Prospective study on immune function in renal transplant patients during perioperative period: A prospective cohort study.

Delayed graft function (DGF) is a type of acute renal failure that is closely linked to the immune system. The objective of this study is to investigate immune trends during the perioperative period of renal transplantation and compare the variations between patients with DGF and immediate graft function (IGF). A total of 48 kidney transplant patients were enrolled. Parameters including stimulated adenosine triphosphatase concentrations (sATP), nonstimulated ATP concentrations, white blood cells, and lymphocyte count were assessed. Patients were categorized into the DGF or IGF group. Clinical information and changes in immune markers were compared. Receiver operating characteristic analysis was performed to determine the sensitivity and specificity in predicting DGF. Additionally, separate immune function analyses were conducted for the 3 infection cases. Following induction immunosuppressive therapy, white blood cells, and neutrophil count showed a significant initial increase followed by a gradual decline. Lymphocyte count, nonstimulated ATP concentrations, and sATP exhibited an initial significant decrease followed by a slow recovery. Immune markers between the DGF and IGF groups were significantly different at day 4 after renal transplantation. Only sATP levels at day 4 after renal transplantation (area under the curve = 0.731, sensitivity = 0.864, specificity = 0.684) demonstrated predictive value for DGF occurrence. Among the 3 infection cases, 2 cases exhibited persistently decreased sATP levels and died within the first month and 6 months, while the remaining case showed a recovery of sATP levels at D9 and survived. These findings indicate that sATP level can potentially serve as a biomarker reflecting the impact of immunosuppressants. Poor recovery of sATP may be associated with DGF, infection, or even mortality.

Risk factors of delayed graft function following living donor kidney transplantation: A meta-analysis.

INTRODUCTION: Delayed graft function (DGF) is a common condition that necessitates dialysis during the first week after transplantation. Although DGF rarely occurs following living-donor kidney transplantation (LDKT), it may eventually lead to acute or chronic graft rejection. This study aimed to assess the risk factors for DGF in patients who underwent LDKT. METHODS: A systematic review and meta-analysis of studies published before August 2022 was conducted using the PubMed, Science Direct, Cochrane, and Directory of Open Access Journal (DOAJ) databases. The review included studies that assessed the incidence of DGF following LDKT, and examined its risk factors, while excluding studies involving deceased donors. Potential risk factors were analyzed using pooled mean differences or odds ratios with 95% confidence intervals (CIs). Review Manager 5.3 was used for the meta-analysis. RESULTS: Among the 13 included studies, 3685 cases of DGF were identified in a total of 113,261 patients (3.25%). Potential risk factors for DGF following LDKT were examined across several aspects, including donor, recipient, donor/recipient relationship, and immunological and intraoperative factors. The identified risk factors included older donors (P = 0.07), male recipients (P < 0.0001), higher recipient body mass index (BMI) (P < 0.0001), non-white recipients (P < 0.0001), pre-existing diabetes (P < 0.0001), pre-existing hypertension (P = 0.01), history of dialysis (P < 0.0001), re-transplantation (P = 0.004), unrelated donor/recipient (P = 0.02), ABO incompatibility (P < 0.0001), higher panel reactive antibody (PRA) levels (P < 0.0001), utilization of right kidney (P < 0.0001), and longer cold ischemia time (CIT) (P = 0.004). CONCLUSION: Several factors related to the donor, recipient, donor/recipient relationship, and immunological and intraoperative aspects were identified as potential risk factors for the development of DGF following LDKT. Addressing and optimizing these factors may improve the long-term outcomes of LDKT.

Effects of Antithymocyte Globulin, Basiliximab, and Induction-Free Treatment in Living Donor Kidney Transplant Recipients on Tacrolimus-Based Immunosuppression.

OBJECTIVES: Induction treatment in renal transplant is associated with better graft survival. However, intensified immunosuppression is known to cause unwanted side effects such as infection and malignancy. Furthermore, the effects of the routine use of immunosuppressants in low-risk kidney transplant recipients are still not clear. In this study, we assessed the first-year safety and efficacy of induction treatment. MATERIALS AND METHODS: We examined first living donor kidney transplant patients who were on tacrolimus based immunosuppression therapy. We formed 3 groups according to the induction status: antithymocyte globulin induction, basiliximab induction, and no induction. We collected outcome data on delayed graft function, graft loss, creatinine levels, estimated glomerular filtration rates, acute rejection episodes, hospitalization episodes, and infection episodes, including cytomegalovirus infection and bacterial infections. RESULTS: We examined a total of 126 patients (age 35 ± 12 years; 65% male). Of them, 25 received antithymocyte globulin, 52 received basiliximab, and 49 did notreceive any induction treatment. We did not observe any statistically significant difference among the 3 groups in terms of acute rejection episodes, delayed graft function, and first-year graft loss. The estimated glomerular filtration rates were similar among the groups. Overall bacterial infectious complications and cytomegalovirus infection showed similar prevalence among all groups. Hospitalization was less common in the induction-free group. CONCLUSIONS: In low-risk patients, induction-free regimens could be associated with a better safety profile without compromising graft survival. Therefore, induction treatment may be disregarded in first living donor transplant patients who receive tacrolimusbased triple immunosuppression treatment.

Recipient myeloperoxidase-producing cells regulate antibody-mediated acute versus chronic kidney allograft rejection.

Antibody-mediated rejection (ABMR) continues to be a major problem undermining the success of kidney transplantation. Acute ABMR of kidney grafts is characterized by neutrophil and monocyte margination in the tubular capillaries and by graft transcripts indicating NK cell activation, but the myeloid cell mechanisms required for acute ABMR have remained unclear. Dysregulated donor-specific antibody (DSA) responses with high antibody titers are induced in B6.CCR5-/- mice transplanted with complete MHC-mismatched A/J kidneys and are required for rejection of the grafts. This study tested the role of recipient myeloid cell production of myeloperoxidase (MPO) in the cellular and molecular components of acute ABMR. Despite induction of equivalent DSA titers, B6.CCR5-/- recipients rejected A/J kidneys between days 18 and 25, with acute ABMR, whereas B6.CCR5-/-MPO-/- recipients rejected the grafts between days 46 and 54, with histopathological features of chronic graft injury. On day 15, myeloid cells infiltrating grafts from B6.CCR5-/- and B6.CCR5-/-MPO-/- recipients expressed marked phenotypic and functional transcript differences that correlated with the development of acute versus chronic allograft injury, respectively. Near the time of peak DSA titers, activation of NK cells to proliferate and express CD107a was decreased within allografts in B6.CCR5-/-MPO-/- recipients. Despite high titers of DSA, depletion of neutrophils reproduced the inhibition of NK cell activation and decreased macrophage infiltration but increased monocytes producing MPO. Overall, recipient myeloid cells producing MPO regulate graft-infiltrating monocyte/macrophage function and NK cell activation that are required for DSA-mediated acute kidney allograft injury, and their absence switches DSA-mediated acute pathology and graft outcomes to chronic ABMR.

ABO Blood Incompatibility Positively Affects Early Graft Function: Single-Center Retrospective Cohort Study.

BACKGROUND: We investigated the association between ABO-incompatible (ABO-I) kidney transplantation and early graft function. METHODS: We retrospectively analyzed 95 patients who underwent living donor kidney transplantation between May 2009 and July 2019. It included 61 ABO-compatible (ABO-C) and 34 ABO-I transplantations. We extracted data on immunologic profile, sex, age, cold ischemic time, type of immunosuppression, and graft function. Two definitions were used for slow graft function (SGF) as follows: postoperative day (POD) 3 serum creatinine level >3 mg/dL and estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m2. Logistic regression analysis was performed to analyze the effect of ABO-I on the incidence of SGF. RESULTS: The characteristics between the ABO-C and ABO-I were not different. ABO-I received rituximab and plasma exchange. Patients also received tacrolimus and mycophenolate mofetil for 2 weeks and prednisolone for 1 week before transplantation as preconditioning. Of the 95 study patients, 19 (20%) and 21 (22%) were identified with SGF according to POD 3 serum creatinine level or eGFR, respectively. Multivariable analysis revealed that ABO-I significantly reduced the incidence of SGF (odds ratio, 0.15; 95% confidence interval, 0.03-0.7; P = .02), and cold ischemic time >150 min increased the incidence of SGF (odds ratio, 6.5; 95% confidence interval, 1.7-25; P = .006). Similar results were identified in POD 3 eGFR. Inferior graft function in patients with SGF was identified up to 6 months after transplantation. CONCLUSION: ABO-I reduces the incidence of SGF, which is associated with an inferior graft function up to 6 months.

Induction with ATG in DCD kidney transplantation; efficacy and relation of dose and cell markers on delayed graft function and renal function.

AIM: We aimed to analyse the efficacy of the Thymoglobulin dose used for induction in controlled DCD kidneys, and its initial impact on blood cell and CD3 count, as predictors of efficacy. METHODS: 140 DCD patients who received ATG induction, were analysed. Intended dose was 1.25 mg/kg/day over 5 days, rounded to nearest 25 mg and not exceeding 125 mg/dose. Outcomes included the total dose in relation with rejection, DGF, graft survival, eGFR. The cell count response to ATG was assessed as predictors of outcome. RESULTS: Graft survival, was 96.2%, 92.4%, 85% at 1, 3 and 5 years. Rejection was 7% at 1 year and associated with eGFR at 3 (p = 0.003) and 5 years. ATG dose was not predictive of rejection but was associated with the day5 leucocyte and lymphocyte count (p < 0.001) and negatively with DGF (p = 0.05). In 31 patients day3 CD3 count was available and it was associated with rejection (p = 0.002), less DGF (p = 0.09), and 3 years eGFR (p = 0.01). CONCLUSION: Thymoglobulin provides excellent results in DCD kidneys that do not significantly differ with small dose variations. In higher doses it reduces DGF. Lymphocytes and CD3 count, may be useful surrogate markers of efficacy and outcome.

Pre-transplant HLA Antibodies and Delayed Graft Function in the Current Era of Kidney Transplantation.

Delayed graft function (DGF) occurs in a significant proportion of deceased donor kidney transplant recipients and was associated with graft injury and inferior clinical outcome. The aim of the present multi-center study was to identify the immunological and non-immunological predictors of DGF and to determine its influence on outcome in the presence and absence of human leukocyte antigen (HLA) antibodies. 1,724 patients who received a deceased donor kidney transplant during 2008-2017 and on whom a pre-transplant serum sample was available were studied. Graft survival during the first 3 post-transplant years was analyzed by multivariable Cox regression. Pre-transplant predictors of DGF and influence of DGF and pre-transplant HLA antibodies on biopsy-proven rejections in the first 3 post-transplant months were determined by multivariable logistic regression. Donor age ≥50 years, simultaneous pre-transplant presence of HLA class I and II antibodies, diabetes mellitus as cause of end-stage renal disease, cold ischemia time ≥18 h, and time on dialysis >5 years were associated with increased risk of DGF, while the risk was reduced if gender of donor or recipient was female or the reason for death of donor was trauma. DGF alone doubled the risk for graft loss, more due to impaired death-censored graft than patient survival. In DGF patients, the risk of death-censored graft loss increased further if HLA antibodies (hazard ratio HR=4.75, P < 0.001) or donor-specific HLA antibodies (DSA, HR=7.39, P < 0.001) were present pre-transplant. In the presence of HLA antibodies or DSA, the incidence of biopsy-proven rejections, including antibody-mediated rejections, increased significantly in patients with as well as without DGF. Recipients without DGF and without biopsy-proven rejections during the first 3 months had the highest fraction of patients with good kidney function at year 1, whereas patients with both DGF and rejection showed the lowest rate of good kidney function, especially when organs from ≥65-year-old donors were used. In this new era of transplantation, besides non-immunological factors, also the pre-transplant presence of HLA class I and II antibodies increase the risk of DGF. Measures to prevent the strong negative impact of DGF on outcome are necessary, especially during organ allocation for presensitized patients.

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction.

New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a "molecular" diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of "immunoquiescent" or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.

Kidney Transplantation and "Sex Mismatch": A 10-Year Single-Center Analysis.

BACKGROUND The effect of a relative disproportion in the size of a transplanted kidney (KT) on graft function and survival is well documented. However, the importance of the H-Y antigen (male donor and female recipient) has not been unambiguously confirmed. MATERIAL AND METHODS Our retrospective analysis consists of 230 deceased donor/recipient pairs. The aim of the study was to determine the effect of sex mismatch between donors and recipients on the function of the graft and the graft and patient survival. RESULTS In the group of male donors, a statistically significantly lower value of the eGFR (estimated glomerular filtration rate) was recorded for female recipients in the fifth year after the KT (=0.0047). The male donor/female recipient group was an independent risk factor for: eGFR (<60 ml/min (CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration) in the third year after KT [HR 0.1618; (P=0.0004)], acute rejection in the first year after KT [HR 1.8992; (P=0.0387)], and the 5-year graft survival was significantly worse in this group. By adjusting the results for age and induction, this group was at significantly higher risk for decreased graft function (eGFR <30 ml/min) if the age of the donor was ≤50 years old and the recipient was >45 years old in the fifth year [HR 11.1676; (P=0.0139)], the age of the donor was ≤50 years old/recipient was ≤45 years old in the third year [HR 1.2500; (P=0.0050)], and also in the fifth year after KT [HR 8.1993; (P=0.0183)]. CONCLUSIONS Based on our analysis, the differences in the incidence of acute rejection episodes as well as in graft survival among the different groups of patients were confirmed. The group with the highest risk, in cases of an acute rejection episode, is a male donor/female recipient.

Assessment of Organ Quality in Kidney Transplantation by Molecular Analysis and Why It May Not Have Been Achieved, Yet.

Donor organ shortage, growing waiting lists and substantial organ discard rates are key problems in transplantation. The critical importance of organ quality in determining long-term function is becoming increasingly clear. However, organ quality is difficult to predict. The lack of good measures of organ quality is a serious challenge in terms of acceptance and allocation of an organ. The underlying review summarizes currently available methods used to assess donor organ quality such as histopathology, clinical scores and machine perfusion characteristics with special focus on molecular analyses of kidney quality. The majority of studies testing molecular markers of organ quality focused on identifying organs at risk for delayed graft function, yet without prediction of long-term graft outcome. Recently, interest has emerged in looking for molecular markers associated with biological age to predict organ quality. However, molecular gene sets have not entered the clinical routine or impacted discard rates so far. The current review critically discusses the potential reasons why clinically applicable molecular quality assessment using early kidney biopsies might not have been achieved yet. Besides a critical analysis of the inherent limitations of surrogate markers used for organ quality, i.e., delayed graft function, the intrinsic methodological limitations of studies assessing organ quality will be discussed. These comprise the multitude of unpredictable hits as well as lack of markers of nephron mass, functional reserve and regenerative capacity.

Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage.

The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney's excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-ß), p16 ink4a , Wnt/ß-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function.

Receptor activator of the NFκB ligand system protects renal function during experimental renal ischemia-reperfusion in mice.

Renal ischemia-reperfusion (I/R) injury is closely associated with delayed graft function and poor long-term graft survival following transplantation. Various pathophysiologies can cause the deterioration of renal function; however, the immune system plays important roles in promoting and protecting renal tissues. Receptor activator of NFκB ligand (RANKL) is a member of the TNF superfamily and is produced by bone-forming osteoblasts; the receptor for RANKL is called RANK. In bone biology, RANKL-RANK signaling has been extensively studied, but its roles in the immune system are still obscure. We investigated the role of the RANK system in I/R injury of the kidney using an experimental mouse I/R model. The left renal pedicles of 10-week-old male mice were clamped for 60 min, and reperfusion and right nephrectomy were simultaneously performed. Separate groups were administered an anti-RANKL antibody and recombinant RANKL (rRANKL) 24 h prior to I/R. After reperfusion for a set period of time, the serum creatinine level was measured, and the left kidney was removed for histological examination and western blotting to evaluate the expression and localization of RANK-associated molecules and cytokines. The serum creatinine levels were significantly elevated after I/R injury. A time-dependent increase in RANKL was observed up to 24 h, whereas RANK was induced for 12 h after reperfusion. RANK was expressed in infiltrating inflammatory cells, which were positive for CD68, a marker of monocytes/macrophages. The pre-treatment with the anti-RANKL antibody significantly impaired renal function and increased the induction of inflammatory cytokines (TNFα and IL-6), Toll-like receptor (TLR4) and MyD88 (all p < .05) compared to the levels in the I/R group. However, rRANKL significantly improved renal function and decreased the levels of inflammatory cytokines (TNFα and IL-6), TLR4 and MyD88 (p < .05) compared to those in the I/R group. The present study is the first to evaluate the role of the RANK system in renal I/R injury. RANKL-RANK signaling affects macrophage function and results in the downregulation of TLR4 and reduction in TNFα and IL-6, leading to improved renal function following I/R injury.

Early Antibody-Mediated Kidney Transplant Rejection Associated With Anti-Vimentin Antibodies: A Case Report.

Improving precision in predicting alloreactivity is an important unmet need and may require individualized consideration of non-HLA antibodies. We report a 21-year-old man with kidney failure from immunoglobulin A nephropathy who met all traditional criteria for a "low-risk" transplant for immune memory. He was unsensitized and received a haplotype-matched living donor kidney transplant from his mother. There were no anti-HLA donor-specific antibodies and flow cross-match was negative. After immediate function, he developed delayed graft function on postoperative day 2. The transplant biopsy specimen was suggestive of antibody-mediated rejection and acute tubular injury with increased vimentin proximal tubular expression compared to the implantation biopsy specimen. He had a history of juvenile idiopathic arthritis, and non-HLA antibody screening demonstrated preformed anti-vimentin antibody. He was successfully treated with plasmapheresis, intravenous immunoglobulin, antithymocyte globulin, and methylprednisolone, with renal recovery. The follow-up biopsy specimen demonstrated decreased vimentin expression with decreased alloinflammation, and graft function remains stable at 1 year posttransplantation (estimated glomerular filtration rate, 62mL/min/1.73m2). We postulate that preformed anti-vimentin autoantibodies bound to vimentin expressed on apoptotic tubular epithelial cells induced by ischemia-reperfusion injury and to constitutively expressed vimentin on peritubular capillaries and podocytes. Our case is suggestive of the involvement of anti-vimentin antibody, for which the pathogenic epitopes may be exposed during ischemia-reperfusion injury.

Induction Therapy in Elderly Kidney Transplant Recipients With Low Immunological Risk.

BACKGROUND: In nonimmunized patients, similar rejection rates are observed for patients who have undergone thymoglobulin (antithymocyte globulins [ATG]) or basiliximab (BSX) therapy. While ATG may improve delayed graft function, it may also be associated with higher infection rates and malignancy risk. We compared survival and clinical outcomes in elderly recipients with low immunological risk according to their induction therapy. METHODS: We conducted a multicentric study on nonimmunized patients ≥65 years of age receiving a first kidney transplant between 2010 and 2017. The principal outcome was patient and graft survival. Secondary outcomes were cumulative probabilities of infection, first acute rejection episode, malignancy, de novo donor specific antibody, posttransplant diabetes (PTD), cardiac complications, estimated glomerular filtration rate, and occurrence of delayed graft function. Cox, logistic, or linear statistical models were used depending on the outcome studied, and models were weighted on the propensity scores. RESULTS: Two hundred and four patients were included in the BSX group and 179 in the ATG group with the average age of 71.0 and 70.5 years, respectively. Patient and graft survival at 3 years posttransplantation were 74% (95% CI, 65%-84%) and 68% (95% CI, 60%-78%) in ATG and BSX group, respectively, without significant difference. Occurrence of PTD was significatively higher in BSX group (23% versus 15%, P = 0.04) due to higher trough levels of Tacrolimus on month 3 (9.48 versus 7.30 ng/mL, P = 0.023). There was no difference in other evaluated outcomes. CONCLUSIONS: In elderly recipients, ATG does not lead to poorer outcomes compared with BSX and could permit lower trough levels of Tacrolimus, thus reducing occurrence of PTD.

Posttransplant Outcomes for cPRA-100% Recipients Under the New Kidney Allocation System.

BACKGROUND: There is concern in the transplant community that outcomes for the most highly sensitized recipients might be poor under Kidney Allocation System (KAS) high prioritization. METHODS: To study this, we compared posttransplant outcomes of 525 pre-KAS (December 4, 2009, to December 3, 2014) calculated panel-reactive antibodies (cPRA)-100% recipients to 3026 post-KAS (December 4, 2014, to December 3, 2017) cPRA-100% recipients using SRTR data. We compared mortality and death-censored graft survival using Cox regression, acute rejection, and delayed graft function (DGF) using logistic regression, and length of stay (LOS) using negative binomial regression. RESULTS: Compared with pre-KAS recipients, post-KAS recipients were allocated kidneys with lower Kidney Donor Profile Index (median 30% versus 35%, P < 0.001) but longer cold ischemic time (CIT) (median 21.0 h versus 18.6 h, P < 0.001). Compared with pre-KAS cPRA-100% recipients, those post-KAS had higher 3-year patient survival (93.6% versus 91.4%, P = 0.04) and 3-year death-censored graft survival (93.7% versus 90.6%, P = 0.005). The incidence of DGF (29.3% versus 29.2%, P = 0.9), acute rejection (11.2% versus 11.7%, P = 0.8), and median LOS (5 d versus 5d, P = 0.2) were similar between pre-KAS and post-KAS recipients. After accounting for secular trends and adjusting for recipient characteristics, post-KAS recipients had no difference in mortality (adjusted hazard ratio [aHR]: 0.861.623.06, P = 0.1), death-censored graft failure (aHR: 0.521.001.91, P > 0.9), DGF (adjusted odds ratio [aOR]: 0.580.861.27, P = 0.4), acute rejection (aOR: 0.610.941.43, P = 0.8), and LOS (adjusted LOS ratio: 0.981.161.36, P = 0.08). CONCLUSIONS: We did not find any statistically significant worsening of outcomes for cPRA-100% recipients under KAS, although longer-term monitoring of posttransplant mortality is warranted.

Endothelial Cell-Derived Interleukin-18 Released During Ischemia Reperfusion Injury Selectively Expands T Peripheral Helper Cells to Promote Alloantibody Production.

BACKGROUND: Ischemia reperfusion injury (IRI) predisposes to the formation of donor-specific antibodies, a factor contributing to chronic rejection and late allograft loss. METHODS: We describe a mechanism underlying the correlative association between IRI and donor-specific antibodies by using humanized models and patient specimens. RESULTS: IRI induces immunoglobulin M-dependent complement activation on endothelial cells that assembles an NLRP3 (NOD-like receptor pyrin domain-containing protein 3) inflammasome via a Rab5-ZFYVE21-NIK axis and upregulates ICOS-L (inducible costimulator ligand) and PD-L2 (programmed death ligand 2). Endothelial cell-derived interleukin-18 (IL-18) selectively expands a T-cell population (CD4+CD45RO+PD-1hiICOS+CCR2+CXCR5-) displaying features of recently described T peripheral helper cells. This population highly expressed IL-18R1 and promoted donor-specific antibodies in response to IL-18 in vivo. In patients with delayed graft function, a clinical manifestation of IRI, these cells were Ki-67+IL-18R1+ and could be expanded ex vivo in response to IL-18. CONCLUSIONS: IRI promotes elaboration of IL-18 from endothelial cells to selectively expand alloreactive IL-18R1+ T peripheral helper cells in allograft tissues to promote donor-specific antibody formation.

The Study of Relationship between Serum Levels of Soluble fms-like Tyrosine Kinase-1 and Soluble Fibrinogen-like Protein 2 with Delayed Graft Function after Kidney Transplantation.

Delayed graft function (DGF) is a transplant complication which means a need to dialysis throughout the first week after transplantation. This study aimed to ascertain the relationship between the two immunomodulatory factors of soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble fibrinogen-like protein 2 (sFGL-2) with DGF after transplantation. This case-control study was done in 2 groups of 58 kidney transplant patients with and without DGF. The control group included the patients who didn't show DGF symptoms. Then, serum levels of sFlt-1and sFGL-2 in all blood samples were measured by ELISA. Serum sFlt-1 and sFGL-2 levels were significantly higher in the DGF group compared to those in the control group (p≤0.001). sFlt-1 and sFGL-2 serum levels significantly affect DGF (p<0.001) in such a way that they may be diagnostic factors of DGF. This study showed a significant relationship between sFlt-1 as well as sFGL-2 and DGF. Therefore, plasma levels of sFlt-1 and sFGL-2 may be used as diagnostic tools to determine the risk of DGF.

Renal Transplantation in High Immunological Risk Patients: A Single-Center Experience.

BACKGROUND: Renal transplantation (RT) in high-risk patients is increasingly performed due to an inadequate organ pool and increased rate of RT after a failed transplantation. Safety and prognosis of RT in such patients with high risk is an ongoing debate. Herein we aimed to present our single-center experience on RT of high-risk patients. METHODS: A total of 89 consecutive RT patients were included into this study in a 10-month period. Patients were divided into 3 groups: the low-risk group (n = 47) with negative panel reactive antibody (PRA), medium-risk group (n = 18) with positive PRA but mean fluorescence intensity (MFI) < 2000, and high-risk group (n = 24) with positive PRA and MFI >2000 or donor specific antibody (DSA) positivity. Groups were compared in terms of demographic features, serum creatinine levels, acute rejection rates, delayed graft function (DGF), and patient or graft loss. RESULTS: Age of the recipients were similar between the groups. Desensitization (7% vs 11% vs 42%, respectively, in low-, medium-, and high-risk groups; P = .001), plasmapheresis (6% vs 11% vs 46%, respectively, P < .001), and rituximab treatments (0% vs 0% vs 25%, respectively, P < .001) were significantly more frequently performed in high-risk patients. Serum creatinine levels at 1 month and 6 months after RT were similar between the groups (P = .43 and P = .71, respectively). Rates of acute rejection (6% vs 6% vs 16%, respectively, P = .52) and DGF (9% vs 11% vs 29%, respectively, P = .15) were similar between the groups. Frequencies of loss of patient or graft were also similar (0% vs 6% vs 4%, P = .15). CONCLUSION: RT may be successfully performed in high-risk patients without an increase in the risk of acute rejection, DGF, or patient/graft loss.

Differential Impact of Delayed Graft Function in Deceased Donor Renal Transplant Recipients With and Without Donor-specific HLA-antibodies.

BACKGROUND: Delayed graft function (DGF) and pretransplant donor-specific HLA-antibodies (DSA) are both regarded as risk factors for rejection and lower graft survival. However, the combined impact of DGF and DSA has not been studied in detail. METHODS: We investigated 375 deceased donor kidney transplantations, which had DSA assignment by single-antigen bead technology and which had surveillance biopsies at 3 of 6 months. Median follow-up time was 6.1 years. RESULTS: DGF occurred in 137 of 375 patients (37%), and DSA were present in 85 of 375 patients (23%). The incidence of DGF was similar in DSA-positive (DSApos)-patients and DSA-negative (DSAneg)-patients (40% versus 36%; P = 0.45). In DSAneg-patients, 5-year graft survival was not different with/without DGF (81% versus 83%; P = 0.48). By contrast, in DSApos-patients, 5-year graft survival was significantly lower with DGF (64% versus 79%; P = 0.01). Moreover, DSApos-patients with DGF had a higher 1-year incidence of subclinical rejection, which were mostly antibody-mediated or mixed rejection phenotypes. Graft loss due to rejection was significantly more frequent in DSApos-patients with DGF (5/34; 15%) compared to DSApos-patients without DGF (2/51; 4%), and DSAneg-patients with/without DGF (3/103; 3% and 4/187; 2%, respectively) (P = 0.005). In a multivariate Cox model, DSA with DGF was an independent predictor for graft (hazard ratio = 2.84 [95% confidence interval, 1.54-5.06]; P = 0.001) and death-censored graft loss (hazard ratio = 4.65 [95% confidence interval, 1.83-11.51]; P = 0.002). CONCLUSIONS: DGF has a much more detrimental impact in DSApos-patients than in DSAneg-patients, which is likely related to a higher incidence of antibody-mediated rejection. If possible, the combined risks of DGF and DSA should be avoided.

Therapeutic concentration achievement and allograft survival comparing usage of conventional tacrolimus doses and CYP3A5 genotype-guided doses in renal transplantation patients.

AIMS: Although cytochromeP450(CYP)3A5 gene polymorphism affects personalized tacrolimus doses, there is no consensus as to whether CYP3A5 genotypes should be determined to adjust the doses. The aims were to compare the therapeutic ranges and clinical outcomes between the conventional and genotype-guided tacrolimus doses. METHODS: This randomized controlled study compared 63 cases of the conventional tacrolimus dose group (0.1 mg/kg/day) with 62 cases of the genotype-guided doses group of 0.125, 0.1 and 0.08 mg/kg for CYP3A5*1/*1, *1/*3, and *3/*3 genotypes for the initial 3 days of kidney transplantation. After day 3, dose adjustment occurred in both groups to achieve therapeutic concentrations. RESULTS: The genotype-guided group had an increased proportion of patients with tacrolimus concentrations in the therapeutic range at the steady state on day 3 (40.3 vs 23.8%, P = .048). A lower proportion of over-therapeutic concentration patients was noted in the genotype-guided group in the CYP3A5*3/*3 genotype (9.7 vs 27%, P = .013). Unexpectedly, more delayed graft functions (DGFs) were in the genotype-guided group (41.9 vs 22.2%, P = .018) especially in the CYP3A5*1/*1 participants who might have had an aggravated DGF by a longer ischaemic time and higher serum donor creatinine levels than in the control group. There were no significant differences of glomerular filtration rates or graft or patient survivals over a median 37-month follow-up period. CONCLUSIONS: Determination of the CYP3A5 genotype improved therapeutic range achievement. CYP3A5*1/*1 patients who have high risks of DGF should be closely monitored because of an increased risk of DGF and reduced glomerular filtration rate with high tacrolimus doses.