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• W2364741317 abstract "Pretransplant autoantibodies to LG3 and angiotensin II type 1 receptors (AT1R) are associated with acute rejection in kidney transplant recipients, whereas antivimentin autoantibodies participate in heart transplant rejection. Ischemia–reperfusion injury (IRI) can modify self-antigenic targets. We hypothesized that ischemia–reperfusion creates permissive conditions for autoantibodies to interact with their antigenic targets and leads to enhanced renal damage and dysfunction. In 172 kidney transplant recipients, we found that pretransplant anti-LG3 antibodies were associated with an increased risk of delayed graft function (DGF). Pretransplant anti-LG3 antibodies are inversely associated with graft function at 1 year after transplantation in patients who experienced DGF, independent of rejection. Pretransplant anti-AT1R and antivimentin were not associated with DGF or its functional outcome. In a model of renal IRI in mice, passive transfer of anti-LG3 IgG led to enhanced dysfunction and microvascular injury compared with passive transfer with control IgG. Passive transfer of anti-LG3 antibodies also favored intrarenal microvascular complement activation, microvascular rarefaction and fibrosis after IRI. Our results suggest that anti-LG3 antibodies are novel aggravating factors for renal IRI. These results provide novel insights into the pathways that modulate the severity of renal injury at the time of transplantation and their impact on long-term outcomes. Pretransplant autoantibodies to LG3 and angiotensin II type 1 receptors (AT1R) are associated with acute rejection in kidney transplant recipients, whereas antivimentin autoantibodies participate in heart transplant rejection. Ischemia–reperfusion injury (IRI) can modify self-antigenic targets. We hypothesized that ischemia–reperfusion creates permissive conditions for autoantibodies to interact with their antigenic targets and leads to enhanced renal damage and dysfunction. In 172 kidney transplant recipients, we found that pretransplant anti-LG3 antibodies were associated with an increased risk of delayed graft function (DGF). Pretransplant anti-LG3 antibodies are inversely associated with graft function at 1 year after transplantation in patients who experienced DGF, independent of rejection. Pretransplant anti-AT1R and antivimentin were not associated with DGF or its functional outcome. In a model of renal IRI in mice, passive transfer of anti-LG3 IgG led to enhanced dysfunction and microvascular injury compared with passive transfer with control IgG. Passive transfer of anti-LG3 antibodies also favored intrarenal microvascular complement activation, microvascular rarefaction and fibrosis after IRI. Our results suggest that anti-LG3 antibodies are novel aggravating factors for renal IRI. These results provide novel insights into the pathways that modulate the severity of renal injury at the time of transplantation and their impact on long-term outcomes. In the immediate posttransplant period, ischemia–reperfusion injury (IRI) to kidney allografts leads to acute kidney injury (AKI) in 20–50% of transplantations from deceased donors (1.Cavaille-Coll M Bala S Velidedeoglu E Summary of FDA workshop on ischemia reperfusion injury in kidney transplantation.Am J Transplant. 2013; 13 (et al): 1134-1148Crossref PubMed Scopus (110) Google Scholar, 2.Irish WD McCollum DA Tesi RJ Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients.J Am Soc Nephrol. 2003; 14 (et al): 2967-2974Crossref PubMed Scopus (177) Google Scholar, 3.Lechevallier E Dussol B Luccioni A Posttransplantation acute tubular necrosis: Risk factors and implications for graft survival.Am J Kidney Dis. 1998; 32 (et al): 984-991Abstract Full Text PDF PubMed Scopus (81) Google Scholar). Posttransplant AKI manifests as delayed graft function (DGF), a condition that refers to the need for dialysis, or the failure of serum creatinine to decrease adequately in the first week after transplantation (4.Yarlagadda SG Coca SG Garg AX Marked variation in the definition and diagnosis of delayed graft function: A systematic review.Nephrol Dial Transplant. 2008; 23 (et al): 2995-3003Crossref PubMed Scopus (282) Google Scholar). DGF is associated with an increased risk of acute rejection (5.Wu WK Famure O Li Y Kim SJ. Delayed graft function and the risk of acute rejection in the modern era of kidney transplantation.Kidney Int. 2015; 88: 851-858Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar) and reduced long-term graft survival in some (6.Legendre C Canaud G Martinez F. Factors influencing long-term outcome after kidney transplantation.Transpl Int. 2014; 27: 19-27Crossref PubMed Scopus (156) Google Scholar, 7.Yarlagadda SG Coca SG Formica Jr, RN Poggio ED Parikh CR. Association between delayed graft function and allograft and patient survival: A systematic review and meta-analysis.Nephrol Dial Transplant. 2009; 24: 1039-1047Crossref PubMed Scopus (536) Google Scholar) but not all studies (8.Boom H Mallat MJ de Fijter JW de Fijter J Zwinderman AH Paul LC. Delayed graft function influences renal function, but not survival.Kidney Int. 2000; 58: 859-862Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 9.Lapointe I Lachance JG Noel R Impact of donor age on long-term outcomes after delayed graft function: 10-year follow-up.Transpl Int. 2013; 26 (et al): 162-169Crossref Scopus (15) Google Scholar). This suggests that undefined factors may synergize with DGF in some patients but not in others to durably alter renal function. Renal epithelial cell injury and death are major hallmarks of AKI. In recent years, however, microvascular damage has emerged as a major contributor to acute and long-term renal dysfunction secondary to AKI (10.Verma SK Molitoris BA. Renal endothelial injury and microvascular dysfunction in acute kidney injury.Semin Nephrol. 2015; 35: 96-107Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). In the acute phases of AKI, injury to the peritubular capillaries (PTC) enhances renal hypoperfusion and tubular cell damage. In the long term, microvascular injury leads to microcapillary rarefaction, promoting interstitial fibrosis and contributing to progression of chronic kidney disease (11.Basile DP. The endothelial cell in ischemic acute kidney injury: Implications for acute and chronic function.Kidney Int. 2007; 72: 151-156Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar). Whether factors implicated in shaping the severity of microvascular damage during AKI could contribute to the long-term impact of AKI on renal function remains to be evaluated. An association between autoantibodies and acute or chronic vascular rejection in kidney, heart and lung transplant patients has been shown in recent years (12.Bharat A Saini D Steward N Antibodies to self-antigens predispose to primary lung allograft dysfunction and chronic rejection.Ann Thorac Surg. 2010; 90 (et al): 1094-1101Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 13.Dragun D Muller DN Brasen JH Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.N Engl J Med. 2005; 352 (et al): 558-569Crossref PubMed Scopus (678) Google Scholar, 14.Gao B Moore C Porcheray F Pretransplant IgG reactivity to apoptotic cells correlates with late kidney allograft loss.Am J Transplant. 2014; 14 (et al): 1581-1591Crossref PubMed Scopus (43) Google Scholar, 15.Jurcevic S Ainsworth ME Pomerance A Antivimentin antibodies are an independent predictor of transplant-associated coronary artery disease after cardiac transplantation.Transplantation. 2001; 71 (et al): 886-892Crossref PubMed Scopus (216) Google Scholar, 16.Mahesh B Leong HS McCormack A Sarathchandra P Holder A Rose ML. Autoantibodies to vimentin cause accelerated rejection of cardiac allografts.Am J Pathol. 2007; 170: 1415-1427Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). Autoantibodies against angiotensin II type 1 receptors (AT1R), vimentin and perlecan LG3 fragment behave as accelerators of rejection in animal models of kidney, heart and/or aortic transplantation (13.Dragun D Muller DN Brasen JH Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.N Engl J Med. 2005; 352 (et al): 558-569Crossref PubMed Scopus (678) Google Scholar, 16.Mahesh B Leong HS McCormack A Sarathchandra P Holder A Rose ML. Autoantibodies to vimentin cause accelerated rejection of cardiac allografts.Am J Pathol. 2007; 170: 1415-1427Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 17.Cardinal H Dieude M Brassard N Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury.Am J Transplant. 2013; 13 (et al): 861-874Crossref PubMed Scopus (86) Google Scholar). In addition to their role in acceleration of rejection, mounting evidence suggests that some types of autoantibodies can also mediate tissue damage associated with IRI (18.Zhang M Alicot EM Carroll MC. Human natural IgM can induce ischemia/reperfusion injury in a murine intestinal model.Mol Immunol. 2008; 45: 4036-4039Crossref PubMed Scopus (38) Google Scholar, 19.Zhang M Carroll MC. Natural IgM-mediated innate autoimmunity: A new target for early intervention of ischemia-reperfusion injury.Expert Opin Biol Ther. 2007; 7: 1575-1582Crossref PubMed Scopus (37) Google Scholar). In animal models of intestinal IRI, the binding of natural autoantibodies to self-antigenic targets leads to enhanced tissue damage through complement activation (20.Zhang M Austen Jr, WG Chiu I Identification of a specific self-reactive IgM antibody that initiates intestinal ischemia/reperfusion injury.Proc Natl Acad Sci USA. 2004; 101 (et al): 3886-3891Crossref PubMed Scopus (185) Google Scholar). Ischemia has been shown to enhance the vasoconstrictive effect of anti-AT1R autoantibodies (17.Cardinal H Dieude M Brassard N Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury.Am J Transplant. 2013; 13 (et al): 861-874Crossref PubMed Scopus (86) Google Scholar, 21.Lukitsch I Kehr J Chaykovska L Renal ischemia and transplantation predispose to vascular constriction mediated by angiotensin II type 1 receptor-activating antibodies.Transplantation. 2012; 94 (et al): 8-13Crossref PubMed Scopus (48) Google Scholar). We showed previously that vascular ischemia greatly enhances the capacity of anti-LG3 antibodies to enhance vascular inflammation (17.Cardinal H Dieude M Brassard N Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury.Am J Transplant. 2013; 13 (et al): 861-874Crossref PubMed Scopus (86) Google Scholar). We hypothesized that IRI can create permissive conditions for autoantibodies such as anti-LG3, anti-AT1R and antivimentin to interact with their antigenic targets and potentially enhance renal damage and renal dysfunction, even in the absence of rejection. To test this hypothesis, we assessed whether these autoantibodies, measured immediately prior to transplantation, were associated with an increased risk of DGF and with lower long-term graft function in kidney transplant recipients. We then turned to an animal model of renal IRI to better understand the mechanisms by which autoantibodies modulate renal injury. We performed a retrospective cohort study of consecutive patients who received kidney transplantation at our center between June 1, 2008, and June 1, 2013. All patients participated in the Centre Hospitalier de l'Université de Montréal (CHUM) clinical and biological database, and sera were banked immediately prior to transplantation. Clinical information was retrieved from the electronic database and complemented by chart review by trained research nurses as needed. Patients entered the cohort on the date of transplantation and were followed until February 1, 2015. The study was approved by our local ethics review board. The primary outcome was the occurrence of DGF. DGF was defined as the need for dialysis in the first posttransplant week, as the failure of serum creatinine to decrease by >10% on the first three postoperative days or as serum creatinine levels >250 μmol/L on postoperative day 5 in the presence of scintigraphic evidence of acute tubular necrosis (4.Yarlagadda SG Coca SG Garg AX Marked variation in the definition and diagnosis of delayed graft function: A systematic review.Nephrol Dial Transplant. 2008; 23 (et al): 2995-3003Crossref PubMed Scopus (282) Google Scholar). The secondary outcome was graft function at 1 year after transplantation, estimated with the MDRD four-variable equation (22.Shaffi K Uhlig K Perrone RD Performance of creatinine-based GFR estimating equations in solid-organ transplant recipients.Am J Kidney Dis. 2014; 63 (et al): 1007-1018Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Anti-AT1R, antivimentin and anti-LG3 antibodies were measured on pretransplant sera. We used a locally developed enzyme-linked immunosorbent assay (ELISA) to measure anti-LG3 IgG antibodies, as described previously (17.Cardinal H Dieude M Brassard N Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury.Am J Transplant. 2013; 13 (et al): 861-874Crossref PubMed Scopus (86) Google Scholar). We used a commercially available ELISA to measure anti-AT1R (One Lambda; Thermo Fisher Scientific, Waltham, MA) and antivimentin antibodies (Antibodies-online.com, Atlanta, GA). For anti-AT1R, the threshold for positivity was >17 U/mL; results between 10 and 17 U/mL were considered intermediate, and results <10 U/mL were considered negative. For antivimentin, values >1.31 (sample positivity index, semiquantitative measurement) were positive; values between 1 and 1.3 were considered intermediate, and values <1 were negative, according to the manufacturer's protocol. We collected data on recipient medical history and demographic characteristics (age, sex, renal disease, number of previous transplantations and pretransplant panel reactive antibodies), donor characteristics (donor type, age, height, weight, hypertension and diabetes), procedural and management characteristics (cold ischemic time, induction type and maintenance immunosuppressive protocol), and posttransplant outcomes (rejection according to the Banff 2013 classification (23.Haas M Sis B Racusen LC Banff 2013 meeting report: Inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions.Am J Transplant. 2014; 14 (et al): 272-283Crossref PubMed Scopus (1061) Google Scholar), graft function, and patient and graft survival). Continuous variables are reported as means and standard deviations, and categorical variables are summarized as proportions. Student t-tests were used to compare between-group differences for continuous variables according to their distribution. Chi-square or Fisher exact tests were used to determine differences between categorical variables. Logistic regression was used to assess whether pretransplant anti-LG3, anti-AT1R and antivimentin antibodies were associated with DGF. The pretransplant autoantibodies were analyzed as categorical variables. After plotting the median of each quartile of the distribution for each antibody against the log odds of cases to controls, we chose a cutoff of 225 (corresponding to the median of the last quartile) for anti-LG3 positivity. Because there was no visual signal for a potential cutoff between anti-AT1R or antivimentin and the outcome, we used the manufacturer's recommended cutoff for positivity. Variables with a p-value <0.05 on univariate analysis were included in the final multivariate model. No other variables were forced into the model to avoid overfitting. Linear regression was used to study the association between graft function at 1 year after transplant and pretransplant anti-LG3 titers. Analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). Adult C57Bl/6 mice (20–25 g) were purchased from Charles River Laboratories (Wilmington, MA), maintained on a 12-h light/dark cycle and fed a normal diet ad libitum. All experiments on mice were approved by the institutional animal care and use committee of the CHUM research center. AKI in mice was carried out, as described previously (24.Wei Q Dong Z. Mouse model of ischemic acute kidney injury: Technical notes and tricks.Am J Physiol Renal Physiol. 2012; 303: F1487-F1494Crossref PubMed Scopus (207) Google Scholar). Briefly, mice were anaesthetized using isoflurane (2%) by inhalation and were placed on a heated surgical pad. A midline incision was made; microvascular clamps were placed on the left renal pedicle for 30 min and then released. The right kidney was removed after the release of microvascular clamps. Naïve C57Bl/6 mice were injected subcutaneously with either recombinant LG3 (50 μg) or phosphate-buffered saline (PBS) and emulsified in incomplete Freund's adjuvant every 2 weeks for a total of four immunizations. Blood was recovered with cardiac puncture at sacrifice 12–14 days after the last immunization. Sera (diluted 1/100) were tested for the presence of anti-LG3 IgG, as described. IgG was isolated from pooled sera of either LG3-immunized mice (anti-LG3 IgG) or PBS-immunized mice (control IgG) using protein A Sepharose CL-4B (Sigma-Aldrich, St. Louis, MO) and quantitated by the Micro BCA assay (Pierce; Thermo Fisher Scientific). For passive transfer of anti-LG3 IgGs, mice received tail-vein intravenous injections of 50 μg anti-LG3 IgG or control IgG. Each group received injections 2 days before surgery, the day of surgery and every other day until sacrifice. Three doses were given to mice that were sacrificed at day 2 after surgery, or four doses was given to those sacrificed at day 7 after surgery. Clamped kidneys were recovered at day 2 or 7 after surgery; tissues were fixed with 10% neutral buffered formalin and were paraffin embedded, according to usual methods. Samples were cut into 4-μm slices. Immunohistochemistry was performed on paraffin-embedded sections using an automated immunostainer (ArtisanLink; Dako, Glostrup, Denmark), according to the manufacturer's protocols. The antibodies used in our study were C4d (1/1600, BI-RC4D; Alpco, Salem, NH), C5b-9 or membrane attack complex (MAC; 1/200, SC5b-9; Quidel, San Diego, CA), CD31 (1/20, CM303A; Biocare Medical, Concord, CA), α-smooth muscle actin (α-SMA; 1/500, clone 1A4; Dako), collagen IV (1/100, AB769; Millipore, Billerica, MA) and caspase 3 (1/50, CP229B; Biocare Medical). Digital images of stained tissues were captured by a Leica DMLS microscope and a Leica DFC420C camera (Leica Microsystems, Wetzlar, Germany). CD31-positive staining was quantified using Visiomorph (Visiopharm, Hoersholm, Denmark). Histopathological scoring was done in renal sections stained with hematoxylin and eosin, as described previously (25.Leemans JC Stokman G Claessen N Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney.J Clin Invest. 2005; 115 (et al): 2894-2903Crossref PubMed Scopus (470) Google Scholar). Briefly, the percentage of damaged tubules in the renal cortex was estimated using a five-point scale based on the following criteria: brush border loss, tubular dilatation, cast deposition and cellular necrosis in 10 randomly selected, nonoverlapping fields (×200 magnification). Lesions were graded on a scale from 0 to 5: 0 indicated normal; 1 indicated mild, involvement of <10% of the cortex; 2 indicated moderate, involvement of 10–25% of the cortex; 3 indicated severe, involvement of 25–50% of the cortex; 4 indicated very severe, involvement of 50–75% of cortex; and 5 indicated extensive damage, involvement of >75% of the cortex (25.Leemans JC Stokman G Claessen N Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney.J Clin Invest. 2005; 115 (et al): 2894-2903Crossref PubMed Scopus (470) Google Scholar). The Vitros CREA method was performed for measurement of serum creatinine using the Vitros CREA Slides and the Vitros Chemistry Products (Vitros 250/350 Chemistry Systems; Ortho Clinical Diagnostics, Raritan, NJ). Levels of blood urea nitrogen (BUN) were measured using the Quantichrom urea assay kit (BioAssay Systems, Hayward, CA). Among the 173 patients included in this study, one died from myocardial infarction immediately after transplantation and another died within 1 year after transplant (Figure 1). Recipient, donor and periprocedural characteristics are shown in Table 1. All patients received tacrolimus, mycophenolate mofetil and prednisone, except for three patients who received cyclosporine in combination with mycophenolate mofetil and prednisone. Patient and graft survival over a median follow-up of 3.5 years were 95% and 89%, respectively. We observed no associations between pretransplant positivity for anti-LG3 and antivimentin antibodies and previous sensitizing events (transplantations, pregnancies or transfusions) or classical autoimmune diseases (lupus erythematosus, anti–neutrophil cytoplasmic antibodies or anti–glomerular basement membrane–associated vasculitis) (Figure S1). Positivity for anti-AT1R was more frequent in retransplant patients (p < 0.01) (Figure S1A). Pretransplant anti-LG3 titers were associated with antivimentin (p = 0.23, 95% confidence interval [CI] 0.08–0.37) but not with anti-AT1R titers (p = 0.15, 95% CI −0.01 to 0.29).Table 1Recipient and donor characteristics (n = 172)CharacteristicsResultsAge in years, mean (SD)50 (12)Male sex, n (%)107 (62)Race, n (%)White149 (86)Black13 (8)Other10 (6)Cause of chronic kidney disease, n (%)1Number of patients exceeds 172 because some patients had two listed causes of chronic kidney disease or received more than one type of induction.Glomerular diseases51 (30)Diabetes25 (15)Hypertension/vascular9 (5)Polycystic kidney diseases39 (23)Autoimmune diseases8 (5)Other47 (27)Pretransplant CDC panel reactive antibodies >20%, n (%)6 (4)First transplantation, n (%)148 (86)Living donor, n (%)69 (40)Deceased donor, n (%)Neurological determination of death96 (56)Donor after cardiocirculatory arrest7 (4)Cold ischemic time in hours, mean (SD)8 (5)Donor age in years, mean (SD)47 (14)Donor with hypertension or diabetes, n (%)21 (12)Donor height in meters, mean (SD)1.67 (0.1)Induction, n (%)1Number of patients exceeds 172 because some patients had two listed causes of chronic kidney disease or received more than one type of induction.Thymoglobulin52 (30)Anti-CD25131 (76)CDC, complement-dependent cytotoxicity; SD, standard deviation.1 Number of patients exceeds 172 because some patients had two listed causes of chronic kidney disease or received more than one type of induction. Open table in a new tab CDC, complement-dependent cytotoxicity; SD, standard deviation. Of the 172 study participants included in the primary outcome analysis, 53 (31%) experienced DGF, as defined above, of whom 12 needed hemodialysis in the first week after transplantation. Pretransplant anti-LG3 titers were higher in patients with DGF compared with those with immediate graft function, whereas pretransplant anti-AT1R and antivimentin antibody titers were similar in both groups (Figure 2). When antibodies were analyzed as dichotomous variables, we also observed a difference in pretransplant positivity status for anti-LG3 antibodies—but not in anti-AT1R or antivimentin—between patients who developed DGF and those who did not (Figure 3). This was also true when anti-AT1R and antivimentin antibodies were classified as positive, intermediate, and negative (data not shown). In univariate analyses, positive pretransplant anti-LG3 status was associated with DGF (odds ratio [OR] 2.57, 95% CI 1.03–6.38, p = 0.04), whereas positive pretransplant anti-AT1R status (OR 1.10, 95% CI 0.42–2.91, p = 0.84) and positive antivimentin status (OR 0.95, 95% CI 0.48–1.89, p = 0.88) were not (Table 2). Rejection was not associated with an increased risk of DGF (OR 1.61, 95% CI 0.50–5.51, p = 0.40). In multivariate analyses, positive pretransplant anti-LG3 status (OR 2.77, 95% CI 1.01–7.68), female sex (OR 0.35, 95% CI 0.16–0.79), donor type (deceased after neurological determination of death vs. living: OR 2.89, 95% CI 1.31–6.36; deceased after cardiocirculatory arrest vs. living: OR 16.00, 95% CI 2.32–110.75), and donor height (OR 0.64 per 10-cm increase, 95% CI 0.44–0.91) were independently associated with DGF.Figure 3Pretransplant positivity status for anti-LG3, anti-AT1R, and antivimentin antibodies in patients with and without DGF.Show full captionThe proportion of patients who were positive for pretransplant anti-LG3 antibodies (titers >225 optical density) was greater in patients who went on to develop DGF than in those who did not (21% vs. 9%, *p = 0.03), whereas the proportions of patients with positive pretransplant antivimentin or anti-AT1R antibodies were similar in patients who went on to develop DGF and in those who did not (antivimentin: 42% vs. 43%, p = 0.87; anti-AT1R: 15% vs. 14%, p = 0.89). ATR1, angiotensin II type 1 receptor; DGF, delayed graft function.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 2Factors associated with delayed graft functionFactorUnivariate OR (95% CI)Multivariate OR (95% CI)Positive pretransplant anti-LG3 titers1Pretransplant anti-LG3 titers >225 optical density, pretransplant antivimentin titers ≥1.31 sample positivity index and pretransplant anti-AT1R antibodies >17 U/mL.2.57 (1.03–6.38)*p < 0.05.2.77 (1.01–7.68)*p < 0.05.Female sex (vs. male)0.32 (0.15–0.67)*p < 0.05.0.35 (0.16–0.79)*p < 0.05.Donor type (vs. living donor)Donor after neurological determination of death2.85 (1.35–6.02)*p < 0.05.2.89 (1.31–6.36)*p < 0.05.Donor after cardiocirculatory arrest11.88 (2.05–68.61)*p < 0.05.16.00 (2.32–110.75)*p < 0.05.Donor height (per 10-cm increase)0.67 (0.48–0.94)0.64 (0.44–0.91)*p < 0.05.Acute rejection in the first 3 weeks after transplant1.66 (0.50–5.51)–Donor age >60 years1.82 (0.77–4.28)–Cold ischemic time (per 1-h increase)1.06 (1.00–1.12)*p < 0.05.–Recipient BMI (per 1-U increase)1.07 (1.00–1.16)–Positive pretransplant antivimentin antibodies1Pretransplant anti-LG3 titers >225 optical density, pretransplant antivimentin titers ≥1.31 sample positivity index and pretransplant anti-AT1R antibodies >17 U/mL.0.95 (0.48–1.89)–Positive pretransplant anti-AT1R antibodies1Pretransplant anti-LG3 titers >225 optical density, pretransplant antivimentin titers ≥1.31 sample positivity index and pretransplant anti-AT1R antibodies >17 U/mL.1.10 (0.42–2.91)AT1R, angiotensin II type 1 receptor; CI, confidence interval; OR, odds ratio.1 Pretransplant anti-LG3 titers >225 optical density, pretransplant antivimentin titers ≥1.31 sample positivity index and pretransplant anti-AT1R antibodies >17 U/mL.* p < 0.05. Open table in a new tab The proportion of patients who were positive for pretransplant anti-LG3 antibodies (titers >225 optical density) was greater in patients who went on to develop DGF than in those who did not (21% vs. 9%, *p = 0.03), whereas the proportions of patients with positive pretransplant antivimentin or anti-AT1R antibodies were similar in patients who went on to develop DGF and in those who did not (antivimentin: 42% vs. 43%, p = 0.87; anti-AT1R: 15% vs. 14%, p = 0.89). ATR1, angiotensin II type 1 receptor; DGF, delayed graft function. AT1R, angiotensin II type 1 receptor; CI, confidence interval; OR, odds ratio. To evaluate whether autoantibodies can negatively affect renal function independent of their role in induction or acceleration of rejection, we evaluated the association between pretransplant autoantibody titers and renal function at 1 year. Among the 171 patients available for this analysis, estimated GFR (eGFR) at 1 year after transplantation was lower in patients with DGF compared with immediate graft function (44 ± 16 vs. 61 ± 22 mL/min per 1.73 m2, p = 0.001). In patients with DGF, eGFR at 1 year after transplantation was significantly lower in patients who had positive pretransplant anti-LG3 antibodies (p = 0.003) (Figure 4). Positive pretransplant anti-LG3 status, but not antivimentin or anti-AT1R status, was associated with reduced eGFR at 1 year after transplantation in patients with DGF (β = −15 mL/min per 1.73 m2, 95% CI −24 to −5) (Table 3). Donor age (β = −3 mL/min per 1.73 m2, 95% CI −19 to 0) and height (β = 4 mL/min per 1.73 m2 per 10-cm increase, 95% CI 1–8) were also associated with 1-year graft function in patients with DGF, whereas rejection and donor type were not (Table 3). We observed no relationship between any of the pretransplant autoantibodies and 1-year graft function in patients with immediate graft function. These results support the notion that in recipients of a renal allograft with DGF, elevated anti-LG3 titers at the time of transplantation durably and negatively affect renal function. This effect was specific to anti-LG3 antibodies; antivimentin and anti-AT1R antibodies were not associated with 1-year graft function.Table 3Factors associated with graft function 1 year after transplantation in patients with delayed graft functionFactorUnivariate β (95% CI)Multivariate β (95% CI)Positive pretransplant anti-LG3 titers1Pretransplant anti-LG3 titers >225 optical density, pretransplant antivimentin titers ≥1.31 sample positivity index and pretransplant anti-AT1R antibodies >17 U/mL.−14 (−25 to −3)*p < 0.05.−15 (−24 to −5)*p < 0.05.Donor age (per 10-year increase)−2 (−5 to 0)−3 (−19 to 0)*p < 0.05.Donor type (reference living donor)Donor after neurological determination of death2 (−8 to 13)2 (−7 to 12)Donor after cardiocirculatory arrest7 (−10 to 24)4 (−11 t" @default.
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• W2364741317 date "2016-12-01" @default.
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• W2364741317 title "Anti-LG3 Antibodies Aggravate Renal Ischemia–Reperfusion Injury and Long-Term Renal Allograft Dysfunction" @default.
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