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Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more (“Rapid3”; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2at follow-up among those with eGFRcrea 60 mL/min/1.73m2or more at baseline (“CKDi25”; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT(2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATMor LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Background: Increased intra-abdominal pressure (PIA) leads to venous congestion in splanchnic and adjoining circulations. The aim is to examine whether PIA in peritoneal dialysis (PD) affects the mobilization of extracellular fluid from the lower body in supine body position.Methods: Patients were studied during a regular peritoneal equilibration test (PET) in supine body position using multifrequency bioimpedance analysis to determine extracellular resistance and absolute volume overload (AVO) in wrist-to-ankle (W2A) as well as in ankle-to-ankle (A2A) configurations. Measurements were taken at baseline (T0) after draining the peritoneal cavity, at T1 shortly after filling with 2 L of standard dialysate, and at T2 before taking the 2 h PET samples. PIA was measured from the column height in the PD catheter. Extracellular resistance in the lower extremities (RL) was taken as half of the A2A resistance.Results: Eighteen patients (56 ± 15 years, 76 ± 21 kg, body mass index (BMI) 26.4 ± 7 kg/m2, 13 men) were studied. After having assumed a supine body position for the duration of 17, 77, and 155 min, AVO continuously decreased from 1.6 ± 1.3 (T0) to 1.2 ± 1.5 (T1) and 1.0 ± 1.4 L (T2). RL significantly increased from 238 ± 57 (T0) to 254 ± 62 (T1) and 264 ± 67 Ohm (T2). This increase was negatively correlated to BMI and PIA measured at any time point, but not to net ultrafiltration volume.Conclusions: Orthostatic fluid shifts from the lower limbs may take up to 2 h in supine PD patients, especially with high BMI and PIA because of venous congestion in splanchnic and adjoining circulations.

Glucagon-like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, the anti-inflammatory action of Glp1r agonism was tested in a nondiabetic, T-cell–mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r−/−mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r−/−mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r−/−mice. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1mRNA expression. Together, Glp1r agonism protects mice from a T-cell–dependent glomerulonephritis model by inhibition of T-cell proliferation, possibly by interacting with their metabolic program. This mechanism may explain in part the renoprotective effects of Glp1r agonism in diabetic nephropathy.

Background The impact of peritoneal filling on hepato-splanchnic perfusion during peritoneal dialysis has not been fully elucidated yet.Methods Measurements were done in 20 prevalent peritoneal dialysis patients during a peritoneal equilibration test (PET) with 2L of standard dialysate. Data were obtained in the drained state at baseline (T0), after instillation (T1), and after 2 h of dwell time (T2). Intra-abdominal pressure (IAP) was measured by Durand's approach. The hepatic clearance index (KI) of indocyanine-green (ICG) was determined as an indirect measure of hepato-splanchnic blood flow. Cardiac index (CI), heart rate (HR), and total peripheral resistance index (TPRI) were derived from continuous arterial pulse analysis. Fluid volume overload (VO) was evaluated by multifrequency bioimpedance analysis. Ejection fraction (EF) was obtained from echocardiographic examination.Results IAP was 5.8 ± 3.5 mmHg at baseline (T0), rose to 9.4 ± 2.8 mmHg after instillation of dialysate (T1), and further to 9.7 ± 2.8 mmHg after 2 h of dwell time (p < 0.001). KI slightly declined from 0.60 ± 0.22 L/min/m2at T0to 0.53 ± 0.15 L/min/m2at T1(p = 0.075), and returned to 0.59 ± 0.22 L/min/m2at T2(p = 0.052). CI, HR, and TPRI did not change significantly. In five patients with an EF < 40% KI was significantly lower at T1(0.42 ± 0.12 L/min/m2; p = 0.039), and further decreased at T2(0.40 ± 0.04 L/min/m2; p = 0.016) compared to patients with normal EF (T1: 0.58 ± 0.15 L/min/m2and T2: 0.67 ± 0.22 L/min/m2).Conclusions Overall, hepatic clearance of ICG as a marker of hepato-splanchnic blood flow is not affected by the filling of the peritoneal cavity.

In early clinical testing, acute addition of alanyl-glutamine (AlaGln) to glucose-based peritoneal dialysis (PD) fluids restored peritoneal cellular stress responses and leukocyte function. This study was designed to test the effect of extended treatment with AlaGln-supplemented PD fluid on biomarkers of peritoneal health. In a double-blinded, randomized crossover design, stable PD patients were treated with AlaGln (8 mM) or placebo added to PD fluid for eight weeks. As primary outcome measures, dialysate cancer-antigen 125 (CA-125) appearance rate and ex vivostimulated interleukin-6 (IL-6) release were assessed in peritoneal equilibration tests. In 8 Austrian centers, 54 patients were screened, 50 randomized, and 41 included in the full analysis set. AlaGln supplementation significantly increased CA-125 appearance rate and ex vivostimulated IL-6 release. AlaGln supplementation also reduced peritoneal protein loss, increased ex vivostimulated tumor necrosis factor (TNF)-α release, and reduced systemic IL-8 levels. No adverse safety signals were observed. All 4 peritonitis episodes occurred during standard PD fluid treatment. A novel AlaGln-supplemented PD fluid improves biomarkers of peritoneal membrane integrity, immune competence, and systemic inflammation compared to unsupplemented PD fluid with neutral pH and low-glucose degradation. A phase 3 trial is needed to determine the impact of AlaGln supplementation on hard clinical outcomes.

Prostaglandin E2(PGE2) signaling is known to modulate inflammation and vascular resistance. Receptors of PGE2[E-type prostanoid receptors (EP)] might be an attractive pharmacological target in immune-mediated diseases such as glomerulonephritis. We hypothesized that selective EP4 antagonism improves nephrotoxic serum nephritis (NTS) by its anti-inflammatory properties. Mice were subjected to NTS and treated with the EP4 antagonist ONO AE3-208 (10 mg·kg body wt−1·day−1] or vehicle starting from disease initiation. In one set of experiments, treatment was started 4 days after NTS induction. Tubular epithelial cells were evaluated in vitro under starving conditions. EP4 antagonist treatment significantly improved the NTS phenotype without affecting blood pressure levels. Remarkably, the improved NTS phenotype was also observed when treatment was started 4 days after NTS induction. EP4 antagonism decreased tubular chemokine (C-X-C motif) ligand (Cxcl) 1 and Cxcl-5expression and thereby subsequently reduced interstitial neutrophil infiltration into the kidney. In vitro, tubular epithelial cells increasingly expressed Cxcl-5mRNA and Cxcl-5 protein when treated with PGE2or an EP4 agonist under starving conditions, which was blunted by EP4 antagonist treatment. Together, EP4 antagonism improves the NTS phenotype, probably by decreasing mainly Cxcl-5 production in tubular cells, thereby reducing renal neutrophil infiltration.

Hintergrund: Im Januar 2016 wurde in der Steiermark das Awareness-Programm „niere.schützen“ mit dem Ziel implementiert, bei Risikopatienten eine chronische Nierenerkrankung frühzeitig zu erkennen und geeignete diagnostische und progressionsverzögernde Maßnahmen auch i.S. einer kardiovaskulären Prävention zu ergreifen. Die für diesen Zweck erstellten Unterlagen in Form eines Überweisungsschemas und einer Begleitinformation wurden für die vorliegende Untersuchung mit zehn niedergelassenen Hausärztinnen und Hausärzten (HÄ) pilotiert. Methoden: Das methodische Vorgehen erfolgte mithilfe von semistrukturierten leitfadengestützten Interviews. Die Praktikabilität wurde mittels allgemeinmedizinischer Fallvignetten überprüft, um Verständlichkeits- und Anwendungsprobleme zu erkennen. Ergebnisse: Die tonbandaufgezeichneten und anonymisierten Interviews von zehn Hausärztinnen und Hausärzten (HÄ) zeigten nach inhaltlicher, kategorisierender Analyse deutlich den Modifikationsbedarf beim Überweisungsschema und der Begleitinformation. Es gelang durch die zusätzliche Praktikabilitätsprüfung anhand der allgemeinmedizinischen Fallvignetten den spezifischen Änderungsbedarf des Überweisungsschemas zu ermitteln, da nur 53 % der Fälle so bearbeitet wurden, wie es dem Überweisungsschema entsprach. Es erfolgte eine Umgestaltung des Überweisungsschemas mit Zusammenfassung und Komprimierung der Information, um dieses möglichst einfach und übersichtlich zu gestalten. Daneben konnten mögliche Barrierefaktoren in der Umsetzung bzw. in der Anwendung, wie z.B. die fehlende Vergütung, dargestellt und an geeigneter Stelle angesprochen werden. Schlussfolgerungen: Der vorliegende Bericht zeigt deutlich die Notwendigkeit der Praktikabilitäts- und Plausibilitätsprüfung einer geplanten Awareness-Maßnahme im niedergelassenen Bereich. Damit können mögliche Verständnis- und Hemmnis-Faktoren im Vorfeld erkannt und vor Einführung eines Programms berücksichtigt werden, um eine möglichst große Akzeptanz dieser geplanten Maßnahme zu erreichen.

Mammalian target of rapamycin (mTOR) inhibitors have been proposed to preserve renal function in patients after orthotopic liver transplantation (OLT) based on estimated glomerular filtration rate (eGFR). The presented study evaluated their effect on renal function in comparison to calcineurin inhibitors (CNIs) defined by measured GFR.

Nephrocalcinosis is characterized by aberrant deposition of calcium in the kidneys and is seen in phosphate nephropathy, primary hyperparathyroidism, and distal renal tubular acidosis. To further evaluate the specific pathophysiologic role of T cells in ectopic calcification, we used DBA/2 mice that are prone to develop nephrocalcinosis and dystrophic cardiac calcinosis. Female DBA/2 mice were depleted of T cells (n= 10) or regulatory T cells (Tregs) (n= 15) using either an anti-CD3ɛ or an anti-CD25 monoclonal antibody and compared with isotype-treated controls (n= 9; n= 15), respectively. After this immunomodulation, the DBA/2 mice were given a high-phosphate diet for 9 days and the degree of calcification was assessed by microcomputed tomography. Successful depletion was confirmed by flow cytometry of splenocytes. In DBA/2 mice, the high-phosphate diet induced a phenotype of nephrocalcinosis and dystrophic cardiac calcinosis. T-cell depletion significantly increased renal calcification in microcomputed tomography (P= 0.022). Concordantly, Treg depletion significantly deteriorated acute phosphate nephropathy (P= 0.039) and was associated with a significantly increased mortality rate (P= 0.004). Immunomodulation had no impact on the amount of cardiac calcification. Semiquantitative histopathologic evaluations with Alizarin Red staining independently confirmed the respective radiologic measurements. In summary, our data suggest a pivotal role of T cells, particularly Tregs, in the progression of nephrocalcinosis and emphasize the fact that inflammation deteriorates the outcome in acute phosphate nephropathy.

Background Pre-dialysis education can guide the choice of the dialysis modality best tailored to meet the needs and preferences of individual patients with chronic kidney disease.Methods In a retrospective single-center cohort study, we evaluated the impact of a pre-dialysis education program on the incidence rates of patients using hemodialysis (HD) and peritoneal dialysis (PD) in our unit. The frequency distribution of dialysis modalities between people attending our education program and people not attending the program (control group) was analyzed for the 4-year period 2004 – 2008.Results From among all the incident chronic kidney disease 5D patients presenting during the 4-year period, we analyzed 227 who started dialysis either with an arteriovenous fistula or a PD catheter. In that cohort, 70 patients (30.8%) took part in the education program, and 157 (69.2%) did not receive structured pre-dialysis counseling. In the group receiving education, 38 patients (54.3%) started with PD, and 32 (45.7%), with HD. In the standard-care group not receiving education, 44 patients (28%) started with PD, and 113 (72%), with HD (p< 0.001).Conclusions Our multidisciplinary pre-dialysis program had a significant impact on the frequency distribution of dialysis modalities, increasing the proportion of patients initiating dialysis with PD.

Pancreas transplantation is an accepted treatment strategy that can result in normalization of blood glucose, but this must be weighed against the risks of a surgical procedure and subsequent immunosuppression. To improve the riskbenefit ratio, pancreas transplantation is typically performed in end-stage renal disease patients who are undergoing simultaneous kidney transplantation or who previously received a renal transplant and are obligated to the use of immunosuppressive medications. As diabetic patients are at high risk for the development of cardiovascular disease, intensive evaluation before transplantation is necessary to minimize the perioperative and postoperative risk.

We established a murine model of phosphate nephropathy with secondary hyperparathyroidism. db/db mice, which develop obesity and type 2 diabetes mellitus, were uninephrectomized at the age of 6 weeks and were fed either standard chow or a phosphorus-rich diet during the next 8 weeks. Thereafter, renal cryosections showed abundant tubular casts with a strong histochemical von Kossa reaction in all db/db mice on the phosphorus-rich diet but none in the controls. X-ray diffraction and Raman spectroscopy proved that these tubular casts consist mostly of hydroxyapatite Ca5(PO4)3(OH). These intraluminal precipitations were located in distal tubuli and collecting ducts and were associated with degenerative tubular changes and peritubular infiltration of T cells and macrophages. In line, kidneys of db/db mice on the phosphorus-rich diet displayed significantly increased mRNA expression of the TH1 cytokines interferon γ, IL-6, and tumor necrosis factor α. In addition, mice developed signs of secondary hyperparathyroidism as shown by elevated serum phosphate, decreased serum calcium, and increased parathyroid hormone, osteopontin, and fibroblast growth factor 23 levels. db/db mice on the phosphorus-rich diet also presented with significantly lower body weight, lower homeostasis model assessment of insulin resistance index, and hypertrophic cardiomyopathy. Thus, we provide a murine model of phosphate nephropathy and secondary hyperparathyroidism, which can be used for future pharmacologic and pathophysiologic studies to analyze the effect of hyperphosphatemia on renal, metabolic, and cardiovascular phenotypes.

T cell immunoglobulin and mucin protein-3 (Tim3) is mainly expressed on the cell surface of T-helper lymphocytes (TH) that negatively regulates TH-type 1 (TH-1) responses. Because blockade of Tim3 aggravates disease activity in TH-1–dependent diseases, we investigated whether Tim3 is involved in the pathogenesis of the TH-1–dependent nephrotoxic nephritis (NTS). We first evaluated Tim3 expression in mice after induction of nephrotoxic serum nephritis (NTS) and then studied the effects of anti-Tim3 treatment toward the course of NTS for up to seven days. Whereas Tim3 expression was undetectable in control mice, we found significantly increased Tim3 expression in kidneys, but not in draining lymph nodes, at one, four, and eight weeks after induction of NTS. Tim3-expressing cells that infiltrated kidneys of mice subjected to NTS turned out to be CD4+T cells rather than CD8+cytotoxic T cells and dendritic cells. Administration of a blocking anti-Tim3 antibody aggravated nephritis as shown by significantly increased albuminuria, respective histological changes, and increased expression of the kidney injury molecule lipocalin-2. In parallel, an increase of infiltrating T cells, macrophages, and macrophage pro-inflammatory cytokine formation as well as increased proliferation and apoptosis in kidneys of anti-Tim3–treated mice was detected. Together, we provide the first evidence that Tim3 is up-regulated in kidneys in NTS and that Tim3 exerts protective roles in the course of disease.

Bortezomib is a well-established treatment option for patients with multiple myeloma (MM). It is a selective and reversible inhibitor of the proteasome that is responsible for the degradation of many regulatory proteins that are involved in apoptosis, cell-cycle regulation, or transcription. Because patients with MM are prone to develop acute renal failure, we evaluated the influence of Bortezomib on renal ischemia-reperfusion injury (IRI). Mice were subjected to renal IRI by having the renal pedicles clamped for 30 min followed by reperfusion for 3, 24, and 48 h. Mice were either pretreated with 0.5 mg/kg body wt Bortezomib or vehicle intravenously 12 h before induction of IRI. Serum creatinine and tubular necrosis were significantly increased in Bortezomib compared with vehicle-treated mice. The inflammatory response was found to be significantly decreased in Bortezomib-treated mice as reflected by a decreased infiltration of CD4+T cells and a significantly decreased Th1 cytokine expression in the kidneys. In contrast, apoptosis was significantly increased in kidneys of Bortezomib-treated mice compared with vehicle-treated controls. Increased numbers of TUNEL-positive cells/mm2and increased mRNA expression of proapoptotic factors were detected in kidneys of Bortezomib-treated mice. Of note, p21, a cell senescence marker, was also significantly increased in kidneys of Bortezomib-treated mice. In summary, we provide evidence that Bortezomib worsens the outcome of renal IRI by leading to increased apoptosis of tubular cells despite decreased infiltrating T cells and proinflammatory mediators.

Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silicoevidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.

Bortezomib has been introduced recently in the therapy of multiple myeloma (MM), a disease that is frequently associated with progressive renal failure. Because bortezomib-based therapy has been reported to lead to a rapid recovery of kidney function in patients with MM, we decided to study its direct effects in proximal tubular epithelial cells (PTCs) compared with glomerular mesangial cells (GMCs). After 24 h of stimulation, 50 nM bortezomib led to a 6.37-fold induction of apoptosis and markedly activated caspase-9 and -3 in GMCs but not in PTCs. In PTCs but not in GMCs, bortezomib led to a strong time-dependent degradation of IkappaB-alpha and to a long-lasting phosphorylation of both NF-kappaBp65 and extracellular signal-regulated kinase 1/2. Microarray analysis in bortezomib-treated PTCs revealed a time-dependent predominance of antiapoptotic genes compared with proapoptotic genes. Bortezomib (50 nM) induced heat shock protein (Hsp) 70 mRNA and protein levels in PTCs, whereas basal and bortezomib-stimulated Hsp70 protein expression was much weaker in GMCs. Moreover, bortezomib induced Bcl-2-associated athanogene (BAG) 3 mRNA and protein expression but inhibited BAG5 mRNA levels in PTCs. These data suggest that the reduced susceptibility of PTCs to bortezomib-induced cell apoptosis is because of cell type-specific effects of this compound on apoptosis/survival genes and pathways. The concept of bortezomib representing a blocker of both NF-kappaB activation and cell survival should be carefully examined in particular renal cell types.

T cells have been implicated in the pathogenesis of renal ischemia-reperfusion injury (IRI). To date existing data about the role of the T cell receptor (Tcr) are contradictory. We hypothesize that the Tcr plays a prominent role in the late phase of renal IRI. Therefore, renal IRI was induced in α/β, γ/δ T cell-deficient and wild-type mice by clamping renal pedicles for 30 min and reperfusing for 24, 48, 72, and 120 h. Serum creatinine increased equally in all three groups 24 h after ischemia but significantly improved in Tcr-deficient animals compared with wild-type controls after 72 h. A significant reduction in renal tubular injury and infiltration of CD4+T-cells in both Tcr-deficient mice compared with wild-type controls was detected. Infiltration of α/β T cells into the kidney was reduced in γ/δ T cell-deficient mice until 72 h after ischemia. In contrast, γ/δ T cell infiltration was equal in wild-type and α/β T cell-deficient mice, suggesting an interaction between α/β and γ/δ T cells. Data from γ/δ T cell-deficient mice were confirmed by in vivo depletion of γ/δ T cells in C57BL/6 mice. Whereas α/β T cell-deficient mice were still protected after 120 h, γ/δ T cell-deficient mice showed a “delayed wild-type phenotype” with a dramatic increase in kidney-infiltrating α/β, Tcr-expressing CD4+T-cells. This report provides further evidence that α/β T cells are major effector cells in renal IRI, whereas γ/δ T cells play a role as mediator cells in the first 72 h of renal IRI.

T cells have been implicated in the pathogenesis of renal ischemia-reperfusion injury (IRI). To date existing data about the role of the T cell receptor (Tcr) are contradictory. We hypothesize that the Tcr plays a prominent role in the late phase of renal IRI. Therefore, renal IRI was induced in /β, / T cell-deficient and wild-type mice by clamping renal pedicles for 30 min and reperfusing for 24, 48, 72, and 120 h. Serum creatinine increased equally in all three groups 24 h after ischemia but significantly improved in Tcr-deficient animals compared with wild-type controls after 72 h. A significant reduction in renal tubular injury and infiltration of CD4+T-cells in both Tcr-deficient mice compared with wild-type controls was detected. Infiltration of /β T cells into the kidney was reduced in / T cell-deficient mice until 72 h after ischemia. In contrast, / T cell infiltration was equal in wild-type and /β T cell-deficient mice, suggesting an interaction between /β and / T cells. Data from / T cell-deficient mice were confirmed by in vivo depletion of / T cells in C57BL/6 mice. Whereas /β T cell-deficient mice were still protected after 120 h, / T cell-deficient mice showed a "delayed wild-type phenotype" with a dramatic increase in kidney-infiltrating /β, Tcr-expressing CD4+T-cells. This report provides further evidence that /β T cells are major effector cells in renal IRI, whereas / T cells play a role as mediator cells in the first 72 h of renal IRI.

In many clinical settings, the duration of renal ischemia and therefore the outcome of acute renal failure cannot be determined adequately. Renal ischemia reperfusion injury is known to shorten telomeres and upregulate stress-induced genes, such as the cyclin-dependent kinase (CDK) inhibitor p21. So far, the expression and role of CDK inhibitors, as well as mouse telomerase reverse transcriptase (mTERT), has not been investigated in a model with variable lasting ischemic periods. Male C57Bl/6 mice were subjected to renal ischemia reperfusion injury by clamping both renal pedicles for 10, 20, 30, and 45 min, and the kidneys were allowed to be reperfused for 3, 24, and 48 h. Expression of different CDK inhibitors and mTERT was evaluated. Mice developed signs of acute renal failure linear to the duration of the ischemic period. Real-time PCR revealed that mTERT was only significantly upregulated in kidneys after short ischemic periods (20 min). In contrast, p21 was constantly upregulated in kidneys after long ischemic intervals (30 and 45 min), but not in kidneys, which were clamped for shorter periods. Mainly, tubular cells contributed to the observed increase in p21 expression. Targeting p21 via the selective p53 inhibitor pifithrin-α was able to prevent acute renal failure when administered immediately before ischemia. The expression of another CDK inhibitor, namely p16, was differentially regulated, depending on the time of reperfusion. Taken together, we detected mTERT and p21 as “indicator” genes for short and long ischemic intervals, respectively. These two proteins might also be possible new therapeutic targets in the treatment and prevention of acute renal failure.

Haemodialysis (HD) with bioincompatible cellulosic membranes like Cuprophan (CU) is considered to influence negatively the clinical outcome of acute and chronic renal failure. In this effect, apart from the disturbance of phagocytosis or oxygen species production by leukocytes, increased apoptosis also has been implicated recently. The objective of this study was to study the effect of HD membranes on apoptosis induction in polymorphonuclear neutrophils (PMN).

P-selectin is a leukocyte adhesion receptor expressed on the surface of activated platelets and endothelial cells. Its role in the pathogenesis of cerebral malaria was explored in a murine model of cerebral malaria. Infection of mice with Plasmodium bergheiANKA led to P-selectin up-regulation in brain vessels of cerebral malaria-susceptible mice but not of cerebral malaria-resistant mice. Treatment of susceptible mice with anti-mouse P-selectin mAb failed to prevent the development of the neurological syndrome. However, P-selectin-deficient mice infected with Plasmodium bergheiANKA had a cumulative incidence of cerebral malaria which was significantly reduced compared to wild-type animals (4.5%versus80%, respectively), despite identical levels of parasitemia, platelet and leukocyte accumulation. To determine whether P-selectin on platelets and/or endothelium was responsible for the microvascular pathology, cerebral malaria was assessed in chimeric mice deficient in platelet or endothelial P-selectin, which were generated by bone marrow transplantation. Mice deficient only in endothelial P-selectin did not show any sign of cerebral malaria (vascular plugging, hemorrhages, or edema), while mice lacking only platelet P-selectin showed signs of cerebral malaria similar to that seen in wild-type mice. These results indicate that endothelial P-selectin plays an important role in the pathogenesis of cerebral malaria.

Hypertension is extremely prevalent after renal transplantation, affecting up to 70 of all patients. An elevation in blood pressure is associated with an increased cardiovascular risk and may also contribute to chronic allograft failure. Renal transplantation provides interesting insights into the pathogenesis of hypertension. Experimental and human data show that the kidney is an essential organ for blood pressure regulation. In clinical practice a differential diagnosis that is based on excretory allograft function has proved useful.

Soft, cuffed, implantable central venous catheters such as the Quinton Permcath (Quinton Instrument Co, Seattle, WA) are increasingly used as permanent access in patients with end-stage renal disease. Their major limitations, besides infection, are thrombosis and inadequate blood flow. To prevent those complications, heparin is conventionally used for priming the Quinton Permcath between dialysis sessions. In this study, we compared recombinant tissue plasminogen activator (rTPA) with heparin for priming the Quinton Permcath in a prospective, randomized, crossover design. Twelve patients were randomly assigned to receive 2,000 IU of heparin or 2 mg of rTPA injected into each catheter lumen at the end of each dialysis session over a period of 4 months, followed by a switch to the other substance. Blood flow rate (flow), venous pressure (VP), and arterial pressure (AP) were monitored at each dialysis session hourly. Flow was significantly greater (P= 0.0001) with rTPA (mean ± SD, 237.7 ± 18.1 and 231.6 ± 12.4 mL/min for the first and second 2 months, respectively) compared with heparin (208.5 ± 10.1 and 206.9 ± 14.2 mL/min for the first and second 2 months, respectively). VP was significantly less (P= 0.0001) with rTPA (135.4 ± 8.2 and 140 ± 15.2 mm Hg for the first and second 2 months, respectively) compared with heparin (160.5 ± 16.1 and 159.2 ± 20.7 mm Hg for the first and second 2 months, respectively). AP was significantly greater (P= 0.0002) with rTPA (–113.5 ± 11.8 and –115.9 ± 12.7 mm Hg for the first and second 2 months, respectively) compared with heparin (–136.5 ± 23.3 and –134.7 ± 25.8 mm Hg for the first and second 2 months, respectively). In addition, fewer complications (flow problems, clotting, and need for fibrinolysis) occurred in the rTPA period. These results show that rTPA is superior to heparin for priming the Quinton Permcath between hemodialysis sessions and can be used as a valuable alternative to conventional heparin in selected patients.

AbstractHemodialyis with cellulose-based membranes is associated with an array of adverse reactions, including leukopenia, pulmonary sequestration and dysfunction of leukocytes. Activation of the alternative pathway of complement due to direct contact of plasma with dialysis membrane is considered to be responsible for the induction of these side effects. In recent years, evidence has accumulated that other neutrophil effector functions such as reactive oxygen intermediate production play an important role as well. Here the importance of burst formation in cooperation with other inflammatory effector functions in the mechanisms of hemodialysis-related adverse effects will be discussed.

In the present study the role of sCD23 determination in the management of renal graft recipients during the early postoperative period has been evaluated. In the majority of patients, increases in sCD23 serum levels were observed up to 3 days before the manifestation of an acute rejection (in 82% of cases) or infection episode (in 73% of cases), but no discrimination between these two clinical events was possible. This rise in sCD23 levels was significantly more pronounced than fluctuations observed in patients with uncomplicated courses or with graft dysfunction due to acute tubular necrosis. Serum levels of sCD23 were not influenced by excretory kidney function. These findings indicate that, in addition to its reflecting B‐cell function, sCD23 may also play a role in immunological processes involving T cells and/or monocytes, thus indicating a broader range of activity of this cytokine‐like molecule than has been previously assumed.

In the present study, we provide evidence that IgG2a monoclonal antibody (mAb) OKT3 is able to induce reactive oxygen intermediate (ROI) formation in polymorphonuclear leukocytes (PMN) when FcγRIIIB as well as FcγRII are bound concomitantly. Inhibition of binding to either FcγR by specific mAb (3G8 or IV. 3, respectively) resulted in complete abrogation of the OKT3‐induced respiratory burst. The effect of OKT3 was independent from its specificity and thus also from its T cell‐activating property, since nonbinding IgG2a isotype controls induced similar amounts of ROI. The IgG2b mAb BMA031 as well as the respective nonbinding isotype control were only minimally effective. With regard to the potential role of PMN activation in inflammation and tissue damage, our findings offer an extended explanation for the generation of initial adverse reactions to OKT3. Thus, one might speculate that the concerted action of cytokines liberated after its administration, what may lead to margination of leukocytes, and activation of PMN via FcγR might produce first‐dose reactions to OKT3 by directing radical‐mediated damage against the endothelium.

Cefpirome is a cephalosporin eliminated primarily by kidneys that requires dosage reduction in patients with renal failure. The pharmacokinetic parameters were studied in 10 patients with end-stage renal disease who were receiving hemodialysis. Repeated intravenous administration of 2 gm cefpirome three times a week resulted in trough levels of 12.2 ± 5.4 μg/ml and peak serum concentrations of 99.6 ± 82.1 μg/ml. After 312 hours of hemodialysis with polysulfone high-flux membranes, 62.3% ± 23.3% of cefpirome was removed. The interdialytic half-life was 9.35 ± 0.99 hours, and the intradialytic half-life was 2.02 ± 0.7 hours.

ABSTRACTThe pharmacokinetic properties of meropenem were investigated in nine critically ill patients treated by continuous venovenous hemofiltration (CVVH). All patients received one dose of 1 g of meropenem intravenously. High-flux polysulfone membranes were used as dialyzers. Meropenem levels were measured in plasma and ultrafiltrate by high-performance liquid chromatography. The total body clearance and elimination half-life were 143.7 ± 18.6 ml/min and 2.46 ± 0.41 h, respectively. The post- to prehemofiltration ratio of meropenem was 0.24 ± 0.06. Peak plasma drug concentrations measured 60 min postinfusion were 28.1 ± 2.7 μg/ml, and trough levels after 6 h of CVVH were 6.6 ± 1.5 μg/ml. The calculated total daily meropenem requirement in these patients with acute renal failure and undergoing CVVH was 2,482 ± 321 mg. Based on these data, we conclude that patients with severe infections who are undergoing CVVH can be treated effectively with 1 g of meropenem every 8 h.

Co-stimulation is a prerequisite for pathogenic activity in T cell-mediated diseases and has been demonstrated to achieve tolerance in organ-specific autoimmunity as a therapeutic target. Here, we evaluated the involvement of the tumor necrosis factor family members CD30 and OX40 in immune-complex mediated kidney disease. In vitrostimulation and proliferation studies were performed with CD4+cells from wild type and CD30/OX40 double knock-out (CD30OX40-/-) mice. In vivostudies were performed by induction of nephrotoxic serum nephritis in wild type, CD30OX40- /-, CD30-/-, OX40-/-, reconstituted Rag1-/-and C57Bl/6J mice treated with αCD30L αOX40L antibodies. CD30, OX40 and their ligands were upregulated on various leukocytes in nephrotoxic serum nephritis. CD30OX40-/-mice, but not CD30-/-or OX40-/-mice were protected from nephrotoxic serum nephritis. Similar protection was found in Rag1-/-mice injected with CD4+T cells from CD30OX40-/-mice compared to Rag1-/-mice injected with CD4+T cells from wild type mice. Furthermore, CD4+T cells deficient in CD30OX40-/-displayed decreased expression of CCR6 in vivo. CD30OX40-/-cells were fully capable of differentiating into disease mediating T helper cell subsets, but showed significantly decreased levels of proliferation in vivoand in vitrocompared to wild type cells. Blocking antibodies against CD30L and OX40L ameliorated nephrotoxic serum nephritis without affecting pan-effector or memory T cell populations. Thus, our results indicate disease promotion via CD30 and OX40 signaling due to facilitation of exaggerated T cell proliferation and migration of T helper 17 cells in nephrotoxic serum nephritis. Hence, co-stimulation blockade targeting the CD30 and OX40 signaling pathways may provide a novel therapeutic strategy in autoimmune kidney disease.

No relevant conflicts of interest to declare.

Abstract 2782