There is increasing evidence that endothelial dysfunction is involved in refractoriness of acute GvHD (aGvHD). Here we investigated the hypothesis that another endothelial complication, ...transplant-associated thrombotic microangiopathy (TMA), contributes to the pathogenesis of aGvHD refractoriness. TMA was retrospectively assessed in 771 patients after allogeneic stem cell transplantation (alloSCT). Incidences of TMA and refractory aGvHD were correlated with biomarkers of endothelial damage obtained before alloSCT for patients receiving or not receiving statin-based endothelial prophylaxis (SEP). Diagnostic criteria for TMA and refractory aGvHD were met by 41 (5.3%) and 76 (10%) patients, respectively. TMA was overrepresented in patients with refractory aGvHD (45.0 vs 2.3% in all other patients, P<0.001). TMA independently increased mortality. Elevated pretransplant suppressor of tumorigenicity-2 and nitrates along with high-risk variants of the thrombomodulin gene were associated with increased risk of TMA. In contrast, SEP abolished the unfavorable outcome predicted by pretransplant biomarkers on TMA risk. Patients on SEP had a significantly lower risk of TMA (P=0.001) and refractory aGvHD (P=0.055) in a multivariate multistate model. Our data provide evidence that TMA contributes to the pathogenesis of aGvHD refractoriness. Patients with an increased TMA risk can be identified pretransplant and may benefit from pharmacological endothelium protection.
Summary
Two different subsets of naturally occurring regulatory T cells (nTregs), defined by their expression of the inducible co‐stimulatory (ICOS) molecule, are produced by the human thymus. To ...examine the differentiation of ICOS+ and ICOS−CD45RA+CD31+ recent thymic emigrant (RTE) Tregs during normal pregnancy and in the presence of pre‐eclampsia or haemolysis elevated liver enzymes low platelet (HELLP)‐syndrome, we used six‐colour flow cytometric analysis to determine the changes in the composition of the ICOS+ and ICOS− Treg pools with CD45RA+CD31+ RTE Tregs, CD45RA+CD31− mature naive (MN) Tregs, CD45RA−CD31+ and CD45RA−CD31− memory Tregs. With the beginning of pregnancy until term, we observed a strong differentiation of both ICOS+ and ICOS−CD45RA+CD31+ RTE, but not CD45RA+CD31− MN Tregs, into CD45RA−CD31− memory Tregs. At the end of pregnancy, the onset of spontaneous term labour was associated with a significant breakdown of ICOS+CD45RA−CD31− memory Tregs. However, in the presence of pre‐eclampsia, there was a significantly increased differentiation of ICOS+ and ICOS−CD45RA+CD31+ RTE Tregs into CD45RA−CD31+ memory Tregs, wherein the lacking differentiation into CD45RA−CD31− memory Tregs was partially replaced by the increased differentiation of ICOS+ and ICOS−CD45RA+CD31− MN Tregs into CD45RA−CD31− memory Tregs. In patients with HELLP syndrome, this alternatively increased differentiation of CD45RA−CD31− MN Tregs seemed to be exaggerated, and presumably restored the suppressive activity of magnetically isolated ICOS+ and ICOS− Tregs, which were shown to be significantly less suppressive in pre‐eclampsia patients, but not in HELLP syndrome patients. Hence, our findings propose that the regular differentiation of both ICOS+ and ICOS−CD45RA+CD31+ RTE Tregs ensures a healthy pregnancy course, while their disturbed differentiation is associated with the occurrence of pre‐eclampsia and HELLP syndrome.
The exquisitely sensitive single antigen bead (SAB) technique was shown to detect human leukocyte antigen (HLA) antibodies in sera of healthy male blood donors. Such false reactions can have an ...impact on critical decisions, especially with respect to the determination of unacceptable HLA‐antigen mismatches in patients awaiting a kidney transplant. We tested pretransplant sera of 534 patients on the kidney waiting list using complement‐dependent cytotoxicity (CDC), enzyme‐linked immunosorbent assay (ELISA) and SAB in parallel. Evidence of HLA antibodies was obtained in 5% of patients using CDC, 14% using ELISA, and 81% using SAB. Among patients without history of an immunizing event, 77% showed evidence of HLA antibodies in SAB. In contrast 98% of these patients were negative in ELISA and CDC. In patients without an immunizing event, SAB‐detected antibodies reacted not always weakly but with mean fluorescence intensity (MFI) values as high as 14 440. High‐MFI‐value antibodies were found in some of these patients with HLA specificities that are rather common in general population, consideration of which would lead to unjustified exclusion of potential kidney donors. False SAB reactions can be unveiled by testing with additional antibody assays. Denial of donor kidneys to recipients based on HLA‐antibody specificities detected exclusively in the SAB assay is not advisable.
The results of this study on the kidney waiting list suggest that denial of donor kidneys to recipients based on HLA antibody specificities detected exclusively in the single‐antigen‐bead assay is not justified. See editorial by Gebel and Bray on page 1951.
Summary
Dysregulations concerning the composition and function of regulatory T cells (Tregs) are assumed to be involved in the pathophysiology of complicated pregnancies. We used six‐colour flow ...cytometric analysis to demonstrate that the total CD4+CD127low+/−CD25+forkhead box protein 3 (FoxP3)+ Treg cell pool contains four distinct Treg subsets: DRhigh+CD45RA‐, DRlow+CD45RA‐, DR‐CD45RA‐ Tregs and naive DR‐CD45RA+ Tregs. During the normal course of pregnancy, the most prominent changes in the composition of the total Treg cell pool were observed between the 10th and 20th weeks of gestation, with a clear decrease in the percentage of DRhigh+CD45RA‐ and DRlow+CD45RA‐ Tregs and a clear increase in the percentage of naive DR‐CD45RA+ Tregs. After that time, the composition of the total Treg cell pool did not change significantly. Its suppressive activity remained stable during normally progressing pregnancy, but decreased significantly at term. Compared to healthy pregnancies the composition of the total Treg cell pool changed in the way that its percentage of naive DR‐CD45RA+ Tregs was reduced significantly in the presence of pre‐eclampsia and in the presence of preterm labour necessitating preterm delivery (PL). Interestingly, its percentage of DRhigh+CD45RA‐ and DRlow+CD45RA‐ Tregs was increased significantly in pregnancies affected by pre‐eclampsia, while PL was accompanied by a significantly increased percentage of DR‐CD45RA‐ and DRlow+CD45RA‐ Tregs. The suppressive activity of the total Treg cell pool was diminished in both patient collectives. Hence, our findings propose that pre‐eclampsia and PL are characterized by homeostatic changes in the composition of the total Treg pool with distinct Treg subsets that were accompanied by a significant decrease of its suppressive activity.
•Mycophenolic acid (MPA) is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and has become a part of the standard therapy after liver transplantation.•MPA levels and ...corresponding IMPDH activity showed a broad interindividual variability and seems to be influenced by several factors, including BMI, kidney function and concomitant medication.•While patients with higher IMPDH inhibition acquires more often CMV infections, insufficient or delayed IMPDH inhibition after MPA administration is associated with non-anastomotic bile duct strictures and reduced re-transplantation-free survival.•Measurement of MPA levels and estimation of corresponding IMPDH activity in liver transplanted patients might be as a useful instrument for monitoring individual MPA dependent immunosuppression.
Due to the development of immunosuppressants, the focus in transplanted patients has shifted from short-term to long-term survival as well as a better adjustment of these drugs in order to prevent over- and under-immunosuppression. Mycophenolic acid (MPA) is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation, where it has become a part of the standard therapy. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic marker of MPA-induced immunosuppression may allow a more accurate assessment of efficacy and aid in limiting toxicity in liver transplanted patients.
Assess IMPDH-inhibition in liver transplant recipients and its impact on biliary/infectious complications, acute cellular rejection (ACR) and liver dependent survival.
This observational cohort study comprises 117 liver transplanted patients that were treated with mycophenolate mofetil (MMF) for at least 3 months. Blood samples (BS) were collected and MPA serum level and IMPDH activity were measured before (t(0)), 30minutes (t(30)) and 2h after (t(120)) MMF morning dose administration. Regarding MPA, we assessed the area under the curve (AUC). Patients were prospectively followed up for one year and assessed for infectious and biliary complications, episodes of ACR and liver dependent survival.
The MPA levels showed a broad interindividual variability at t(0) (2.0±1.8ng/ml), t(30) (12.7±9.0ng/ml) and t(120) (7.5±4.3ng/ml). Corresponding IMPDH activity was at t(o) (23.2±9.5 nmol/h/mg), at t(30) (16.3±8.8 nmol/h/mg) and t(120) (18.2±8.7 nmol/h/mg). With regard to MPA level we found no correlation with infectious or biliary complications within the follow-up period. Patients with baseline IMPDH(a) below the median had significant more viral infections (6 (10.2%) vs. 17 (29.3%); P=0.009) with especially more cytomegalovirus (CMV) infections (1 (3.4%) vs. 6 (21.4%); P=0.03)). Furthermore, patients with baseline IMPDH(a) above the median developed more often non-anastomotic biliary strictures (8 (13.6%) vs. 1 (1.7%), P=0.03). We found the group reaching the combined clinical endpoint of death and re-transplantation showing significantly lower MPA baseline values (t(0) 0.9±0.7 vs. 2.1±1.8μg/ml Mann-Whitney-U: P=0.02). We calculated a simplified MPA(AUC) with the MPA level at baseline, 30 and 120minutes after MPA administration. Whereas we found no differences with regard to baseline characteristics at entry into the study patients with MPA (AUC) below the median experienced significantly more often the combined clinical endpoint (12.1% (7/58) vs. 0.0% (0/57); P=0.002) and had a reduced actuarial re-transplantation-free survival (1.0 year vs. 0.58 years; Log-rank: P=0.007) during the prospective one-year follow-up period. In univariate and multivariate analysis including gender, age, BMI, ACR, MPA (AUC) and IMPDH(a) only BMI, MPA (AUC) and IMPDH(a) were independently associated with reduced actuarial re-transplantation-free survival.
MPA-levels and IMPDH-activity in liver transplanted patients allows individual risk assessment. Patients with higher IMPDH inhibition acquire more often viral infections. Insufficient IMPDH inhibition is associated with development of non-anastomotic bile duct strictures and reduced re-transplantation-free survival.
Chronic kidney disease (CKD) is increasingly recognized as a global health problem. The conditions leading to CKD, the health impact of CKD and the prognosis differ markedly between affected ...individuals. In particular, renal failure and cardiovascular mortality are competing risks for CKD patients. Opportunities for targeted intervention are very limited so far and require an improved understanding of the natural course of CKD, of the risk factors associated with various clinical end points and co-morbidities as well as of the underlying pathogenic mechanisms.
The German Chronic Kidney Disease (GCKD) study is a prospective observational national cohort study. It aims to enrol a total of 5000 patients with CKD of various aetiologies, who are under nephrological care, and to follow them for up to 10 years. At the time of enrolment, male and female patients have an estimated glomerular filtration rate (eGFR) of 30-60 mL/min×1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min×1.73 m2. Standardized collection of biomaterials, including DNA, serum, plasma and urine will allow identification and validation of biomarkers associated with CKD, CKD progression and related complications using hypothesis-driven and hypothesis-free approaches. Patient recruitment and follow-up is organized through a network of academic nephrology centres collaborating with practising nephrologists throughout the country.
The GCKD study will establish one of the largest cohorts to date of CKD patients not requiring renal replacement therapy. Similarities in its design with other observational CKD studies, including cohorts that have already been established in the USA and Japan, will allow comparative and joint analyses to identify important ethnic and geographic differences and to enhance opportunities for identification of relevant risk factors and markers.
Background
The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been ...established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy.
Methods
Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high‐volume transplant centres.
Results
Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty‐three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non‐invasive impact on the clinical management of the patient; grade B complications require non‐surgical intervention; and grade C complications require invasive surgical intervention.
Conclusion
A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.
Antecedentes
La incidencia de complicaciones linfáticas tras el trasplante renal (post‐kidney‐transplantation lymphatic, PKTL) varía considerablemente en la literatura. Esto se debe en parte a que no se ha establecido una definición universalmente aceptada. Este estudio tuvo como objetivo proponer una definición aceptable para las complicaciones PKTL y un sistema de clasificación de la gravedad basado en la estrategia de tratamiento.
Métodos
Se realizó una búsqueda sistemática de la literatura relevante en MEDLINE y Web of Science. Se logró un consenso para la definición y la clasificación de gravedad de las PKTL entre veinte centros de trasplante de alto volumen.
Resultados
En 32 de los 87 estudios incluidos se definía la linforrea/linfocele. Sesenta y tres artículos describían como se trataban las PKTL, pero ninguno calificó la gravedad de las mismas. La definición propuesta para la linforrea fue la de un débito diario superior a 50 ml de líquido (no orina, sangre o pus) a través del drenaje o del orificio cutáneo tras su retirada, más allá del 7º día postoperatorio del trasplante renal. La definición propuesta para linfocele fue la de una colección de líquido de tamaño variable adyacente al riñón trasplantado, tras haber descartado un urinoma, hematoma o absceso. Las PKTL de grado A fueron aquellas con escaso impacto o que no requirieron tratamiento invasivo; las PKTL de grado B fueron aquellas que precisaron intervención no quirúrgica y las PKTL de grado C aquellas en que fue necesaria la reintervención quirúrgica.
Conclusión
Se propone una definición clara y una clasificación de gravedad basada en la estrategia de tratamiento de las PKTLs. La definición propuesta y el sistema de calificación en 3 grados son razonables, sencillos y fáciles de comprender, y servirán para estandarizar los resultados de las PKTL y facilitar las comparaciones entre los diferentes estudios.
A clear definition and severity grading for lymphatic complications after kidney transplantation is proposed based on the management strategy. The proposed definition and three‐level grading system are generally reasonable, not complicated, and easy to understand; they will allow standardization of results relating to lymphatic complications after kidney transplantation and better comparisons between studies.
Valuable consensus
Aims/hypothesis
We hypothesised that diabetic patients would differ from those without diabetes in regard to the handling of glucose-derived reactive metabolites, evidenced by triosephosphate ...intermediates (TP
INT
) and methylglyoxal (MG), irrespective of the type of diabetes, plasma glucose level or HbA
1c
value.
Methods
To test this hypothesis, erythrocytes were isolated from patients with type 1 (
n
= 12) and type 2 (
n
= 12) diabetes with varying blood glucose and HbA
1c
levels. These were then compared with erythrocytes isolated from individuals without diabetes (
n
= 10), with respect to MG, as determined by HPLC, and TP
INT
, as determined by endpoint enzymatic assays.
Results
The concentrations of intracellular TP
INT
and MG were significantly elevated in erythrocytes from diabetic patients. Normalisation of either TP
INT
or MG to intracellular glucose concentration (nmol glucose/mgHb) confirmed that erythrocytes from diabetic patients accumulated more reactive metabolites than did those from healthy controls.
Conclusions/interpretation
Diabetic patients can be characterised by an increased formation of TP
INT
and MG. The 25-fold increase of MG in type 1 and the 15-fold increase in type 2 diabetes, together with a several-fold increase in TP
INT
and decreased glyceraldehyde-3-phosphate dehydrogenase activity even under normal glucose conditions, imply that normalising glucose level cannot completely prevent late diabetic complications until this acquired error of metabolism has been restored.
Background
Kidney transplantation (KTx) is considered to be the treatment of choice for end stage renal disease. One of the most challenging dilemmas in KTx is the shortage of suitable organs. The ...live donor nephrectomy is considered a unique operation performed on healthy donors, which provides a superior outcome in the recipients.
Several surgical techniques have been developed so far to minimize donor postoperative complications as much as possible without compromising the quality of the kidney. The development of a minimally invasive surgery, laparoscopic live donor nephrectomy (LDN), was based on this concept.
Materials and Methods
By searching the pubmed, we reviewed the most evidence based clinical studies specifically randomized clinical trials and meta-analyses to give an overview of the efficacy and safety of LDN versus ODN.
Results
The advantages of a LDN vs. a conventional open donor nephrectomy (ODN) are a smaller incision, better wound cosmetics, a lower rate of incisional hernia and adhesion, less postoperative pain, shorter hospitalization, and earlier return to work. Some concerns are longer operative and warm ischemic times, long-term learning curve for surgeons, and the risk of more serious complications than during an ODN.
Conclusion
Overall, the review of literature shows that a LDN provides less postoperative pain, a shorter hospital stay, a shorter period of rehabilitation, and earlier return to normal work and physical activities in comparison to the conventional open flank nephrectomy but is comparable to the mini muscle splitting approach. The complication rate is generally lower in centers accustomed to performing LDNs; however, complications can be life threatening and could impose significant costs to the health system. Weighing the longer operation and warm ischemic time, as well as the risk of more serious complications against the advantages of a LDN mandates a precise indication. The risk-benefit assessment for choosing one procedure should be done meticulously. Even though the short-term graft function in both techniques is comparable, there is a lack of enough long-term outcome analyses. Finally, in any transplant center, the cost of the laparoscopic procedure should be considered.
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