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Summary: 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.

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 two 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 (e.g. ICG Ingress) and donor, recipient, periprocedural, 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.

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.

The outcome after living kidney donation was assumed to be comparable to that of the general population. However, recent register studies reveal negative changes in kidney function, quality of life and fatigue. Avoiding methodological issues of previous studies, the Safety of the Living Kidney Donor (SoLKiD) cohort study analyzed the outcome of donors in a multicenter and interdisciplinary fashion. Donor data were collected pre-donation and two-, six- and 12-months post-donation in 20 German transplantation centers. Primary parameters were kidney function, quality of life, and fatigue. Secondary endpoints were blood pressure, hemoglobin, hemoglobin A1c, body mass index, depression and somatization. Parameters were analyzed with non-parametric statistical tests and a mixed model regression for changes in time, their clinical relevance and interaction encompassing 336 donors with mean age of 52 years. Most of the physical secondary parameters, depression, and quality of life showed little or no changes and regained their pre-donation level. Kidney function decreased significantly with a 37% loss of glomerular filtration rate and an increase of donors with chronic kidney disease stage 3 from 1.5% pre-donation to about 50%. Donors consistently showed increased fatigue and somatization. Mental fatigue increased from 10.6% to 28.1%. The main influencing factors for decreased kidney function and increased fatigue were their respective pre-donation levels, and donor age for kidney function and subject stress level in fatigue. Thus, our study showed that a significant number of donors developed clinically relevant changes in physical and mental health and emphasizes the urgent need to inform potential donors about these risks.

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.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.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.DKT provides an opportunity to successfully use postmortal kidneys even from donors aged80 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.

Was ist neu? Steroidfreie Immunsuppression Der Verzicht auf Steroide nach Nierentransplantation kann einen Diabetes mellitus verhindern, ohne dass ein gehäuftes Auftreten von akuten Abstoßungen bei Patienten mit niedrigem immunologischem Risiko beobachtet werden konnte. Risiken der Lebendspende Die Lebendnierenspende ist eine wichtige Alternative zur postmortalen Nierenspende, allerdings bestehen perioperative und längerfristige Risiken für den Spender. Patienteninformation bei Dialyse Seit Jahren ist bekannt, dass die Wahl eines Nierenersatzverfahrens am besten in einem Prozess der partizipativen Entscheidungsfindung (shared decision making) erreicht wird. Nun liegt eine kontrollierte Studie (CORETH-Projekt, Halle) vor. Die Zufriedenheit mit der Verfahrenswahl hängt vom Grad der Information ab; Patientenschulungen wie das Nierenstark-Training der Deutschen Nierenstiftung können eingesetzt werden. Dialysezugang Der Dialysezugang, Peritonealdialysekatheter und insbesondere der Hämodialyse-Shunt sind mittlerweile als Verfahren standardisiert und weiterentwickelt worden. Das neu-aufgelegte deutschlandweite interdisziplinäre Zertifizierungsverfahren von Shuntzentren bietet weitere qualitative Entwicklungsmöglichkeiten und Expertise. Dialysattemperatur Die Dialysattemperatur kann zur Kreislaufstabilisierung reduziert werden. In der „slow extended“-Form der Dialysebehandlung ist diese Maßnahme gut etabliert. In der intermittierenden Dialysebehandlung muss auf Nebenwirkungen geachtet werden und zugunsten des gewünschten Effektes abgewogen werden. Der Effekt auf die Dialyseeffizienz ist bislang unklar.

Was ist neu? Auftreten einer chronischen Niereninsuffizienz Epidemiologische Studien deuten klar auf einen Einfluss der asymptomatischen Hyperurikämie in der Entwicklung einer chronischen Niereninsuffizienz hin. Allerdings ist die Frage, ob eine erhöhte Harnsäure ursächlich für die Ausbildung einer Niereninsuffizienz ist oder lediglich einen Surrogatparameter darstellt, noch nicht abschließend geklärt. Progression der chronischen Niereninsuffizienz und Mortalität Der Zusammenhang der asymptomatischen Hyperurikämie mit einer Progression einer bestehenden chronischen Niereninsuffizienz ist weit weniger eindeutig, gut belegt ist jedoch die Assoziation mit einer erhöhten Mortalität. Transplantatfunktion und Mortalität nach Nierentransplantation Neben einer Assoziation mit einem Progress einer chronischen Niereninsuffizienz finden sich vergleichbare Daten bzgl. eines Transplantatverlustes nach Nierentransplantation. Einfluss der Intervention auf die Progression Neben der Therapie der Gicht erscheint die Senkung des Harnsäurespiegels ebenfalls positive Effekte auf die renale Funktion zu haben. Ergebnisse kleinerer Studien sind hierzu sehr vielversprechend, müssen aber in größeren, randomisierten Studien, bestätigt werden, um verbindliche Empfehlungen zur Therapie der asymptomatischen Hyperurikämie aussprechen zu können. Senkung der Harnsäure durch SLGT2-Inhibitoren Subgruppenanalysen zeigen, dass SLGT2-Inhibitoren neben ihrer glukosurischen auch eine urikosurische Wirkung besitzen und den Harnsäurespiegel signifikant senken können. Inwieweit dies zum nephroprotektiven Effekt dieser Substanzen beiträgt, müssen weitere Subgruppenanalysen und/oder Studien noch beantworten.

Peritonealdialyse und Herzinsuffizienz Peritonealdialyse (PD) bei Herzinsuffizienz fuhrt zu einer signifikanten Abnahme des Korpergewichts, zu einer signifikanten Verbesserung des NYHA-Stadiums und zu einer deutlich geringeren Hospitalisationsrate. Die Diuretikadosis, die linksventrikulare Funktion und die GFR sind durch die PD nicht signifikant verandert. Icodextrin und Insulinresistenz Die Insulinresistenz wird durch Icodextrin im Vergleich zu den konventionellen glukosehaltigen Losungen der PD verbessert, insbesondere bei Diabetikern. Auch Stoffwechselgesunde profitieren davon. Aldosteron-Antagonisten bei Dialysepatienten Aldosteronantagonisten sind bei Dialysepatienten mit Herzinsuffizienz vorteilhaft. Das Risiko einer Hyperkaliamie scheint jedoch auch bei diesen Patienten bedeutsam. Magnesiumspiegel als Risikofaktor Magnesiummangel ist mit einer hoheren Mortalitat verknupft. Diese Assoziation ist insbesondere dann bedeutsam, wenn ein Albuminmangel vorliegt. Asymptomatische Bakteriurie nach Nierentransplantation Die asysmptomatische Bakteriurie stellt ein haufiges Problem nach Nierentransplantation dar. Unter bestimmten Umstanden kann diese ohne Therapie bleiben. Hohe Variabilitat der Tacrolimus-Talspiegel Schwankende Spiegel von Tacrolimus konnen verschiedene Ursachen haben und werden mit verschiedenen Endpunkten nach Nierentransplantation assoziiert. Unter Berucksichtigung dieses Koeffizienten erscheint es moglich, Risikopatienten zu identifizieren und intensiver zu kontrollieren und ggf. besser zu behandeln.

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.

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.In this large retrospective analysis of prospectively collected data, transplant recipients from 1995 to 2015 were examined for patient and death-censored graft survival.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 of140 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.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.

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.

Renal transplantation in HIV-positive patients with end-stage renal disease has in recent years become a successful treatment option. We report two patients who underwent renal transplantation using a combination of basiliximab, calcineurin inhibitors, mycophenolate mofetil (MMF), and steroids with a "non-interacting" antiretroviral combination therapy consisting of stavudine or abacavir, lamivudine, and nevirapine. We observed no acute rejection but a BK polyomavirus infection in both patients. In conclusion, a quadruple immunosuppression with an interleukin 2 receptor antagonist, a calcineurin inhibitor, MMF, and steroids appears to be advisable to prevent high rates of acute rejection, but if possible thereafter immunosuppression should be tapered rapidly (eg, MMF stop, prednisolone dose 5 mg/d). The selection of antiretroviral agents should avoid compounds that interact severely with the immunosuppression used.

Whether organs from donors after brain death (DBD) with acute kidney injury (AKI) should be accepted for transplantation is still a matter of debate.This was a retrospective, center-based, matched cohort study of 33 renal transplant patients who received a renal allograft from a DBD with AKI. Sixty-five kidney transplants without donor AKI transplanted directly before and after the index transplantation served as controls.All AKI donors were classified according to RIFLE criteria: 9.1 % Risk, 54.6 % Injury, and 36.4 % Failure. Mean serum creatinine was 2.41 ± 0.88 mg/dL at procurement and 1.06 ± 0.32 mg/dL on admission. AKI donors had lower 24-h urine production (3.22 ± 1.95 vs. 4.59 ± 2.53 L, p = 0.009) and received more frequently noradrenaline (93.9 vs. 72.3 %, p = 0.02) and/or adrenaline (15.2 vs. 1.5 %, p = 0.02). Recipient and transplant characteristics were similar except a more favorable HLA match in control patients (p = 0.01). Hemodialysis posttransplant was more frequently used in AKI recipients (14/33 [42.4 %] vs. 18/65 [27.7 %], p = 0.17). While significant elevations in serum creatinine were noted in these patients until 10 days after transplantation, this difference lost statistical significance by day 14. One-year graft survival was very similar when comparing the groups (93.6 % [95 % CI 76.8-98.4 %] vs. 90.3 % [95 % CI 79.6-95.5 %], log rank p = 0.58).Kidneys from AKI donors can be transplanted with excellent intermediate prognosis and should not be discarded.

Epidemiologische Studien deuten klar auf einen Einfluss der asymptomatischen Hyperurikämie in der Entwicklung einer chronischen Niereninsuffizienz hin. Allerdings ist die Frage, ob eine erhöhte Harnsäure ursächlich für die Ausbildung einer Niereninsuffizienz ist oder lediglich einen Surrogatparameter darstellt, noch nicht abschließend geklärt. PROGRESSION: der chronischen Niereninsuffizienz und Mortalität Der Zusammenhang der asymptomatischen Hyperurikämie mit einer Progression einer bestehenden chronischen Niereninsuffizienz ist weit weniger eindeutig, gut belegt ist jedoch die Assoziation mit einer erhöhten Mortalität. TRANSPLANTATFUNKTION UND MORTALITäT NACH NIERENTRANSPLANTATION: Neben einer Assoziation mit einem Progress einer chronischen Niereninsuffizienz finden sich vergleichbare Daten bzgl. eines Transplantatverlustes nach Nierentransplantation.Neben der Therapie der Gicht erscheint die Senkung des Harnsäurespiegels ebenfalls positive Effekte auf die renale Funktion zu haben. Ergebnisse kleinerer Studien sind hierzu sehr vielversprechend, müssen aber in größeren, randomisierten Studien, bestätigt werden, um verbindliche Empfehlungen zur Therapie der asymptomatischen Hyperurikämie aussprechen zu können. SENKUNG DER HARNSäURE DURCH SLGT2-INHIBITOREN: Subgruppenanalysen zeigen, dass SLGT2-Inhibitoren neben ihrer glukosurischen auch eine urikosurische Wirkung besitzen und den Harnsäurespiegel signifikant senken können. Inwieweit dies zum nephroprotektiven Effekt dieser Substanzen beiträgt, müssen weitere Subgruppenanalysen und/oder Studien noch beantworten.

Transplant international (2017). doi:10.1111/tri.13110, Published by Wiley-Blackwell, Oxford [u.a.]

In gut selektionierten Einzelfallen konnen postmortale Spendernieren trotz bei Organentnahme bestehendem ANV/AKI mit guten Ergebnissen hinsichtlich der Transplantatfunktion und des Transplantatuberlebens transplantiert werden. Ein ANV/AKI ist unmittelbar nach Nierentransplantation auch bei guter Nierenfunktion des Spenders sehr haufig (> 90 %), da auch die schwerste Form des ANV/AKI entsprechend der verzogerten Transplantationsfunktionsaufnahme mit postoperativer Dialysenotwendigkeit innerhalb der ersten 7 Tage (DGF: Delayed Graft Function) bereits bei ca. 20–30 % der Nierentransplantationsempfanger nachweisbar ist. Risikofaktoren fur das postoperative Auftreten eines ANV/AKI bzw. einer DGF umfassen u. a. ECD-Spender (erweiterte Spenderkriterien), lange kalte Ischamiezeit (CIT), hohes Spenderkreatinin, hohes Spenderalter, weiblicher Spender, Spenderatherosklerose, DCD-Spender (nach Herztod), Risikofaktoren des Empfangers wie mannliches Geschlecht, Diabetes, Hypertonie, Atherosklerose, Dialysedauer, Retransplantation, PRA/HLA-Mismatch und Sirolimustherapie. Auch im Langzeitverlauf nach Nierentransplantation ist das Auftreten eines ANV/AKI haufig meist im Rahmen eines prarenalen ANV/AKI bei Flussigkeitsverlusten (z. B. Diarrhoen), Medikamententoxizitat (z. B. NSAID, CNI) und Infektionen (z. B. Urosepsis, Pneumonie).

Single nucleotide polymorphisms (SNPs) have been associated with an increased incidence of invasive aspergillosis (IA) after allogeneic stem cell transplantation (allo-SCT). We analyzed 41 patients with proven/probable IA after allo-SCT for an association of SNPs, within the TLR2, TLR4, TLR5, TLR9, and NOD2/CARD15 genes, with susceptibility to IA. The control group consisted of 130 patients who had allo-SCT but did not develop IA. While no association was found for donor SNPs and the recipients’ risk of IA, analysis of recipient SNPs showed a significant association between the presence of recipient TLR5-Stop SNP (1174C> T) and the incidence of IA (P = 0.004). Multivariate analysis demonstrated that the recipient TLR5-Stop SNP appeared as an independent risk factor for IA after allo-SCT. Our study suggests that TLR5 is involved in host defense against Aspergillus fumigatus, and that the recipient TLR5-Stop SNP represents a risk factor for the development of IA after allo-SCT.

A shift from anti- to proinflammatory steroid hormones has been observed in chronic inflammation. We tested the hypothesis that this shift occurs also in kidney transplant rejection together with a rise of urinary catecholamine degradation product concentrations as a consequence of locally produced cytokines, thus further promoting rejection.We examined 8 patients with an early rejection episode in the protocol biopsy ∼2 weeks, 9 with biopsy-proven rejection at 2-3 months, and 18 without rejection, both at 2 weeks and 3 months after transplantation. Metanephrine, normetanephrine, and 2- and 16-hydroxyestrogens concentrations were measured by EIA.The median urinary concentrations of normetanephrine, but not metanephrine, were significantly higher in acute kidney transplant rejection in the first 2 weeks after transplantation (P.05). During acute kidney transplant rejection at 2-3 months, but not in the first 2 weeks, after transplantation, 2-, but not 16-hydroxyestrogens, concentrations were significantly decreased (P.05).We demonstrated that the downstream product of noradrenaline conversion normetanephrine was elevated in kidney transplant rejection in the first weeks after transplantation. This change may promote rejection together with an important proinflammatory and mitogenic steroid hormone shift, which becomes increasingly relevant over time.

The role of specific subtypes of infiltrating cells in acute kidney allograft rejection is still not clear and was so far not examined by different analyzing methods under standardized conditions of an experimental kidney transplantation model. Immunohistochemical staining of CD3, CD20 and CD68 was performed in rat allografts, in syngeneically transplanted rats and in control rats with a test duration of 6 and 28 days. The detailed expression and localization of infiltrating cells were analyzed manually in different kidney compartments under light microscope and by the two different morphometric software programs. Data were correlated with the corresponding kidney function as well as with histopathological classification. The information provided by the morphometric software programs on the infiltration of the specific cell types after renal transplantation was in accordance with the manual analysis. Morphometric methods were solid to analyze reliably the induction of cellular infiltrates after renal transplantation. By manual analysis we could clearly demonstrate the detailed localization of the specific cell infiltrates in the different kidney compartments. Besides infiltration of CD3 and CD68 infiltrating cells, a robust infiltration of CD20 B-cells in allogeneically transplanted rats, even at early time points after transplantation was detected. Additionally an MHC class I expression could reliable be seen in allogeneically transplanted rats. The infiltration of B-cells and the reliable antigen presentation might act as a silent subclinical trigger for subsequent chronic rejection and premature graft loss.

Acute transplant rejection is the leading cause of graft loss in the first months after kidney transplantation. Lipoxygenase products mediate pro- and anti-inflammatory actions and thus we aimed to correlate the histological reports of renal transplant biopsies with urinary lipoxygenase products concentrations to evaluate their role as a diagnostic marker. This study included a total of 34 kidney transplant recipients: 17 with an acute transplant rejection and 17 controls. LTE4, LTB4, 12-HETE and 15-HETE concentrations were measured by enzyme immunoassay. Urinary lipoxygenase product concentrations were not significantly changed during an acute allograft rejection. Nevertheless, LTB4 concentrations correlated significantly with the body temperature (P ≤ 0.05) 3 months after transplantation, and 12- and 15-HETE concentrations correlated significantly with renal function (P ≤ 0.05) 2 weeks after transplantation. In conclusion, our data show a correlation for LTB4 with the body temperature 3 months after transplantation and urinary 12- and 15-HETE concentrations correlate positively with elevated serum creatinine concentrations but do not predict acute allograft rejection.

Highlights • Pancreatitis, panniculitis and polyarthritis syndrome is a very rare manifestation of pancreatitis with panniculitis and polyarthritis with intraosseous fat necrosis. • A rare differential diagnosis of unclear polyarthritis, panniculitis or osteonecrosis. • Surgical treatment, if possible can lead to complete remission., 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.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12865-017-0194-z) contains supplementary material, which is available to authorized users.

Highlights • Pretransplant DSA have a deleterious impact on graft survival only in the presence of high pretransplant serum levels of sCD30. • The majority of patients with pretransplant DSA might be transplanted safely without special pretreatment measures. Kidney transplantation in the presence of donor-specific HLA antibodies (DSA) is associated with a high failure rate due to antibody-mediated rejection. Many centers avoid transplantations if DSA are present. Others perform such transplantations after removal of DSA by apheresis under potent immunosuppression. We provide strong evidence that DSA positive recipients reject their grafts at a high rate only if the immune activation marker sCD30 is also high, suggesting that T-cell help from an activated immune system is necessary for pretransplant DSA to exert a deleterious effect on the graft. High-risk patients with DSA and sCD30 may benefit from special treatment measures. The presence of DSA alone may not be deleterious., 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

Item does not contain fulltext 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.

Das akute Nierenversagen (ANV) jeglicher Ursache ist eine haufige Erkrankung bei hospitalisierten Patienten mit signifikantem Anstieg von Mortalitat, Morbiditat sowie der Krankenhausverweildauer bzw. der Krankenhauskosten. Die medikamenteninduzierte Schadigung der Nierenfunktion tritt dabei primar in Patienten mit bestehenden Risikofaktoren wie praexistenter Niereninsuffizienz, Dehydratation/Hypotension, hoherem Lebensalter oder Diabetes mellitus auf, wobei das auslosende Medikament bei umfangreichen Therapien mitunter schwer zu definieren ist. Pathophysiologisch tragen zu dieser Krankheitsentitat hamodynamische Ursachen, intrinsische tubulointerstitielle Schadigungen sowie die intrarenale (tubulare) Obstruktion durch Prazipitate bei, teils mit entsprechender klinischer Symptomatik. Klinisch steht das akute Nierenversagen einhergehend mit Hyperhydratation mit/ohne Lungenodem sowie fehlender Clearance von toxischen Metaboliten im Vordergrund. Bei insgesamt guter Prognose des medikamentos-toxischen ANVs, insbesondere bei fruhzeitigem Absetzen des auslosenden Agens, sind dennoch immer wieder schwere Verlaufe mit zum Teil chronischer Funktionsverschlechterung bis hin zur Dialysepflichtigkeit zu beobachten. Erkennen und Beachten von Risikofaktoren mit Identifikation von Risikopatienten kann helfen entsprechende Vorsichtsmasnahmen zu veranlassen. Insbesondere in der Intensivmedizin sollte das Erkennen mit nachfolgender Prophylaxe essenzieller Bestandteil der taglichen Routine sein, da diese Patientengruppe typischerweise dem hochsten Risiko unterliegt.

Die Dreifach („Triple“)-Therapie, bestehend aus Kalzineurininhibitor, Mycophenolsaure und Steroid stellt nach (Nieren-)Transplantation nach wie vor die Standardtherapie dar, wobei eine steroidfreie Immunsuppression und eine kalzineurininhibitorfreie (mTOR-Inhibitoren- oder Belatacept-basierte) Therapie zunehmend Verbreitung erfahren. Standard ist in vielen Zentren zudem eine Induktionstherapie mit Basiliximab oder ATG/ALG. Bei einer Funktionsverschlechterung des transplantierten Organs ist eine konsequente Abklarung unter Einschluss einer Biopsie sowie Untersuchungen zur Organperfusion erforderlich, um eine situationsgerechte Therapie z. B. bei humoraler Rejektion oder BK-Nephropathie zu ermoglichen. Das Langzeituberleben des Patienten mit funktionierendem Transplantat wird zu einem grosen Teil durch das Auftreten von Herz-Kreislauf-Erkrankungen bestimmt. Bei diesen kardiovaskularen Hochrisikopatienten sollten aggressive praventive bzw. therapeutische Interventionen durchgefuhrt werden. Dies umfasst eine Blutdrucksenkung unter 140/90 mmHg (Kalziumantagonist, Diuretikum, ACE-Hemmer, Betablocker als Mittel der 1. Wahl), eine Statintherapie (Fluvastatin und Pravastatin sind am besten untersucht), eine Diabeteseinstellung (Ziel-HbA1c ca. 7%), die Vermeidung von Gewichtszunahmen posttransplant sowie Nikotinkarenz. Das Tumorrisiko ist nach Transplantation etwa 4-fach erhoht; insbesondere betrifft dies Hauttumoren, Lymphome und Nieren-/Blasentumoren. Neben der ohnehin fur die Allgemeinbevolkerung empfohlenen Tumorvorsorge sind u. a. regelmasige dermatologische und sonographische Untersuchungen (Leber bei Virus-Hepatitis, Eigennieren) zu empfehlen. Die hohe Immunsuppression birgt besonders im ersten halben Jahr ein hohes Infektionsrisiko. Transplantationsbedingte Infektionen (ZVK, Wundinfektionen, nosokomiale Pneumonien, Harnwegsinfektion bei BDK), De-novo-Infektionen bzw. endogene Reaktivierungen von Virusinfektionen insbesondere der Herpesgruppe (HSV, VZV, CMV) stehen im Vordergrund. Die Komplexitat des Krankheitsspektrums von Transplantierten macht eine interdisziplinare Betreuung und eine enge Zusammenarbeit zwischen dem Transplantationszentrum und den betreuenden niedergelassenen Arzten notwendig.

We tested the hypothesis that increased urinary cytokine concentrations may indicate an acute kidney transplant rejection. Eight patients with an early rejection in their protocol biopsy about 14days after transplantation (group A), 9 patients with a biopsy proven rejection 2-3months after transplantation (group B) and 18 patients without acute rejection in their protocol biopsies both at 14days and 3months (group C, represents the control group) were chosen for this study. At the time of biopsy, the mean urinary concentration of interleukin 6 (IL6), soluble IL6 receptor (sIL6R), tumor necrosis factor receptor 1 (TNFR1), and soluble vascular cell adhesion molecule -1 (sVCAM-1) were significantly higher in patients with an early acute transplant rejection, i.e. in group A compared to patients in the control group (p0.01). Additionally we found already 14days after transplantation significantly higher concentrations of urinary sIL6R and sVCAM-1 in group B patients who suffered of late acute rejection compared to patients with no acute rejection (group C, p0.05). No significant correlation could be shown for interleukin 1 receptor antagonist (IL1ra), TNF, and TNFR2. In conclusion, elevated urinary concentrations of IL6, sIL6R, TNFR1 and sVCAM-1 clearly indicate an early acute transplant rejection. Especially sVCAM-1 may also serve as an early marker of an upcoming late rejection. However, further studies are warranted to verify the value of individual cytokine profiles to predict acute rejection episodes.

Background/Aims: The prevalence of cardiovascular disease in renal transplant recipients is markedly higher than in the general population due to the high prevalence of traditional cardiovascular risk factors, renal transplant function impairment and treatment with immunosuppressive drugs that affect blood pressure, cholesterol and blood glucose levels. Methods: Cross-sectional analysis using our renal transplant clinic cohort investigating (1) the cardiovascular risk factors present in this cohort, and (2) estimating their impact on the risk of coronary artery disease (CAD) by using the Framingham algorithm. Results: Control of modifiable cardiovascular risk factors in 231 renal transplant recipients is suboptimal, i.e. 47.2% of patients are hypertensive, 10.3% actively smoke, 39.4% have serum cholesterol concentrations >200 mg/dl, and 19.7% have diabetes mellitus. Blood pressure, age, hyperlipidemia, smoking and diabetes modulate the estimated CAD risk in males and females. Furthermore, a short time period (less than 1 year) since transplantation and increased serum creatinine levels negatively influenced the CAD risk in this patient population. Conclusion: According to current guidelines, the control of modifiable cardiovascular risk factors in renal transplant recipients is suboptimal. The decreasing CAD risk over time after transplantation may be due to the reduction of immunosuppressive drugs with time and survival bias., OA-Komponente aus Allianzlizenz

Aging of the population and improvements in diabetes therapy have led to an increased number of older pancreas transplant candidates. The aim of our retrospective study was to evaluate pancreas transplantation (PT) outcomes in patients ≥ 50 years, as limited data exist in these patients. We analyzed 398 consecutive pancreas transplant patients from June 1994 to June 2009 for different outcomes (patient/graft survival, rejection rate, and surgical complications) between the age groups ≥ 50 years (n = 69) and

To date, the impact of the TLR (Toll-like receptor) system on early and late kidney transplantation outcome, such as ARE (acute rejection episodes) or cardiovascular morbidity and mortality, has still not been elucidated conclusively. Genetically determined alterations in TLR expression exhibit a possibility to evaluate their role in transplantation. In the present study, we sought to determine a comprehensive genotype–phenotype association with early and late allograft outcomes. We studied 11 SNPs (single nucleotide polymorphisms) in TLR2, TLR3, TLR4, TLR5, TLR9 and within a co-molecule CD14 in 265 patients receiving their first kidney transplant and the association of these with the occurrence of DGF (delayed graft function), ARE or MACE (major adverse cardiovascular events). ARE were significantly more frequent in patients carrying the TLR3 TT/CT allele (43.8 compared with 25.8%; P=0.001) as were rates of DGF (21.4 compared with 12.0%; P=0.030). Furthermore, TLR9 was significantly involved in the occurrence of MACE (TLR9 −1237; P=0.030). Interestingly, there was no significant effect of any TLR polymorphism on graft survival or renal function and the incidence of any infection, including CMV (cytomegalovirus) infection. In conclusion, our present study in renal transplant recipients suggests that the TLR system may be involved in both acute rejection and MACE. Modulation of the TLR system may be a promising target in future therapeutic strategies.

Although islet transplantation is an effective treatment for Type 1 diabetes, primary engraftment failure contributes to suboptimal outcomes. We tested the hypothesis that islet isolation and transplantation activate innate immunity through TLR expressed on islets. Murine islets constitutively express TLR2 and TLR4, and TLR activation with peptidoglycan or LPS upregulates islet production of cytokines and chemokines. Following transplantation into streptozotocin-induced diabetic, syngeneic mice, islets exposed to LPS or peptidoglycan had primary graft failure with intra- and peri-islet mononuclear cell inflammation. The use of knockout mice showed that recipient CD8(+) T cells caused engraftment failure and did so in the absence of islet-derived DC. To mimic physiological islet injury, islets were transplanted with exocrine debris. Transplantation of TLR2/4(-/-) islets reduced proinflammatory cytokine production and improved islet survival. Stressed islets released the alarmin high-mobility group box protein 1 (HMGB1) and recombinant HMGB1 (rHMGB1) induced NFkB activation. NFkB activation was prevented in the absence of both TLR2 and TLR4. rHMGB1 pretreatment also prevented primary engraftment through a TLR2/4-dependent pathway. Our results show that islet graft failure can be initiated by TLR2 and TLR4 signaling and suggest that HMGB1 is one likely early mediator. Subsequent downstream signaling results in intra-islet inflammation followed by T-cell-mediated graft destruction.

Background An important role of TLR2 has been shown in various experimental models of renal ischaemia/reperfusion injury. To study the expression of TLR2 in renal allograft rejection systematically, we established an experimental rat transplantation model. Methods TLR2 expression was analysed in 99 human renal allograft biopsies, and in rat allografts at Day 6 and 28 after experimental renal transplantation. To discriminate whether regulation of TLR2 was following immunological processes after allogeneic transplantation or was a consequence from ischaemia/reperfusion injury, control animals subjected to syngeneic transplantation or to ischaemia/reperfusion damage were also investigated. Results TLR2 mRNA was significantly elevated in rat allografts with acute rejection on Day 6 and decreased spontaneously towards Day 28. TLR2 induction correlated with renal function and TLR2 excretion in the urine of transplanted rats. TLR2 staining was also significantly increased in human allografts with acute rejection. TLR2 protein could be localized in tubular epithelial cells and vascular endothelial cells, and in CD68- and CD4-positive infiltrating cells. Conclusions TLR2 is markedly up-regulated in both experimental and human acute renal allograft rejection. Our data suggest a role for TLR2 during allogen-dependent graft damage after renal transplantation.

Die sekundare Hypertonie kann in Einzelfallen durch verschiedene gleichzeitig vorliegende Erkrankungen bedingt sein wie bei dem hier vorgestellten Patienten, der zwei mogliche Grunde aufwies. Auswartige Magnetresonanzuntersuchungen eines 58-jahrigen Patienten wiesen eine 60- bis 70%ige exzentrische Stenose der linken Nierenarterie sowie eine inhomogene Raumforderung der linken Nebenniere nach. Nach einer perkutanen transluminalen Angioplastie zeigte sich eine persistierende Erhohung des Plasmaaldosterons. Die Aufnahme des Patienten in die Klinik der Autoren erfolgte bei Verdacht auf einen primaren Hyperaldosteronismus. Eine seitengetrennte Nebennierenvenenblutentnahme ergab einen primaren Hyperaldosteronismus durch ein unilaterales Adenom, woraufhin eine laparoskopische Adrenalektomie links durchgefuhrt wurde. Die atherosklerotisch bedingte Nierenarterienstenose fuhrt uber eine Stimulation des Renin-Angiotensin-Systems haufig zu einer sekundaren Hypertonie. Gleiches gilt fur Erkrankungen der Nebennieren, insbesondere bei inadaquater Aldosteronproduktion im Sinne eines primaren Hyperaldosteronismus. Das gleichzeitige Auftreten zweier moglicher Ursachen eines sekundaren Hypertonus ist zwar selten, muss jedoch differentialdiagnostisch und differentialtherapeutisch in Erwagung gezogen werden. Die mutmasliche pathophysiologische Relevanz sollte die Reihenfolge der therapeutischen Masnahmen vorgeben.

Background At present, inflammation is considered to be one of the key players in the development and maintenance of atherosclerosis, with ample impact on renal transplant outcomes. Interleukin-6 (IL-6) levels and the underlying genetically determined “high-producer” status impact cardiovascular morbidity and mortality. In end-stage renal disease (ESRD) patients, the role of genetically determined IL-6 differences in cardiovascular and renal outcomes of kidney transplantation is controversial. In this study, we sought to clarify the influence of IL-6 haplotypes on cardiovascular and renal outcomes among kidney transplant recipients. Methods Three hundred fifty-two first kidney transplant patients were genotyped for the two “clade” IL-6 polymorphisms ( −174 G/C and 1888 G/T) and two missense polymorphisms (Pro32Ser, Asp162Val), which are known to influence IL-6 levels and outcome. Results We observed four IL-6 haplotypes among our population: CCAG: 57.0%, CCAT: 2.8%, GCAT: 39.2%, GCTT: 1.0%. After stratifying the haplotypes into diplotypes in three different models, we failed to observe associations with early or late graft outcomes, or with all-cause or cardiovascular mortality. These findings were also confirmed when we separately analyzed each polymorphism. Conclusion Despite evidence of associations in other transplant and ESRD cohorts, we could not confirm any association between IL-6 haplotypes/diplotypes and cardiovascular or graft-related outcomes among our population at high risk for inflammatory diseases.

An important role of TNF interacting with TNFR2 has been shown in different models of ischemic, nephrotoxic and immune-mediated renal injury. To systematically evaluate the expression of TNFR2 in renal allograft rejection, we investigated human renal allograft biopsies and, in addition, established an experimental transplantation model in rats to verify the human data under standardized conditions. The expression of TNFR2 was analyzed in 96 human renal allograft biopsies with different disease entities. In a 6-day and a 28-day experimental protocol, TNFR2 was examined in kidney specimens and in the urine of control, uni-nephrectomized and transplanted rats ± cyclosporine treatment (n = 114). In human biopsies and in rat allografts on day 6 with acute allograft rejection, significantly elevated expression of TNFR2 was observed in tubular epithelial cells, podocytes, B cells and monocytes/macrophages. The expression level was associated with renal function. The TNFR2 expression level at day 28 was significantly lower compared to day 6. TNFR2 is markedly upregulated both in human and experimental acute renal allograft rejection. Our data are robust and consistent between different species, suggesting a role for TNFR2 in the early course of rejection.

While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to kidney injury induced by ischemia and reperfusion, the relevance of TLR4 activation to allograft injury in human kidney transplants is unknown. Here we show that TLR4 is constitutively expressed within all donor kidneys but is significantly higher in deceased-, compared with living-donor organs. Tubules from deceased- but not living-donor kidneys also stained positively for high-mobility group box-1 (HMGB1), a known endogenous TLR4 ligand. In vitro stimulation of human tubular cells with HMGB1, in a TLR4-dependent system, confirmed that HMGB1 can stimulate proinflammatory responses through TLR4. To assess the functional significance of TLR4 in human kidney transplantation, we determined whether TLR4 mutations that confer diminished affinity for HMGB1 influence intragraft gene-expression profiles and immediate graft function. Compared with kidneys expressing WT alleles, kidneys with a TLR4 loss-of-function allele contained less TNFα, MCP-1, and more heme oxygenase 1 (HO-1), and exhibited a higher rate of immediate graft function. These results represent previously undetected evidence that donor TLR4 contributes to graft inflammation and sterile injury following cold preservation and transplantation in humans. Targeting TLR4 signaling may have value in preventing or treating postischemic acute kidney injury after transplantation.

We have previously shown that HLA-DQA1, a peptide derived from a highly conserved region of MHC class II, prevents alloreactive T cell priming and effector function in vivo, although underlying mechanisms are obscure. In this study, we demonstrate that 28% of mice treated with HLA-DQA1 combined with low-dose rapamycin achieved permanent engraftment of fully MHC-disparate islet allografts and significantly prolonged survival in the remaining animals (log rank, p < 0.001). Immunohistologic examination of the grafts from HLA-DQA1/rapamycin-treated animals revealed up-regulated expression of TGF-ß and FoxP3. In vivo administration of blocking anti-TGF-ß or depleting anti-CD25 mAb augmented T cell alloimmunity and prevented the long-term engraft induced by HLA-DQA1. In vitro experiments further showed that HLA-DQA1 induced differentiation of CD4+ T cells into CD4+CD25+FoxP3+ regulatory T cells. Together, these data provide the first demonstration that HLA-DQA1, a MHC class II-derived peptide, can prolong allograft survival via a TGF-β and regulatory T cell-dependent mechanisms.

A 51-year-old renal transplant recipient presented with marked renal function deterioration 13 months after renal transplantation. After exclusion of ureteral obstruction, transplant artery stenosis and acute rejection, the diagnosis of a severe renal vein stenosis was made by an MR scan. After angiographic confirmation of the stenosis, treatment was attempted with percutaneous stent angioplasty. The long-term clinical course was favorable, with marked improvement in renal function. Transplant renal vein stenosis is a rare, but potentially curable, cause of renal allograft functional deterioration.

Background: The chemokine system plays an important role in the pathogenesis of acute rejection or atherosclerosis. Three polymorphisms in the promoter region of the chemokine RANTES (−403G/A, −28G/C, In1.1T/C) are associated with a different expression of this chemokine as well as the occurrence of cardiovascular disease. Therefore, we investigated the impact of these three polymorphisms on the outcome after renal transplantation. Methods: In 261 patients receiving their first kidney transplant, we genotyped the RANTES promoter polymorphisms (−403G/A, −28G/C, In1.1T/C) by real-time PCR. Results: For the RANTES −403G/A and for the intronic polymorphism In1.1T/C, we found a significantly higher rate of recurrent acute rejection episodes (−403G/A: 11.1 vs. 31.0%, In1.1T/C: 11.8 vs. 33.0%). For the overall rate of acute rejection, we observed no significant differences according to the RANTES promoter polymorphisms. The other tested variables (DGF, graft survival, renal function) were not associated with one of the three polymorphisms. Conclusion: Our data indicate a relevant role of RANTES in kidney transplantation, particularly for the occurrence of recurrent acute rejection. To clarify the role of the analysed polymorphisms for long-term survival, especially for the occurrence of cardiovascular events, larger studies in the future are needed.

Background: Living kidney donation helps to avoid or reduce the time period of dialysis and on waiting lists in patients requiring a new organ. Mini-incision donor nephrectomy (MIDN) shows to result in better clinical outcome in comparison with traditional open donor nephrectomy (ODN). This study was performed to evaluate the impact of different surgical procedures on the quality of life (QoL) in patients that underwent donor nephrectomy. Methods: The aim of the study was to detect differences in QoL assessed with the Short Form-36 Version 2 (SF-36v2) questionnaire between MIDN (n = 34) and ODN (n = 36). Furthermore, the development of QoL from prior to surgery until one yr afterwards, as well as outcomes of QoL in comparison with norm-based scores was investigated. Results: Sixty-one of 70 patients, which is 87% (MIDN: 86%, ODN: 88%) resent a whole set questionnaires. QoL was similar at all time-points (prior to surgery, one wk, three months and one yr) in both groups. A tendency of better QoL in MIDN (Bodily Pain) after one wk was detectable (p = 0.075). Physical Component Summaries (PCS) significantly decreased from prior to surgery until one wk after surgery (p = 0.001) and improved significantly until three months (MIDN: p = 0.006, ODN: p = 0.001) and also until one yr after surgery (p = 0.002). Mental Component Summaries (MCS) were stable throughout the whole investigated time period. In comparison with norm-based scores, MIDN (p = 0.005) and ODN (p = 0.001) showed significantly higher PCS prior to, lower scores one wk after (p = 0.001), similar scores three months after and better scores (MIDN: p = 0.023, ODN: 0.015) one yr after surgery. Mental Component Scores were similar in both prior to and one wk after surgery. After three months and one yr scores were significantly better in MIDN (three months: p = 0.049, one yr: p = 0.037) and ODN (three months: 0.020, one yr: 0.073). Conclusion: Quality of life after living donor nephrectomy is not influenced by the surgical technique. Nevertheless the standardized instrument of the SF-36v2 Health Survey is a useful, practicable and universally interpretable tool to gain and estimate recovery from surgical procedures in the perioperative period and its development thereafter.