Consensus on definition and severity grading of lymphatic complications after kidney transplantation.

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.

Differentiation of ICOS+ and ICOS- recent thymic emigrant regulatory T cells (RTE T regs) during normal pregnancy, pre-eclampsia and HELLP syndrome.

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) T regs 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(-) T reg pools with CD45RA(+) CD31(+) RTE T regs, CD45RA(+) CD31(-) mature naive (MN) T regs, 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 T regs, into CD45RA(-) CD31(-) memory T regs. At the end of pregnancy, the onset of spontaneous term labour was associated with a significant breakdown of ICOS(+) CD45RA(-) CD31(-) memory T regs. However, in the presence of pre-eclampsia, there was a significantly increased differentiation of ICOS(+) and ICOS(-) CD45RA(+) CD31(+) RTE T regs into CD45RA(-) CD31(+) memory T regs, wherein the lacking differentiation into CD45RA(-) CD31(-) memory T regs was partially replaced by the increased differentiation of ICOS(+) and ICOS(-) CD45RA(+) CD31(-) MN Tregs into CD45RA(-) CD31(-) memory T regs. In patients with HELLP syndrome, this alternatively increased differentiation of CD45RA(-) CD31(-) MN T regs seemed to be exaggerated, and presumably restored the suppressive activity of magnetically isolated ICOS(+) and ICOS(-) T regs, 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 T regs ensures a healthy pregnancy course, while their disturbed differentiation is associated with the occurrence of pre-eclampsia and HELLP syndrome.

Comparison of the laparoscopic versus open live donor nephrectomy: an overview of surgical complications and outcome.

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.

[Modern immunosuppression after solid organ transplantation]. / Moderne Immunsuppression nach Organtransplantation.

The one common factor in solid organ transplantation is the need for lifelong maintenance immunosuppression. Drug regimens after organ transplantation typically comprise a combination of different immunosuppressive drugs. In most cases a triple drug regimen with different mechanisms of action is used. The aim is to improve both patient and graft survival while minimizing potential side effects of immunosuppressive medication. The basis of most immunosuppressive regimens is calcineurin inhibitors in combination with mycophenolic acid. There are various stages of immunosuppression after solid organ transplantation involving induction therapy, initial and long-term maintenance therapy. In each phase an individual combination of immunosuppressants is set up depending on the risk profile of the individual patient to prevent transplant rejection and organ loss. Based on these considerations, concepts of calcineurin inhibitor or steroid reduction have been established in transplant medicine in recent years. The key role in terms of development of new immunosuppressive strategies is taken by kidney transplantation, the most common solid organ transplantation performed.

Influence of test technique on sensitization status of patients on the kidney transplant waiting list.

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 success of assisted reproduction technologies in relation to composition of the total regulatory T cell (Treg) pool and different Treg subsets.

STUDY QUESTION: Are there differences in composition of the total regulatory T cell (Treg) pool and distinct Treg subsets (naïve CD45RA(+)-Tregs, HLA-DR(-)- and HLA-DR(+)-memory Tregs) between successfully and non-successfully IVF/ICSI-treated women? SUMMARY ANSWER: Non-successfully IVF/ICSI-treated women have a decreased percentage of naïve CD45RA(+)-Tregs and an increased percentage of HLA-DR(-)-memory Tregs within the total Treg pool. WHAT IS KNOWN ALREADY: Immunosuppressive Tregs play a significant role in human reproduction and studies have shown that their number and function are reduced in reproductive failure and complications of pregnancy such as pre-eclampsia and preterm labor. However, no data exist concerning the importance of Tregs for a successful outcome following assisted reproduction technologies. STUDY DESIGN, SIZE, DURATION: Blood samples were obtained from 210 women undergoing IVF/ICSI treatment, where 14 patients were excluded due to biochemical pregnancy or missed abortion. Age control blood samples were collected from 20 neonates and 176 healthy female volunteers. The study was performed between October 2010 and March 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this study, we determined prospectively the quantity and composition of the total CD4(+)CD127(low+/-)CD25(+)FoxP3(+)-Treg pool and three different Treg subsets (naïve CD45RA(+)-Tregs, HLA-DR(-)- and HLA-DR(+)-memory Tregs) in all women undergoing IVF/ICSI treatment. We examined whether there were differences between those who became pregnant (n = 36) and those who did not (n = 160). The blood samples were collected within 1 h before the embryo transfer and analyzed by six-color flow cytometry. In order to evaluate these results with regard to the normal age-related changes in composition of the total Treg pool, the same analysis was performed using samples of umbilical cord blood and from healthy female volunteers aged between 17 and 76 years. The composition of the total Treg pool was documented for successfully IVF/ICSI-treated women (n = 5) throughout their pregnancy and we assessed the suppressive activity of each Treg subset in pregnant (n = 10) compared with non-pregnant women (n = 10) using suppression assays. MAIN RESULTS AND ROLE OF CHANCE: The percentage of CD4(+)CD127(low+/-)CD25(+)FoxP3(+)-Tregs within the total CD4(+)-T cell pool did not change with age and did not differ between IVF/ICSI-treated women who did or did not become pregnant. For the total Treg pool, the percentage of the naïve CD45RA(+)-Tregs decreased continuously, while the percentage of HLA-DR(-)- and HLA-DR(+)-memory Tregs increased with aging. From the age of about 40 years, the increase in HLA-DR(+)-memory Tregs in particular became less pronounced, indicating that conversion of naïve CD45RA(+)Tregs into HLA-DR(+)-memory Tregs decreases with age. Women who did not achieve a pregnancy with IVF/ICSI were older than those who did (P < 0.01). However, multiple logistic regression analysis revealed that irrespective of age, the percentage of naïve CD45RA(+)-Tregs within the total Treg pool was decreased (P < 0.05), while the percentage of HLA-DR(-)-memory Tregs was increased (P < 0.01) in women who did not become pregnant compared with those who did. At the beginning of pregnancy, naïve CD45RA(+)-Tregs showed a major decrease but increased again during pregnancy and these cells showed a higher suppressive activity (P < 0.0001) in pregnant compared with non-pregnant women. LIMITATIONS, REASONS FOR CAUTION: There was a large variation in the percentages of the Treg subsets within the total Treg pool between successfully and non-successfully IVF/ICSI-treated women. Therefore, their determination would not allow us to predict the IVF/ICSI outcome with sufficient specificity and sensitivity. We did not examine the antigen specificity of the Treg subsets and therefore could not discern whether the naïve CD45RA(+)-Tregs recognized maternal or paternal antigens. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that Tregs, especially the naïve CD45RA(+)-Treg subset, may play a role in determining the probability of both becoming pregnant and maintenance of the pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the German Research Council (DFG) grant STE 885/3-2 (to A.S.). All authors declare to have no conflict of interest.

Cytomegalovirus infection of the major duodenal papilla in a renal allograft recipient with severe biliary obstruction and acalculous cholecystitis.

Cytomegalovirus (CMV) can cause severe infections with serious consequences in renal transplant recipients. Disseminated CMV infections can affect almost every organ, but obstructive cholestasis and cholangitis, as a consequence of a CMV-induced papillitis, is extremely rare. We are reporting a rare case of obstructive cholestasis and cholecystitis due to CMV-related inflammation of the major duodenal papilla in a 60-year-old woman 3 months after renal transplantation. In addition, the patient suffered from a disseminated CMV infection with ulcerative esophagitis and gastritis. Because of the severe CMV infection, failure of the renal graft occurred. Obstructive cholestasis was resolved through internal stenting, and the progressive cholecystitis necessitated an emergency cholecystectomy. Following antiviral therapy with ganciclovir, the gastrointestinal ulcerations regressed and renal function was restored. Diagnosis of the CMV-related disease was established only in tissue samples, whereas standard serologic tests had failed.

Is diabetes an acquired disorder of reactive glucose metabolites and their intermediates?

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.

Pregnancy-associated diseases are characterized by the composition of the systemic regulatory T cell (Treg) pool with distinct subsets of Tregs.

Dysregulations concerning the composition and function of regulatory T cells (T(regs)) are assumed to be involved in the pathophysiology of complicated pregnancies. We used six-colour flow cytometric analysis to demonstrate that the total CD4(+) CD127(low+/-) CD25(+) forkhead box protein 3 (FoxP3)(+) T(reg) cell pool contains four distinct T(reg) subsets: DR(high+) CD45RA(-), DR(low+) CD45RA(-), DR(-) CD45RA(-) T(regs) and naive DR(-) CD45RA(+) T(regs). During the normal course of pregnancy, the most prominent changes in the composition of the total T(reg) cell pool were observed between the 10th and 20th weeks of gestation, with a clear decrease in the percentage of DR(high+) CD45RA(-) and DR(low+) CD45RA(-) T(regs) and a clear increase in the percentage of naive DR(-) CD45RA(+) T(regs). After that time, the composition of the total T(reg) 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 T(reg) cell pool changed in the way that its percentage of naive DR(-) CD45RA(+) T(regs) was reduced significantly in the presence of pre-eclampsia and in the presence of preterm labour necessitating preterm delivery (PL). Interestingly, its percentage of DR(high+) CD45RA(-) and DR(low+) CD45RA(-) T(regs) was increased significantly in pregnancies affected by pre-eclampsia, while PL was accompanied by a significantly increased percentage of DR(-) CD45RA(-) and DR(low+) CD45RA(-) T(regs). The suppressive activity of the total T(reg) 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 T(reg) pool with distinct T(reg) subsets that were accompanied by a significant decrease of its suppressive activity.

High-risk human papillomavirus in non-melanoma skin lesions from renal allograft recipients and immunocompetent patients.

BACKGROUND: High-risk human papillomaviruses (HR-HPVs) can be detected in a proportion of non-melanoma skin cancers. Data on prevalence are inconclusive, but are essential to estimate the relevance of HR-HPV, particularly with regard to prophylactic HPV vaccines for skin cancer prevention. METHODS: High-risk human papillomavirus DNA was investigated in 140 non-melanoma skin lesions from 54 immunocompetent patients and 33 immunosuppressed renal allograft recipients. Expression of p16(INK4a), a marker for HR-HPV oncogene expression in the uterine cervix, and of p53 and pRB was evaluated immunohistochemically. RESULTS: The highest prevalence of HR-HPV was found in squamous cell cancer (SCC) (46.2% (6 out of 13) in immunosuppressed and 23.5% (4 out of 17) in immunocompetent patients). High-risk human papillomavirus positivity was accompanied by diffuse p16(INK4a) expression in most SCC (P<0.001) and basal cell cancers (P=0.02), while almost all SCC in situ were p16(INK4a) positive irrespective of HR-HPV presence (P=0.66). Diffuse p16(INK4a) expression was associated with lack of pRB expression (P=0.001). p53 was strongly expressed in 40.0% (56 out of 140) of the lesions irrespective of HR-HPV presence. CONCLUSION: High-risk human papillomavirus can be detected in lesions of keratinised squamous epithelia. The association of HR-HPV with diffuse p16(INK4a) expression might indicate HR-HPV oncogene expression in a proportion of lesions. Overexpression of p53 suggests p53 pathway alterations in HR-HPV-positive and -negative lesions.

Henoch-Schönlein purpura in adults is not uncommon in elderly patients with an adverse prognosis.

BACKGROUND: Henoch-Schönlein purpura (HSP) is a fairly common disease in children and adolescents. There are only limited data available for adults. METHODS: A retrospective analysis was conducted to study renal manifestations in patients with HSP treated in our institution between 1982 and 2007. We divided our adult cohort according to age - under or over 60 years - to examine differences in elderly patients. RESULTS: HSP was identified in 2.2% of patients referred to us for kidney biopsy. Purpuric lesions and renal involvement were found in all patients. An important triggering factor for the development of HSP in our series was chronic alcohol intake. Forty percent of our patients fulfilled the WHO criteria for alcoholics. Renal involvement was particularly prominent in patients over 60 years of age. At disease onset, estimated glomerular filtration rate (eGFR) was 63% lower in the elderly. Within a median follow-up of 8 years, renal function was significantly better in younger adults than in the elderly. 32% of the elderly have shown Modification of Diet in Renal Disease (MDRD) < 20 ml/min/1.73 m2 in contrast to only 7% in patients < 60 years. Furthermore, significantly more elderly patients reached end-stage renal failure. CONCLUSION: The data indicate that renal manifestation of HSP in the elderly is severe and its outcome relatively poor, and worsens when compared to patients < 60 years.

Immunosuppression after kidney transplantation.

Today kidney transplantation features excellent short-term outcomes with decreasing acute rejection episodes. In contrast, improvement of long-term allograft survival is much less impressive over the last decades. Thus, the goal of current immunosuppressive therapies is keeping the balance between the reduction of acute rejection episodes and organ specific and systemic side effects. With the development of a broad armamentarium of new immunosuppressive agents with different mechanisms of action, the minimization or avoidance of corticosteroids and calcineurin inhibitors became feasible.

Advanced calibration kit for scanning microwave microscope: Design, fabrication, and measurement.

We present in this paper a new design of a capacitive calibration kit for scanning microwave microscopy (SMM). As demonstrated by finite element modelings, the produced devices are highly independent of material parameters due to their lateral configuration. The fabrication of these gold-based structures is realized by using well established clean-room techniques. SMM measurements are performed under different conditions, and all capacitive structures exhibit a strong contrast with respect to the non-capacitive background. The obtained experimental data are employed to calibrate the used SMM tips and to extract the capacitance of produced devices following a method based on the short-open-load calibration algorithm for one-port vector network analyzers. The comparison of experimental capacitance and nominal values provided by our models proves the applicability of the used calibration approach for a wide frequency range.

Vasogenic Brain Edema During Maintenance Hemodialysis : Preliminary Results from Tract-based Spatial Statistics and Voxel-based Morphometry.

BACKGROUND: Hemodialysis (HD), especially when first initiated, can cause neurological deterioration. Presumably this is due to transient cerebral edema, which has been observed using diffusion weighted magnetic resonance imaging (MRI) in experimental and human studies; however, this has not been investigated under maintenance hemodialysis (mHD). Moreover, there are no studies to date investigating regional effects of mHD on grey and white matter volumes. METHODS: In this study eight patients with end stage renal disease (ESRD) were examined immediately before and after mHD sessions with multimodal MRI, including diffusion tensor imaging (DTI) and high-resolution structural imaging. Additionally, eight healthy, age-matched and sex-matched controls were examined for comparison. Data were analyzed using tract-based spatial statistics and voxel-based morphometry. RESULTS: At baseline, ESRD patients had significantly reduced values of fractional anisotropy (FA) and axial diffusivity as well as bilaterally reduced grey matter volume in the insula, compared with controls. After the mHD session, FA further decreased while axial, radial, and mean diffusivity significantly increased ubiquitously throughout the white matter. Voxel-based morphometry revealed a corresponding significant increase in white matter volume in the central right hemisphere and splenium, as well as in cortical grey matter in the anterior medial frontal and cingulate cortex. None of the patients showed neurological deterioration. CONCLUSION: In this study ESRD patients showed white matter changes indicative of chronic microstructural damage when compared with healthy controls, as previously reported. In addition, patients showed signs of a transient extracellular cerebral edema, which has not yet been observed in the absence of neurological symptoms.

Effect of mycophenolic acid on inosine monophosphate dehydrogenase (IMPDH) activity in liver transplant patients.

BACKGROUND: 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. AIM: Assess IMPDH-inhibition in liver transplant recipients and its impact on biliary/infectious complications, acute cellular rejection (ACR) and liver dependent survival. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Borderline rejection after renal transplantation--to treat or not to treat.

According to the Banff classification of renal allograft pathology, the category borderline changes defines changes insufficient for a diagnosis of acute rejection. The relationship between borderline changes and acute renal allograft rejection still remains unclear. The appropriate clinical management for patients showing such changes is controversial. One possible interpretation of the high incidence of subacute tubulitis is that these changes in the absence of graft dysfunction are of no consequence and that treatment with intensified immunosuppression is unnecessary and perhaps harmful. Another view, consistent with the high incidence of CAN in late protocol biopsy studies, is that immunosuppression has become so powerful, that rejection may not even be manifested by a rising serum creatinine. Borderline changes should be used as part of an algorithm, but not as the only criterion, for therapeutic decision making. Based on the weak evidence of existing studies, in our patients with clinical borderline rejection, we have to weigh the individual immunological risk against the potential side effects of increased immunosuppression. Even in the knowledge that a majority of patients with borderline infiltrates will not progress into rejection, in many transplant centers, borderline rejection is treated with additional steroids or augmentation of maintenance immunosuppression.

Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers after renal transplantation.

Renin-angiotensin system blockade retards the progression of diabetic and non-diabetic chronic kidney disease of the native kidneys. Though most patients suffer from a significant renal insufficiency (chronic kidney disease stage III) and a concomitant heart disease after renal transplantation, there is up to now no evidence supporting the use of inhibitors of the renin-angiotensin system in these patients. We wish to summarize the available evidence on the use of inhibitors of the renin-angiotensin system after renal transplantation. We specifically discuss potential beneficial as well as adverse effects of a renin-angiotensin system blockade. In addition, we review their influence on morphologic and biochemical markers as well as on renal function, graft and patient survival after renal transplantation.

Simultaneous pancreas-kidney transplantation in type 1 diabetes.

The outcome of simultaneous pancreas-kidney (SPK) transplantation in type 1 diabetes has dramatically improved in recent years because of optimized surgical techniques and new immunosuppressive drug regimens. Normoglycemia is followed by stabilization or even regression of diabetic lesions, i.e., of heart and kidneys. However, these effects are only visible after more than five yr of normoglycemia (achieved by a functioning allograft). This is also a likely explanation for the conflicting results of studies that investigated patient or kidney graft survival in SPK transplantation compared to kidney transplantation alone. Most studies had too short follow-up periods, i.e., less than five yr, to compare effectively different transplant strategies in patients with type 1 diabetes and therefore failed to discover a survival benefit in favor of simultaneously transplanted patients. Recent data now indicate that, with a longer follow-up, there is an increasing survival benefit for simultaneously transplanted patients compared to patients who received a single kidney transplant. This is paralleled by the comparison of simultaneously transplanted patients to patients who received a single kidney transplant from a living donor. A survival benefit for the combined procedure was here visible after 10 yr of follow-up. We give a short overview on SPK transplantation, with a focus on the effects of this procedure on diabetic complications as well as patient and kidney graft survival.

A single center experience of combined liver kidney transplantation.

With advancements in the operative techniques, patient survival following liver transplantation (LTx) has increased substantially. This has led to the acceleration of pre-existing kidney disease because of immunosuppressive nephrotoxicity making additional kidney transplantation (KTx) inevitable. On the other hand, in a growing number of patients on the waiting list to receive liver, long waiting time has resulted in adverse effect of decompensated liver on the kidney function. During the last two decades, the transplant community has considered combined liver kidney transplantation (CLKTx) to overcome this problem. The aim of our study is to present an overview of our experience as well as a review of the literature in CLKTx and to discuss the controversy in this regard. All performed CLKTx (n = 22) at our institution as well as all available reported case series focusing on CLKTx are extracted. The references of the manuscripts were cross-checked to implement further articles into the review. The analyzed parameters include demographic data, indication for LTx and KTx, duration on the waiting list, Model for End-Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) score, immunosuppressive regimen, post-transplant complications, graft and patient survival, and cause of death. From 1988 to 2009, a total of 22 CLKTx were performed at our institution. The median age of the patients at the time of CLKTx was 44.8 (range: 4.5-58.3 yr). The indications for LTx were liver cirrhosis, hyperoxaluria type 1, polycystic liver disease, primary or secondary sclerosing cholangitis, malignant hepatic epithelioid hemangioendothelioma, cystinosis, and congenital biliary fibrosis. The KTx indications were end-stage renal disease of various causes, hyperoxaluria type 1, polycystic kidney disease, and cystinosis. The mean follow-up duration for CLKTx patients were 4.6 +/- 3.5 yr (range: 0.5-12 yr). Overall, the most important encountered complications were sepsis (n = 8), liver failure leading to retransplantation (n = 4), liver rejection (n = 3), and kidney rejection (n = 1). The overall patient survival rate was 80%. Review of the literature showed that from 1984 to 2008, 3536 CLKTx cases were reported. The main indications for CLKTx were oxalosis of both organs, liver cirrhosis and chronic renal failure, polycystic liver and kidney disease, and liver cirrhosis along with hepatorenal syndrome (HRS). The most common encountered complications following CLKTx were infection, bleeding, biliary complications, retransplantation of the liver, acute hepatic artery thrombosis, and retransplantation of the kidney. From the available data regarding the need for post-operative dialysis (n = 673), a total of 175 recipients (26%) required hemodialysis. During the follow-up period, 154 episodes of liver rejection (4.3%) and 113 episodes of kidney rejection (3.2%) occurred. The cumulative 1, 2, 3, and 5 yr survival of both organs were 78.2%, 74.4%, 62.4%, and 60.9%, respectively. Additionally, the cumulative 1, 2, 3, and 5 yr patient survival were 84.9%, 52.8%, 45.4%, and 42.6%, respectively. The total number of reported deaths was 181 of 2808 cases (6.4%), from them the cause of death in 99 (55%) cases was sepsis. It can be concluded that there is still no definitive evidence of better graft and patient survival in CLKTx recipients when compared with LTx alone because of the complexity of the exact definition of irreversible kidney function in LTx candidates. Additionally, CLKTx is better to be performed earlier than isolated LTx and KTx leading to the avoidance of deterioration of clinical status, high rate of graft loss, and mortality. Shorter graft ischemia time and more effective immunosuppressive regimens can reduce the incidence of graft malfunctioning in CLKTx patients. Providing a model to reliably determine the need for CLKTx seems necessary. Such a model can be shaped based upon new and precise markers of renal function, and modification of MELD system.

Optimal blood pressure control versus additional immunosuppressive therapy in idiopathic membranous nephropathy - a retrospective analysis.

The treatment of idiopathic membranous nephropathy (MN) with nephrotic syndrome comprises immunosuppressive therapy and antihypertensive treatment with the blockade of the renin-angiotensin system (RAS). Given the relatively benign natural history of MN, an immunosuppressive-free therapeutic regimen should be considered as the primary treatment option. In a single-center, retrospective analysis we compared the outcome of 54 patients with biopsy-proven idiopathic MN 12, 24 and 60 months after initiation of therapy. All patients had RAS-blocking agents and 36 patients received additionally an immunosuppressive regimen. In both groups the patients initially had a nephrotic proteinuria (median 8.7 vs. 6.0 g/day, n.s.). Median blood pressure reduction was comparable after 12, 24 and 60 months in both groups. The median evolution of proteinuria during therapy after 12, 24 and 60 months was 3.4, 1.7 and 1.1 g/day in the group with immunosuppression compared to 3.0, 1.1 and 0.32 g/day in the non-immunosuppressive group. After 60 months no patient developed endstage renal failure. The number of severe side effects was significantly higher in patients with immunosuppression. Regarding renal function and reduction of proteinuria, patients with idiopathic MN treated without immunosuppressive therapy but with measures to ensure optimal blood pressure control and the full blockade of RAS had a similar outcome after 60 months as compared to patients who received additional immunosuppressive therapy.