Podocytes play a key role in maintaining the blood-urine barrier for high-molecular-weight proteins. They are considered to be terminally differentiated, and podocyte loss cannot be compensated by regenerative proliferation. Various diseases leading to podocyte damage and loss result in proteinuria and cause nephrotic syndrome. Therefore, direct therapeutical strategies to protect podocytes in disease situations are a logical concept to prevent disease or to delay disease progression. Acquired podocytopathies like idiopathic focal segmental glomerulosclerosis and minimal change disease are historically considered as immunological diseases. Therefore, immunosuppressive agents such as steroids and calcineurin inhibitors are the commonly used treatment strategies. However, the causative disease mechanisms behind these treatment strategies remain elusive. Recent evidence shows that immunosuppressive agents, in addition to the effect on the immune system, directly influence the unique structure and function of podocytes. In this context, the actin cytoskeleton of the podocyte and cytokines such as vascular endothelial growth factor play a pivotal role. In this review, we summarize the direct effects on podocytes obtained in vivo and in vitro after treatment with calcineurin inhibitors, mTOR inhibitors and glucocorticoids. These direct effects could play a key role in the treatment concepts of podocytopathies with an important impact on the long-term renal function in patients with pharmacological immunosuppression.

Objective To evaluate whether invasive coronary angiography or computed tomography (CT) should be performed in patients clinically referred for coronary angiography with an intermediate probability of coronary artery disease.Design Prospective randomised single centre trial.Setting University hospital in Germany.Participants 340 patients with suspected coronary artery disease and a clinical indication for coronary angiography on the basis of atypical angina or chest pain.Interventions 168 patients were randomised to CT and 172 to coronary angiography. After randomisation one patient declined CT and 10 patients declined coronary angiography, leaving 167 patients (88 women) and 162 patients (78 women) for analysis. Allocation could not be blinded, but blinded independent investigators assessed outcomes.Main outcome measure The primary outcome measure was major procedural complications within 48 hours of the last procedure related to CT or angiography.Results Cardiac CT reduced the need for coronary angiography from 100% to 14% (95% confidence interval 9% to 20%, P<0.001) and was associated with a significantly greater diagnostic yield from coronary angiography: 75% (53% to 90%) v 15% (10% to 22%), P<0.001. Major procedural complications were uncommon (0.3%) and similar across groups. Minor procedural complications were less common in the CT group than in the coronary angiography group: 3.6% (1% to 8%) v 10.5% (6% to 16%), P=0.014. CT shortened the median length of stay in the angiography group from 52.9 hours (interquartile range 49.5-76.4 hours) to 30.0 hours (3.5-77.3 hours, P<0.001). Overall median exposure to radiation was similar between the CT and angiography groups: 5.0 mSv (interquartile range 4.2-8.7 mSv) v 6.4 mSv (3.4-10.7 mSv), P=0.45. After a median follow-up of 3.3 years, major adverse cardiovascular events had occurred in seven of 167 patients in the CT group (4.2%) and six of 162 (3.7%) in the coronary angiography group (adjusted hazard ratio 0.90, 95% confidence interval 0.30 to 2.69, P=0.86). 79% of patients stated that they would prefer CT for subsequent testing. The study was conducted at a University hospital in Germany and thus the performance of CT may be different in routine clinical practice. The prevalence was lower than expected, resulting in an underpowered study for the predefined primary outcome.Conclusions CT increased the diagnostic yield and was a safe gatekeeper for coronary angiography with no increase in long term events. The length of stay was shortened by 22.9 hours with CT, and patients preferred non-invasive testing.Trial registration ClinicalTrials.gov NCT00844220.

The G protein-coupled V 2 vasopressin receptor is crucially involved in water reabsorption in the renal collecting duct. Mutations in the human V 2 vasopressin receptor gene cause nephrogenic diabetes insipidus. Many of the disease-causing mutants are retained intracellularly by the quality control system of the early secretory pathway. It was previously thought that quality control system is restricted to the endoplasmic reticulum (ER). Here, we have examined the retention mechanisms of eight V 2 vasopressin receptor mutants. We show that mutants L62P, DL62-R64 and S167L are trapped exclusively in the ER. In contrast, mutants R143P, Y205C, InsQ292, V226E and R337X reach the ER/Golgi intermediate compartment (ERGIC) and are rerouted to the ER. The ability of the mutant receptors to reach the ERGIC is independent of their expression levels. Instead, it is determined by their folding state. Mutant receptors in the ERGIC may be sorted into retrograde transport vesicles by an interaction of an RXR motif in the third intracellular loop with the coatomer complex I. Our data show that disease-causing mutants of a particular membrane protein may be retained in different compartments of the early secretory pathway and that the folding states of the proteins determine their retention mechanism. The neurohypophysial hormone 8-arginine vasopressin (AVP, or antidiuretic hormone) regulates antidiuresis via the G protein-coupled V 2 vasopressin receptor (V 2 R) (1). The receptor is expressed in the basolateral membrane of principal cells, the main cell type of the renal collecting duct. Upon AVP binding, the receptor activates the G s / adenylyl cyclase system. The subsequent rise in intracellular cAMP levels leads to the activation of the protein kinase A and to the fusion of aquaporin 2 (AQP2)-bearing vesicles with the apical and basolateral membrane by an as yet incompletely understood mechanism (AQP2 shuttle) (2). The redistribution of AQP2 in the plasma membrane increases the water permeability of the epithelium and thereby greatly facilitates water reabsorption.Mutations in the V 2 R gene cause X-linked nephrogenic diabetes insipidus (NDI), a disease characterized by the kidney's inability to respond to AVP (3); the consequence is a profound diuresis. To date, more than 150 distinct NDI-causing mutations in the V 2 R gene have been described (3, see also

ur understanding of postcontrast acute kidney injury (AKI) (1,2) is limited by the lack of randomized control groups in clinical studies (3). Moreover, a recent reassessment of the risk resulting from exposure to contrast agents has questioned the existence of postcontrast AKI (4). While there is agreement that intra-arterial contrast agent administration can cause AKI (5), retrospective studies suggest that intravenous contrast material administration for CT has a similar risk of AKI to noncontrast CT (6-8). The latter finding was corroborated in a metaanalysis of 28 observational studies comparing CT studies performed with or without intravenous contrast material administration (9), while no randomized clinical trial has yet compared intravenous and intra-arterial contrast agent administration in relationship to AKI (10). Although the exact underlying mechanisms are poorly understood (11), the intravenous route of contrast agent administration may reduce AKI compared with intra-arterial injection (12) by avoiding microembolization from the aorta to the kidneys (13) and reducing peak contrast agent concentration in the renal arteries (14). However, a recent paired cohort study found minimal differences between patients who received both intravenous and intra-arterial contrast agents, with AKI frequencies of 9.9% and 11%, respectively (15). Similar findings with minimal differences in AKI rates were obtained by Karlsberg et al (16) in an intraindividual comparison of CT angiography (7.6%) and peripheral angiography (8.7%). On the other hand, a nonrandomized study showed a higher rate of AKI after catheterization (4.4%) than after CT (1.2%) (17), and large observational studies