Vedat Schwenger

Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR–β3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.

Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans

Studies of mutations affecting lifespan in Caenorhabditis elegans show that mitochondrial generation of reactive oxygen species (ROS) plays a major causative role in organismal aging. Here, we describe a novel mechanism for regulating mitochondrial ROS production and lifespan in C. elegans: progressive mitochondrial protein modification by the glycolysis‐derived dicarbonyl metabolite methylglyoxal (MG). We demonstrate that the activity of glyoxalase‐1, an enzyme detoxifying MG, is markedly reduced with age despite unchanged levels of glyoxalase‐1 mRNA. The decrease in enzymatic activity promotes accumulation of MG‐derived adducts and oxidative stress markers, which cause further inhibition of glyoxalase‐1 expression. Over‐expression of the C. elegans glyoxalase‐1 orthologue CeGly decreases MG modifications of mitochondrial proteins and mitochondrial ROS production, and prolongs C. elegans lifespan. In contrast, knock‐down of CeGly increases MG modifications of mitochondrial proteins and mitochondrial ROS production, and decreases C. elegans lifespan.

Malignancy in Renal Transplantation

Eberhard Ritz : Feature Editor An increased incidence of malignant tumors in transplant recipients was recognized as early as in the 1970s, and this effect was ascribed to the administration of immunosuppressive medication ([1,2][1][⇓][2]). In the early days of transplantation medicine, however

C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction

OBJECTIVE Establishing Caenorhabditis elegans as a model for glucose toxicity–mediated life span reduction. RESEARCH DESIGN AND METHODS C. elegans were maintained to achieve glucose concentrations resembling the hyperglycemic conditions in diabetic patients. The effects of high glucose on life span, glyoxalase-1 activity, advanced glycation end products (AGEs), and reactive oxygen species (ROS) formation and on mitochondrial function were studied. RESULTS High glucose conditions reduced mean life span from 18.5 ± 0.4 to 16.5 ± 0.6 days and maximum life span from 25.9 ± 0.4 to 23.2 ± 0.4 days, independent of glucose effects on cuticle or bacterial metabolization of glucose. The formation of methylglyoxal-modified mitochondrial proteins and ROS was significantly increased by high glucose conditions and reduced by mitochondrial uncoupling and complex IIIQo inhibition. Overexpression of the methylglyoxal–detoxifying enzyme glyoxalase-1 attenuated the life-shortening effect of glucose by reducing AGE accumulation (by 65%) and ROS formation (by 50%) and restored mean (16.5 ± 0.6 to 20.6 ± 0.4 days) and maximum life span (23.2 ± 0.4 to 27.7 ± 2.3 days). In contrast, inhibition of glyoxalase-1 by RNAi further reduced mean (16.5 ± 0.6 to 13.9 ± 0.7 days) and maximum life span (23.2 ± 0.4 to 20.3 ± 1.1 days). The life span reduction by glyoxalase-1 inhibition was independent from the insulin signaling pathway because high glucose conditions also affected daf-2 knockdown animals in a similar manner. CONCLUSIONS C. elegans is a suitable model organism to study glucose toxicity, in which high glucose conditions limit the life span by increasing ROS formation and AGE modification of mitochondrial proteins in a daf-2 independent manner. Most importantly, glucose toxicity can be prevented by improving glyoxalase-1–dependent methylglyoxal detoxification or preventing mitochondrial dysfunction.

Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy

Diabetic nephropathy is a growing health concern with characteristic sterile inflammation. As the underlying mechanisms of this inflammation remain poorly defined, specific therapies targeting sterile inflammation in diabetic nephropathy are lacking. Intriguingly, an association of diabetic nephropathy with inflammasome activation has recently been shown, but the pathophysiological relevance of this finding remains unknown. Within glomeruli, inflammasome activation was detected in endothelial cells and podocytes in diabetic humans and mice and in glucose-stressed glomerular endothelial cells and podocytes in vitro. Abolishing Nlrp3 or caspase-1 expression in bone marrow–derived cells fails to protect mice against diabetic nephropathy. Conversely, Nlrp3-deficient mice are protected against diabetic nephropathy despite transplantation of wild-type bone marrow. Pharmacological IL-1R antagonism prevented or even reversed diabetic nephropathy in mice. Mitochondrial reactive oxygen species (ROS) activate the Nlrp3 inflammasome in glucose or advanced glycation end product stressed podocytes. Inhibition of mitochondrial ROS prevents glomerular inflammasome activation and nephropathy in diabetic mice. Thus, mitochondrial ROS and Nlrp3-inflammasome activation in non-myeloid-derived cells aggravate diabetic nephropathy. Targeting the inflammasome may be a potential therapeutic approach to diabetic nephropathy.

Damage to the Peritoneal Membrane by Glucose Degradation Products Is Mediated by the Receptor for Advanced Glycation End-Products

Peritoneal dialysis is limited by morphologic changes of the peritoneal membrane. Use of peritoneal dialysis fluids (PDF) that contain glucose degradation products (GDP) generates advanced glycation end-products (AGE) within the peritoneal cavity. It is unknown whether peritoneal damage is causally related to AGE-receptor for AGE (RAGE) interaction. The effects of PDF were compared with different amounts of GDP on morphologic changes of the peritoneal membrane in 48 wild-type (WT) and 48 RAGE-deficient mice. PDF (1 ml) were instilled twice daily over a period of 12 wk. Groups with eight animals each received no manipulation (sham); sham instillation (sham i.p.); or filter-sterilized, glucose-free, conventional low GDP- or high GDP PDF. In vitro (generation of AGE fluorescence in PDF) and in vivo (immunohistochemistry for carboxymethyllysine), a GDP-dependent increase of AGE formation occurred. Inflammation and neoangiogenesis were augmented in WT mice that were treated with high GDP accompanied by upregulation of CD3+ T cells, increased NF-kappaB binding activity, increased lectin, and vascular endothelial growth factor expression. Furthermore, pronounced submesothelial fibrosis was found with increased expression of TGF-beta1. Exposure to low GDP resulted in only mild inflammation and neoangiogenesis (compared with sham i.p.) and no fibrosis in WT mice. The findings in WT contrasted with those in RAGE-deficient mice, which showed no increased inflammation (CD3+ T cells and NF-kappaB binding activity), neoangiogenesis (by lectin and vascular endothelial growth factor expression), or fibrosis (expression of TGF-beta1) after long-term exposure to GDP-containing PDF. Peritoneal damage by GDP in PDF is dependent at least in part on AGE-RAGE interaction.

Cardiac biomarkers and survival in haemodialysis patients

Background  In dialysis patients, cardiac troponin T (cTNT) is often elevated despite the absence of acute myocardial ischaemia, and amino‐terminal pro‐B‐natriuretic peptide (NT‐proBNP) is markedly higher compared to non‐haemodialysis patients. In a longitudinal observation, we evaluated the association of cTNT and NT‐proBNP on cardiovascular morbidity and mortality in haemodialysis patients with and without fluid overload.

Sustained low efficiency dialysis using a single-pass batch system in acute kidney injury - a randomized interventional trial: the REnal Replacement Therapy Study in Intensive Care Unit PatiEnts

Th e authors noticed after the publication of their article [1] an error in their methods. Under “Randomization and treatment assignments”, the Asahi APS 650 membrane was used together with the Octo Nova device (Octo Nova, Diamed, Köln, Germany) and not the Prisma device as indicated in the manuscript. Th is section should therefore read as follows; “Patients randomly assigned to the CVVH-group (Prisma, Gambro Hospal, Lyon, France and Octo Nova, Diamed, Köln, Germany) were treated with 35 ml/kg per hour replacement fl uid in predilution. Treatment was scheduled for 24-h and blood fl ow was maintained between 100 and 120 ml/min. For all CVVH treatments, high-fl ux fi lters (AN69-M100, Gambro Hospal, Lyon, France and Asahi Kasei APS-650, Asahi Kasei Medical Co, Ltd., Japan) were used.” In addition, the funding of this study was erroneously deleted in-house and should read as follows; “Grant of the European Nephrology and Dialysis Institute, Bad Homburg, Germany”.

Hypertension after renal transplantation.

With current immunosuppression, elevated blood pressure is found in almost 90% of renal graft recipients. Major causes of this are impairment of renal function (secondary to chronic allograft nephropathy or less frequently recurrence of primary renal disease), the use of calcineurin inhibitors as immunosuppressants, uncontrolled renin secretion by the shrunken kidneys of the recipient, stenosing lesions of the transplant artery (or the upstream arteries of the recipient), polycytemia, and genetic predisposition to hypertension of the graft donor. Even minor degrees of blood pressure elevation have a significant impact on survival of the recipient and on graft survival, presumably by amplifying vascular injury to the graft. In this respect, elevation of systolic blood pressure and an abnormal circadian blood pressure profile are of particular relevance. In contrast to previous opinion, angiotensin converting enzyme inhibitors are indicated in treatment, but given the causal role of sodium retention and graft vasoconstriction, diuretics and calcium channel blockers remain mainstays of antihypertensive treatment in the renal allograft recipient.

CRP levels in autoimmune disease can be specified by measurement of procalcitonin.

SummaryAutoimmune diseases (AID) are prone to infection particularly under immunosuppression. The differentiation of infection from active AID is often difficult. In order to specify the diagnostic value of measurement of procalcitonin (PCT) in AID 81 patients with anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis were analyzed, 27 with rheumatoid arthritis and 25 patients with systemic lupus erythematosus at various stages of the disease. Although PCT levels (95th percentile) were below 0.5 ng/ml in patients with active systemic lupus erythematosus and rheumatoid arthritis, the cutoff for normal values (95th percentile) in patients with active ANCA-positive vasculitis was 0.89. Therefore PCT levels of <1 ng/ml are recommended as cutoff for invasive infections in patients with ANCA-positive vasculitis. In view of the increased mortality under immunosuppression in patients with AID and additional bacterial infection the measurement of PCT is helpful when an infectious origin is suspected.