Aliskiren and the dual complement inhibition concept

In this issue of Clinical Kidney Journal, Plasse et al. report on the use of high-dose aliskiren as an adjunct therapy in a patient treated with eculizumab for haemolytic uraemic syndrome (HUS). This follows the recent description of the complement factor 3 (C3) activating activity of the enzyme renin and the successful therapeutic use of the direct renin inhibitor aliskiren in three cases of C3 glomerulopathy/dense deposit disease. We discuss the potential clinical and pathophysiological implications of these reports on nephropathies linked to complement, from HUS to C3 glomerulopathy to immunoglobulin A nephropathy as well as the concept of dual complement inhibition for kidney diseaseResearch by the authors was supported by FIS CP14/00133, PI16/ 02057, PI18/01366, PI19/00588, PI19/00815, DTS18/00032, ERAPerMed- JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009), Fondos FEDER, FRIAT, Sociedad Española de Nefrología, Comunidad de Madrid B2017/BMD-3686 CIFRA2-CM

MYH9-related disease : it does exist, may be more frequent than you think and requires specific therapy

Altres ajuts: Sources of support: FIS/Fondos FEDER (REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM. Salary support: ISCIII Rio Hortega to M.V.P.-G.In this issue of ckj, Tabibzadeh et al. report one of the largest series of patients with MYH9 mutations and kidney disease. The cardinal manifestation of MYH9-related disease is thrombocytopenia with giant platelets. The population frequency of pathogenic MYH9 mutations may be at least 1 in 20 000. The literature abounds in misdiagnosed cases treated for idiopathic thrombocytopenic purpura with immune suppressants and even splenectomy. Additional manifestations include neurosensorial deafness and proteinuric and hematuric progressive kidney disease (at some point, it was called Alport syndrome with macrothrombocytopenia), leucocyte inclusions, cataracts and liver enzyme abnormalities, resulting in different names for different manifestation combinations (MATINS, May-Hegglin anomaly, Fechtner, Epstein and Sebastian syndromes, and deafness AD 17). The penetrance and severity of kidney disease are very variable, which may obscure the autosomal dominant inheritance. A correct diagnosis will both preclude unnecessary and potentially dangerous therapeutic interventions and allow genetic counselling and adequate treatment. Morphological erythrocyte, granulocyte and platelet abnormalities may allow the future development of high-throughput screening techniques adapted to clinical peripheral blood flow cytometers

Phosphate, microbiota and ckd

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventu-ally, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed. Recent data have identified a potential role of the gut microbiota in mineral bone disorders. Thus, parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched in the Th17 cell-inducing taxa segmented filamentous bacteria. Furthermore, the microbiota was required for PTH to stimulate bone formation and increase bone mass, and this was dependent on bacterial production of the short-chain fatty acid butyrate. We review current knowledge on the relationship between phosphate, microbiota and CKD-MBD. Topics include microbial bioactive compounds of special interest in CKD, the impact of dietary phosphate and phosphate binders on the gut microbiota, the modulation of CKD-MBD by the microbiota and the potential therapeutic use of microbiota to treat CKD-MBD through the clinical translation of concepts from other fields of science such as the optimization of phosphorus utilization and the use of phosphate-accumulating organisms.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 860329, FIS/Fondos FEDER (PI18/01366, PI20/00744, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071, ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-C

Abeta from APP/PS1 Alzheimer mice hippocampus induced synaptic damage in vivo and in vitro

We aim to investigate the effects of Abeta from young APP/PS1 mouse model of Alzheimer`s disease (AD) on the synaptic integrity, as the loss of synapses strongly correlates with cognitive deficits in patients. Plaque-associated abnormal swellings of neuronal processes represent the first indicator of disease development and might compromise neuronal integrity and synaptic function. Here, we examined the synaptic nature of dystrophic neurites, and the reduction of both synapses and vesicles density in presynaptic terminals along with the progressive accumulation of autophagic structures and Abeta within hippocampal synaptosomes during the aging. We analysed both the direct synaptotoxic effect of plaques in the hippocampus of this model and also the repercussion of the soluble (S1) fraction in neuronal cultures. Hippocampal synapses were observed under both optic and electron microscopy. Synapses and vesicle density were quantified in periplaque and control (plaque-free) areas by electron microscopy. Primary neuronal cultures were incubated for 48 hours with 6-month-old APP/PS1 and wild-type S1 fractions. In addition, Abeta immunodepletion was carried out with different anti-Abeta antibodies and the levels of synaptic proteins were measured by Western-blot (WB). Both synapse number and synaptic-vesicles density were significantly decreased in young APP/PS1 mice, close to the Abeta deposits, in several hippocampal layers. Importantly, there was a correlation between the synaptic deficiencies and the distance to plaques, which presented oligomeric forms in their periphery. Some presynaptic elements were abnormally swollen, containing autophagic vesicles. In addition, we found by WB a decrease in several hippocampal synaptic markers as early as 4 months of age in this model, and also in neuronal cultures incubated with S1 fractions. Significantly, the neuronal reduction in VGLUT was reversed after Abeta immunodepletion. Plaque-associated oligomeric Abeta induced an early deleterious effect on synapses that correlates with memory deficits in young APP/PS1 mice. Moreover, soluble Abeta derived from these transgenic mice reduced synaptic protein content in vitro, which was restored after immunodepletion of Abeta species. Therefore, this model produced synaptotoxic Abeta and may represent a valuable tool to test novel treatments to protect synapses as an early therapeutic approach for AD.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Association of kidney fibrosis with urinary peptides: a path towards non-invasive liquid biopsies?

Chronic kidney disease (CKD) is a prevalent cause of morbidity and mortality worldwide. A hallmark of CKD progression is renal fibrosis characterized by excessive accumulation of extracellular matrix (ECM) proteins. In this study, we aimed to investigate the correlation of the urinary proteome classifier CKD273 and individual urinary peptides with the degree of fibrosis. In total, 42 kidney biopsies and urine samples were examined. The percentage of fibrosis per total tissue area was assessed in Masson trichrome stained kidney tissues. The urinary proteome was analysed by capillary electrophoresis coupled to mass spectrometry. CKD273 displayed a significant and positive correlation with the degree of fibrosis (Rho = 0.430, P = 0.0044), while the routinely used parameters (glomerular filtration rate, urine albumin-to-creatinine ratio and urine protein-to-creatinine ratio) did not (Rho = -0.222; -0.137; -0.070 and P = 0.16; 0.39; 0.66, respectively). We identified seven fibrosis-associated peptides displaying a significant and negative correlation with the degree of fibrosis. All peptides were collagen fragments, suggesting that these may be causally related to the observed accumulation of ECM in the kidneys. CKD273 and specific peptides are significantly associated with kidney fibrosis; such an association could not be detected by other biomarkers for CKD. These non-invasive fibrosis-related biomarkers can potentially be implemented in future trials

Relationship between olive oil consumption and ankle-brachial pressure index in a population at high cardiovascular risk

The aim of this study was to ascertain the association between the consumption of different categories of edible olive oils (virgin olive oils and olive oil) and olive pomace oil and ankle-brachial pressure index (ABI) in participants in the PREDIMED-Plus study, a trial of lifestyle modification for weight and cardiovascular event reduction in individuals with overweight/obesity harboring the metabolic syndrome. Methods: We performed a cross-sectional analysis of the PREDIMED-Plus trial. Consumption of any category of olive oil and olive pomace oil was assessed through a validated food-frequency questionnaire. Multivariable linear regression models were fitted to assess associations between olive oil consumption and ABI. Additionally, ABI ≤1 was considered as the outcome in logistic models with different categories of olive oil and olive pomace oil as exposure. Results: Among 4330 participants, the highest quintile of total olive oil consumption (sum of all categories of olive oil and olive pomace oil) was associated with higher mean values of ABI (beta coefficient: 0.014, 95% confidence interval [CI]: 0.002, 0.027) (p for trend = 0.010). Logistic models comparing the consumption of different categories of olive oils, olive pomace oil and ABI ≤1 values revealed an inverse association between virgin olive oils consumption and the likelihood of a low ABI (odds ratio [OR] 0.73, 95% CI [0.56, 0.97]), while consumption of olive pomace oil was positively associated with a low ABI (OR 1.22 95% CI [1.00, 1.48]). Conclusions: In a Mediterranean population at high cardiovascular risk, total olive oil consumption was associated with a higher mean ABI. These results suggest that olive oil consumption may be beneficial for peripheral artery disease prevention, but longitudinal studies are needed

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100 years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good