A European Multi-Center Analysis of Extracorporeal Photopheresis as Therapy for Chronic Lung Allograft Dysfunction.

Extracorporeal photopheresis (ECP) is used by few lung transplant centers to treat chronic lung allograft dysfunction (CLAD). Although reported results suggest a beneficial effect on CLAD progression, evidence is limited to single center experiences. The aim of this study is to analyze outcomes of ECP in a large multicenter European cohort. The primary endpoint was patient survival after initiation of ECP. This study included 631 patients, 87% suffered from bronchiolitis obliterans syndrome (BOS), and 13% had restrictive allograft syndrome (RAS). Long-term stabilization was achieved in 42%, improvement in 9%, and no response in 26%. Within the first 12 months of therapy, 23% of patients died. Patients' survival after initiation of ECP at 5 years was 56% in stable, 70% in responders, and 35% in non-responders (p = 0.001). In multivariable Cox regression, both stabilization (HR: 0.48, CI: 0.27-0.86, p = 0.013) and response (HR: 0.11, CI: 0.04-0.35, p < 0.001) to ECP were associated with survival. Absolute FEV1 at baseline was also protective (HR: 0.09, CI: 0.01-0.94, p = 0.046). RAS phenotype was the only risk factor for mortality (HR: 2.11, 1.16-3.83, p = 0.006). This study provides long-term outcomes of ECP use in CLAD patients in the largest published cohort to date. Two-thirds of the cohort had a sustained response to ECP with excellent long-term results.

Detection of impaired renal allograft function in paediatric and young adult patients using arterial spin labelling MRI (ASL-MRI).

The study aimed to discriminate renal allografts with impaired function by measuring cortical renal blood flow (cRBF) using magnetic resonance imaging arterial spin labelling (ASL-MRI) in paediatric and young adult patients. We included 18 subjects and performed ASL-MRI on 1.5 T MRI to calculate cRBF on parameter maps. cRBF was correlated to calculated glomerular filtration rate (GFR) and compared between patient groups with good (GFR ≥ 60 mL/min/1.73 m2) and impaired allograft function (GFR < 60 mL/min/1.73 m2). Mean cRBF in patients with good allograft function was significantly higher than in patients with impaired allograft function (219.89 ± 57.24 mL/min/100 g vs. 146.22 ± 41.84 mL/min/100 g, p < 0.008), showing a highly significant correlation with GFR in all subjects (r = 0.75, p < 0.0001). Also, the diffusion-weighted imaging (DWI-MRI) apparent diffusion coefficient (ADC) and Doppler measurements of peak-systolic and end-diastolic velocities and the resistive index (PS, ED, RI) were performed and both methods showed no significant difference between groups. ADC implied no correlation with GFR (r = 0.198, p = 0.464), while PS indicated moderate correlation to GFR (r = 0.48, p < 0.05), and PS and ED moderate correlation to cRBF (r = 0.58, p < 0.05, r = 0.56, p < 0.05, respectively). Cortical perfusion as non-invasively measured by ASL-MRI differs between patients with good and impaired allograft function and correlates significantly with its function.

Optical Coherence Tomography in Cardiac Allograft Vasculopathy: State-of-the-Art Review.

Cardiac allograft vasculopathy (CAV) is a challenging complication of heart transplantation. CAV pathophysiology is incompletely understood, standard screening modalities such as angiography have significant limitations, and currently available therapies have only modest efficacy in preventing progression. Optical coherence tomography is a light-based technique that provides microscopic level catheter-based intravascular imaging and has dramatically expanded our understanding of CAV, demonstrating it to be a complex, heterogeneous, and dynamic process. This review covers characteristics and uses of optical coherence tomography, including vessel characterization, serial use to assess progression of disease, guiding percutaneous intervention, and monitoring response to CAV therapies. We also discuss the potential of optical coherence tomography in providing individualized assessment and enable customized CAV therapies, which may lead to improvements in long-term transplant outcomes.

Elevated levels of circulating mitochondrial DNA predict early allograft dysfunction in patients following liver transplantation.

BACKGROUND AND AIM: The role of circulating mitochondrial DNA (cmtDNA) in transplantation remains to be elucidated. cmtDNA may be released into the circulation as a consequence of liver injury; yet recent work also suggests a causative role for cmtDNA leading to hepatocellular injury. We hypothesized that elevated cmtDNA would be associated with adverse events after liver transplantation (LT) and conducted an observational cohort study. METHODS: Twenty-one patients were enrolled prospectively prior to LT. RESULTS: Postoperative complications were observed in 47.6% (n = 10). Seven patients (33.3%) had early allograft dysfunction (EAD), and six patients (28.5%) experienced acute cellular rejection within 6 months of LT. cmtDNA levels were significantly elevated in all recipients after LT compared with healthy controls and preoperative samples (1 361 937 copies/mL [IQR 586 781-3 399 687] after LT; 545 531 copies/mL [IQR 238 562-1 381 015] before LT; and 194 562 copies/mL [IQR 182 359-231 515] in healthy controls) and returned to normal levels by 5 days after transplantation. cmtDNA levels were particularly elevated in those who developed EAD in the early postoperative period (P < 0.001). In all patients, there was initially a strong overall positive correlation between cmtDNA and plasma hepatocellular enzyme levels (P < 0.05). However, the patients with EAD demonstrated a second peak in cmtDNA at postoperative day 7, which did not correlate with liver function tests. CONCLUSIONS: The early release of plasma cmtDNA is strongly associated with hepatocellular damage; however, the late surge in cmtDNA in patients with EAD appeared to be independent of hepatocellular injury as measured by conventional tests.

The causes and frequency of kidney allograft failure in a low-resource setting: observational data from Iraqi Kurdistan.

BACKGROUND: In the developing world, transplantation is the most common long-term treatment for patients with end-stage renal disease, but rates and causes of graft failure are uncertain. METHODS: This was a retrospective outcomes study of renal transplant patients seen in Iraqi Kurdistan nephrology clinics in the year 2019. In 2019, 871 renal transplant patients were registered and outcomes followed through 12/31/2020. Indicated renal biopsies were obtained on 431 patients at 1 day to 18 years post-transplantation. Outcomes were compared with United States Renal Data System (USRDS) living donor reports. RESULTS: All donors were living. The recipient age was 38.5 ± 13.3 years, 98.2% were < 65 years old, 3.7% had previous transplants, and 2.8% had pretransplant donor-specific antibodies (DSA). Gehan-Breslow estimated failure rates for all-cause, return to HD, and death with functional graft were 6.0, 4.2, and 1.9% at 1 year and 18.1, 13.7, and 5.1% at 5 years post-engraftment (USRDS 2000; 1 year: 7.0, 5.0, 2.6%; 5 year: 22.3, 15.2, 10.6%. USRDS 2010; 1 year: 3.7, 2.4, 1.4%; 5 year: 15.3, 9.6, 7.3%). The median graft survival was 15 years. Acute tubular injury (ATI), infarction, and acute T cell-mediated rejection accounted for 22.2% of graft loss, with > 75% of these failures taking place in the first year. Most graft failures occurred late, at a median post-transplant time of 1125 (interquartile range, 365-2555) days, and consisted of interstitial fibrosis and tubular atrophy (IF/TA) (23.8%), transplant glomerulopathy (13.7%), and acquired active antibody-mediated rejection (12.0%). The significant predictors of graft loss were C4d + biopsies (P < 0.01) and advanced IF/TA (P < 0.001). CONCLUSIONS: Kurdistan transplant patients had graft failure rates similar to living donors reported by the USRDS for the year 2000 but higher than reported for 2010. Compared to USRDS 2010, Kurdistan patients had a moderate excess of HD failures at one and 5 years post-engraftment. Nevertheless, prolonged survival is the norm, with chronic disorders and acquired DSA being the leading causes of graft loss.

Synergistic impact of pre-sensitization and delayed graft function on allograft rejection in deceased donor kidney transplantation.

The aim of this study is to investigate whether or not delayed graft function (DGF) and pre-transplant sensitization have synergistic adverse effects on allograft outcome after deceased donor kidney transplantation (DDKT) using the Korean Organ Transplantation Registry (KOTRY) database, the nationwide prospective cohort. The study included 1359 cases between May 2014 and June 2019. The cases were divided into 4 subgroups according to pre-sensitization and the development of DGF post-transplant [non-pre-sensitized-DGF(-) (n = 1097), non-pre-sensitized-DGF(+) (n = 127), pre-sensitized-DGF(-) (n = 116), and pre-sensitized-DGF(+) (n = 19)]. We compared the incidence of biopsy-proven allograft rejection (BPAR), time-related change in allograft function, allograft or patient survival, and post-transplant complications across 4 subgroups. The incidence of acute antibody-mediated rejection (ABMR) was significantly higher in the pre-sensitized-DGF(+) subgroup than in other 3 subgroups. In addition, multivariable cox regression analysis demonstrated that pre-sensitization combined with DGF is an independent risk factor for the development of acute ABMR (hazard ratio 4.855, 95% confidence interval 1.499-15.727). Moreover, DGF and pre-sensitization showed significant interaction (p-value for interaction = 0.008). Pre-sensitization combined with DGF did not show significant impact on allograft function, and allograft or patient survival. In conclusion, the combination of pre-sensitization and DGF showed significant synergistic interaction on the development of allograft rejection after DDKT.

Can uric acid blood levels in renal transplant recipients predict allograft outcome?

BACKGROUND: Hyperuricemia is common after renal transplantation, especially in those receiving calcineurin inhibitors. Little, however, is known about the relationship between uric acid (UA) levels and allograft outcome. METHODS: We conducted a retrospective single-center analysis (N = 368) in order to assess UA blood levels post-transplant association with allograft outcome. For this study, a median serum UA level of all measured UA levels from 1 month to 1 year post renal transplantation was calculated. RESULTS: Patients were divided into 2 groups based on the median UA level measured between 1 and 12 months post-transplant. Those with median UA level ≥ 7 and ≥ 6 mg/dL (N = 164) versus median UA level < 7 and < 6 mg/dL for men and women respectively (N = 204) had lower GFR values at 1, 3 and 5 years posttransplant (mean GFR ± SD of 43.4 ± 20.6 and 58 ± 19.9 at 3 years post-transplant, p < 0.001). In multivariate models, UA levels were no longer significantly associated with renal allograft function. In a multivariate cox proportional hazard model, UA level was found to be independently associated with increased risk for death-censored graft loss (HR of 1.3, 95% CI 1.0-1.7, p < 0.05 for every increase of 1 mg/dL in UA level). CONCLUSION: Hyperuricemia was found to be associated with increased death- censored graft loss but not with allograft function. Increased UA levels were not found to be an independent predictor of long-term allograft function despite the known association of hyperuricemia with the progression of cardiovascular and renal disease.

Renal allograft function in kidney transplant recipients infected with SARS-CoV 2: An academic single center experience.

BACKGROUND: Kidney transplant recipients are a unique cohort in regard to SARS-CoV 2 susceptibility and clinical course, owing to their immunosuppressed state and propensity for kidney injury. The primary purpose of this study is to ascertain if, in kidney transplant recipients, SARS-CoV 2 infection impacts long term renal allograft function. METHODS: This retrospective, single-center study reviewed 53 kidney transplant recipients with a positive SARS-CoV-2 PCR at NMH from January 1, 2020 to June 30, 2020. RESULTS: Change in eGFR from baseline kidney function prior to infection to 90 days after the first positive SARS-CoV 2 test was +1.76%, -17.5% and -23.16% the mild, moderate and severe disease groups respectively. There was a significant decline in kidney function in the moderate and severe disease cohorts as compared to the mild disease cohort, with respective p values of p = 0.0002 and p = 0.021. Relative to the mild disease cohort, the moderate and severe disease cohorts also demonstrated significantly increased risk of developing AKI (66%, 85%), both with p values of P = 0.0001. CONCLUSIONS: Clinically severe SARS-CoV 2 infection is associated with greater risk of acute kidney injury and greater decline in renal allograft function at 90 days post infection, compared to mild disease.

Data-Driven Kidney Transplant Phenotyping as a Histology-Independent Framework for Biomarker Discovery.

BACKGROUND: In transplant medicine, clinical decision making largely relies on histology of biopsy specimens. However, histology suffers from low specificity, sensitivity, and reproducibility, leading to suboptimal stratification of patients. We developed a histology-independent immune framework of kidney graft homeostasis and rejection. METHODS: We applied tailored RNA deconvolution for leukocyte enumeration and coregulated gene network analysis to published bulk human kidney transplant RNA transcriptomes as input for unsupervised, high-dimensional phenotype clustering. We used framework-based graft survival analysis to identify a biomarker that was subsequently characterized in independent transplant biopsy specimens. RESULTS: We found seven immune phenotypes that confirm known rejection types and uncovered novel signatures. The molecular phenotypes allow for improved graft survival analysis compared with histology, and identify a high-risk group in nonrejecting transplants. Two fibrosis-related phenotypes with distinct immune features emerged with reduced graft survival. We identified lysyl oxidase-like 2 (LOXL2)-expressing peritubular CD68+ macrophages as a framework-derived biomarker of impaired allograft function. These cells precede graft fibrosis, as demonstrated in longitudinal biopsy specimens, and may be clinically useful as a biomarker for early fibrogenesis. CONCLUSIONS: This study provides a comprehensive, data-driven atlas of human kidney transplant phenotypes and demonstrates its utility to identify novel clinical biomarkers.

Effect of Delayed Graft Function on the Outcome and Allograft Survival of Kidney Transplanted Patients from a Deceased Donor.

BACKGROUND: In kidney transplantation (KT), delayed graft function (DGF) is a significant early complication observed in the first week. The study aimed to investigate the impact of DGF on the outcome, allograft, and patient survival after KT with organs from deceased donors. METHODS: This retrospective study was conducted using 304 KT patients who received an organ from deceased donors from 2008 to 2018. The patients were divided into 2 groups, DGF positive (DGF+) and DGF negative (DGF-). The database containing the clinical, laboratory, and immunologic information of donors and recipients was statistically analyzed using the SSPS program. RESULTS: In this study, 189 (62.17%) were DGF+ and 115 (37.83%) were DGF-. Until 6 months after KT, the estimate glomerular filtration rate was better in group DGF-, but it was similar between the groups during 10-year follow-up. Graft losses were higher in DGF+ group than in the DGF- (P = .046). The serum creatinine level was persistently higher in DGF+ group until the sixth month (P ≤ .05). Allograft survival rates were better in patients who were DGF- (P = .033). Those who had DGF for more than 15 days had a worse graft survival (P = .003), but in 10 year follow-up, patient survival rates were similar (P = .705). CONCLUSION: DGF+ patients were associated with dialysis time before KT, ischemia time, and the donors' clinical status, such as age, organ quality, and serum creatinine. All these factors had a great impact on graft survival but not on patient survival.

Chronic Allograft Injury.

With the incremental improvements in long-term kidney transplant survival, there is renewed focus on what causes failure of the transplanted allograft. Over the past decade, our understanding of the injuries that lead to loss of graft function over time has evolved. Chronic allograft injury includes both immune-mediated and nonimmune-mediated injuries, which may involve the organ donor, the recipient, or both. The targets of injury include the kidney tubular epithelium, the endothelium, and the glomerulus. As a response to injury, there are the expected tissue remodeling and repair processes. However, if inflammation persists, which is not uncommon in the transplant setting, the resulting maladaptive response is matrix deposition and/or fibrosis. This ultimately leads to declining graft function and, finally, failure. With our advancing knowledge of the multiple etiologies and mechanisms, enhanced by more recent cohort studies in humans, there is an opportunity to identify those at greater risk to initiate new strategies to ameliorate the process. Although the most recent studies focus on immune-mediated injuries, there is a critical need to identify both markers of injury and mechanisms of injury. In this review, we highlight the findings of recent studies, highlight the potential therapeutic targets, and identify the continued unmet need for understanding the mechanisms of late graft failure.

Regulatory and Effector Cell Disequilibrium in Patients with Acute Cellular Rejection and Chronic Lung Allograft Dysfunction after Lung Transplantation: Comparison of Peripheral and Alveolar Distribution.

BACKGROUND: The immune mechanisms occurring during acute rejection (AR) and chronic lung allograft dysfunction are a challenge for research and the balance between effector and regulatory cells has not been defined completely. In this study, we aimed to elucidate the interaction of effector cells, mainly Th17, Th1 and Th2, and regulatory cells including (CD4+CD25+CD127low/-) T reg cells and phenotypes of B regs, CD19+CD24hiCD38hi, CD19+CD24hiCD27hi and CD19+CD5+CD1d+. METHODS: Bronchoalveolar lavage cells (BAL) and peripheral blood mononuclear cells (PBMCs) from stable lung transplanted (LTx )subjects (n = 4), AR patients (n = 6) and bronchiolitis obliterans syndrome (BOS) (n = 6) were collected at the same time. Cellular subsets were detected through flow cytometry. RESULTS: A predominance of Th17 cells subtypes in the PBMCs and BAL and a depletion of Tregs, that resulted in decrease Treg/Th17 ratio, was observed in the AR group. CD19+CD24hiCD38hi Bregs resulted increased in BAL of AR patients. Th1 cells predominance and a reduction of Tregs cells was observed in BAL from AR patients. Moreover, multivariate analysis showed interdependences within studied variables revealing that effector cells and regulatory cells can effectively discriminate patients' immunological status. CONCLUSIONS: In AR, BOS and stable lung transplant, regulatory and effector cells clearly demonstrated different pathways of activation. Understanding of the balance of T cells and T and B regulatory cells can offers insights into rejection.

Exploring the Complexity of Death-Censored Kidney Allograft Failure.

BACKGROUND: Few studies have thoroughly investigated the causes of kidney graft loss (GL), despite its importance. METHODS: A novel approach assigns each persistent and relevant decline in renal function over the lifetime of a renal allograft to a standardized category, hypothesizing that singular or multiple events finally lead to GL. An adjudication committee of three physicians retrospectively evaluated indication biopsies, laboratory testing, and medical history of all 303 GLs among all 1642 recipients of transplants between January 1, 1997 and December 31, 2017 at a large university hospital to assign primary and/or secondary causes of GL. RESULTS: In 51.2% of the patients, more than one cause contributed to GL. The most frequent primary or secondary causes leading to graft failure were intercurrent medical events in 36.3% of graft failures followed by T cell-mediated rejection (TCMR) in 34% and antibody-mediated rejection (ABMR) in 30.7%. In 77.9%, a primary cause could be attributed to GL, of which ABMR was most frequent (21.5%). Many causes for GL were identified, and predominant causes for GL varied over time. CONCLUSIONS: GL is often multifactorial and more complex than previously thought.

Assessment of chronic allograft injury in renal transplantation using diffusional kurtosis imaging.

BACKGROUND: Chronic allograft injury (CAI) is a significant reason for which many grafts were lost. The study was conducted to assess the usefulness of diffusional kurtosis imaging (DKI) technology in the non-invasive assessment of CAI. METHODS: Between February 2019 and October 2019, 110 renal allograft recipients were included to analyze relevant DKI parameters. According to estimated glomerular filtration rate (eGFR) (mL/min/ 1.73 m2) level, they were divided to 3 groups: group 1, eGFR ≥ 60 (n = 10); group 2, eGFR 30-60 (n = 69); group 3, eGFR < 30 (n = 31). We performed DKI on a clinical 3T magnetic resonance imaging system. We measured the area of interest to determine the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) of the renal cortex and medulla. We performed a Pearson correlation analysis to determine the relationship between eGFR and the DKI parameters. We used the receiver operating characteristic curve to estimate the predicted values of DKI parameters in the CAI evaluation. We randomly selected five patients from group 2 for biopsy to confirm CAI. RESULTS: With the increase of creatinine, ADC, and MD of the cortex and medulla decrease, MK of the cortex and medulla gradually increase. Among the three different eGFR groups, significant differences were found in cortical and medullary MK (P = 0.039, P < 0.001, P < 0.001, respectively). Cortical and medullary ADC and MD are negatively correlated with eGFR (r = - 0.49, - 0.44, - 0.57, - 0.57, respectively; P < 0.001), while cortical and medullary MK are positively correlated with eGFR (r = 0.42, 0.38; P < 0.001). When 0.491 was set as the cutoff value, MK's CAI assessment showed 87% sensitivity and 100% specificity. All five patients randomly selected for biopsy from the second group confirmed glomerulosclerosis and tubular atrophy/interstitial fibrosis. CONCLUSION: The DKI technique is related to eGFR as allograft injury progresses and is expected to become a potential non-invasive method for evaluating CAI.

Pretransplant Calculated Panel Reactive Antibody in the Absence of Donor-Specific Antibody and Kidney Allograft Survival.

BACKGROUND AND OBJECTIVES: Panel reactive antibody informs the likelihood of finding an HLA-compatible donor for transplant candidates, but has historically been associated with acute rejection and allograft survival because testing methods could not exclude the presence of concomitant donor-specific antibodies. Despite new methods to exclude donor-specific antibodies, panel reactive antibody continues to be used to determine the choice of induction and maintenance immunosuppression. The study objective was to determine the clinical relevance of panel reactive antibody in the absence of donor-specific antibodies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective observational study of kidney allograft survival among 4058 zero HLA-A-, B-, DR-, and DQB1-mismatched transplant recipients without antibodies to donor kidney antigens encoded by these HLA gene loci. RESULTS: Among 4058 first and repeat transplant recipients, patients with calculated panel reactive antibody (cPRA) 1%-97% were not at higher risk of transplant failure, compared with patients with cPRA of 0% (death censored graft loss: hazard ratio, 1.07; 95% confidence interval, 0.82 to 1.41). Patients with cPRA ≥98% had a higher risk of graft loss from any cause including death (hazard ratio, 1.39; 95% confidence interval, 1.08 to 1.79) and death censored allograft failure (hazard ratio, 1.78; 95% confidence interval, 1.27 to 2.49). In stratified analyses, the higher risk of graft loss among patients with cPRA ≥98% was only observed among repeat, but not first, transplant recipients. In subgroup analysis, there was no association between cPRA and graft loss among living related transplant recipients. CONCLUSIONS: Calculated panel reactive antibody is poorly associated with post-transplant immune reactivity to the allograft in the absence of donor-specific antibody. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_01_25_CJN13640820_final.mp3.

Trends in Discard of Kidneys from Hepatitis C Viremic Donors in the United States.

BACKGROUND AND OBJECTIVES: Kidneys from hepatitis C virus (HCV) viremic donors have become more commonly accepted for transplant, especially after effective direct-acting antiviral therapy became available in 2014. We examined the contemporary trend of kidney discard from donors with HCV seropositivity and viremia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the Organ Procurement and Transplantation Network were used to identify deceased donor kidneys recovered for transplant. The exposure was donor HCV antibody status in the first analyses, and donor HCV antibody and viremia status in the second analyses. Multilevel, multivariable logistic regression was used to assess the association of these HCV exposure measures with kidney discard, adjusted for donor characteristics. Multilevel analyses were conducted to account for similar kidney discard pattern within clusters of organ procurement organizations and regions. RESULTS: Among 225,479 kidneys recovered from 2005 to 2019, 5% were from HCV seropositive donors. Compared with HCV seronegative kidneys, the odds of HCV seropositive kidney discard gradually declined, from a multivariable-adjusted odds ratio (aOR) of 7.06 (95% confidence interval [95% CI], 5.65 to 8.81) in 2014, to 1.20 (95% CI, 1.02 to 1.42) in 2019. Among 82,090 kidneys with nucleic acid amplification test results in 2015-2019, 4% were from HCV viremic donors and 2% were from aviremic seropositive donors. Compared with HCV aviremic seronegative kidneys, the odds of HCV viremic kidney discard decreased from an aOR of 4.89 (95% CI, 4.03 to 5.92) in 2018, to 1.48 (95% CI, 1.22 to 1.81) in 2019. By 2018 and 2019, aviremic seropositive status was not associated with higher odds of discard (2018: aOR, 1.13; 95% CI, 0.88 to 1.45; and 2019: aOR, 0.97; 95% CI, 0.76 to 1.23). CONCLUSIONS: Despite the decrease in kidney discard in recent years, kidneys from viremic (compared with aviremic seronegative) donors still had 48% higher odds of discard in 2019. The potential of these discarded organs to provide successful transplantation should be explored.

HLA antibodies are associated with deterioration of kidney allograft function irrespective of donor specificity.

BACKGROUND: Donor-specific antibodies are associated with high immunological risk and poor allograft outcome. Risk and clinical relevance of non-donor-specific HLA antibodies is less clear. METHODS: A retrospective single-center study was conducted in all patients receiving a first kidney transplant at the University hospital of Zürich between 01/2006 and 02/2015. Patients were stratified into 3 groups having either no HLA antibodies at all (NoAB), HLA antibodies with donor specificity (DSA) and HLA antibodies without donor specificity (NonDSA). Allograft outcome was assessed using the slope of the estimated glomerular filtration rate (eGFR slope) starting at 12 months after transplantation. RESULTS: During a median follow-up of 1808 days HLA antibodies were detected in 106 of 238 eligible patients (44%). Out of these, 73 patients (69%) had DSA and 33 patients (31%) had NonDSA only. Medium-term allograft function, as determined by eGFR slope over three years, improved in patients with NoAB (months 12-48: +0.7 ml/min/1.73 m2) but deteriorated significantly in patients with both DSA (months 12-48: -1.5 ml/min per1.73 m2/year, p = 0.015) and NonDSA (months 12-48: -1.8 ml/min per1.73 m2/year, p = 0.03) as compared to the group with NoAB. CONCLUSION: Both, donor-specific and non-donor-specific HLA antibodies are associated with medium-term kidney allograft dysfunction as compared to patients with no HLA antibodies.

Orthotopic grafting of decellularized human nipple: Setting the stage and putative mechanism of healing.

A complex skin structure (such as a nipple) can be successfully decellularized under conditions that prevent extracellular matrix crosslinking or undue matrix degradation [1]. This treatment removes cellular antigens, thus mitigating immunorejection concerns and enabling allogeneic transplantation for nipple reconstruction after mastectomy. Non-human primate studies have shown that host-mediated re-vascularization and re-epithelization of the decellularized nipples occurs within six weeks and nipple projection is maintained over the same timeframe [1]. The mechanisms by which a decellularized graft located on the surface of the body heals are incompletely understood, but are likely to follow a similar path to decellularized allografts that are implanted within the body, with some modifications. The following is a description of probable temporal events leading to healing under this circumstance.

TNF, IL-6, and IL-10 cytokines levels and their polymorphisms in renal function and time after transplantation.

Cytokine polymorphisms can influence their plasma levels and thus affect the immune response in renal transplantation. A total of 146 renal transplant recipients (RTR) were classified into groups according to the estimated glomerular filtration rate (R1: < 60 and R2: ≥ 60 mL/min/1.73 m2) and time after transplantation (T1: 1 to 24, T2: 25 to 60, T3: 61 to 120, and T4: > 120 months after transplantation). The polymorphisms were genotyped by single specific primer-polymerase chain reaction. IL-10 was measured by ELISA and IL-6, and TNF levels were determined using Miliplex®. A higher frequency of the - 308G allele and the - 308G/G genotype, low-producer, was observed in the R1 group compared with R2. In addition, a higher frequency of the - 308A carriers, high-producer, was found in the R2 group. However, no significant difference was observed in cytokine levels when both groups were compared. Higher levels of IL-6 were observed in T1 compared with T2 and T4 groups. Lower IL-6 levels were found in T2 compared with T3 group. Lower levels of IL-10 were also found in T1 group in relation to T2, while higher levels of this cytokine were observed in T2 group compared with T3. The results suggest that the - 308G > A polymorphism in the TNF gene is associated with filtration function after renal transplantation, and IL-6 and IL-10 levels change according to the time after transplantation. Thus, the joint evaluation of - 308G > A polymorphism in TNF gene and IL-6 and IL-10 levels would provide a broader and effective view on the clinical monitoring of RTR.