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Nephrotic syndrome is in adult patients mainly due to membranous nephropathy (MN) characterized by thickening of the glomerular basement membrane (GBM) and immune complex formation between podocytes and the GBM. Autoantibodies directed against the M-type phospholipase A2 receptor (PLA2R) and thrombospondin 1 domain-containing 7 A (THSD7A) can be used as diagnostic biomarkers. THSD7A seems to be of direct pathogenic significance as is suggested by experimental models and plasmapheresis in humans. Recently, further antigens like NELL-1 (neural tissue encoding protein with EGF-like repeats-1), exostosin 1 and 2 have been discovered. Thus, MN should be classified into antibody positive and antibody negative MN. More specific immunosuppressive treatments directed against B-cells and antibody production like rituximab have been introduced in addition to already existing immunosuppressive protocols including steroids, chlorambucil, cyclophosphamide, and calcineurin inhibitors. Antibody removal using immunoadsorption or plasmapheresis leads to short-term reduction in proteinuria and might be indicated only in patients with very severe proteinuria and complications. Studies are needed to identify a more specific immunosuppression directed against the production and effects of autoantibodies in order to protect the kidneys from autoimmune mediated tissue damage and to identify patients who require an immunosuppressive treatment, as the remission rate is high in patients with MN.

Objectives Seroprevalence studies of SARS-CoV-2 have shown that there is a high number of undiagnosed missing cases. Seroprevalence of SARS-CoV-2 in people living with HIV (PLWH) is lacking. Therefore, we conducted a prospective cross-sectional study to estimate the seroprevalence of SARS-CoV-2 among PLWH without known diagnosis of COVID-19 in the south-west of Germany. Methods Serological testing for SARS-CoV-2 immunoglobulin G (IgG) antibodies based on two assays was performed in PLWH who visited the outpatient HIV centre of two hospitals from April to June 2020. Additionally, patients had to answer questionnaires about possible COVID-19-related symptoms and predefined risk factors. Moreover, we tested 50 non-HIV-infected patients receiving post- or pre-exposure (PEP/PrEP) HIV prophylaxis. Results In all, 594 (488 male, 106 female) PLWH (median age 51 years) and 50 PEP/PrEP-users were included in the study. The estimated seroprevalence of the PLWH cohort was 1.85% (11/594), with 11 positive tested cases in the cohort. Among all patients, only five had COVID-19-related symptoms. One PCR-positive patient did not show any antibody response in repeatedly carried out tests. None of the patients was hospitalized due to COVID-19. Three PrEP users were tested positive. Three patients had been previously diagnosed with SARS-COV-2 infection before inclusion. The used questionnaire did not help to detect SARS-CoV-2 positive patients. Conclusions Despite the limitation of being only a snapshot in time because of the ongoing pandemic, to our knowledge this is the largest study so far on seroprevalence of SARS-CoV-2 in PLWH in Germany. Our study suggests that the seroprevalence of SARS-CoV-2 in PLWH is comparable to those previously reported for parts of the general German population and that the questionnaire used here might not be the best tool to predict COVID-19 diagnosis.

Rates of thrombosis and bleeding episodes are both increased in patients with advanced chronic kidney disease (CKD). The pathogenic mechanisms of thrombosis in these patients include platelet activation, increased formation of platelet-leukocyte conjugates, and platelet-derived microparticles, as well as effects of uremic toxins on platelets. On the other side of the coin, platelet hyporeactivity mediated by uremic toxins and anemia contributes to the increased bleeding risk in advanced CKD. Platelets also contribute to the inflammatory environment, thus increasing the risk of cardiovascular diseases in these patients. This review provides insights into the altered platelet function in advanced stages of CKD and their relationship with risks of thrombosis and bleeding. Particularly, the effect of dialysis on platelets will be discussed. Furthermore, therapeutic options with respect to thrombotic disorders as well as bleeding in patients with CKD are reviewed.

Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m2). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.

The objective of this registry is to collect data on real-life treatment conditions for patients for whom multiple organ dialysis with Advanced Organ Support (ADVOS) albumin hemodialysis is indicated.This registry was performed under routine conditions and without any study-specific intervention, diagnostic procedures, or assessments. Data on clinical laboratory tests, health status, liver function, vital signs, and examinations were collected (DRKS-ID: DRKS00017068). Mortality rates 28 and 90 days after the first ADVOS treatment, adverse events and ADVOS treatment parameters, including treatment abortions, were documented.This analysis was performed 2 years after the first patient was included on January 18, 2017. As of February 20, 2019, 4 clinical sites in Germany participated and enrolled 118 patients with a median age of 60 (IQR: 45, 69) of whom 70 were male (59.3%). Patients had a median SOFA Score of 14 (IQR: 11, 16) and a predicted mortality of 80%. The median number of failing organs was 3 (IQR: 2, 4).Four hundred twenty nine ADVOS treatments sessions were performed with a median duration of 17 hours (IQR: 6, 23). A 5.8% of the ADVOS sessions (25 of 429) were aborted due to device related errors, while 14.5% (62 of 429) were stopped for other reasons. Seventy nine adverse events were documented, 13 of them device related (all clotting, and all recovered without sequels).A significant reduction in serum creatinine (1.5 vs 1.2 mg/dl), blood urea nitrogen (24 vs 17 mg/dl) and bilirubin (6.9 vs 6.5 mg/dl) was observed following the first ADVOS treatment session. Blood pH, bicarbonate (HCO3-) and base excess returned to the physiological range, while partial pressure of carbon dioxide (pCO2) remained unchanged. At the time of the analysis, 28- and 90-day mortality were 60% and 65%, respectively, compared to an expected ICU-mortality rate of 80%. SOFA score was an independent predictor for outcome in a multivariable logistic regression analysis.The reported data show a high quality and completion of all participating centers. Data interpretation must be cautious due to the small number of patients, and the nature of the registry, without a control group. However, the data presented here show an improvement of expected mortality rates. Minor clotting events similar to other dialysis therapies occurred during the treatments. CA extern

Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the "GPIHBP1 autoantibody syndrome" and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody-based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.

Contains fulltext : 226016.pdf (Publisher’s version ) (Closed access) In several deceased donor kidney allocation systems, organs from elderly donors are allocated primarily to elderly recipients. The Eurotransplant Senior Program (ESP) was implemented in 1999, and since then, especially in Europe, the use of organs from elderly donors has steadily increased. The proportion of ≥60-year-old donors reported to the Collaborative Transplant Study (CTS) by European centers has doubled, from 21% in 2000-2001 to 42% in 2016-2017. Therefore, in the era of organ shortage it is a matter of debate whether kidney organs from elderly donors should only be allocated to elderly recipients or whether

Background: We evaluated the Kidney Donor Risk Index (KDRI) scoring system for kidney transplantation in the Eurotransplant Senior Program (ESP) that allocates kidneys from older donors to older recipients (≥65 years). Material and methods: We retrospectively analyzed data of 37 kidney transplant recipients and 36 kidney donors who participated in kidney transplantation program according to the ESP at our center from January 2004 until December 2013. Results: Mean recipient and donor age was 67.9±2.6 and 70.5±4.0 years respectively. The mean KDRI score was 1.7±0.27. Uncensored graft survival after 1 year and 5 years was 64.2% and 53.7% respectively. Subgroup analysis showed that in kidney transplantation with KDRI >1.83, graft survival was significantly reduced compared to lower KDRI subgroups. KDRI was significantly correlated with serum creatinine level at discharge (r=0.4). Conclusions: ESP kidneys represent a group of high-risk grafts with high KDRI scores. Higher KDRI scores in ESP kidneys was associated with reduced postoperative short-term and long-term graft outcomes. KDRI might be useful in decision-making for selecting donors for ESP kidney transplantation.

Thrombin converts fibrinogen to fibrin and activates blood and vascular cells in thrombo-inflammatory diseases. Platelets are amplifiers of thrombin formation when activated by leukocyte- and vascular cell-derived thrombin. CD36 on platelets acts as sensitizer for molecules with damage-associated molecular patterns, thereby increasing platelet reactivity. Here, we investigated the role of CD36 in thrombin-generation on human platelets, including selected patients with advanced chronic kidney disease (CKD). Platelets deficient in CD36 or blocked by anti-CD36 antibody FA6.152 showed impaired thrombin generation triggered by thrombin in calibrated automated thrombography. Using platelets with congenital function defects, blocking antibodies, pharmacological inhibitors, and factor-depleted plasma, CD36-sensitive thrombin generation was dependent on FXI, fibrin, and platelet signaling via GPIbα and SFKs. CD36-deficiency or blocking suppressed thrombin-induced platelet αIIbβ3 activation, granule exocytosis, binding of adhesion proteins and FV, FVIII, FIX, FX, but not anionic phospholipid exposure determined by flow cytometry. CD36 ligated specifically soluble fibrin, which recruited distinct coagulation factors via thiols. Selected patients with CKD showed elevated soluble fibrin plasma levels and enhanced thrombin-induced thrombin generation, which was normalized by CD36 blocking. Thus, CD36 is an important amplifier of platelet-dependent thrombin generation when exposure of anionic phospholipids is limited. This pathway might contribute to hypercoagulability in CKD.

Many patients with chronic kidney disease (CKD) receive anticoagulation or antiplatelet therapy due to atrial fibrillation, coronary artery disease, thromboembolic disease, or peripheral artery disease. The treatment usually includes vitamin K antagonists (VKAs) and/or platelet aggregation inhibitors. The direct oral anticoagulants (DOAC) inhibiting factor Xa or thrombin represent an alternative for VKAs. In patients with acute and chronic kidney disease, caution is warranted, as DOACs can accumulate as they are partly eliminated by the kidneys. Thus, they can potentially increase the bleeding risk in patients with CKD. In patients with an estimated glomerular filtration rate (eGFR) above 60 mL/min, DOACs can be used safely with greater efficacy and safety as compared to VKAs. In patients with CKD 3, DOACs are as effective as VKAs with a lower bleeding rate. The more the renal function declines, the lower is the advantage of DOACs over VKAs. Thus, use of DOACs should be avoided in patients with an eGFR below 30 mL/min, particularly, the compounds with a high renal elimination. Available data suggest that DOACs can also be used safely in older patients. In this review, use of DOACs in comparison with VKAs, heparins, and heparinoids, together with special considerations in patients with impaired renal function will be discussed.

Antibodies against THSD7A (thrombospondin type 1 domain-containing protein 7A) have been proposed to play a causal role in the development of nephrotic syndrome in patients with THSD7A antibody–positive membranous nephropathy. We hypothesized that removal of these antibodies from plasma could lead to a rapid reduction in proteinuria. Using immunoadsorption to reduce THSD7A antibodies led to a rapid reduction in proteinuria in 2 patients with THSD7A antibody–positive membranous nephropathy. Moreover, our findings support and strengthen the pathogenic role of the antibodies in the development of nephrotic syndrome in patients with THSD7A antibody–positive membranous nephropathy. Taken together, these 2 cases suggest that immunoadsorption could be a useful tool in the treatment of patients with THSD7A antibody–positive membranous nephropathy.

Patients with chronic kidney disease (CKD) have an increased risk of thrombosis as well as bleeding episodes. Platelet activation, platelet–leukocyte conjugates and platelet-derived microparticles together with an activation of endothelial cells can all confer pro-thrombotic effects in platelets. Furthermore, platelets can contribute to the inflammatory state in patients with CKD and thus together with their thrombosis promoting effect can also contribute to the increased cardiovascular risk of these patients. The bleeding risk in patients with CKD can be augmented by increased concentrations of uraemic toxins, anaemia and altered endothelial cell function all contributing to an impaired platelet function. However, platelets can also be directly involved in the pathogenesis of renal diseases such as thrombotic microangiopathy, immune complex-mediated renal disease, anti-GBM glomerulonephritis and antibody-mediated rejection after kidney transplantation as they can promote inflammatory responses after their activation. The following chapter gives an overview about the mechanisms involved in thrombosis and bleeding promoting effects of platelets in patients with CKD as well as the mechanisms behind the direct pathogenic effects of platelets in several renal diseases.

Introduction: Medication adherence was only studied in a limited number of potential organ recipients. So far medication adherence was not evaluated by utilizing electronic monitoring systems in dialysis and liver cirrhosis patients. The main objective of the present study was to measure the medication adherence of patients suffering from end stage kidney or liver disease by an objectified method. Methods: Adult liver cirrhosis patients taking propranolol and dialysis patients taking phosphate binders, each medication 3 times daily, were eligible to be enrolled in the study protocol. Medication adherence was measured electronically with MEMS™-containers over a period of 6 months in each patient. Results: 34 patients suffering from liver cirrhosis and 36 dialysis patients participated in the study and were analysed per protocol. The Dosing Adherence (DA) rate differed significantly (p

The coagulation system has gained much interest again as new anticoagulatory substances have been introduced into clinical practice. Especially patients with renal failure are likely candidates for such a therapy as they often experience significant comorbidity including cardiovascular diseases that require anticoagulation. Patients with renal failure on new anticoagulants have experienced excessive bleeding which can be related to a changed pharmacokinetic profile of the compounds. However, the coagulation system itself, even without any interference with coagulation modifying drugs, is already profoundly changed during renal failure. Coagulation disorders with either episodes of severe bleeding or thrombosis represent an important cause for the morbidity and mortality of such patients. The underlying reasons for these coagulation disorders involve the changed interaction of different components of the coagulation system such as the coagulation cascade, the platelets and the vessel wall in the metabolic conditions of renal failure. Recent work provides evidence that new factors such as microparticles (MPs) can influence the coagulation system in patients with renal insufficiency through their potent procoagulatory effects. Interestingly, MPs may also contain microRNAs thus inhibiting the function of platelets, resulting in bleeding episodes. This review comprises the findings on the complex pathophysiology of coagulation disorders including new factors such as MPs and microRNAs in patients with renal insufficiency.

Sowohl ein akutes Nierenversagen als auch eine akute Lungenfunktionsstorung sind mit einer erheblichen Morbiditat und Mortalitat assoziiert und beeinflussen die Prognose betroffener Patienten entscheidend. Bei gleichzeitigem Vorliegen beider Krankheitsbilder erhoht sich die Mortalitat noch einmal deutlich. Neuere klinische und experimentelle Untersuchungen zeigen, dass eine direkte Wechselwirkung zwischen beiden Krankheitsbildern besteht. So konnte in experimentellen Modellen gezeigt werden, dass ein akutes Nierenversagen zu einer direkten Beeintrachtigung der Lungenfunktion fuhrt. Umgekehrt mehren sich die Hinweise, dass auch eine akute respiratorische Insuffizienz zu einer Nierenfunktionsverschlechterung fuhren kann. Die direkte Wechselwirkung zwischen einem akutem Nierenversagen und einer Lungenfunktionsverschlechterung liefert eine Erklarung fur die schlechte Prognose beider Krankheitsbilder. Kenntnisse uber die Epidemiologie und die pathophysiologischen Zusammenhange sind somit von entscheidender Bedeutung, um neue Konzepte fur die Behandlung betroffener Patienten zu entwickeln und somit ihre Prognose zu verbessern. Diese Arbeit fasst die aktuellen epidemiologischen Zusammenhange zwischen akutem Nierenversagen und akuter Lungenfunktionsverschlechterung zusammen und vermittelt eine Ubersicht uber die zugrunde liegenden pathophysiologischen Mechanismen.

Wundschmerzen treten bei nahezu allen Patienten nach einer Lebendnierenspende auf. Insgesamt sind die Wundschmerzen gut beherrschbar und scheinen die Lebensqualitat nach einer Lebendorganspende nicht wesentlich zu vermindern. Ihre Intensitat hangt einerseits von der Schnittfuhrung zur Entnahme des Organs entsprechend der Entnahmetechnik ab. Dabei haben Patienten nach einer offenen Lebendspende einen Interkostalschnitt, der mehr Schmerzen verursacht als ein Schnitt in der Leistenregion nach laparoskopischer Nierenspende. Direkt nach der Operation erhalten die Patienten eine sogenannte Spinalanasthesie mit einer Schmerzpumpe zur Applikation von Opioiden. Die Schmerzen werden im weiteren Verlauf mit „peripheren“ und „zentralen“ Analgetika ohne nephrotoxische Nebenwirkungen behandelt. Unter dem Aspekt der Immunsuppression und sonstigen Begleitmedikationen sollten Cyp-neutrale Analgetika zum Einsatz kommen. Bei einer zusatzlichen oder vordergrundigen neuropathischen Komponente ist die Kombination mit Koanalgetika (Antikonvulsiva, Antidepressiva) sinnvoll. NSAIDs, Coxibe (Stufe-1-Analgetika) und Morphin sollten vermieden werden. Uber das Vorkommen chronischer Schmerzen nach einer Lebendnierenspende ist mangels Daten nur wenig bekannt. Sicherlich hangt die Schmerzintensitat auch von individuellen Faktoren ab, sodass eine begleitende psychosomatische Behandlung erforderlich sein kann. Die Vermeidung einer Schmerzchronifizierung sollte immer ein Bestandteil in den Therapieentscheidungen sein.

Chronic rejection is a poorly understood entity albeit a frequent cause of graft failure. Despite the advent of new immunosuppressive agents, neither the slope of graft destruction nor the frequency is ameliorated. There are a number of hypothesis which try to explain the conundrum of chronic graft destruction: ongoing rejection, antibody-mediated rejection, poor choice of organs, hyperfiltration, calcineurin inhibitors (CNI) nephrotoxicity and non-compliance among them. None of these hypotheses can explain all features of the process, thus, it is likely that they act in combination. What seems to be clear is a beneficial effect of early angiotensin-converting enzyme (ACE)/AT1 blocker treatment. It is less clear, however, whether a reduction or a switch from CNIs to other immunosuppressants prolongs graft survival. This review highlights the pathophysiological aspects that are important for the development of chronic allograft damage in the context of possible treatment options.

Progressive impairment of renal function can lead to uremia, which is associated with an increased risk of bleeding as well as thrombosis. Furthermore, many patients with chronic kidney disease (CKD) have an indication for an anticoagulation or antiplatelet therapy due to atrial fibrillation, coronary artery disease, thromboembolic disease, or peripheral artery disease. The treatment usually includes vitamin-K antagonists (VKAs) and/or platelet aggregation inhibitors. The direct oral anticoagulants (DOACs) inhibiting factor Xa or thrombin activity represent an alternative for heparins and VKAs. However, DOACs can further aggravate the bleeding risk in CKD patients. This is related to a combination of an accumulation of the substance due to the reduced renal clearance, an inhibition of thrombin-mediated platelet activation, and uremia associated factors such as impaired coagulation, platelet function, and platelet-vessel wall interactions. Furthermore, platelet aggregation inhibitors can also influence the bleeding risk, particularly if they are administered in combination with anticoagulants in patients with advanced CKD. In this review we discuss the different mechanisms leading to the increased risk of bleeding and thrombosis as well as the different options and problems related to an antiplatelet or anticoagulation therapy in CKD patients.

Objective: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity. Methods: Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients ( n = 33), untreated RRMS patients ( n = 13), and healthy controls ( n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients. Results: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untreated patients and healthy controls. Whereas group comparison for CD4+IL-17+ numbers also differed, CD4+IFN-γ+ and CD4+IL-22+ counts were not increased. CD4+IL-17+ cells not only expressed but also secreted IL-17. In natalizumab-treated patients, IL-17+ cell frequency was found to correlate with T1-hypointense lesions, but was not an indicator for rebound activity after treatment discontinuation, except in one patient who experienced a fulminant rebound, and interestingly, in whom the highest IL-17+ cell levels were observed. Conclusion: Increased lymphocytes and CD4+IL-17+ cells in the blood of RRMS patients receiving natalizumab corroborate the drug’s mechanism of action, that is, blocking transmigration to CNS. Correlation between IL-17-expressing lymphocytes and T1-hypointense lesions underlines the important role of these cells in the disease pathology.

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.

Summary We compared steady-state pharmacokinetics of mycophenolate mofetil (MMF) – Myfenax® (Teva) and CellCept® (Roche) – in stable kidney transplant recipients (KTRs). This was an international, multi-centre, randomized, open-label, two-treatment, two-sequence crossover study with a 3-month follow-up. We included KTRs at least 12 months post-transplantation with stable renal graft function for at least 3 months. The maintenance treatment consisted of MMF in combination with tacrolimus with or without steroids. At the end of the two treatment periods, 6-h or 12-h PK studies of mycophenolic acid (MPA) were performed. A total of 43 patients (mean age: 50.7 ± 13.5 years; 19 females, 24 males) were randomized. Estimates of test to reference ratios (90% CIs) were 0.959 (0.899; 1.023) h*μg/ml for AUC(0–tau) and 0.873 (0.787; 0.968) μg/ml for Cmax. Estimates for AUC(0–6h) were 0.923 (0.865; 0.984) h*μg/ml and 0.985 (0.877; 1.106) μg/ml for Cmin. Thus, AUC(0–tau), AUC(0–6h), and Cmin of MPA were within the predefined margins. Cmax was somewhat outside of these margins in this set of patients. The numbers and types of adverse events were not different between the two treatments. The steady-state pharmacokinetics of MPA as well as adverse events are comparable for Myfenax® and CellCept® in tacrolimus-treated stable KTRs. (EudraCT-No.: 2009-010562-31; ClinicalTrials.Gov number: NCT00991510)

Background: Due to anatomical reasons a position-dependent renal allograft artery stenosis is being discussed (e.g. only in patient’s upright position). The tortuous course of the allograft artery complicates the direct, angle-dependent measurement of maximum systolic flow velocities (vmax). So indirect signs such as intraparenchymal vmax and resistance index might be helpful, but it is unknown how these values change physiologically when patient’s body position changes. Patients and methods: We examined renal allografts of 60 patients (38 male, 22 female) with stable graft function using B-Mode-, colour-coded duplex-sonography and pulsed-wave-Doppler. We measured vmax and RI-values of three interlobar arteries in the cortex and allograft artery in the hilus in patients standing upright and in horizontal position. Corresponding values were analyzed for significant differences. Results: Intraparenchymal RI-values and vmax were significantly reduced in patients upright compared to the horizontal position (16 %, MW=0.59 vs. MW=0.70, p < 0.001 resp. 6 %, MW=30.18 cm/s vs. MW=32.17 cm/s, p = 0.045). Similar results could be detected in the renal hilus. Conclusions: Patients with stable graft-function show significant, position-dependent differences of the intraparenchymal and hilar RI-values and maximal systolic flow velocities. These changes of Doppler parameters has to be kept in mind for the correct diagnosis of a position dependent allograft artery stenosis.

Chronic transplant dysfunction, a major impediment to long-term allograft survival, is caused by several factors including an ongoing alloimmune response termed chronic rejection. To define some of these factors further, we selected 107 patients mismatched to their donors from 623 patients transplanted at a single center. Patients were categorized according to their immunosuppressive treatment and further divided into those with stable or chronic allograft dysfunction. Donor human lymphocyte antigen allopeptide-specific T-cell lines were then generated from stable patients and those with biopsy-proven chronic allograft nephropathy. Increased amounts of CD4+CD25+ regulatory T cells (Tregs) and Treg-associated gene expression profiles were found in cell lines derived from the patients with stable compared with those with chronic allograft dysfunction. Furthermore, a higher percentage of Tregs was found in patients with stable graft function on tacrolimus-based compared with cyclosporine-based immunosuppression protocols. Patients with stable graft function had a significantly higher expression of interleukin (IL)-4 and IL-10, whereas the cytokines IL-2, IL-17, and interferon-γ were significantly higher in patients with allograft dysfunction in vitro. Thus, enhancing the operational role of naturally occurring donor-specific Tregs in allograft recipients by adjusting the immunosuppression protocol may be advantageous particularly for patients with ongoing chronic rejection.

Pan CR, Schmaderer C, Roos M, von Eynatten M, Sollinger D, Lutz J, Heemann U, Baumann M. Comparing aortic stiffness in kidney transplant recipients, hemodialysis patients, and patients with chronic renal failure. Clin Transplant 2011: 25: E463–E468. © 2011 John Wiley & Sons A/S. Abstract: Background: The poor cardiovascular survival of patients with renal insufficiency is improved by transplantation. Carotid-femoral pulse wave velocity (PWV) is able to predict independently overall and cardiovascular mortality. PWV is elevated in renal insufficiency. Consequently, PWV may change according to the improvement in renal function after kidney transplantation. Methods: In a cross-sectional setting, PWV was determined in 40 renal transplant recipients (RTx) and compared to the PWV of 40 age- and gender-matched patients with comparable renal insufficiency (CKD) and 40 age- and gender-matched hemodialysis patients (HD). Results: RTx and CKD patients had comparable eGFR (RTx: 42.9 ± 18.4, CKD: 48.3 ± 29.1 mL/min/1.73 m2) and protein/creatinine ratio (RTx: median 172.5, 25th percentile 97.75, 75th percentile 344.5, CKD: median 183.272, 25th percentile 100.00, 75th percentile 470.00 mg/g creatinine). There was no significant difference in PWV between RTx 3–12 months post-transplant and CKD or HD patients (RTx: 9.65 ± 1.57, CKD: 9.98 ± 3.91, HD: 10.27 ± 2.89 m/s; n = 20 pairs). Similarly, PWV in transplant patients >12-month post-transplant was similar to that of CKD and HD patients (RTx: 9.71 ± 2.23, CKD: 9.36 ± 2.74, HD: 9.84 ± 3.41 m/s; n = 20 pairs). Discussion: We could not detect significant differences in PWV comparing RTx with age- and gender-matched CKD patients.

Background Spontaneously hypertensive rats (SHRs) are characterized by capillary rarefaction, which may contribute to blood pressure elevation. We hypothesized that capillary rarefaction involves a suppressed angiogenesis; renin inhibition influences anti-angiogenesis homeostasis by acting on angiopoietins; transient renin blockade reduces anti-angiogenesis thereby ameliorating long-lasting blood pressure and cardiac hypertrophy in SHRs. Methods First, serum angiopoietin-1 and angiopoietin-2 were measured in 2-month old normotensive Wistar-Kyoto rats (WKYs) and SHRs after renin inhibition (aliskiren: 1 and 10mg/kg per day) or placebo. Second, 4-week old SHRs were prehypertensively treated with aliskiren (1 and 10mg/kg per day) or placebo for 4 weeks. After 4 weeks of 'drug holiday' 12-week old SHRs were given L-nitro-arginine methyl ester (L-NAME) (25mg/kg per day) for a 4-week interval to promote capillary rarefaction. Thereafter, mean arterial pressure (MAP), cardiacremodeling, capillary density, pAkt/Akt as marker for cellular survival, pro-angiogenic genes and systemic angiopoietins were investigated. Results Baseline angiopoietin levels were similar between WKYs and SHRs. Renin inhibition increased angiopoietin-1 in SHR and reduced angiopoietin-2 in both WKY and SHR blood pressure independently. Prehypertensive renin inhibition reduced MAP and cardiac hypertrophy in adult SHRs. This was associated with higher cardiac capillary density, pAkt/Akt, pro-angiogenic expression pattern and serum angiopoietin-1, whereas angiopoietin-2 was lower as compared to vehicle-pretreated SHRs. These results were independent of prehypertensive blood pressure lowering by aliskiren. Conclusion We conclude that renin inhibition modulates anti-angiogenesis signaling independently of blood pressure by increasing angiopoietin-1/angiopoietin-2 ratio. This promotes in SHR stabilization of endothelial cells, favors pro-angiogenic action and consequently results in higher capillary density. J Hypertens 29: 266-272

Erythropoietin (EPO) protects the kidneys from ischemia/reperfusion (I/R) injury; however, the exact signalling mechanisms are not fully understood. The serum and glucocorticoid-regulated kinase 1 (SGK1) is an anti-apoptotic protein kinase regulated through the phosphatidylinositol 3-kinase (PI3-kinase) pathway by cellular stimuli, hormones and growth factors. The objective of the present study was to examine the role of SGK1 in the renoprotective effects of EPO in renal I/R injury. In vitro, cultures of HEK293 cells were exposed to 16h hypoxia. Incubation with EPO at a doses of 400U/ml exerted a protective effect on cell death assessed by LDH release and Annexin V FACS analysis. This was paralleled by up-regulation of SGK1 expression, as well as phosphorylation. Downregulation of SGK1 expression by small interfering RNA technique ameliorated the anti-apoptotic effect of EPO treatment. In an in vivo rat model of unilateral renal I/R injury, rats were treated with 500U/kg EPO 24h prior to ischemia. EPO resulted in less severe tissue injury and ameliorated the elevation in creatinine and urea nitrogen levels 24h after reperfusion. Furthermore, SGK1 expression and phosphorylation were higher in EPO compared to vehicle-treated rats as demonstrated by real-time PCR, Western blot and immunofluorescence technique. We conclude that EPO protects from renal I/R injury and SGK1 might contribute to the mediation of EPO effects under ischemic conditions.

The cellular prion protein (PrPC) is a GPI-anchored cell-surface protein. A small subset of PrPC molecules, however, can be integrated into the ER-membrane via a transmembrane domain (TM), which also harbors the most highly conserved regions of PrPC, termed the hydrophobic core (HC). A mutation in HC is associated with prion disease resulting in an enhanced formation of a transmembrane form ((PrP)-Pr-ctm), which has thus been postulated to be a neurotoxic molecule besides PrPSc. To elucidate a possible physiological function of the transmembrane domain, we created a set of mutants carrying microdeletions of 2-8 aminoacids within HC between position 114 and 121. Here, we show that these mutations display reduced propensity for transmembrane topology. In addition, the mutants exhibited alterations in the formation of the Cl proteolytic fragment, which is generated by a-cleavage during normal PrPC metabolism, indicating that HC might function as recognition site for the protease(s) responsible for PrPC alpha-cleavage. Interestingly, the mutant G113V, corresponding to a hereditary form of prion disease in humans, displayed increased (PrP)-Pr-Ctm topology and decreased alpha-cleavage in our in vitro assay. In conclusion, HC represents an essential determinant for transmembrane PrP topology, whereas the high evolutionary conservation of this region is rather based upon preservation of PrPC alpha-cleavage, thus highlighting the biological importance of this cleavage. (C) 2010 Elsevier Inc. All rights reserved.

Background Little data exist on the relationship between potassium level and infarct size after ST-segment elevation acute myocardial infarction (STEMI). We investigated the influence of potassium levels on infarct size measured with single photon emission computed tomography (SPECT) in patients with STEMI after mechanical reperfusion. Methods The study included 598 patients. Potassium measurements at baseline and 2 SPECT examinations, at baseline and 7–14 days after intervention, were performed. Infarct size in the 7–14 days SPECT and salvage index were the primary outcome analyses. Results Tertiles of baseline potassium were: 4.37 mEq/L (3rd tertile). In potassium 1st, 2nd and 3rd tertiles, the infarct size in the 7–14 days SPECT (median [25th–75th percentiles]) was 9.0% [2.0%–21.8%], 10.0% [3.5%–22.0%] and 12.0% [5.0%–25.5%] of left ventricle (p = 0.026); salvage index was 0.50 [0.26–0.84], 0.56 [0.26–0.81] and 0.40 [0.23–0.75] (p = 0.09). Patients with anterior infarction in upper potassium tertile had greater infarct size compared with patients in lower potassium tertile (p = 0.049). After adjustment in multivariable analysis, potassium was an independent correlate of infarct size in the 7–14 days SPECT (p = 0.05). Conclusions In patients with STEMI, higher baseline potassium levels are associated with a larger scintigraphic infarct size.

OBJECTIVE Markers reliably identifying vascular damage and risk in diabetic patients are rare, and reports on associations of serum adiponectin with macrovascular disease have been inconsistent. In contrast to existing data on serum adiponectin, this study assesses whether urinary adiponectin excretion might represent a more consistent vascular damage marker in type 2 diabetes. RESEARCH DESIGN AND METHODS Adiponectin distribution in human kidney biopsies was assessed by immunohistochemistry, and urinary adiponectin isoforms were characterized by Western blot analysis. Total urinary adiponectin excretion rate was measured in 156 patients with type 2 diabetes who had a history of diabetic nephropathy and 40 healthy control subjects using enzyme-linked immunosorbent assay. Atherosclerotic burden was assessed by common carotid artery intima-media-thickness (IMT). RESULTS A homogenous staining of adiponectin was found on the endothelial surface of glomerular capillaries and intrarenal arterioles in nondiabetic kidneys, whereas staining was decreased in diabetic nephropathy. Low-molecular adiponectin isoforms (∼30–70 kDa) were detected in urine by Western blot analysis. Urinary adiponectin was significantly increased in type 2 diabetes (7.68 ± 14.26 vs. control subjects: 2.91 ± 3.85 μg/g creatinine, P = 0.008). Among type 2 diabetic patients, adiponectinuria was associated with IMT (r = 0.479, P < 0.001) and proved to be a powerful independent predictor of IMT (β = 0.360, P < 0.001) in multivariable regression analyses. In a risk prediction model including variables of the UK Prospective Diabetes Study coronary heart disease risk engine urinary adiponectin, but not the albumin excretion rate, added significant value for the prediction of increased IMT (P = 0.007). CONCLUSIONS Quantification of urinary adiponectin excretion appears to be an independent indicator of vascular damage potentially identifying an increased risk for vascular events.

True alloantigen-specific tolerance is the ultimate goal of solid organ transplantation, eliminating the need for long-term immunosuppression. Recent evidence suggests that Th1-derived cytokines are associated with rejection and Th2-derived cytokines with long-term allograft survival, but the roles of these subsets in rejection and tolerance are incompletely understood. Here, we analyzed the functional and regulatory capacities of T cell clones derived from tolerant and rejecting rats (Wistar rat donors, Lewis rat recipients). We generated and subcloned T cell lines from lymphocytes derived from either acutely rejecting grafts or from the grafts of CTLA4-Ig–treated tolerant rats. Pretransplantation adoptive transfer of T cell clones generated from rejected grafts (Th1 clones) accelerated acute rejection or promoted development of chronic rejection, whereas transfer of T cell clones generated from tolerized grafts (Th2 clones) protected rats from acute rejection and progressive organ dysfunction. When Th1 and Th2 clones were injected simultaneously, Th2 clones specifically regulated activation of Th1 clones. Rats that received injections of Th2 clones accepted long-term donor-specific skin grafts but acutely rejected third-party skin grafts. Tolerant rats treated with Th2 clones demonstrated an increased number of regulatory CD4 + CD25 + Foxp3 + cells and strong mononuclear cell staining for IL-10 but negligible IFN-γ, IL-17, and IL-23 compared with untreated rats or those treated with Th1 clones. In summary, these results demonstrate the regulatory functions of Th2 cells in a clinically relevant allogeneic transplant model and provide new insight into the functional role of Th2 cells in preventing the process of chronic rejection.

AIM: To evaluate the association between fetuin-A level (AHSG), its encoding gene (Thr256Ser) and arterial function in subjects with normal kidney function. INTRODUCTION: The aortic pulse wave velocity (aPWV) is a predictor for cardiovascular mortality. Fetuin-A is a calcification inhibitor and correlates negatively with increased vascular stiffness in dialysis patients. The fetuin-A polymorphism (Thr256Ser) is associated with reduced fetuin levels and accelerated vascular calcification in dialysis patients. Little is known about the role of fetuin-A as an independent predictor for the development of arterial stiffness in healthy subjects. MATERIALS AND METHODS: We studied 116 subjects with normal kidney function (age 47+/-12 years, 50 females and 66 males) of the FLEMENGHO study. Calcium measurements, plasma fetuin-A, its encoding gene (Thr256Ser) and indexes of arterial stiffness, such as aPWV and arterial distensibility, were determined. RESULTS: Fetuin-A levels were negatively correlated with aPWV (r=-0.21, p=0.029). After an adjustment for multiple covariables, fetuin-A levels were independently associated with aPWV (r=-0.30, p=0.022) in males but not in females. Male fetuin-A SerSer carrier had lower fetuin-A levels and higher aPWV (fetuin-A: 61.9+/-29.0 microg/ml; aPWV: 14.3+/-0.9 m/s) as compared to ThrThr (fetuin-A: 109.9+/-54.9 microg/ml; aPWV: 6.4+/-1.3 m/s) and ThrSer carrier (fetuin-A: 100.8+/-52.5 microg/ml; aPWV: 6.6+/-1.3 m/s). Other calcium variables were not significantly associated with arterial stiffness. CONCLUSION: With respect to common calcium variables, only fetuin-A level showed an inverse relation with aPWV in men with normal renal function. Male fetuin-A SerSer carriers demonstrate particularly high aortic stiffness, possibly implying a status of increased cardiovascular risk. ispartof: Regulatory Peptides vol:154 issue:1 pages:39-43 ispartof: location:Netherlands status: published

Background: Adiponectin is an adipocyte-derived hormone circulating in different multimer complexes. The high–molecular-weight (HMW) complex is likely the active form of this protein and has been recognized as a risk marker for type 2 diabetes and coronary artery disease (CAD). Because quantification of HMW adiponectin by Western blot analysis is time-consuming, novel ELISAs have been developed to simplify measurements in clinical research. However, these enzyme immunoassays have not been cross-validated in larger patient groups. We evaluated 2 individual ELISA systems by comparison to Western blotting for measurement of the distribution of HMW adiponectin in healthy individuals and patients with CAD and type 2 diabetes. Methods: We measured HMW adiponectin in 204 individuals (83 CAD patients, 81 type 2 diabetes patients, and 40 healthy controls). Correlations, range of agreement, and imprecision of HMW concentrations obtained using 2 commercial ELISAs (#1, ALPCO Diagnostics; #2, Millipore) were evaluated by comparison with quantitative Western blotting. Result: Adiponectin results of the ELISAs were significantly correlated with those obtained by Western blotting (both r > 0.75, P < 0.001). Deming regression and Bland-Altman analyses indicated high agreement among the 3 immunoassays. The median difference between HMW adiponectin concentrations measured by ELISA and by Western blot was +0.4 mg/L for ELISA #1 and −0.4 mg/L for ELISA #2 with 95% of value differences Conclusions: Selective measurement of HMW adiponectin by ELISA is feasible; however, individual differences among immunoassays must be considered. The evaluated ELISAs exhibit analytical characteristics that allow their use as equivalent for Western blot analysis in larger clinical and epidemiological groups.

Background: Chronic kidney disease (CKD) is characterized by increased cerebrovascular risk. Retinal vessel analysis (RVA) is an accepted measure of the retinal microvasculature, mirrors hypertension and cardiovascular morbidity. Epidemiological studies demonstrate narrower retinal arterioles with declining renal function. The effect of CKD on the retinal microcirculation remains uncertain. Methods: RVA was performed in 34 non-diabetic CKD patients and 33 age-matched volunteers with normal renal function. Retinal photographs were digitized, vascular lumen diameters measured and the ratio of retinal arteriolar and venular lumen diameters (AVR) calculated. Office blood pressure (BP) was measured and cardiovascular risk factors assessed. Results: AVR was lower in CKD patients as compared to age-matched volunteers (0.77 ± 0.05 vs. 0.86 ± 0.06; p < 0.05). In particular, retinal arterioles were narrower in CKD patients as compared to volunteers (169.6 ± 20.4 vs. 189.5 ± 14.2 µm; p < 0.01). In CKD, estimated glomerular filtration rate, BP and renin-angiotensin system blocker independently predicted AVR. Moreover, retinal arteriolar diameter independently predicted renal function (β = 0.33; p < 0.05). Conclusion: CKD narrowed retinal arterioles suggesting an extended effect of CKD on the cerebral microvasculature. This study shows that in CKD patients, renal function, BP status and renin-angiotensin system blockade independently predict AVR as a marker for microvascular damage and that retinal microvasculature can predict renal function.

The serum- and glucocorticoid-inducible kinase 1 (SGK1) is a serine threonine protein kinase activated through the phosphatidylinositol 3-kinase (PI3-kinase) pathway and counteracting apoptosis. Protein expression and activation of SGK1 are increased in various models of cell stress. The present study explored the role of SGK1 in renal hypoxia/ischemia induced apoptosis. HEK 293 cells were exposed in vitro to hypoxia/reoxygenation (H/R), which increased SGK1 transcript levels, SGK1 protein abundance and SGK1 phosphorylation. H/R injury further enhanced the percentage of apoptotic cells, an effect significantly blunted by prior SGK1 overexpression. In vivo renal ischemia/reperfusion (I/R) injury increased SGK1 transcript levels and SGK1 protein abundance. I/R enhanced apoptosis, an effect significantly more pronounced in gene targeted mice lacking SGK1. In conclusion, SGK1 is up-regulated and counteracts apoptosis following H/R in vitro and ischemia in vivo.

The purpose of this study was to analyse the outcome and its influencing factors in patients whose therapy was converted from calcineurin inhibitors (CNI) to sirolimus (SRL) due to chronic allograft nephropathy (CAN). Therapies of 78 patients (44 men) with CAN from three European transplant centres were converted from CNI therapy to SRL and followed 24 months. Slopes for creatinine clearance before and after conversion were calculated. Influencing factors were analysed by a multivariance analysis. The slope of the creatinine clearance improved significantly (−0.90 vs. −0.34 ml min−1 month−1; p