Late Steroid Withdrawal Following AB0-Incompatible Renal Transplantation.

BACKGROUND: Current evidence on steroid withdrawal following AB0-incompatible (AB0i) renal transplantation is low. We compared clinical outcomes of patients who agreed to late steroid withdrawal and patients who remained on steroid treatment. METHODS: Steroid withdrawal was carried out in 11 patients at ≥12 months after transplantation (group W). For comparison, we analyzed 19 patients who remained on triple immunosuppression including steroids (group M). Minimum follow-up was 24 months following transplantation and 12 months after steroid withdrawal. RESULTS: Baseline characteristics, including observation times, were not different between groups W and M. Graft survival was 100% in group W compared with 84% (16/19) in group M (P = .15). In group M, 1 patient experienced graft failure because of suspected antibody-mediated rejection (ABMR) following temporary cessation of mycophenolate treatment after a diagnosis of cryptococcal pneumonia. Two patients died with functioning graft because of sepsis. In group W, we observed 1 episode of ABMR following steroid withdrawal. At the end of follow-up, estimated glomerular filtration rates (eGFR) were 54 (19-91) versus 60 (15-85) mL/min/1.73 m2 in group W versus M, respectively (P = .67). CONCLUSIONS: Late steroid withdrawal following AB0i transplantation is feasible at a moderate risk of rejection. We recommend close monitoring of renal function and HLA antibodies during and after steroid withdrawal. On the other hand, the occurrence of severe infections causing death and graft loss in patients on triple maintenance immunosuppression including steroids should remind us to consider the overall immunosuppressive burden.

[Sporadic Lymphangioleiomyomatosis (sLAM) and Tuberous Sclerosis Complex (TSC) - Pulmonary Manifestations]. / Sporadische Lymphangioleiomyomatose (sLAM) und Tuberöse-Sklerose-Komplex (TSC) ­ Pulmonale Manifestationen.

Lymphangioleiomyomatosis (LAM) is a rare multi-system disorder affecting predominantly women of childbearing age. The disease entity is divided in sporadic LAM (sLAM) and LAM associated with tuberous sclerosis complex (TSC). In up to 50 % of female TSC-patients pulmonary involvement (TSC-LAM) can be found, with first clinical symptoms usually starting between 25 and 30 years of age. Progressive deterioration of lung function of 3 - 11 % of diffusion capacity per year has been described, that's why all female TSC patients should be screened for LAM (pulmonary function testing, 6-minute walk test, high-resolution chest CT scan). MTOR inhibitors such as Everolimus or Sirolimus are implemented in the treatment of TSC/LAM and found to control disease burden. Screening for all organ manifestations in TSC is recommended and allows to improve prognosis and to prevent complications in TSC.

Treatment of renal angiomyolipoma in tuberous sclerosis complex (TSC) patients.

In adult tuberous sclerosis complex (TSC) patients, renal complications are the leading cause of death. Beginning in childhood, up to 80 % of patients develop renal angiomyolipoma characterized by a size-dependent risk of life-threatening bleeding. After discovery of the two causative genes, TSC1 and TSC2, and the role of mammalian target of rapamycin (mTOR) regulation in the pathogenesis of TSC, an increasing number of clinical studies evaluating mTOR inhibition in TSC patients have shown impressive results in many organ manifestations, such as brain, lung, and kidney. For renal angiomyolipoma, mTOR inhibitor treatment fundamentally changed the approach from preventive embolization or even partial nephrectomy to everolimus treatment in order to preserve kidney function.

Successful Recovery of Acute Renal Transplant Failure in Recurrent Hepatitis C Virus-Associated Membranoproliferative Glomerulonephritis.

Recurrence of hepatitis C virus (HCV)-associated membranoproliferative glomerulonephritis (MPGN) in the kidney transplant may lead to continuous graft deterioration and the need for further renal replacement therapy. The novel direct-acting antiviral agents (DAAs) allow a highly effective and interferon-free treatment option for chronic HCV-infected patients. Data on the therapeutic safety and efficacy in HCV-infected renal transplant patients are sparse, especially for patients with severe renal impairment. We report the case of a 63-year-old female HCV-positive renal transplant patient with biopsy-proven recurrence of MPGN in the renal graft 3 years after transplant. Because of rapid loss of transplant function and consecutive need for hemodialysis, we initiated a combined anti-HCV-directed therapy regimen consisting of daclatasvir and simeprevir over 12 weeks. Viral clearance of HCV was obtained as early as 2 weeks after start of treatment. No adverse therapy-associated side effects were observed, and immunosuppressive dosing remained unchanged. Importantly, graft function fully recovered and hemodialysis was stopped 2 mo after the end of daclatasvir/simeprevir treatment. We report the first case of successful recovery of dialysis-dependent renal transplant failure after treatment of recurrent HCV-associated MPGN in a kidney transplant recipient by curing the underlying HCV infection with a combination of novel DAAs.

Risk Evaluation and Outcome of Pneumocystis jirovecii Pneumonia in Kidney Transplant Patients.

Pneumocystis jirovecii pneumonia (PJP) affects immunocompromised patients. As a result of effective prophylaxis in the 1st months after kidney transplantation, PJP is increasingly diagnosed in the long term after transplantation. The present study evaluates course and outcome of PJP in a single transplant center from 2010 to 2015. Twenty-three patients presented with PJP at a mean of 53.7 ± 50.2 months after transplantation. Of these, 3 patients underwent ABO-incompatible (ABO-i) living-donor transplantation and 3 patients were treated with the use of belatacept. For risk estimation, 3 control cohorts were defined: a control group of all kidney transplant patients presenting for routine follow up (n = 575), all patients transplanted in an ABO-i setting (n = 45), and all patients treated with belatacept in our clinic (n = 69). Mortality in patients with PJP was 3/23 (13%) and graft loss after PJP was 3/23 (13%) resulting in patient and graft survivals of 87% and 73.9%, respectively. All patients were without PJP prophylaxis at time of diagnosis. Five of the 23 PJP patients received rejection therapy or dose escalation of immunosuppression 6 months before PJP infection, and 1 patient experienced acute rejection within 6 months after PJP treatment. In the course of PJP, 8 patients developed acute respiratory insufficiency. At time of PJP diagnosis, patients presented with severe lymphopenia (mean ± SD lymphocyte count, 0.64 ± 0.27/nL; normal range: 1.5-3/nL). Patients after ABO-i transplantation, as well as patients treated with belatacept, showed an increased risk for PJP (7.3% and 4.3%, respectively); however, in belatacept patients, other risk factors, such as age, low estimated glomerular filtration rate (eGFR), and lymphopenia seemed to contribute to this increased risk.

The impact of adverse reactions to injectable filler substances on quality of life: results from the Berlin Injectable Filler Safety (IFS) - study.

BACKGROUND: Injectable filler substances are commonly used in aesthetic medicine. Adverse reactions are rare, but may cause severe impact on quality of life (QoL). To the best of our knowledge, data on the impact of adverse reactions caused by injectable filler substances on QoL is missing. OBJECTIVE: To evaluate the impact of adverse filler reactions on the QoL. MATERIAL AND METHODS: The Injectable Filler Safety (IFS) - study is a partially population-based registry for adverse reactions due to injectable filler substances. In 2008, the Dermatology Life Quality Index (DLQI) questionnaire was added to the questionnaires of the IFS study. For this analysis, only patients with a completed DLQI were included in the analysis. RESULTS: One hundred and four patients of the IFS study were analysed. A total of 88.5% were female with an average age of 49.2 years. Here, 50.0% were treated with biodegradable and 40.4% with permanent fillers. The most common adverse reactions were nodule formation and hardening. Most patients experienced mild to moderate adverse reactions. Impact on QoL was moderate with an average of 8.9 (±8.4 SD) in patients with adverse reactions to biodegradable and 10.5 (±9.4 SD) to permanent products. However, 24.0% and 13.4% showed a large or a very large impact on QoL. CONCLUSION: Adverse reactions to injectable filler products can have a considerable impact on the QoL, comparable to severe chronic inflammatory skin diseases such as psoriasis.

[Immunosuppression and its use in kidney transplantation]. / Immunsuppression und Ergebnisse in der Nierentransplantation.

BACKGROUND: Current immunosuppressive protocols effectively prevent acute rejection of renal allografts. Extensive drug toxicity and the deleterious effects of long-term immunosuppression are associated with significant morbidity and mortality. OBJECTIVES: The purpose of this article is to provide an overview over modern immunosuppressants and their unwanted side effects and to discuss strategies for improved long-term transplant survival. METHODS: Review of the current topic-related literature and discussion of our own experience. RESULTS: The use of antibody induction together with an initial combination therapy of calcineurin inhibitors, mycophenolate and steroids is recommended and results in excellent early outcomes. Detrimental effects include an increased incidence of infections, malignomas, and cardiovascular diseases. Long-term transplant survival is impaired by extensive drug toxicity and the frequent development of donor specific antibodies. Reduction of overall cumulative exposure to immunosuppressants or the reduction of specific toxic drugs such as calcineurin inhibitors and steroids may improve long-term results. Alternative immunosuppressants like mTOR inhibitors and belatacept appear to be effective and safe but their long-term effects on patient and allograft survival needs to be established in clinical trials. CONCLUSIONS: Current immunosuppressants provide effective protection from renal allograft rejection. However, their use is complicated by serious side effects. In the future, development of novel immunosuppressants and optimization of minimization strategies may help to improve long-term success after kidney transplantation.

Parenteral anticoagulants in heart disease: current status and perspectives (Section II). Position paper of the ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease.

Anticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases.

[Injectable fillers: adverse reactions and their management]. / Injizierbare Füllmaterialien: Nebenwirkungen und Management.

Injectable fillers are one of the corner stones of aesthetic medicine. In general they are safe to use. However, adverse reactions may occur. These reactions may be acute, subacute or delayed, e.g. after decades. It is important to know these reactions and to be prepared so that they can be adequately treated, in view of the clinical symptoms, the injected material and if applicable other diseases/treatments that might trigger these reactions. Last but not least, all reactions should be reported either to specialized registries or regulatory agencies. Only then we are able to learn more about these reactions and their best possible treatment.

[Adverse reaction to fillers. Diagnosis and management]. / Komplikationen auf injizierbare Füllmaterialien. Diagnose und Therapie.

Injectable fillers are an established component of aesthetic medicine. In general they are safe to use. However, adverse reactions are possible for the whole spectrum of products. These reactions can occur immediately, subacute or delayed, e.g. after years. Erythema, edema, abscesses, nodule formation or even ulcerations can be observed. A correct diagnoses of these reactions is important to allow an appropriate treatment, taking into consideration the clinic, the injected material and if applicable other diseases/treatments that might contribute to these reactions. All of these reactions should be reported either to specialized registries and/or to the appropriate national agencies. Only then will we be able to learn more about these reactions and the best possible treatment.

Efficacy of systemic therapies for moderate-to-severe psoriasis: a systematic review and meta-analysis of long-term treatment.

BACKGROUND: Despite the chronicity of psoriasis, most systematic reviews focus on short-term treatment. METHODS: The systematic search strategy and results from the German Psoriasis Guidelines were adapted. To update the data a literature search in Medline, Embase and the Cochrane Library was conducted. The proportion of participants achieving ≥75% decrease in Psoriasis Area and Severity Index (PASI) as well as Dermatology Life Quality Index (DLQI) reduction at different time points were assessed. Trials were summarized with respect to time periods and study designs. Suitable trials were included in a meta-analysis. Particular attention was paid to statistical approaches of handling dropouts. RESULTS: A total of 33 articles including 27 trials totaling 6575 patients with active treatment were included in the systematic review. Seven randomized controlled trials were eligible for the meta-analysis. Over a 24 week treatment period infliximab [risk difference (RD) 78%, 95% confidence interval (CI) 72-83%] and ustekinumab 90 mg every 12 weeks (RD 77%, 95% CI 71-83%) were the most efficacious treatments. Adalimumab (RD: 60%, 95% CI 45-74%) showed results within the range of different etanercept dosages (etanercept 50 mg once weekly: RD 62%, 95% CI, 52-72%), (etanercept 25 mg twice weekly: RD 45%, 95% CI 34-56%), (etanercept 50 mg twice weekly: RD 56%, 95% CI 49-62%) and (etanercept 50 mg twice weekly until week 12, then 25 mg twice weekly: RD 50%, 95% CI 42-57%). After 24 weeks a decrease in efficacy for inflximab, adalimumab and etanercept was observed. CONCLUSIONS: More sufficient data is required to draw reliable conclusions in extended long-term treatment and head-to-head comparisons are necessary.

Adverse reactions caused by consecutive injections of different fillers in the same facial region: risk assessment based on the results from the Injectable Filler Safety study.

BACKGROUND: The combination of different injectable fillers in one area is considered to increase the risk of adverse reactions. OBJECTIVES: To characterize adverse reactions in patients who received more than one filler in the same facial region. METHODS: Data (up to July 2009) of the Injectable Filler Safety Study, a German-based registry for adverse filler reactions, was analysed descriptively. All cases were discussed individually. RESULTS: In 22 of the 161 patients (13.7%), two or more different fillers were injected consecutively into the same facial region. All patients were female with an average age of 50.6 (SD 13.6) years. In 12 of the 22 patients (54.5%), a specific filler could be attributed to the adverse reactions whereas in the other 10 patients (45.5%), the filler was not clearly attributable to one filler substance causing the adverse reactions. CONCLUSIONS: With the continuous changes in the filler market, the combination of different fillers in one area becomes more likely. Based on our data, there is not a lot of evidence that the combination of different injectable fillers, specifically biodegradable fillers, in the same region increases the risk of adverse reactions.

Overexpression of p150, a part of the large subunit of the eukaryotic translation initiation factor 3, in colon cancer.

BACKGROUND: P150, a 150 kDa protein, was isolated from virally and oncogene-transformed mouse cell lines, partially purified and cloned. P150 is part of the large subunit of the eukaryotic translation initiation factor 3 with sequence homology to centrosomin A. A significant correlation between p150 expression and malignancy in breast, cervical and esophageal cancer have recently been demonstrated. MATERIALS AND METHODS: Here, 110 colorectal carcinomas of different grades and stages, including lymph node and liver metastases were compared to adjacent normal mucosa by immunohistochemistry of P150. Western blot analysis of selected cases confirmed the expression levels determined by immunohistochemistry. Additionally, immuno-electron and laser scanning microscopy (LSM) was performed. RESULTS: All investigated carcinomas revealed high levels of p150 protein compared to normal adjacent mucosa. The staining intensity was slightly heterogeneous, and positivity was correlated to the tumor grade with statistically significant differences of p150 expression between normal and neoplastic mucosa (p<0.0001, Kruskal-Wallis test). Western blots confirmed higher expression levels of p150 in the tumor. Immunogold labelling and LSM investigation showed high expression levels of p150 on the rough endoplasmic reticulum and polyribosomes, indicating that p150 is translationally active in these tumors. CONCLUSION: Thus, we propose that p150 plays an important role in development and growth of colorectal carcinomas. Furthermore, p150 expression might provide us with reliable information on the biological behaviour of tumors and the clinical course of the disease.

Safety and efficacy of the tumor necrosis factor antagonists.

Psoriasis is one of the most common systemic inflammatory diseases and affects the quality of life of the affected persons profoundly. Further knowledge of the pathogenesis and new biotechnological techniques have made it possible to develop new targeted therapies, such as antibodies against tumor necrosis factor (TNF)-alpha. Today, 3 TNF inhibitors, infliximab, adalimumab, and Etanercept, have been approved for the treatment of psoriasis arthritis, psoriasis, and other indications like Crohn's disease, depending on the distinct substance by the European Medicines Agency. Golimumab was approved in September 2009 for the use in psoriasis arthritis, respectively. These substances have added new effective treatment options to the therapeutic armamentarium of psoriasis. To use these new treatments for the best of our patients, it is important to know the correct application, the advantages, as well as contraindications or possible adverse effects of the substances. This article provides an update on the TNF-alpha inhibitors with emphasis on practical daily use. Most data are on the basis of high-quality studies and official guidelines, but if necessary, data from recent publications or clinical expertise have been added. In summary, with TNF inhibitors we have gained effective new treatment options showing a favorable safety profile when paying attention to safety aspects before and during therapy (screening, monitoring).

Ultraviolet light downregulates CD95 ligand and TRAIL receptor expression facilitating actinic keratosis and squamous cell carcinoma formation.

Long-term ultraviolet light exposure of human skin epidermis in Caucasians is associated with an increased risk for the development of melanoma and nonmelanoma skin cancers. Ultraviolet radiation not only induces DNA damage in epidermal cells, it also interferes with skin homeostasis, which is maintained by a unique distribution pattern of apoptosis-inducing and apoptosis-preventing molecules. We demonstrate that, beside CD95 ligand, TRAIL and TRAIL receptors also function as important sensors in the human epidermis preserving skin integrity and preventing cell transformation. Ultraviolet irradiation extensively changes the expression pattern of some of these molecules, diminishing their sensor function. In particular, CD95 ligand and to a somewhat lesser extent TRAIL receptors are downregulated upon ultraviolet light exposure. CD95 ligand downregulation is not due to protein degradation as in situ hybridization experiments strongly support a transcriptional regulation. The downregulation of these molecules with sensor function increases the risk that aberrant cells are less efficiently eliminated. This concept is supported by the fact that the expression of these molecules is also low or absent in actinic keratosis, a precancerous state that has developed as the consequence of long-term ultraviolet exposure. Progression to invasive neoplasms is then accompanied by an upregulation of CD95 ligand and a downregulation of CD95 and of the TRAIL receptors. The high expression of CD95 ligand, TRAIL, and FLIP in squamous cell carcinoma may then contribute to the immune escape of the tumor, whereas the lack of expression of CD95 and TRAIL receptors prevents autolysis of the tumor.

Green fluorescent protein as a novel tool to measure apoptosis and necrosis.

BACKGROUND: Several apoptosis-detecting methods are currently available. Many of them are work intensive and require the additional use of antibodies, dyes, specific substrates, or enzymatic reactions. A simple, fast, and reliable method was developed to test for apoptosis or necrosis using mouse and human cell lines (e.g., Jurkat, A20.2J, and PB3c cells) stably transfected with a vector coding for green fluorescent protein (GFP) as indicator cells. METHODS: Apoptosis in GFP-transfected cell lines was induced either by soluble Fas-Ligand (sFasL), recombinant human TRAIL (rhTRAIL), or interleukin-3 (IL-3) deprivation. Necrosis was induced by polyclonal anti-A20 and complement treatment of GFP-transfected A20. Cells were analyzed by flow cytometry for GFP fluorescence. Propidium iodide and Annexin V staining were used to confirm the results obtained with the GFP-method. RESULTS: Live GFP-transfected cells show a strong fluorescence intensity, which is significantly diminished upon induction of apoptosis, whereas necrotic GFP-transfected cells almost completely lose their GFP-associated fluorescence. Apoptosis but not necrosis of GFP-transfected cells was blocked by the use of a caspase inhibitor. The results are highly comparable to conventional apoptosis-detecting methods. CONCLUSIONS: The advantage of our GFP-based assay compared with other methods is the analysis of apoptosis or necrosis without the necessity for additional staining or washing steps, making it an ideal tool for screening apoptotic or necrotic stimuli.