit of IgG4. However, in this cohort of patients, IgG4 appeared coincidently to IgG1, and we have previously seen excellent function in patients when IgG4 DSA exists alone.