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.

The aim of this study was to establish a nonviral method for gene delivery to the rat kidney. To this purpose, a panel of reagents was tested, including a monocationic lipid, DOTAP, a polycationic lipid, DOGS (or Transfectam), and three different forms of the cationic polymer polyethylenimine (PEI). A comparison among these compounds was performed in vivo, using luciferase as reporter gene. Complexes containing 10 microg of DNA were injected into the left renal artery of rats and allowed to remain in contact with the kidney for 10 min. Forty-eight hours later, luciferase expression levels in kidney extracts were measured. Kidneys injected with DNA complexed to the branched, 25-kD PEI polymer (PEI 25k) yielded activity levels significantly higher than control, sham-operated kidneys (2.7 x 10(4) vs. 5.2 x 10(3) RLU/kidney, respectively), whereas the other transfecting agents did not yield significant activity over controls. PEI 25k was therefore chosen for further optimization of transfection conditions. Dose-dependent luciferase expression was shown for 10, 50, and 100 microg of PEI-complexed DNA, reaching maximal levels of 2.4 x 10(5) RLU/kidney at 100 microg DNA. The optimal PEI nitrogen/DNA phosphate molar ratio was 10 equivalents. Luciferase activity peaked at 2 days, was still significantly higher than controls at 7 days, and was undetectable at 14 days post-injection. Using beta-galactosidase (beta-Gal) as a reporter, transgene expression was localized almost exclusively in proximal tubular cells.

This is a randomized trial (ATHENA study) in de novo kidney transplant patients to compare everolimus versus mycophenolic acid (MPA) with similar tacrolimus exposure in both groups, or everolimus with concomitant tacrolimus or cyclosporine (CsA), in an unselected population. In this 12-month, multicenter, open-label study, de novo kidney transplant recipients were randomized to everolimus with tacrolimus (EVR/TAC), everolimus with CsA (EVR/CsA) or MPA with tacrolimus (MPA/TAC), with similar tacrolimus exposure in both groups. Non-inferiority of the primary end point (estimated glomerular filtration rate [eGFR] at month 12), assessed in the per-protocol population of 338 patients, was not shown for EVR/TAC or EVR/CsA versus MPA/TAC. In 123 patients with TAC levels within the protocol-specified range, eGFR outcomes were comparable between groups. The mean increase in eGFR during months 1 to 12 post-transplant, analyzed post hoc, was similar with EVR/TAC or EVR/CsA versus MPA/TAC. The incidence of treatment failure (biopsy proven acute rejection, graft loss or death) was not significant for EVR/ TAC but significant for EVR/CsA versus MPA/TAC. Most biopsy-proven acute rejection events in this study were graded mild (BANFF IA). There were no differences in proteinuria between groups. Cytomegalovirus and BK virus infection were significantly more frequent with MPA/TAC. Thus, everolimus with TAC or CsA showed comparable efficacy to MPA/TAC in de novo kidney transplant patients. Non-inferiority of renal function, when pre-specified, was not shown, but the mean increase in eGFR from month 1 to 12 was comparable to MPA/TAC.

Inflammatory reactions in the graft have a pivotal influence on acute as well as long-term graft function. The main reasons for an inflammatory reaction of the graft tissue are rejection episodes, infections as well as ischemia/ reperfusion

In vivo administration of low doses of lipopolysaccharide (LPS) to rodents can protect these animals from subsequently administrated, usually lethal doses of endotoxin or LPS. In this study we tested the effects of LPS pretreatment on ischemia/reperfusion injury in the kidney. Male C57/B1 mice were pretreated with different doses of LPS or phosphate-buffered saline on days -4 and -3. The right kidney was removed, and the vessels of the left kidney were clamped for 30 or 45 minutes on day 0. Creatinine levels and survival of animals were monitored. To test the involvement of cytokines, additional animals were harvested before ("time 0") and 15 minutes, 1, 2, 8, and 16 hours after reperfusion for histology, immunohistochemistry, terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay, and reverse transcriptase-polymerase chain reaction analysis (including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, inducible nitric oxide synthase (iNOS), and interferon (IFN)-gamma messenger RNA (mRNA)). In controls, renal ischemia of 30 minutes was nonlethal, whereas 73% of the animals died within 48 +/- 18 hours, after 45 minutes of ischemia. All different doses of LPS protected the animals from lethal renal ischemia/reperfusion injury. Starting at similar levels, serum creatinine increased significantly in controls but not in LPS-pretreated animals over time. As early as 2 hours after reperfusion, tubular cell damage was significantly more pronounced in controls than in LPS-treated mice. In controls, tubules deteriorated progressively until 8 hours of reperfusion. At this time, more than 50% of tubular cells were destroyed. This destruction was accompanied by a pronounced leukocytic infiltration, predominantly by macrophages. In contrast, LPS pretreatment prevented the destruction of kidney tissue and infiltration by leukocytes. The terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay revealed significantly more apoptotic cells in controls compared with LPS-pretreated animals. IL-1, IFN-gamma, and iNOS mRNA expression did not differ between the groups throughout the time points examined. However, the expression of TNF-alpha mRNA was significantly increased at 2 hours and IL-6 mRNA was significantly down-regulated before ischemia and shortly after reperfusion in the LPS-pretreated kidneys. Therefore, we found that sublethal doses of LPS induced cross-tolerance to renal ischemia/reperfusion injury. Our data suggest that increased TNF-alpha and reduced IL-6 mRNA expression might be responsible. However, more studies are needed to decipher the exact mechanism.

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.

It is of particular importance in kidney transplantation to understand the underlying mechanisms and effects of ischemia/reperfusion on the graft as this knowledge also opens strategies to prevent or treat ischemia/reperfusion injury after transplantation in order to improve graft outcome.

Hypertension causes cardiac hypertrophy characterized by low-grade inflammation. Toll-like receptors (TLRs), members of the innate immune system, contribute to cardiac failure. We hypothesized that hypertension is accompanied by enhanced TLR4 expression and activity. Cardiac TLR4 expression was determined in untreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY;4,8, 16 weeks). Besides, hearts of 8-week-old rats were stimulated with the endogenous TLR4 ligand heparansulfate (HS); the proinflammatory mRNA pattern was assessed (tumor necrosis factor-a (TNF-a), interleukin (IL)-6, monocyte chemotactic protein (MCP)-1). Additionally, we induced hypertension in WKY by L-NAME (N x -nitro-L-argininemethylester hydrochloride). In both hypertension models the effect of ramipril on TLR4 density was assessed. Cardiac TLR4 distribution was investigated by fluorescence-activated cell sorting analysis. Blood pressure (BP) and heart weight/body weight ratio (HW/BW) were elevated in SHR. Constitutive TLR4 expression was augmented in adolescent and adult, but not young SHR compared with WKY. TLR4 staining was pronounced in cardiomyocytes. HS entailed an aggravated TNF-a and IL-6 mRNA response in cardiac tissue, which was significantly pronounced in SHR. Ramipril (10 mg kg À1 per day) reduced BP, HW/BW and TLR4 expression in SHR. L-NAME also augmented TLR4 expression in WKY. Ramipril (1 mg kg À1 per day) lowered BP but TLR4 expression remained unaffected. High-dose ramipril (10 mg kg À1 per day) however decreased TLR4 expression. Starting from adolescence SHR demonstrated enhanced cardiac TLR4 expression. TLR4 was also upregulated in L-NAME induced hypertension. Thus, enhanced TLR4 expression might be linked to the development and maintenance of hypertension. Finally, the antihypertensive, anti-inflammatory action of angiotensin-converting-enzyme inhibition had no effect on TLR4 expression in therapeutic doses but in a high-dose model.