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We addressed if hyperfiltration can be assessed transcutaneously in male diabetic obese mice (BTBR ob/ob ) at 12 and 24 wk and how this relates to glomerular parameters indicative for hyperfiltration. Transcutaneous assessment of FITC-Sinistrin clearance [transcutaneous assessment of glomerular filtration rate (tGFR)] was compared against classical plasma clearance. Kidney from SV620C-01-PEI perfused mice were harvested at 24 wk and processed for tissue clearing and classical histology. Perfusion patterns of glomerular capillaries, glomerular size, and vasodilation of the afferent arterioles were assessed. Although at 12 wk FITC-Sinistrin half-life (t 1/2 ) for both tGFR and plasma clearance suggested hyperfiltration, this was not significant anymore at 24 wk. In kidneys of diabetic mice the diameter of the afferent arteriole was significantly larger and positively correlated with glomerular size. Glomerular perfusion pattern in these mice was heterogeneous ranging from non- to well-perfused glomeruli. Nonperfused glomerular areas displayed a strong periodic acid-Schiff's (PAS) positive staining. Collectively our data demonstrate that tGFR is a valid method to detect hyperfiltration. Hyperfiltration occurs early in BTBR ob/ob mice and disappears with disease progression as a consequence of a reduced filtration surface. It remains to be assessed if tGFR is also a valid method in diabetic mice with severely compromised renal function. NEW & NOTEWORTHY tGFR measurement is a relatively new method to assess kidney function in conscious rodents, which can be repeated multiple times in the same animal to track the course of the disease and/or the effect of potential treatments. Since the literature was inconclusive on the suitability of this technique in obese mice, we validated it for the first time against classical plasma clearance in the commonly used BTBR ob/ob mouse model.

The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls ( p < 0.001- p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = -0.5068, p = 0.0031; Pearson r = -0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression., Competing Interests: The authors have declared that no competing interests exist.

Background: N-acetylcysteine (NAC) has been proposed to prevent radiocontrast nephropathy in high-risk patients., Methods: The effect of single-dose and prolonged administration of NAC before application of either the ionic, high-osmolar radiocontrast agent diatrizoate sodium (DTZ) or the nonionic, low-osmolar radiocontrast agent iohexol (IOH) in a rat model combining uninephrectomy, salt depletion, and administration of indomethacin was explored. Arterial blood pressure and total, cortical, and medullary blood flow were continuously recorded in anesthetized Sprague-Dawley rats., Results: NAC had no effect on renal hemodynamics in control rats. Both DTZ and IOH induced biphasic changes in renal blood flow and cortical renal blood flux and persistently reduced medullary blood flux. Neither single-dose nor prolonged administration of NAC prevented the hemodynamic changes following administration of DTZ or IOH, respectively. Acute prophylactic administration of NAC prevented increased urinary ET excretion after injection of IOH and, to a smaller degree, of DTZ. Both an ionic, high-osmolar (DTZ) and a nonionic, low-osmolar (IOH) radiocontrast agent induce marked changes in renal hemodynamics in salt-depleted rats treated with indomethacin., Conclusions: Renal perfusion is not affected by NAC application in a model of experimental contrast nephropathy in rats. Other effects of NAC might thus account for the presumed renoprotective properties., (Copyright © 2011 S. Karger AG, Basel.)

Chronic allograft nephropathy and (cardiovascular) death with functioning graft are major causes of late graft loss. NOD2/CARD15 (nucleotide oligomerization domain-2/caspase-recruiting activating domain-15), an intracellular receptor that is part of the innate immunity repertoire, has convincingly been shown to be involved in infection/inflammation-associated diseases. Specifically, NOD2/CARD15 polymorphisms are clearly associated with Crohn's disease and transplant-associated mortality after bone marrow transplantation. The aim of this study was to clarify the relevance of NOD2/CARD15-haplotypes in kidney transplantation. Three hundred fifty-two patients receiving their first kidney transplant were genotyped for the three major NOD2/CARD15 polymorphisms, R702W, G908R, and 1007fs with subsequent reconstruction of the different haplotypes. Four different NOD2/CARD15 haplotypes were observed in our population [CG(-): 89.8%, CGC: 3.5%, CC(-): 1.6%, TG(-): 5.1%]. After stratifying the different haplotypes into diplotypes (wild type: CG(-)/CG(-), n=284, mutated haplotype, n=68) we found a significant association with all-cause and cardiovascular mortality, also after adjusting to different covariates, and (only) in univariate analysis with graft survival. In conclusion, we found different effects of the NOD2/CARD15 haplotypes on disorders, like cardiovascular and all-cause mortality,which may be considered at least in part as chronic inflammation-driven. Further studies are needed to confirm and work out the association between these disorders and the NOD2/CARD15 haplotypes.

N-acetylcysteine (NAC) has been suggested to prevent radiocontrast-induced nephropathy (RCIN) in patients with a reduced renal function. However, clinical studies have not been demonstrating this effect consistently. Also, reviews and meta-analyses dealing with the question of prevention of RCIN by NAC have been controversial. Nearly all investigators used serum creatinine as surrogate end point of their trials, and changes in serum creatinine concentrations are thought to reflect the extent of renal injury as primary outcome. In a recent study, an effect of NAC on creatinine values and estimated glomerular filtration rate without any effect on cystatin C levels has been shown in volunteers with a normal renal function. Therefore, before renal protective effects of NAC in RCIN are proposed, any direct effects of NAC on creatinine, urea, and estimated glomerular filtration rate should be addressed. In future trials, the glomerular filtration rate should preferentially be measured directly, or at least additional markers of the renal function (e.g., serum cystatin C) have to be assessed. Furthermore, additional 'hard' end points, i.e., hospital morbidity, mortality, or dialysis dependency, should be considered in the design of future studies of RCIN., (Copyright 2004 S. Karger AG, Basel)

Background/aims: The aim of this study was to examine the effects of a biocompatible and a nonbiocompatible hemodialysis membrane on the secretion of cytokines and their specific antagonists as well as on the expression of adhesion molecules., Methods: A crossover study using cuprophane (CU) and polysulfone (PS) dialyzers and measurements of serum tumor necrosis factor (TNF)-alpha, soluble TNF receptors, interleukin (IL)-6, IL-6 receptor, IL-2 receptor, IL-1 receptor antagonist and the adhesion molecules intercellular adhesion molecule 1, endothelial leukocyte adhesion molecule and vascular cell adhesion molecule was performed in 19 hemodialysis patients. 44 healthy volunteers served as controls., Results: All of the measured cytokines and cytokine antagonists as well as all adhesion molecules were significantly elevated in hemodialysis patients compared to controls. There was a significant increase in TNF-alpha during a dialysis session with a CU dialyzer, but only a moderate increase using a PS dialyzer. None of the other cytokines and adhesion molecules were changed during a dialysis session. We were also able to show an upregulation of adhesion molecules in dialysis patients., Conclusion: Our study clearly demonstrates that levels of inflammatory cytokines as well as their antagonists and adhesion molecules are elevated in patients on hemodialysis therapy. Baseline values before the start of a dialysis session did not show any differences with regard to the usage of CU or PS dialysis membranes. However, CU dialyzers led to a significantly greater stimulation of TNF-alpha during the dialysis session in comparison to PS membranes, suggesting a higher degree of bioincompatibility., (Copyright 2003 S. Karger AG, Basel)

Background: The incidence of acute renal failure (ARF) after cardiac surgery remains high, despite improvements in surgical techniques and perioperative care, and is associated with an unacceptably high mortality. The adenosine receptor antagonist theophylline has been shown to confer some benefit in experimental and clinical ARF due to ischaemia, contrast media and various nephrotoxic agents., Methods: In a double-blind, randomized, placebo-controlled trial, the effectiveness of theophylline for prevention of renal impairment after elective coronary artery bypass grafting (CABG) was evaluated. Fifty-six patients with normal renal function received a bolus of 4 mg/kg and a subsequent continuous infusion of 0.25 mg/kg/h theophylline (n=28) or isotonic saline (n=28) for up to 96 h. Serum creatinine concentrations were measured preoperatively and daily until day 5 after surgery, and the glomerular filtration rate (GFR) ([(51)Cr]EDTA-clearance) was determined preoperatively, and at days 1, 3 and 5 after surgery., Results: Serum creatinine and GFR were the same in both groups. The number of patients with increases of serum creatinine > or =0.4 mg/dl were five in the theophylline group and four in the placebo group. Volumes of infused fluid and urine volumes were not different between groups, both ranging from approximately 7.5 to 8 l during the first 24 h after surgery. The number of patients with termination of study medication due to presumed side effects was not different between placebo and theophylline groups., Conclusions: Theophylline administration for renal protection after CABG appears to be ineffective in a pilot study in well-hydrated patients. However, the statistical power of our study was not sufficient to exclude a possible protective effect of theophylline. The present study demonstrated the feasability of a larger trial with theophylline or one of the new specific adenosine A1 receptor antagonists in the setting of ARF after cardiac surgery.

Free vitamin D is the biologically active form of vitamin D. Vitamin D deficiency is associated with cardiovascular disease, the most common cause of mortality in hemodialysis patients. The goal of our current study was to investigate the relation between blood concentrations of free 25-hydroxyvitamin D with cardiovascular events in end-stage chronic kidney disease patients on hemodialysis, because this is unknown so far. We measured free vitamin D levels in 117 stable consecutive prevalent patients in September as a surrogate of vitamin D exposure during the past 6 months, and recorded the number of cardiovascular events during the previous 6 months defined as hospitalization due to heart failure, episodes of acute coronary syndrome, and stroke. Fourteen events occurred during the observation period. In patients without any cardiovascular events the free vitamin D levels were significantly higher as compared to those with cardiovascular events (patients without events: 5.68 [4.37–9.27] pg/mL; patients with events: 4.74 [3.46–5.37] pg/mL, p = 0.015). This finding remained stable after multiple regression analysis considering confounding factors such as age, time on dialysis, preexisting diabetes, hypertension, and coronary heart disease. In conclusion, our study shows that free vitamin D serum concentrations are independently associated with major cardiovascular events in chronic kidney disease patients on dialysis. [ABSTRACT FROM AUTHOR]

Low serum carnosinase (CN-1) concentrations are associated with low risk for development of diabetic nephropathy (DN) in patients with type 2 diabetes (T2D). Although CN-1 is expressed in the kidney, urinary CN-1 (CNU) excretion and its pathological relevance in patients with T2D have not been investigated to date. The present study therefore assessed the extent of CNU excretion in healthy subjects (n = 243) and in patients with T2D (n = 361) enrolled in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1) in relation to functional renal parameters. CNU was detected in a high proportion of healthy individuals, 180 (74%); median CNU excretion was 0.25 mg/24 h [(IQR 0-0.65 mg/24 h]. In patients with T2D the prevalence and extent of CNU increased in parallel with albuminuria (r = 0.59, p < 0.0001; median CNU 0.1 vs 0.2 vs 1.5 mg/24 h, p < 0.0001; prevalence of CNU 61 vs. 81 vs. 97% p < 0.05 in normo- (n = 241), micro- (n = 80) and macroalbuminuria (n = 40), respectively). Patients with estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 displayed higher median CNU excretion rates in comparison to patients with preserved eGFR (> 90 ml/min/1.73 m2) (1.36 vs 0.13 mg/24 h, p < 0.05). Backward stepwise multivariate linear regression analysis revealed albuminuria, eGFR and glycosuria to be independent factors of CNU excretion rates, all together explaining 37% of variation of CNU excretion rates (R2 = 0.37, p < 0.0001). These results show for the first time that CN-1 can be detected in urine and warrants prospective studies to assess the relevance of CNU for renal function deterioration in diabetes patients. [ABSTRACT FROM AUTHOR]

Carnosinase 1 (CN1) has been postulated to be a susceptibility factor for developing diabetic nephropathy (DN). Although its major substrate, carnosine, is beneficial in rodent models of DN, translation of these findings to humans has been hampered by high CN1 activity in human serum resulting in rapid degradation of carnosine. To overcome this hurdle, we screened a protease-directed small-molecule library for inhibitors of human recombinant CN1. We identified SAN9812 as a potent and highly selective inhibitor of CN1 activity with a Ki of 11 nM. It also inhibited CN1 activity in human serum and serum of transgenic mice-overexpressing human CN1. Subcutaneous administration of 30 mg/kg SAN9812 led to a sustained reduction in circulating CN1 activity in human CN1 transgenic (TG) mice. Simultaneous administration of carnosine and SAN9812 increased carnosine levels in plasma and kidney by up to 100-fold compared to treatment-naïve CN1-overexpressing mice. To our knowledge, this is the first study reporting on a potent and selective CN1 inhibitor with in vivo activity. SAN9812, also called carnostatine, may be used to increase renal carnosine concentration as a potential therapeutic modality for renal diseases linked to glycoxidative conditions. [ABSTRACT FROM AUTHOR]

Aims: The continuing growth of the population with end-stage renal disease (ESRD) in the past two decades has been recognized as a global health burden. In 2002, a definition of chronic kidney disease (CKD) was introduced and different categories of CKD have been reported in the general population. In this study, we examined the prevalence of CKD in primary health care in Germany. Subjects and methods: From 2004 to 2007 the prevalence of CKD was estimated in the Diabetes Cardiovascular Risk-Evaluation Targets and Essential Data for Commitment of Treatment (DETECT) study using the Simplified Modification of Diet in Renal Disease (MDRD) and the CKD Epidemiology Collaboration (CKD-EPI) equations. A sample of 4,080 subjects were analysed with detailed laboratory and comorbidity assessment from 851 primary care centres across Germany. Results: The prevalence of CKD (≤60 ml/min/1.73 m) was 27.9 % estimated by CKD-EPI equation (MDRD eGFR 36.1 %) and the prevalence of CKD increased with age and during follow-up. The overall decline in eGFR per year was −1.83 ml/min/year (CKD-EPI). Women have shown a higher decline in eGFR than men. The prevalence of CKD was highest in coronary artery disease patients, followed by diabetes mellitus and arterial hypertension. Individuals with diabetes mellitus have shown the highest progress developing CKD. Conclusion: In this representative sample of patients seeking medical advice in primary care, the prevalence of impaired kidney function was almost one third. Given the therapeutic implications, our results call for focused measures to increase the awareness of CKD in primary care. [ABSTRACT FROM AUTHOR]

Background Although it has been shown that a vagus nerve stimulation of brain dead (BD) donors leads to an improvement of renal function in recipients in an acute allograft rejection model, its influence on chronic allograft nephropathy is still unknown. In the present study, we assessed the influence of donor vagus nerve stimulation on survival, renal function and histology in a chronic allograft model. Methods Brain death was induced in Fisher rats, and electro-stimulation of the vagus nerve was applied in one group (BD + vagus) during the whole course of BD (6 h). Unstimulated BD Fisher donor rats served as controls. Allogeneic Lewis rats were used as recipients and no immunosuppressive medication was administered. Blood and urine samples were collected every second week. Banff classification was assessed from harvested allografts. Results Vagal stimulation of BD donors resulted in an improved survival of recipients. Long-term renal function was significantly better in these recipients as reflected by improved creatinine clearance. Banff classification revealed significantly reduced vasculopathy and less tubulopathy in the BD + vagus group. Conclusions In conclusion, our data demonstrate a long-lasting beneficial effect of vagus nerve stimulation in BD donors on the renal transplantation outcome. Hence, activation of the cholinergic anti-inflammatory pathway in BD donors may represent a novel therapeutic modality to reduce chronic allograft nephropathy without any side effects for the recipient. [ABSTRACT FROM PUBLISHER]

Background: Diabetes mellitus type 2 (DM2) is highly associated with increased risk for chronic kidney disease (CKD), end stage renal disease (ESRD) and cardiovascular morbidity. Epidemiological and genetic studies generate hypotheses for innovative strategies in DM2 management by unravelling novel mechanisms of diabetes complications, which is essential for future intervention trials. We have thus initiated the DIAbetes COhoRtE study (DIACORE). Methods: DIACORE is a prospective cohort study aiming to recruit 6000 patients of self-reported Caucasian ethnicity with prevalent DM2 for at least 10 years of follow-up. Study visits are performed in University-based recruiting clinics in Germany using standard operating procedures. All prevalent DM2 patients in outpatient clinics surrounding the recruiting centers are invited to participate. At baseline and at each 2-year follow-up examination, patients are subjected to a core phenotyping protocol. This includes a standardized online questionnaire and physical examination to determine incident micro- and macrovascular DM2 complications, malignancy and hospitalization, with a primary focus on renal events. Confirmatory outcome information is requested from patient records. Blood samples are obtained for a centrally analyzed standard laboratory panel and for biobanking of aliquots of serum, plasma, urine, mRNA and DNA for future scientific use. A subset of the cohort is subjected to extended phenotyping, e.g. sleep apnea screening, skin autofluorescence measurement, non-mydriatic retinal photography and non-invasive determination of arterial stiffness. Discussion: DIACORE will enable the prospective evaluation of factors involved in DM2 complication pathogenesis using high-throughput technologies in biosamples and genetic epidemiological studies. [ABSTRACT FROM AUTHOR]

Background/Aims: We identified carnosinase-1 (CN-1) as risk-factor for diabetic nephropathy (DN). Carnosine, the substrate for CN-1, supposedly is a protective factor regarding diabetic complications. In this study, we hypothesized that carnosine administration to diabetic rats might protect the kidneys from glomerular apoptosis and podocyte loss. Methods: We examined the effect of oral L-carnosine administration (1g/kg BW per day) on apoptosis, podocyte loss, oxidative stress, AGEs and hexosamine pathway in kidneys of streptozotocin-induced diabetic Wistar rats after 3 months of diabetes and treatment. Results: Hyperglycemia significantly reduced endogenous kidney carnosine levels. In parallel, podocyte numbers significantly decreased (-21% compared to non-diabetics, p<0.05), apoptotic glomerular cells numbers increased (32%, compared to non-diabetic, p<0.05) and protein levels of bax and cytochrome c increased (175% and 117%). Carnosine treatment restored carnosine kidney levels, prevented podocytes loss (+23% compared to diabetic, p<0.05), restrained glomerular apoptosis (-34% compared to diabetic; p<0.05) and reduced expression of bax and cytochrome c (-63% and -54% compared to diabetics, both p<0.05). In kidneys of all diabetic animals, levels of ROS, AGEs and GlcNAc-modified proteins were increased. Conclusion: By inhibition of pro-apoptotic signaling and independent of biochemical abnormalities, carnosine protects diabetic rat kidneys from apoptosis and podocyte loss. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to kidney injury induced by ischemia and reperfusion, the relevance of TLR4 activation to allograft injury in human kidney transplants is unknown. Here we show that TLR4 is constitutively expressed within all donor kidneys but is significantly higher in deceased-, compared with living-donor organs. Tubules from deceased- but not living-donor kidneys also stained positively for high-mobility group box-1 (HMGB1), a known endogenous TLR4 ligand. In vitro stimulation of human tubular cells with HMGB1, in a TLR4-dependent system, confirmed that HMGB1 can stimulate proinflammatory responses through TLR4. To assess the functional significance of TLR4 in human kidney transplantation, we deter- mined whether TLR4 mutations that confer diminished affinity for HMGB1 influence intragraft gene-expression profiles and immediate graft function. Compared with kidneys expressing WT alleles, kidneys with a TLR4 loss-of-function allele contained less TNFα, MCP-1, and more heme oxygenase 1 (Ho-1), and exhibited a higher rate of immediate graft function. These results represent previously undetected evidence that donor TLR4 contributes to graft inflammation and sterile injury following cold preservation and transplantation in humans. Targeting TLR4 signaling may have value in preventing or treating postischemic acute kidney injury after transplantation. [ABSTRACT FROM AUTHOR]

Living kidney donation helps to avoid or reduce the time period of dialysis and on waiting lists in patients requiring a new organ. Mini-incision donor nephrectomy (MIDN) shows to result in better clinical outcome in comparison with traditional open donor nephrectomy (ODN). This study was performed to evaluate the impact of different surgical procedures on the quality of life (QoL) in patients that underwent donor nephrectomy. Methods: The aim of the study was to detect differences in QoL assessed with the Short Form-36 Version 2 (SF-36v2) questionnaire between MIDN (n = 34) and ODN (n = 36). Furthermore, the development of QoL from prior to surgery until one yr afterwards, as well as outcomes of QoL in comparison with norm-based scores was investigated. Results: Sixty-one of 70 patients, which is 87% (MIDN: 86%, ODN: 88%) resent a whole set questionnaires. QoL was similar at all time-points (prior to surgery, one wk, three months and one yr) in both groups. A tendency of better QoL in MIDN (Bodily Pain) after one wk was detectable (p = 0.075). Physical Component Summaries (PCS) significantly decreased from prior to surgery until one wk after surgery (p = 0.001) and improved significantly until three months (MIDN: p = 0.006, ODN: p = 0.001) and also until one yr after surgery (p = 0.002). Mental Component Summaries (MCS) were stable throughout the whole investigated time period. In comparison with norm-based scores, MIDN (p = 0.005) and ODN (p = 0.001) showed significantly higher PCS prior to, lower scores one wk after (p = 0.001), similar scores three months after and better scores (MIDN: p = 0.023, ODN: 0.015) one yr after surgery. Mental Component Scores were similar in both prior to and one wk after surgery. After three months and one yr scores were significantly better in MIDN (three months: p = 0.049, one yr: p = 0.037) and ODN (three months: 0.020, one yr: 0.073). Conclusion: Quality of life after living donor nephrectomy is not influenced by the surgical technique. Nevertheless the standardized instrument of the SF-36v2 Health Survey is a useful, practicable and universally interpretable tool to gain and estimate recovery from surgical procedures in the perioperative period and its development thereafter. [ABSTRACT FROM AUTHOR]

Cyclooxygenases (COX) are known to be involved in inflammatory kidney diseases. However, there are no data available about the expression of COX-1 and only preliminary reports about the expression of COX-2 in biopsies of patients undergoing acute renal allograft rejection. We conducted this prospective study to analyze the expression, distribution, and cellular localization of COX-1 and -2 and thus to elucidate the role of COX in human kidney transplantation. One hundred forty-four biopsies were included from patients without rejection and unaltered morphology ( n = 60), with acute interstitial rejection ( n = 7), with acute vascular rejection ( n = 21), with chronic allograft nephropathy ( n = 16), without rejection but with various other lesions ( n = 40). COX-1 and -2 expression was localized in each biopsy by immunohistochemistry. We found a highly significant up-regulation of COX-1 in vessels and in infiltrating interstitial cells of patients with acute allograft rejection compared with biopsies with well-preserved tissue. Also, COX-2 expression was significantly elevated in infiltrating interstitial cells of biopsies with acute rejection. This is the first prospective study demonstrating a significant induction of both COX-1 and -2 in human allograft biopsies with acute rejection after renal transplantation. [ABSTRACT FROM AUTHOR]

Background/Aims: The role of COX-2 for renal function during renal development, for physiology and pathophysiology of renal diseases and the side effects of available COX-2 inhibitors, has gained increasing interest. We aimed therefore to review the respective role of renal COX-2. Methods: Review of relevant recent publications in the field, and in addition of in part unpublished data obtained in our laboratories. Results: COX-2 is 'constitutively' localized in the kidney i.e. in macula densa, TALH, interstitial cells, and is of utmost importance for normal renal development. Renal COX-2 is regulated by for example sodium and volume intake, angiotensin II, glucocorticoids often involving specific COX-2 promotor response elements. COX-2 derived prostanoids are required for preservation of renal blood flow and glomerular filtration especially in states of fluid deficit, they promote natriuresis, and furthermore may stimulate renin secretion during low-sodium intake/loop diuretic use. Conversely, COX-2 inhibitors decrease glomerular filtration, and renal perfusion, sometimes even causing acute renal failure. In addition, COX-2 inhibitors cause sodium retention, edema formation, cardiac failure and hypertension. The role of COX-2 derived prostanoids in renal The role of COX-2 for renal function during renal development, for physiology and pathophysiology of renal diseases and the side effects of available COX-2 inhibitors have recently gained increasing interest. This has been documented by three international meetings mainly devoted to renal effects of COX-2 held in Regensburg May 25-26, 2000, and June 7-8, 2002 [1-3] and in Marburg July 13-14, 2001, as well as by excellent reviews focusing either on basic or clinical aspects of renal COX-2 [4, 5]. The rapid increase of knowledge dealing with renal COX-2 made a summary of what is known now appear to be of interest for both clinicians and basic scientists interested in this field. [ABSTRACT FROM AUTHOR]

The intracellular free calcium concentration ([Ca2+]i) is a central regulator of renin secretion and the contractility of vascular smooth muscle cells. As [Ca2+]i results from calcium influx and calcium extrusion, we were interested in the role of the Na+/Ca2+-exchanger as an important calcium-extrusion pathway in the regulation of renin secretion. Therefore, we investigated the effects of inhibiting the Na+/Ca2+-exchanger, either by reducing the extracellular sodium concentration ([Na+]e) or using pharmacological tools, on renin secretion and vascular resistance in the isolated perfused rat kidney model. Stepwise reductions of [Na+]e led to progressive (up to sevenfold) increases in renal vascular resistance ([Na+]e 7 mM) whilst renin secretion rates were not altered significantly. Similarly, pharmacological blockade of the Na+/Ca2+-exchanger by benzamil (100 µM) or KB-R7943 (30 µM) resulted in significant vasoconstrictions without altering basal renin secretion rates. Also renin secretion that was pre-stimulated by isoproterenol (10 nM), blockade of macula densa salt transport by bumetanide (100 µM) or lowering the perfusion pressure to 40 mmHg was not attenuated by Na+/Ca2+-exchanger inhibition, although the vascular resistance increased significantly. In contrast, angiotensin II (100 pM) reduced pre-stimulated renin secretion values by 50%. The subsequent lowering of the [Na+]e however did not augment the inhibition of renin secretion, although the renal vascular resistance increased markedly. We conclude that the Na+/Ca2+-exchanger has no functional role in the regulation of [Ca2+]i in juxtaglomerular cells controlling renin secretion, whereas it markedly affects the preglomerular vascular smooth muscle cells of the renal vasculature. [ABSTRACT FROM AUTHOR]

Cyclosporine A attenuates the natriuretic action of loop diuretics by inhibition of renal COX-2 expression. Background. It is known that inhibition of cyclooxygenase (COX) impairs the renal actions of loop diuretics. Recently, we found that cyclosporine A (CsA) inhibits renal COX-2 expression. Therefore, we examined the interferences of CsA with the renal actions of loop diuretics. Method. We investigated the renal effects of furosemide administration (12 mg/day subcutaneously) in male Sprague-Dawley rats receiving in addition vehicle, CsA (15 mg/kg × day), rofecoxib (10 mg/kg × day), or a combination of both. Results. CsA, rofecoxib, and their combination lowered the furosemide-induced increase of prostaglandin E2 (PGE2) and of 6-keto prostaglandin F1α (6-keto PGF1α) excretion by 55% and by 70%. They also lowered furosemide stimulated renal excretion of sodium and water by about 65% and 60%. Basal as well as furosemide-induced stimulation of plasma renin activity (PRA) and of renal renin mRNA was further enhanced by CsA. In contrast, rofecoxib attenuated the furosemide-induced rise of PRA and of renin mRNA, both in the absence and in the presence of CsA. In addition, the increase in plasma 6-keto PGF1α levels by furosemide was further enhanced by CsA and was attenuated by rofecoxib. Conclusion. Taken together, our data suggest that CsA acts as an antinatriuretic, likely by the inhibition of COX-2–mediated renal prostanoid formation. Since the furosemide-induced stimulation of the renin system is not attenuated by CsA but by COX-2 inhibition, we speculate that extrarenal COX-2–derived prostanoids may be involved in the stimulation of the renin system by CsA and by loop diuretics. [ABSTRACT FROM AUTHOR]

The kidney-specific chloride channels CLC-K1/2 and their functionally important subunit barttin, by mediating solute transport in medulla, contribute to the osmotic gradient. We sought to determine whether they themselves are regulated by variations of osmolality. The expression of CLC-K1 and barttin mRNA and protein was significantly increased in a distal convoluted tubule cell line after a shift to high osmolar medium. This upregulation paralleled that of serum and glucocorticoid-inducible kinase 1 (SGK1), a gene known to be upregulated by cell shrinkage. Specific knockdown of SGK1 or addition of the p38 MAPK pathway inhibitor SB203580 abolished the induction of SGK1, CLC-K1 and barttin by high osmolarity suggesting that a functional MAPK pathway is required to mediate osmotic-driven induction of all three genes. The physiological relevance of our in vitro data was confirmed by water deprivation of male C57BL6 mice, which caused a significant increase in serum osmolality along with induction of CLC-K1, barttin and SGK1. Our study shows that change in intracellular volume, because of high osmolality, result in SGK1 upregulation and the subsequent increase of CLC-K1/barttin expression in distal renal tubular cells in vivo and in vitro.Kidney International (2008) 74, 1170–1177; doi:10.1038/ki.2008.312; published online 9 July 2008 [ABSTRACT FROM AUTHOR]

C-reactive protein as predictor of death in end-stage diabetic nephropathy: Role of peripheral arterial disease. Background. Patients with diabetes type 2 receiving dialysis therapy have a poor survival prognosis, mainly due to cardiovascular events. Increased C-reactive protein (CRP) levels, important in atherosclerosis, are associated with an increased risk for cardiovascular events. However, to date no study has shown the predictive value of CRP in relation to peripheral arterial disease stage. Methods. We enrolled all 445 prevalent patients with diabetic nephropathy receiving maintenance hemodialysis in 30 centers in Southern Germany from August 1999 to January 2000 for prospective study until December 2003. At inclusion, CRP and a complete clinical phenotype, including peripheral arterial disease Fontaine Stage were determined. The primary end point was all-cause mortality. Results. A total of 305 (68.5%) patients died. An increased log CRP at study inclusion was significantly associated with an increase in hazard ratio (HR) by multivariate Cox regression for all-cause (HR= 1.5, P= 0.002) and cardiac death (HR= 1.76, P= 0.02) in the entire collective. This result was applicable only to patients with peripheral arterial disease Fontaine stage IV ( N= 190, multivariate HR= 1.75 for all-cause mortality, P= 0.006). Possibly due to inadequate power, we observed only an insignificant trend for CRP as predictor of all-cause death in patients without peripheral arterial disease or with less severe forms of peripheral arterial disease (HR= 1.36, P= 0.08). Conclusion. In contrast to patients with peripheral arterial disease stage IV, patients with less severe atherosclerosis and elevated CRP are, if any, at less risk for cardiovascular mortality, possibly due to the difference in extent of affected vasculature and thus activated platelets and coagulation. Before judging the predictive value of CRP for mortality, peripheral vessel status should be determined. [ABSTRACT FROM AUTHOR]

The chemokine receptor 5Δ32 mutation is associated with increased renal survival in patients with IgA nephropathy.Background.Chemokine receptor 5 (CCR5) plays an important role in the recruitment of monocytes and T cells in inflammation and experimental studies suggest that CCR5 might be involved in the pathogenesis of IgA nephropathy. A mutation in theCCR5gene (CCR5Δ32), leading to a nonfunctional receptor, was recently described. We therefore evaluated the potential role of this mutation on renal survival in patients with IgA nephropathy.Methods.The distribution of the CCR5Δ32 genotype was determined by polymerase chain reaction (PCR) analysis in 228 patients with biopsy-proven IgA nephropathy. In 190 patients with available demographic and clinical follow-up data, the effect of the mutation on the clinical outcome was analyzed using the Log-rank test and the Cox proportional hazard model. In vitro, the influence of the CCR5Δ32 genotype on the chemotactic response of monocytes was assessed.Results.Of the 190 patients, 158 (83.2%) had a CCR5 wild-type genotype, 29 (15.3%) were heterozygous, and three patients had a homozygous CCR5Δ32 genotype (1.6%). Renal survival was significantly longer in patients with the CCR5Δ32 genotype than in the wild-type group (Log-rankP<0.001). Using the multivariate Cox proportional hazard model, the CCR5Δ32 genotype was identified as an independent factor associated with a lower risk to develop end-stage renal disease (ESRD)[hazard ratio (HR) 0.23, 95% CI 0.09 to 0.57,P= 0.002]. In vitro analysis of monocytes from CCR5Δ32 carriers showed a reduced chemotactic response to CCR5 ligands in vitro.Conclusion.Our study demonstrates an independent role of the CCR5Δ32 genotype for the clinical outcome in IgA nephropathy. In vitro experiments revealed a reduced chemotactic response of monocytes from CCR5Δ32 carriers, thus pointing out a possible pathophysiologic explanation for the beneficial effect of the CCR5Δ32 genotype. [ABSTRACT FROM AUTHOR]

Several letters to the editor, as well as the authors' reply on their article "Associations of Kidney Disease Measures With Mortality and End-Stage Renal Disease in Individuals With and Without Hypertension: A Meta-Analysis" published in the November 10, 2012 issue are presented.