Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury

To explore the role of the kallikrein-kinin system in relation to ischemia/reperfusion injury in the kidney, we generated mice lacking both the bradykinin B1 and B2 receptor genes (B1RB2R-null, Bdkrb1-/-/Bdkrb2-/-) by deleting the genomic region encoding the two receptors. In 4-month-old mice, blood pressures were not significantly different among B1RB2R-null, B2R-null (Bdkrb2-/-), and WT mice. After 30 min of bilateral renal artery occlusion and 24 h of reperfusion, mortality rates, renal histological and functional changes, 8-hydroxy-2'-deoxyguanosine levels in total DNA, mtDNA deletions, and the number of TUNEL-positive cells in the kidneys increased progressively in the following order (from lowest to highest): WT, B2R-null, and B1RB2R-null mice. Increases in mRNA levels of TGF-beta1, connective tissue growth factor, and endothelin-1 after ischemia/reperfusion injury were also exaggerated in the same order (from lowest to highest): WT, B2R-null, and B1RB2R-null. Thus, both the B1 and B2 bradykinin receptors play an important role in reducing DNA damage, apoptosis, morphological and functional kidney changes, and mortality during renal ischemia/reperfusion injury.     

Restrospective analysis of the renal biopsy activity in Piedmont

The Piedmont Group of Clinical Nephrology has compared the activity of 18 nephrology centers in the region Piedmont/Valle d'Aosta with regard to renal biopsy (RB). Data on the RBs performed in every nephrology unit, taking into account their entire experience (in some cases spanning more than 30 years), were analyzed. 3396 RBs were performed between 1996 and 2011. Thirty to forty percent were done in patients aged >-65 years (1568 in patients >-65 years, 29 in patients >-85 years). 598 BRs were performed in children over the last 20 years. The following contraindications to RB were considered: chronic renal failure by 8 centers (44.4%), serum creatinine (SCr >3 mg/dL) by 3 centers, longitudinal renal size <8 cm by 3 centers, and renal cortex thickness <1 cm by 2 centers. 1798 RBs were performed in patients with SCr >2 mg/dL and 275 in patients on dialysis. The percentage of RBs performed in patients with SCr >2 mg/dL ranged from 27% to 55% between centers. As regards RB in the course of acute renal failure in an ANCA-positive context, 4 centers allowed administration of corticosteroids and 8 centers administration of immunosuppressive treatment as well, even in the absence of histological data. In drug-related nephropathies, RB was considered indicated to confirm the farhypothesis of immunoallergic interstitial nephropathy either if the responsible drug was not among the traditional ones known to induce tubulo-interstitial renal disease or if the pharmacological hypothesis seemed no longer sufficient to justify the renal presentation. All centers but one were against performing RB in case of atheroembolic disease. Three centers performed RB in the intensive care unit. As regards RB in patients undergoing treatment with anticoagulants, aspirin was discontinued 5-14 days before the procedure (mean 8 days) and given again 7-15 days afterwards (mean 11.4 days). Ten centers replaced the anticoagulants with low-dose heparin, which was discontinued the day before the procedure; 11 centers asked advice from cardiologists. RB was repeated in 113 cases after a delay of 1 month to 8 years from the first RB. Our analysis shows uniformity in the approach to RB in this Italian region, with some differences compared with the literature: particular attention was paid to severely critical patients, elderly patients, and patients treated with anticoagulant drugs.     

Renal biopsy in elderly adults over 75 years of age

The results of 177 renal biopsies (RB) in patients over 75 years of age were analysed. The three most frequent histological types were: Overall: membranous nephritis (MN), minimal change disease (MCD) and IgA Nephropathy (IgAN); In nephrotic syndrome (51% of RB): MN (36%), MCD (33%) and amyloidosis (12%); In chronic renal failure without nephrotic syndrome (25% of RB): chronic interstitial nephritis (17%), benign nephrosclerosis (12%) and IgAN (12%); In acute or progressive renal failure (18% of RB): acute tubular necrosis (36%), crescentic GN (16%) and IgAN (12%). Isolated proteinuria was most frequently associated with IgAN. In only 40% of patients was the medical history relevant, and only in selected cases it allowed for accurate prediction of the histological findings. Our data favor a more liberal use of biopsy in the elderly patients.     

European Practice Database: comparative results of the year 1 pilot project

The European Practice Database (EPD) project, developed by the Research Board (RB) of EDTNA/ERCA, intended to collect data on renal practice at centre level in different European countries. During the pilot phase of the project (2002-2003), Czech Republic, Italy (North East) and England (North) participated with two thirds of all their eligible dialysis centres. Comparative results presented in this paper focus on centre size and patient characteristics, peritoneal and haemodialysis techniques, transplantation, infection control and the employment of technicians, dietitians and social workers in dialysis centres. At centre level, EPD results will enable in-depth evaluation of personal practice. International comparison of the results will stimulate further research and the development of new guidelines.     

Association of polymorphisms in IL-12/IFN-gamma pathway genes with susceptibility to pulmonary tuberculosis in Indonesia

Upon infection with mycobacteria the IL-12/IFN-gamma axis plays an essential role in the activation of cell-mediated immunity required for the elimination of pathogens. Mutations in genes of the IL-12/IFN-gamma axis are known to cause extreme susceptibility to infection with environmental mycobacteria, and subtle variations in these genes may influence susceptibility to more virulent mycobacteria. We analyzed the distribution of polymorphisms in four essential genes from the IL-12/IFN-gamma axis, IL12B, IL12RB1, IFNG and IFNGR1, in 382 pulmonary tuberculosis patients and 437 healthy controls from an endemic region in Jakarta, Indonesia. The IL12RB1 gene was sequenced in a subset of individuals. Nine known single nucleotide polymorphisms (SNPs) and two new silent variations, 135G>A and 1056C>T, were detected in IL12RB1. Six functional SNPs (-2C>T, 467G>A, 641A>G, 1312C>T, 1573G>A, 1781G>A) in IL12RB1, an IL12B promoter insertion/deletion polymorphism and CA repeats in IFNG and IFNGR1 were analyzed in the cohort. The IFNGR1 allele CA(12) (p=0.004) and genotype CA(12)/CA(12) (p=0.01; OR 0.5) were associated with protection from pulmonary tuberculosis. Interestingly, IL12B promoter heterozygosity was associated with protection from tuberculosis in BCG-vaccinated individuals (p=0.03; OR=0.6). This new finding supports the role that IL-23-of which IL12B encodes a subunit--plays in generation of memory T cells.     

The Research Board of EDTNA/ERCA: research activities and deliverables

The Research Board (RB) of EDTNA/ERCA was formed ten years ago to provide opportunities for our members to participate in collaborative research projects at a European level. It provides educational support in research methodology via workshops at conference and in articles published in the Journal. The group has completed a total of seven collaborative research projects in diverse areas of renal care and has recently developed an ambitious new project, the European Practice Database (EPD). The EPD project aims to capture the current practice of renal care professionals in European centres on a three-year repeating cycle. The results of projects are presented at conference and at international scientific meetings by invitation and abstract submission. Recommendations, guidelines or educational material are produced collaboratively with the renal multi-disciplinary community.     

Prevalence of subcutaneous, labial and rectal amyloid lesions in patients wi histologically confirmed renal amyloidosis

Our work is to evaluate the biopsies rectal (RB), cutaneous and one about the accessory salivary glands (ASGB) in the diagnosis of amyloidosis renal through 20 cases of renal amyloidosis confirmed by renal biopsy in unit of nephrology and hemodialysis in UHC lbn Rochd from February 1996 to January 1998. The mean age of our patients was 39 years old (15-80) with a male predominance of (4/1). The infectious pathology has been the most frequent cause (70%) which consisted essentially in the tuberculosis and the surinfection on dilatation of the bronchi. All the patients had nephrologic symptomatology dominated by the nephrotic syndrome. The 4 biopsies were practised in the 20 patients. Wright's reaction practised in all renal biopsy confirmed the AA nature of the amyloidosis. The amylo?d deposits were noticed in 100% of renal needle biopsy, 80% of accessory gland biopsy, 75% of rectal biopsy and in 35% of cutaneous biopsy. The association of RB and ASGB was positive in 90% of the cases. If the renal biopsy gave more positivity than the other biopsies, it caused complications that were severe sometimes. Also, the biopsy of the ASG, the simple technique is very reliable in the recognition of the amylosis and seems to be the best diagnostic test for this affection.     

Epigenetic inactivation of INK4/CDK/RB cell cycle pathway in acute leukemias

Dysregulation of cell cycle is important in oncogenesis. We analyzed the inactivation of the INK4 family CKI/CDK/RB pathway by gene promoter hypermethylation in leukemogenesis. The methylation-specific polymerase chain reaction (MSP) with primers for methylated (M-MSP) and unmethylated (U-MSP) alleles of the p15, p16, p18, and RB genes was used to study five leukemic cell lines, 50 acute myeloid leukemia (AML) and 25 acute lymphoblastic leukemia (ALL) samples. None of the leukemic cell lines showed p18 and RB methylation. p15 was methylated in Raji, while p16 was methylated in U937 and Raji. In NB4 and Jurkat, both alleles of p15 and p16 appeared to be deleted. At diagnosis, p15 methylation occurred in 29 (58%) AML patients, and 10 (40.0%) ALL patients. p16 methylation occurred in two (4%) AML and two (8%) ALL patients. Only one each of AML and ALL patients had concurrent p15 and p16 methylation. None of the patients had methylation of p18 or RB. In AML, p15 methylation was associated with M2 subtype (p=0.018). Patients with and without p15 methylation had similar complete remission (CR) rates and projected 5-year overall survival (OS) or disease-free survival (DFS). Therefore, methylation inactivation of the INK4/CDK/RB pathway in leukemia involved primarily p15 and occasionally p16, but not p18 or RB. In AML, p15 gene methylation was associated with the M2 subtype, but was not prognostic for CR, OS, or DFS.     

Association of IL12RB1 polymorphisms with pulmonary tuberculosis in adults in Morocco

Five disease-causing genes, including the IL12RB1 gene that encodes the beta 1 chain of the receptor for interleukin (IL)-12 (IL-12R beta 1), are known to be associated with the syndrome of Mendelian susceptibility to mycobacterial diseases. Some IL-12R beta 1-deficient patients present with tuberculosis as the only clinical phenotype. A comprehensive genetic study of IL12RB1 was conducted among 101 Moroccan families, including 157 offspring (age, >15 years) who had culture-positive pulmonary tuberculosis (PTB). The promoter, exons, and flanking intron regions of IL12RB1 in 40 randomly selected patients with PTB were entirely sequenced, leading to the detection of 19 variants (including 10 novel mutations). Blood cells obtained from individuals who were homozygous for any of the 13 most common variants responded to IL-12, indicating that these polymorphisms were not loss-of-function mutations. By use of a family-based study, 2 promoter polymorphisms that were in strong linkage disequilibrium were found to be associated with PTB, especially -2C-->T (odds ratio for CT or TT vs. CC, 2.69 [95% confidence interval, 1.19-6.09]). This result suggests that IL12RB1 polymorphisms might influence the risk of development of PTB in adults.     

Vasculorenal accidents in pregnancy. Prognostic value of renal biopsy

Our study is an attempt to determine whether, after a vasculo-renal accident (VRA) in pregnancy, renal biopsy (RB) is of interest to determining the outcome specially of blood pressure. Starting from the 201 RB we systematically performed in such patients we may conclude: first, the onset of clinical and biological troubles do not allow to postulate the existing kidney lesions. Minimal changes observed in 31 women appeared early 9 times and during the last trimester 22 times. Most of the cases observed were preeclampsia (n = 108). The clinical or biological troubles were observed 44 times within the first months of the pregnancy and in 64 patients at the end of it. A specific group isolated concerns predominant vascular lesions (n = 44). Forward troubles were observed 16 times and 28 times during the third trimester. Second: a follow up has been possible for 1 to 5 years in 145 patients. A permanent hypertension occurred out of the 80 preeclamptic women, meanwhile among the 40 women with predominant vascular lesions, 60 p. 100 developed a permanent hypertension. Thus RB provides interesting data on renal lesions revealing sometimes (n = 18) a specific nephropathy (most of them were a glomerulopathy). Furthermore predominant vascular lesions suggest hypertension to recur in later pregnancy or become permanent.     

A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes

Aims/hypothesis

The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes.

Methods

We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) inhibitor and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in rat models of the metabolic syndrome—the obese spontaneously hypertensive (SHROB) rat and the obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat. In SHROB rats we studied the ability of RB394 to prevent metabolic syndrome phenotypes, while in ZSF1 obese diabetic rats we compared RB394 with the ACE inhibitor enalapril in the treatment of type 2 diabetes and associated comorbid conditions. RB394 (10 mg/kg daily) and enalapril (10 mg/kg daily) were administered orally for 8 weeks.

Results

RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA_1c, improved glucose tolerance, reduced blood pressure and improved lipid profiles in obese ZSF1 rats. A reduction in liver fibrosis and hepatosteatosis was evident in RB394-treated obese ZSF1 rats. Unlike RB394, enalapril did not demonstrate any positive effects in relation to diabetes, hyperlipidaemia or liver dysfunction in obese ZSF1 rats. RB394 ameliorated diabetic nephropathy by reducing renal interstitial fibrosis and renal tubular and glomerular injury in obese diabetic ZSF1 rats. Intriguingly, enalapril demonstrated a weaker action against diabetic nephropathy in obese ZSF1 rats.

Conclusions/interpretation

These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.

     

Association and clonal distribution of trisomy 12 and 13q14 deletions in chronic lymphocytic leukaemia

The coexistence of trisomy 12 and deletions of chromosome 13 (13q12-q32) has rarely been observed in chronic lymphocytic leukaemia (CLL). Fluorescence in situ hybridization (FISH) performed on 600 consecutive CLL patients revealed the association of trisomy 12 and 13q14 deletion, of at least one of the three markers analysed (RB1, D13S319 and D13S25), in 55 cases (9% of 600 and 46% of 120 trisomy 12 cases). Trisomy 12 and isolated RB1 deletion were seen in 14/120 cases, trisomy 12 and D13S319/D13S25 deletion with diploid RB1 in 19/118, and trisomy 12 and deletion encompassing the three 13q markers studied in 22/118 cases. The heterogenous distribution of trisomy 12 and 13q deletions within the neoplastic B cells suggests that they are secondary rather than primary events in CLL leukaemogenesis.     

血小板活化因子在急性胰腺炎大鼠并发肾损伤中病理生理作用

目的:本文旨在观察血小板活化因子在急性出血坏死性胰腺炎(AHNP)大鼠肾损伤发生中作用。方法:159只SD大鼠随机分三组:假手术组、AHNP非治疗组和AHNP BN(52021)治疗祖。采用胰管内注入5％牛磺胆酸钠溶液诱导大鼠AHNP,应用~(86)Rb组织摄取法测定肾脏相对血流量及组织灌注量,并测定血小板聚集率(PAgR)。结果:与非治疗组相比较,BN(52021)治疗组肾脏相对血流量、组织灌注量显著提高;PAgR下降;肾脏病理损害减轻。结论:血小板活化因子参与了急性出血坏死性胰腺炎大鼠肾损害的发生。     

Association between HLA and Red Cell Antigens

The variation in the reactivity of red blood cells (RBC) with HLA haemagglutinins was studied, and the influence of some variable factors evaluated. A comparison of the HLA reactivity of RBC with automated and manual methods, showed the superiority of the Auto-Analyzer technique. The similarity in the nature and behaviour of HLA RBC antigens and the related Chido and Rg antigens is discussed. Inhibition/adsorption experiments were performed, and the results did not support the theory that HLA antigens on RBC originate from serum-HLA-active substance. The strength of the HLA reactivity of RBC from a donor was shown to vary from time to time without evidence of clinical disease.     

Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase by the orally active inhibitor mixanpril: a potential therapeutic approach in hypertension.

In the treatment of cardiovascular disease, it could be of therapeutic interest to associate the hypotensive effects due to the inhibition of angiotensin II formation with the diuretic and natriuretic responses induced by the protection of the endogenous atrial natriuretic peptide (ANP). Investigation of this hypothesis requires an orally active compound able to simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), which is involved in renal ANP metabolism. Such compounds have been rationally designed by taking into account the structural characteristics of the active site of both peptidases. Among them, RB 105, N-[(2S,3R)-2-mercaptomethyl-1-oxo-3-phenylbutyl]-(S)-alanine, inhibited NEP and ACE with Ki values of 1.7 +/- 0.3 nM and 4.2 +/- 0.5 nM, respectively. Intravenous infusion of RB 105 in conscious spontaneously hypertensive rats prevented the pressor response to exogenous angiotensin I and potentiated the natriuretic response to ANP. Infusion of RB 105, at 2.5, 5, 10, 25, and 50 mg/kg per hr decreased blood pressure dose-dependently in conscious catheterized spontaneously hypertensive rats and increased diuresis and natriuresis. Infusion of RB 105 as a bolus of 25 mg/kg followed by 25 mg/kg per hr similarly decreased blood pressure and increased natriuresis in three different models of hypertension (renovascular, deoxycorticosterone acetate-salt, and spontaneously hypertensive rats). Mixanpril, a lipophilic prodrug of RB 105 (ED50 values when given orally to mice, 0.7 mg/kg for NEP; 7 mg/kg for ACE), elicited dose-dependent hypotensive effects of long duration in spontaneously hypertensive rats after oral administration [-37 mmHg for 50 mg/kg twice a day (1 mmHg = 133 Pa) and is therefore the first dual NEP/ACE inhibitor potentially useful for clinical investigations.     

A randomized, partially blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system in patients with acute coronary syndromes: design and rationale of the RADAR Phase IIb trial

Anticoagulants are the cornerstone of current acute coronary syndrome (ACS) therapy; however, anticoagulation regimens that aggressively reduce ischemic events are almost uniformly associated with more bleeding. REG1, an anticoagulation system, consists of RB006 (pegnivacogin), an RNA oligonucleotide factor IXa inhibitor, and RB007 (anivamersen), its complementary controlling agent. Phase I and IIa studies defined predictable relationships between doses of RB006, RB007, and degree of antifactor IX activity. The efficacy and safety of REG1 for the treatment of patients with ACS managed invasively and the safety of reversing RB006 with RB007 after cardiac catheterization are unknown. Randomized, partially-blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system compared to unfractionated heparin or low molecular heparin in subjects with acute coronary syndrome (RADAR) is designed to assess both the efficacy of the anticoagulant RB006 and the safety of a range of levels of RB006 reversal with RB007. The objectives of RADAR are (1) to determine the safety of a range of levels of RB006 reversal with RB007 after catheterization, (2) to confirm whether a dose of 1 mg/kg RB006 results in near-complete inhibition of factor IXa in patients with ACS, and (3) to assess the efficacy of RB006 as an anticoagulant in patients with ACS undergoing percutaneous coronary intervention.     

Levels of retinoblastoma protein expression in newly diagnosed acute myelogenous leukemia

The relationship between the level of retinoblastoma protein (RB) expression and the survival of 113 newly diagnosed acute myelogenous leukemia (AML) patients was studied. Western blotting was used to determine the level of RB protein present in peripheral blood leukemia cells and results were confirmed in 26 patients by immunohistochemistry. The leukemic cells from 22/113 AML patients (19%) contained RB protein at levels that were equal to or less than the level of RB observed in the mononuclear cell fraction of peripheral blood from normal individuals (Low RB). Levels of RB greater than that of normal blood (Elevated RB) were seen in 91 patients (81%). The median survival of patients with low RB was significantly shorter than that seen in patients with elevated RB, 12 weeks versus 40 weeks (P = .02). Remission induction frequency was 36% in low RB patients compared with 68% in AML patients with elevated RB (P = .01). Multivariate analysis showed that low RB protein level was an independent prognostic factor predictive or poor survival after allowing for other known prognostic factors. These data suggest that a low level of the RB protein at the time of diagnosis is associated with shortened survival in AML patients because of inferior response to conventional therapy. Monitoring of the RB level could identify a subgroup of AML patients with an extremely poor prognosis when treated with chemotherapy alone, who would be eligible for alternative therapeutic strategies.     

Patient phenotype profiling in heart failure with preserved ejection fraction to guide therapeutic decision making. A scientific statement of the Heart Failure Association,the European Heart Rhythm Association of the European Society of Cardiology,and the European Society of Hypertension

Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium–glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype-based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence-based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy.