Polyvascular disease, pulse pressure and mortality.

Background: Peripheral arterial disease (PAD), coronary artery disease (CAD) and carotid stenosis (CS) are robust predictors of mortality. The value of individual vascular beds in polyvascular disease (PVD) to predict mortality in patients with atherosclerotic burden is not clear. Therefore, we have examined the predictive value of PAD, CAD and CS in patients at intermediate to high risk of cardiovascular (CV) disease. Patients and methods: In our retrospective observational study we analyzed baseline data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, a monocentric cohort study of 3316 patients referred to coronary angiography. Results: As the number of atherosclerotic vascular beds increased, the hazard ratios (HRs) for both all-cause mortality and CV mortality significantly increased in a multivariate analysis after adjusting for age, sex, body mass index, diabetes mellitus and estimated glomerular filtration rate, with HRs of 1.36 (95%CI: 1.11-1.68), 2.56 (95%CI: 2.01-3.26), 2.84 (95%CI: 1.93-4.17) and 1.56 (95%CI: 1.19-2.06), 2.70 (95%CI: 1.97-3.72), 3.50 (95%CI: 2.19-5.62), respectively. The combination of PAD with either CAD or CS was associated with higher HRs for all-cause (HR 2.81 and 7.53, respectively) and CV (HRs 2.80 and 6.03, respectively) mortality compared with the combination of CAD and CS (HRs 1.94 and 2.43, respectively). The presence of PVD was associated with higher age, systolic blood pressure, pulse pressure (PP; a marker of vascular stiffness), former smoking and inversely with lower eGFR. Conclusions: We show that as the number of atherosclerotic vascular beds increases, all-cause and CV mortality rates increase in parallel. Simultaneous prevalence of PAD is associated with significantly higher all-cause and CV mortality rates compared with CS coexistence. Furthermore, increasing atherosclerotic load may contribute to vascular stiffness and impaired renal function.

Kidney Transplantation After Rescue Allocation-the Eurotransplant Experience: A Retrospective Multicenter Outcome Analysis.

BACKGROUND: At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P < 0.001), whereas other outcomes (mortality, death with functioning graft (DwFG)) were not significantly different. None of the 3 outcomes were significantly different when comparing RA with SA within the ESP program. CONCLUSIONS: Facing increased waiting times and mortality on dialysis due to donor shortage, this study reveals encouragingly positive DDRT outcomes following RA. This supports the extension of RA to more patients and as an alternative tool to enable transplantation in patients in countries with prohibitively long waiting times or at risk of deterioration.

Quantitative Assessment of Intraoperative Laser Fluorescence Angiography With Indocyanine Green Predicts Early Graft Function After Kidney Transplantation.

OBJECTIVE: This study was designed to demonstrate the predictive ability of quantitative indocyanine green (ICG) fluorescence angiography for the short-term postoperative outcome, the occurrence of delayed graft function (DGF), and long-term graft survival. SUMMARY BACKGROUND DATA: DGF is a relevant problem after kidney transplantation; sufficient microperfusion of the allograft is crucial for postoperative organ function. Fluorescence angiography with ICG can serve as an intraoperative quality control of microperfusion. METHODS: This prospective diagnostic study, conducted in 2 German transplantation centers from November 2015 to October 2018, included 128 consecutive kidney transplantations. Intraoperative assessment of the allograft microperfusion was performed by near-infrared fluorescence angiography with ICG; a software was used for quantitative analysis. The associations between perfusion parameters (eg, ICG Ingress) and donor, recipient, peri-procedural, and postoperative characteristics were evaluated. RESULTS: DGF occurred in 23 (24%) kidney recipients from deceased donors. ICG Ingress ( P = 0.0027), donor age ( P = 0.0452), recipient age ( P = 0.0139), and recipient body mass index ( P = 0.0017) were associated with DGF. ICG Ingress correlated significantly with recipient age (r = -0.27662, P = 0.0016), cold and warm ischemia time (r = -0.25204, P = 0.0082; r = -0.19778, P = 0.0283), operating time (r = -0.32208, P = 0.0002), eGFR on postoperative days 1 (r =+0.22674, P = 0.0104) and 7 (r = +0.33189, P = 0.0001). The cutoff value for ICG Ingress was 106.23 AU with sensitivity of 78.3% and specificity of 80.8% ( P < 0.0001) for the prediction of DGF. CONCLUSION: Fluorescence angiography with ICG allows intraoperative quantitative assessment of microperfusion during kidney transplantation. The parameter ICG Ingress reflects recipient and procedure characteristics and is able to predict the incidence of DGF. TRIAL REGISTRATION: Clinicaltrials.gov: NCT-02775838.

Patient and Graft Survival After Dual Kidney Transplantation With Marginal Donors in Comparison to Matched Control Groups.

BACKGROUND: Postmortal organ donor rates remain low in Germany, whereas donor age has been increasing considerably in the last decades. As a consequence of low donation rates older and more marginal donor kidneys are accepted for transplantation. However, procured kidneys from very old a/o marginal donors may be considered as not suitable for transplantation as a single organ and subsequently be discarded. However, dual transplantation of both kidneys from such donors may provide an opportunity to nevertheless use these organs for renal transplantation, thereby providing the twofold nephron mass as a single kidney transplantation. METHODS: We compared in this retrospective analysis the outcome of 10 recipients of a dual kidney transplantation (DKT) with 40 matched recipients of a single kidney transplantation (SKT). Recipients were matched for donor and recipient age (ie, a maximum age difference of ±10 years in a ratio of 1:4 for DKT vs SKT recipients). In addition, a second SKT control group of 10 SKT recipients being transplanted immediately before each DKT recipient with a kidney from a donor aged ≥65 years was used for comparison. All renal transplant recipients were observed for up to 3 years or until July 31, 2020. RESULTS: Mean donor and recipient age was 77.2 ± 4.6/75.1 ± 6.6/82.1 ± 7.9 and 66.4 ± 5.8/66.1 ± 6.0/64.8 ± 8.4 for SKT group 1/SKT group 2/DKT, respectively. Procurement serum creatinine concentrations were significantly higher in the DKT group in comparison to the SKT control group 1 (P = .019) as was the rate of transplant artery atherosclerosis (P = .021). Furthermore, Kidney Donor Profile Index, and Kidney Donor Risk Index were significantly higher (P = .0138/P = .064, and P < .001/P = .038) in the DKT group than in SKT group 1 and 2. Rates of acute rejection and delayed graft function were not significantly different between groups, though biopsy-proven acute rejection was numerically higher in the SKT groups. Patient survival and overall and death-censored graft survival rates were also not significantly different between groups, although they tended to be higher after DKT. CONCLUSIONS: DKT provides an opportunity to successfully use postmortal kidneys even from donors aged >80 years and a Kidney Donor Profile Index ≥95% for renal transplantation. DKT may thereby increase the available pool of donors to better serve patients with end-stage renal disease on the waiting list.

Association of double product and pulse pressure with cardiovascular and all-cause mortality in the LURIC study.

Systolic (SBP) and diastolic blood pressure (DBP) and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is considered as an easily available marker of vascular stiffness and the double product (DP) as a marker of cardiac workload. Therefore, we have examined the predictive value of PP and DP in the Ludwigshafen Risk and Cardiovascular Health study, a monocentric cohort study of 3316 patients referred to coronary angiography. An increase of SBP or PP by 1mmHg increased the risk of CVM with hazard ratios of 1.009 (95% CI, 1.005-1.012) and 1.016 (1.012-1.020), respectively. Increasing DP by 100 mm Hg/min was associated with a 1.010 (1.007-1.013) higher risk of CVM. In patient subgroups with coronary artery disease (CAD) and heart failure (HF), PP and DP predicted CVM better than SBP or MAP. In a multivariate analysis adjusted for sex, BMI, diabetes, eGFR, hazard ratios for CVM for z-standardized PP, DP, SBP, and HR were 1.20, 1.16, 1.12, and 1.14. After adding age to the multivariate analysis, only DP and HR remained significant. We provide evidence that PP and DP are powerful predictors of CVM and all-cause mortality in a CV medium- to high-risk population, especially in patients with CAD and HF. While DP proved to be an independent predictor of cardiovascular and all-cause mortality also in multivariate analysis, PP was no independent predictor in our cohort with widespread antihypertensive treatment (>85%). PP is associated with age, presence of diabetes, obesity, and impaired renal function.

Long-Term Kidney Transplant Outcomes: Role of Prolonged-Release Tacrolimus.

Tacrolimus has significantly improved outcomes for kidney transplant patients and remains the cornerstone of immunosuppressive therapy. While improvements in short-term outcomes in transplantation have been achieved in recent years, maintaining long-term graft survival remains a challenge in kidney transplantation. Minimizing risk factors for poor long-term kidney graft function and survival, and modifying tacrolimus regimens in the early and maintenance phases post-transplantation are essential to maintain long-term kidney transplant outcomes. Tacrolimus has a narrow therapeutic window, resulting in a tightly defined range of optimal drug exposure. Underimmunosuppression is associated with long-term risks, such as the development of donor-specific antibodies and antibody-mediated rejection, with a high possibility of a decline in kidney function and progression to graft failure. Conversely, prolonged overimmunosuppression carries a risk of drug-related adverse events. This review provides an overview of the differences in the formulation, delivery, and pharmacokinetic profiles between immediate- and prolonged-release tacrolimus and evaluates the effect of prolonged-release tacrolimus on the risk factors for poor outcomes in kidney transplantation. Recent evidence is used to provide guidance on target tacrolimus trough levels in the early and maintenance phases post-transplantation, with a view to improving long-term kidney graft function.

Pulse Pressure and Outcome in Kidney Transplantation: Results From the Collaborative Transplant Study.

BACKGROUND: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) are important predictors of graft and patient survival in renal transplantation. Pulse pressure (PP), the difference between systolic and diastolic pressure, has been associated with cardiovascular and renal morbidity in nontransplant epidemiological studies and clinical trials. METHODS: In this large retrospective analysis of prospectively collected data, transplant recipients from 1995 to 2015 were examined for patient and death-censored graft survival. RESULTS: In 43 006 recipients, a higher 1-year PP was significantly associated with inferior 10-year patient and death-censored graft survival. In patients 60 years or older, SBP but not DBP was associated with 10-year survival, an effect that was pronounced in patients with a normal SBP of <140 mm Hg and an increased PP of 60 mm Hg or greater, highlighting the superior impact of PP on survival in elderly recipients. In recipients 60 years or older, higher PP was associated with increased mortality due to circulatory system diseases but not to infection or cancer. The combination of PP 60 mm Hg or greater and high SBP of 140 mm Hg or greater showed the strongest association with death-censored graft survival across all age groups. CONCLUSIONS: We found convincing evidence that PP 1-year posttransplant is predictive of patient survival, especially in elderly recipients with normal SBP. Combined analysis of SBP and PP showed that high PP confers additional predictive information for patient survival beyond that derived from analysis of SBP alone. With regard to prediction of death-censored graft survival, the combination of high SBP and high PP showed the best correlation across all age groups.

Donor Dopamine Does Not Affect Liver Graft Survival: Evidence of Safety From a Randomized Controlled Trial.

Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 µg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.

Clinical validation of a novel enzyme-linked immunosorbent spot assay-based in vitro diagnostic assay to monitor cytomegalovirus-specific cell-mediated immunity in kidney transplant recipients: a multicenter, longitudinal, prospective, observational study.

Impaired cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) is a major cause of CMV reactivation and associated complications in solid-organ transplantation. Reliably assessing CMV-CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T-Track® CMV, a novel IFN-γ ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE-I CMV proteins, to monitor CMV-CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate-risk renal transplant recipients. CMV-CMI, CMV viral load, and clinical complications were monitored over 6 months post-transplantation. Ninety-five percent and 88-92% ELISpot assays were positive pre- and post-transplantation, respectively. CMV-specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65-specific response was ninefold higher in patients with self-clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T-Track® CMV is a highly sensitive IFN-γ ELISpot assay, suitable for the immunomonitoring of CMV-seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV-related clinical complications (ClinicalTrials.gov Identifier: NCT02083042).

Validation of T-Track® CMV to assess the functionality of cytomegalovirus-reactive cell-mediated immunity in hemodialysis patients.

BACKGROUND: Uncontrolled cytomegalovirus (CMV) replication in immunocompromised solid-organ transplant recipients is a clinically relevant issue and an indication of impaired CMV-specific cell-mediated immunity (CMI). Primary aim of this study was to assess the suitability of the immune monitoring tool T-Track® CMV to determine CMV-reactive CMI in a cohort of hemodialysis patients representative of patients eligible for renal transplantation. Positive and negative agreement of T-Track® CMV with CMV serology was examined in 124 hemodialysis patients, of whom 67 (54%) revealed a positive CMV serostatus. Secondary aim of the study was to evaluate T-Track® CMV performance against two unrelated CMV-specific CMI monitoring assays, QuantiFERON®-CMV and a cocktail of six class I iTAg™ MHC Tetramers. RESULTS: Positive T-Track® CMV results were obtained in 90% (60/67) of CMV-seropositive hemodialysis patients. In comparison, 73% (45/62) and 77% (40/52) positive agreement with CMV serology was achieved using QuantiFERON®-CMV and iTAg™ MHC Tetramer. Positive T-Track® CMV responses in CMV-seropositive patients were dominated by pp65-reactive cells (58/67 [87%]), while IE-1-responsive cells contributed to an improved (87% to 90%) positive agreement of T-Track® CMV with CMV serology. Interestingly, T-Track® CMV, QuantiFERON®-CMV and iTAg™ MHC Tetramers showed 79% (45/57), 87% (48/55) and 93% (42/45) negative agreement with serology, respectively, and a strong inter-assay variability. Notably, T-Track® CMV was able to detect IE-1-reactive cells in blood samples of patients with a negative CMV serology, suggesting either a previous exposure to CMV that yielded a cellular but no humoral immune response, or TCR cross-reactivity with foreign antigens, both suggesting a possible protective immunity against CMV in these patients. CONCLUSION: T-Track® CMV is a highly sensitive assay, enabling the functional assessment of CMV-responsive cells in hemodialysis patients prior to renal transplantation. T-Track® CMV thus represents a valuable immune monitoring tool to identify candidate transplant recipients potentially at increased risk for CMV-related clinical complications.

Pancreatitis, panniculitis and polyarthritis (PPP-) syndrome caused by post-pancreatitis pseudocyst with mesenteric fistula. Diagnosis and successful surgical treatment. Case report and review of literature.

INTRODUCTION: Pancreatitis, panniculitis and polyarthritis syndrome is a very rare extra-pancreatic complication of pancreatic diseases. PRESENTATION OF CASE: While in most cases this syndrome is caused by acute or chronic pancreatitis, we report a case of a 62-year-old man presenting with extensive intraosseous fat necrosis, polyarthritis and panniculitis caused by a post-pancreatitis pseudocyst with a fistula to the superior mesenteric vein and extremely high blood levels of lipase. This became symptomatic 2.5 years after an episode of acute pancreatitis and as in most cases abdominal symptoms were absent. Treatment by surgical resection of the pancreatic head with the pseudocyst and mesenteric fistula led to complete remission of all symptoms. DISCUSSION: A review of the literature revealed that all publications are limited to case reports. Most authors hypothesize that an unspecific damage can cause a secretion of pancreatic enzymes to the bloodstream leading to a systemic lipolysis and fat tissue necrosis, especially of subcutaneous tissue, bone marrow, inducing panniculitis, polyarthritis and osteonecrosis. Even if caused by an acute pancreatitis abdominal symptoms are often mild or absent in most cases leading to misdiagnosis and poor prognosis. CONCLUSION: While symptomatic treatment with NSAR and cortisone showed poor to moderate response, causal treatment can be successful depending on the underlying pancreatic disease.

Donor-specific antibodies require preactivated immune system to harm renal transplant.

BACKGROUND: It is an unresolved issue why some kidney transplant recipients with pretransplant donor-specific HLA antibodies (DSA) show a high transplant failure rate, whereas in other patients DSA do not harm the graft. We investigated whether help from preactivated T-cells might be necessary for DSA to exert a deleterious effect. METHODS: The impact of pretransplant DSA and immune activation marker soluble CD30 (sCD30) on 3-year graft survival was analyzed in 385 presensitized kidney transplant recipients. FINDINGS: A deleterious influence of pretransplant DSA on graft survival was evident only in patients who were positive for the immune activation marker sCD30. In the absence of sCD30 positivity, 3-year graft survival was virtually identical in patients with or without DSA (83.1±3.9% and 84.3±2.8%, P=0.81). A strikingly lower 3-year graft survival rate of 62.1±6.4% was observed in patients who were both sCD30 and DSA positive (HR 2.92, P<0.001). Even in the presence of strong DSA with ≥5000 MFI, the 3-year graft survival rate was high if the recipients were sCD30 negative. INTERPRETATION: Pretransplant DSA have a significantly deleterious impact on graft survival only in the presence of high pretransplant levels of the activation marker sCD30.

High-urgency kidney transplantation in the Eurotransplant Kidney Allocation System: success or waste of organs? The Eurotransplant 15-year all-centre survey.

BACKGROUND: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial. METHODS: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups. RESULTS: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome. CONCLUSIONS: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.

Efficacy and safety of tacrolimus compared with ciclosporin-A in renal transplantation: 7-year observational results.

The European Tacrolimus versus Ciclosporin-A Microemulsion (CsA-ME) Renal Transplantation Study demonstrated that tacrolimus decreased acute rejection rates at 6 months. Primary endpoints of this investigator-initiated, observational 7-year follow-up study were acute rejection rates, patient and graft survival rates, and a composite endpoint (BPAR, graft loss, and patient death). We analyzed data from the original intent-to-treat population (n = 557; 286 tacrolimus, 271 CsA-ME). A total of 237 tacrolimus and 208 CsA-ME patients provided data. At 7 years, Kaplan-Meier estimated rates of patients free from BPAR were 77.1% in the tacrolimus arm and 59.9% in the CsA-ME arm, graft survival rates amounted to 82.6% and 80.6%, and patient survival rates to 89.9% and 88.1%. Estimated combined endpoint-free survival rates were 60.2% in the tacrolimus arm and 47.0% in the CsA-ME arm (P = <0.0001). A higher number of patients from the CsA-ME arm crossed over to tacrolimus during 7 year follow-up: 19.7% vs. 7.9% (P = <0.002). More patients in the tacrolimus group stopped steroids and received immunosuppressive monotherapy. Significantly, more CsA-ME patients received lipid-lowering medication and experienced cosmetic and cardiovascular adverse events. Tacrolimus-treated renal transplant recipients had significantly higher combined endpoint-free survival rates mainly driven by lower acute rejection rates despite less immunosuppressive medication at 7 years.