Effect of pre-treatment with catecholamines on cold preservation and ischemia/reperfusion-injury in rats

Treatment of organ donors with catecholamines reduces acute rejection episodes and improves long-term graft survival after renal transplantation. The aim of this study was to investigate the effect of catecholamine pre-treatment on ischemia/reperfusion (I/R)- and cold preservation injury in rat kidneys. I/R-injury was induced by clamping the left kidney vessels for 60 min along with a contralateral nephrectomy. Cold preservation injury was induced by storage of the kidneys for 24 h at +4°C in University of Wisconsin solution, followed by syngeneic transplantation. Rats were pre-treated with either dopamine (DA), dobutamine (DB), or norepinephrine (2, 5, and 10 μg/kg/min, each group) intravenously via an osmotic minipump for 24 h before I/R- and cold preservation injury. Pre-treatment with DA (2 or 5 μg/kg/min) and DB (5 μg/kg/min) improved recovery of renal function after I/R-injury and dose dependently reduced mononuclear and major histocompatibility complex class II-positive cells infiltrating the kidney after I/R-injury. One day after I/R-injury, upregulation of transforming growth factor (TGF)-β 1 and 2 and phosphorylation of p42/p44 mitogen-activated protein kinases was observed in kidneys of animals treated with DA or DB. DA (5 μg/kg/min) and DB (5 μg/kg/min) pre-treatment reduced endothelial cell damage after 24 h of cold preservation. Only DA pre-treatment improved renal function and reduced renal inflammation after 24 h of cold preservation and syngeneic transplantation. Our results demonstrate a protective effect of pre-treatment with catecholamines on renal inflammation and function after I/R- or cold preservation injury. This could help to explain the potent organoprotective effects of catecholamine pre-treatment observed in human kidney transplantation

Serotonin and Dopamine Protect from Hypothermia/Rewarming Damage through the CBS/ H2S Pathway

Biogenic amines have been demonstrated to protect cells from apoptotic cell death. Herein we show for the first time that serotonin and dopamine increase H2S production by the endogenous enzyme cystathionine-β-synthase (CBS) and protect cells against hypothermia/rewarming induced reactive oxygen species (ROS) formation and apoptosis. Treatment with both compounds doubled CBS expression through mammalian target of rapamycin (mTOR) and increased H2S production in cultured rat smooth muscle cells. In addition, serotonin and dopamine treatment significantly reduced ROS formation. The beneficial effect of both compounds was minimized by inhibition of their re-uptake and by pharmacological inhibition of CBS or its down-regulation by siRNA. Exogenous administration of H2S and activation of CBS by Prydoxal 5′-phosphate also protected cells from hypothermic damage. Finally, serotonin and dopamine pretreatment of rat lung, kidney, liver and heart prior to 24 h of hypothermia at 3°C followed by 30 min of rewarming at 37°C upregulated the expression of CBS, strongly reduced caspase activity and maintained the physiological pH compared to untreated tissues. Thus, dopamine and serotonin protect cells against hypothermia/rewarming induced damage by increasing H2S production mediated through CBS. Our data identify a novel molecular link between biogenic amines and the H2S pathway, which may profoundly affect our understanding of the biological effects of monoamine neurotransmitters

Deguelin Attenuates Reperfusion Injury and Improves Outcome after Orthotopic Lung Transplantation in the Rat

The main goal of adequate organ preservation is to avoid further cellular metabolism during the phase of ischemia. However, modern preservation solutions do rarely achieve this target. In donor organs hypoxia and ischemia induce a broad spectrum of pathologic molecular mechanisms favoring primary graft dysfunction (PGD) after transplantation. Increased hypoxia-induced transcriptional activity leads to increased vascular permeability which in turn is the soil of a reperfusion edema and the enhancement of a pro-inflammatory response in the graft after reperfusion. We hypothesize that inhibition of the respiration chain in mitochondria and thus inhibition of the hypoxia induced mechanisms might reduce reperfusion edema and consecutively improve survival in vivo. In this study we demonstrate that the rotenoid Deguelin reduces the expression of hypoxia induced target genes, and especially VEGF-A, dose-dependently in hypoxic human lung derived cells. Furthermore, Deguelin significantly suppresses the mRNA expression of the HIF target genes VEGF-A, the pro-inflammatory CXCR4 and ICAM-1 in ischemic lungs vs. control lungs. After lung transplantation, the VEGF-A induced reperfusion-edema is significantly lower in Deguelin-treated animals than in controls. Deguelin-treated rats exhibit a significantly increased survival-rate after transplantation. Additionally, a downregulation of the pro-inflammatory molecules ICAM-1 and CXCR4 and an increase in the recruitment of immunomodulatory monocytes (CD163+ and CD68+) to the transplanted organ involving the IL4 pathway was observed. Therefore, we conclude that ischemic periods preceding reperfusion are mainly responsible for the increased vascular permeability via upregulation of VEGF. Together with this, the resulting endothelial dysfunction also enhances inflammation and consequently lung dysfunction. Deguelin significantly decreases a VEGF-A induced reperfusion edema, induces the recruitment of immunomodulatory monocytes and thus improves organ function and survival after lung transplantation by interfering with hypoxia induced signaling

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) Diagnostics and treatment

Minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS) are rare diseases that are usually manifested with a nephrotic syndrome and are most likely caused by an as yet unknown permeability factor. While MCD by definition has not yet led to a loss of renal function, FSGS is characterized by the formation of glomerular scars with progressive chronic renal insufficiency. It is important to note that in FSGS the isolated detection of these scars (lesions) in the biopsy is not sufficient for the diagnosis of primary FSGS. Relevant differential diagnoses (adaptive FSGS and genetic FSGS) appear identical under the light microscope, but they can be distinguished on the basis of the clinical picture (especially by the nephrotic syndrome). Therapeutically, the effectiveness of a consistent supportive treatment and especially a well-adjusted blood pressure is generally underestimated. With this treatment the progressive loss of renal function can be effectively slowed down or stopped. In MCD and primary FSGS with nephrotic syndrome immunosuppressive treatment is indicated, mostly using high-dose glucocorticoids and over prolonged periods of time. We recommend referring patients to specialized outpatient clinics, which can be helpful with their experience in diagnostics and treatment and, if necessary, inclusion in clinical trials

Crystalline deposits in the cornea and various areas of the kidney as symptoms of an underlying monoclonal gammopathy: a case report

Background Plasma cell dyscrasias (PCD) are characterized by an abnormal production of intact monoclonal immunoglobulins or parts such as heavy or light chains. In most cases, the monoclonal protein (also termed paraprotein) is produced by a clonal plasma cell population. The production of monoclonal proteins can result in deposits of various types and localization depending on the type, amount, and electrochemical properties of the paraprotein. One histopathologic presentation, albeit rare, are crystalline deposits. They can form in various organs and hence cause a wide spectrum of symptoms. Case presentation A 49-year-old man presented to the emergency department with eyestrain and foreign body sensation after overhead drilling. Examination of the eyes revealed crystalline deposits in the cornea of both eyes. After additional diagnostic testing, deposits were attributed to free light chains. Monoclonal gammopathy of undetermined significance (MGUS) was diagnosed according to serum electrophoresis and immunofixation. Four years later, new onset of proteinuria was detected. A percutaneous biopsy of the kidney showed severe light chain podocytopathy with secondary focal segmental glomerulosclerosis (FSGS) and light chain proximal tubulopathy (LCPT). In these lesions, crystalline deposits identical to the corneal deposits were found in ultrastructural and immunofluorescent analysis. The patient was diagnosed with monoclonal gammopathy of renal significance (MGRS), and a plasma cell directed therapy was initiated. Conclusions PCD can present with a wide array of symptoms and are notoriously difficult to diagnose. Extrarenal manifestations such as crystalline deposits in the cornea are one possible manifestation. The case presented herein emphasizes the notion that extrarenal paraprotein deposits warrant a thorough search for the underlying clonal disease

Nephrotic syndrome in childhood and adolescence. Summary of the AWMF guidelines considering special aspects of diagnostics and treatment in adults

Background. Despite fulfilling the criteria for an orphan disease, idiopathic nephrotic syndrome (NS) in children is the most frequent glomerular disease in this age group. At the same time NS in children is aheterogeneous disease and in order to assess the individual facets of the disease aclassification using the following criteria is helpful: etiology, age at onset, histology and responsiveness to initial standard treatment with glucocorticoids. As for prognosis the differentiation between steroid-sensitive (SSNS) and steroid-resistant nephrotic syndromes (SRNS) is most important because SRNS is arisk factor for developing end-stage renal disease. High cumulative doses of glucocorticoids or prolonged administration in the initial treatment do not influence the risk of a relapse. Genetic testing is highly advisable in patients with SRNS to avoid unnecessary and ineffective immunosuppressive therapy. Methods. This manuscript gives an overview on the management of SSNS and SRNS and provides insights into the different diagnostic and therapeutic approaches in pediatric and adult medicine. Furthermore, associated risks and potential long-term side effects of treatment are described. Conclusion. Frequently relapsing NS and SRNS are still challenging to treat. The use of steroids and immunosuppressive maintenance therapy has severe long-term side effects. The optimal treatment of adult patients with childhood onset SSNS and infrequent relapses remains unclear