Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

An archaeal compound as a driver of Parkinson’s disease pathogenesis

Patients with Parkinson’s disease (PD) exhibit differences in their gut microbiomes compared to healthy individuals. Although differences have most commonly been described in the abundances of bacterial taxa, changes to viral and archaeal populations have also been observed. Mechanistic links between gut microbes and PD pathogenesis remain elusive but could involve molecules that promote α-synuclein aggregation. Here, we show that 2-hydroxypyridine (2-HP) represents a key molecule for the pathogenesis of PD. We observe significantly elevated 2-HP levels in faecal samples from patients with PD or its prodrome, idiopathic REM sleep behaviour disorder (iRBD), compared to healthy controls. 2-HP is correlated with the archaeal species Methanobrevibacter smithii and with genes involved in methane metabolism, and it is detectable in isolate cultures of M. smithii. We demonstrate that 2-HP is selectively toxic to transgenic α-synuclein overexpressing yeast and increases α-synuclein aggregation in a yeast model as well as in human induced pluripotent stem cell derived enteric neurons. It also exacerbates PD-related motor symptoms, α-synuclein aggregation, and striatal degeneration when injected intrastriatally in transgenic mice overexpressing human α-synuclein. Our results highlight the effect of an archaeal molecule in relation to the gut-brain axis, which is critical for the diagnosis, prognosis, and treatment of PD.

Aspectos nutricionales en diálisis

Los pacientes con IRC presentan frecuentemente desnutrición, fundamentalmente una vez iniciada la diálisis, al añadirse factores propios de la técnica dialítica a los previamente existentes. La desnutrición conlleva un mayor riesgo de morbi-mortalidad global y fundamentalmente cardiovascular. Factos como la calidad de diálisis, la pérdida de nutrientes y más recientemente la existencia de una reacción inflamatoria crónica subyacente (bioincompatibilidad), contribuyen al desarrollo de desnutrición. Es preciso una intervención nutricional precoz y proporcional a la situación individual del paciente.Giltzurruneko gutxiegitasun kronikoa duten gaixoek askotan desnutrizioa jasan ohi dute, batez ere dialisia hasi ondoren, jadanik aurretik bazeuden faktoreei dialisi teknikari dagozkionak gehitzen zaizkielako. Desnutrizioak morbilitate-heriotza arrisku orokor handiagoa dakar, funtsean kardiobaskular motakoa. Dialisiaren kalitatea, elikagaien galera eta, berrikiago, azpian dagoen hantura erreakzio kronikoa (biobateragaiztasuna) bezalako faktoreek desnutrizioa garatzen laguntzen dute. Beharrezkoa da nutrizio interbentzio goiztiarra eta gaixo bakoitzaren egoeraren araberakoa.Les patients avec IRC souffrent fréquemment de malnutrition, fondamentalement parce qu'une fois la dialyse commencée, des facteurs propres à la technique dialytique s'ajoutent à ceux qui existaient auparavant. Des faits tels que la qualité de la dialyse, la perte de substances nutritives et plus récemment l'existence d'une réaction inflammatoire chronique sous-jacente (bioincompatibilité), contribuent au développement de la malnutrition. Une intervention nutritive précoce et proportionnelle à la situation individuelle du patient est nécessaire.Patients with chronic kidney insufficiency usually suffer malnutrition, fundamentally once the dialysis has been initiated, as factors pertaining to the dialysis technique are added to other previously existing factors. Malnutrition implies a higher risk of global morbidity-mortality, fundamentally of a cardiovascular character. Factors such as the quality of the dialysis, the loss of nutrients and more recently the existence of a chronic underlying inflammatory reaction (bio-incompatibility), contribute to the development of malnutrition. An early nutritional intervention that is proportional to the patient's individual situation becomes necessar

Hemodiafiltración con reinfusión endógena del ultrafiltrado (HFR): hacia una diálisis convectiva, difusiva y adsortiva

Resumen: La hemodiafiltración con reinfusión endógena del ultrafiltrado (HFR) es una técnica de diálisis caracterizada por un cartucho de resina con poder adsorbente que combina los mecanismos difusión, convección y adsorción en un solo esquema terapéutico. Después de cerca de 20 años de experiencia clínica con HFR, el presente artículo revisa la evidencia acumulada con esta técnica, planteando si la adición de la adsorción, como tercer mecanismo depurativo, debería ser el siguiente paso en el tratamiento de los pacientes en hemodiálisis. La HFR, a pesar de producir una extensa eliminación de toxinas urémicas, ha demostrado reducir la pérdida de nutrientes y componentes fisiológicos durante la sesión de diálisis frente a la hemodiafiltración on-line, mitigando el estado inflamatorio y el estrés oxidativo en esta población. Además de su facilidad de uso, la técnica también es altamente biocompatible y puede utilizarse en situaciones de un acceso vascular comprometido. En base a estas observaciones, la HFR parece ser una técnica especialmente útil para pacientes con elevada comorbilidad, incluyendo aquellos con fragilidad, desnutrición o enfermedad cardiovascular. En esta revisión, como panel de consenso de nefrólogos con experiencia clínica en HFR, examinamos la literatura existente y resumimos nuestros puntos de vista sobre cómo usar esta técnica, qué perfil de paciente puede ser más adecuado para la HFR, y cómo prescribir y monitorizar de manera práctica esta modalidad de diálisis. Abstract: Hemodiafiltration with endogenous reinfusion of the ultrafiltrate (HFR) is a dialysis technique characterized by a resin cartridge with adsorptive properties that combines the mechanisms of diffusion, convection, and adsorption in a single therapeutic regimen. After nearly 20 years of clinical experience with HFR, this article reviews the accumulated evidence with this technique, considering whether adsorption reduction, as a third purification mechanism, should be the next step in the treatment of hemodialysis patients. HFR, beyond producing an extensive removal of uremic toxins, has demonstrated to reduce the loss of nutrients and other physiological components during the dialysis session as compared to online hemodiafiltration, ameliorating the inflammatory state and oxidative stress in this population. In addition to its ease of use, the technique is also highly biocompatible and can be used in patients with a compromised vascular access. Based on these observations, HFR appears to be an especially useful therapy for high-comorbidity patients, including those with frailty, malnutrition, or cardiovascular disease. In this review, we, as a consensus panel of nephrologists experienced with HFR, survey existing literature and summarize our views on when to use this technique, which patients may be best suited for HFR, and how to effectively prescribe and monitor this modality of dialysis in daily clinical practice

Decreased excretion of nitrate and nitrite in essential hypertensives with renal vasoconstriction

Most hypertensive patients exhibit increased renal vascular resistance (RVR). This study was designed to investigate whether there exists any relationship between RVR and the production of nitric oxide (NO) in patients with essential hypertension. The study was performed in 49 non-treated patients with mild-to-moderate essential hypertension, and 20 age- and sex-matched normotensive subjects on a controlled sodium diet. Renal hemodynamics was measured in terms of the clearance of para-aminohippuric acid and inulin. Urinary excretion of nitrate and nitrite (NO3- plus NO2-) was determined as an index of NO production. As compared with normotensives, hypertensive patients exhibited higher (P < 0.001) RVR and lower (P < 0.05) urinary excretion of NO3- plus NO2-. With the 100% confidence (upper) limit of the normotensive population as a cut-off point, a subgroup of 30 hypertensives had an abnormally high RVR. The excretion of NO3- plus NO2- was lower (P < 0.005) in hypertensives with high RVR than in normotensives and the remaining hypertensives. No differences were found in the urinary excretion of NO3- plus NO2- between normotensives and hypertensives with normal RVR. Statistically significant associations were seen between diastolic blood pressure and RVR (r = 0.341, P < 0.05) and urinary excretion of NO3- plus NO2- (r = -0.387, P < 0.01) in all hypertensives. These results indicate that there is a subgroup (61%) of hypertensive patients with diminished urine levels of NO3- plus NO2- in which RVR is abnormally increased. Thus, it is suggested that in essential hypertension a diminished renal ability to produce NO by the endothelium may be involved in exaggerated renal vasoconstriction

Decreased excretion of nitrate and nitrite in essential hypertensives with renal vasoconstriction

Most hypertensive patients exhibit increased renal vascular resistance (RVR). This study was designed to investigate whether there exists any relationship between RVR and the production of nitric oxide (NO) in patients with essential hypertension. The study was performed in 49 non-treated patients with mild-to-moderate essential hypertension, and 20 age- and sex-matched normotensive subjects on a controlled sodium diet. Renal hemodynamics was measured in terms of the clearance of para-aminohippuric acid and inulin. Urinary excretion of nitrate and nitrite (NO3- plus NO2-) was determined as an index of NO production. As compared with normotensives, hypertensive patients exhibited higher (P < 0.001) RVR and lower (P < 0.05) urinary excretion of NO3- plus NO2-. With the 100% confidence (upper) limit of the normotensive population as a cut-off point, a subgroup of 30 hypertensives had an abnormally high RVR. The excretion of NO3- plus NO2- was lower (P < 0.005) in hypertensives with high RVR than in normotensives and the remaining hypertensives. No differences were found in the urinary excretion of NO3- plus NO2- between normotensives and hypertensives with normal RVR. Statistically significant associations were seen between diastolic blood pressure and RVR (r = 0.341, P < 0.05) and urinary excretion of NO3- plus NO2- (r = -0.387, P < 0.01) in all hypertensives. These results indicate that there is a subgroup (61%) of hypertensive patients with diminished urine levels of NO3- plus NO2- in which RVR is abnormally increased. Thus, it is suggested that in essential hypertension a diminished renal ability to produce NO by the endothelium may be involved in exaggerated renal vasoconstriction

Ecological niche and bet-hedging strategies for Triodia (R.Br.) seed germination

Background and Aims: Regeneration dynamics in many arid zone grass species are regulated by innate seed dormancy mechanisms and environmental cues (temperature, moisture and fire) that result in infrequent germination following rainfall. This study investigated bet-hedging strategies associated with dormancy and germination in arid zone Triodia species from north-west Australia, by assessing (1) the effects of the mechanical restriction imposed by the indehiscent floral bracts (i.e. floret) covering the seed and (2) the impact of dormancy alleviation on florets and cleaned seeds (i.e. florets removed) when germinated under water stress. Methods: The initial dormancy status and germination for six species were tested on intact florets and cleaned seeds, across temperatures (10–40 °C) with and without the fire-related stimulant karrikinolide (KAR1), and under alternating light or constant dark conditions. Physiological dormancy alleviation was assessed by wet/dry cycling florets over a period of 10 weeks, and germination was compared against untreated florets, and cleaned seeds across a water potential gradient between 0 and –1.5 MPa. Key Results: Florets restricted germination (<45 %) at all temperatures and, despite partial alleviation of physiological dormancy (wet/dry cycling for 8 weeks), intact florets germinated only at high water potentials. Cleaned seeds showed the highest germination (40–90 %) across temperatures when treated with KAR1, and germinated at much lower water potentials (–0.4 and –0.9 MPa). Triodia pungens was the most responsive to KAR1, with both seeds and florets responding, while for the remaining five species, KAR1 had a positive effect for seeds only. Conclusions: Only after seed dormancy was alleviated by removing florets and when KAR1was applied did germination under water stress increase. This suggests that seeds of these Triodia species are cued to recruit following fire and during periods of high precipitation. Climate change, driven by large shifts in rainfall patterns, is likely to impact Triodia recruitment further in arid zone grasslands

An archaeal compound as a driver of Parkinson’s disease pathogenesis

Patients with Parkinson’s disease (PD) exhibit differences in their gut microbiomes compared to healthy individuals. Although differences have most commonly been described in the abundances of bacterial taxa, changes to viral and archaeal populations have also been observed. Mechanistic links between gut microbes and PD pathogenesis remain elusive but could involve molecules that promote α-synuclein aggregation. Here, we show that 2-hydroxypyridine (2-HP) represents a key molecule for the pathogenesis of PD. We observe significantly elevated 2-HP levels in faecal samples from patients with PD or its prodrome, idiopathic REM sleep behaviour disorder (iRBD), compared to healthy controls. 2-HP is correlated with the archaeal species Methanobrevibacter smithii and with genes involved in methane metabolism, and it is detectable in isolate cultures of M. smithii. We demonstrate that 2-HP is selectively toxic to transgenic α-synuclein overexpressing yeast and increases α-synuclein aggregation in a yeast model as well as in human induced pluripotent stem cell derived enteric neurons. It also exacerbates PD-related motor symptoms, α-synuclein aggregation, and striatal degeneration when injected intrastriatally in transgenic mice overexpressing human α-synuclein. Our results highlight the effect of an archaeal molecule in relation to the gut-brain axis, which is critical for the diagnosis, prognosis, and treatment of PD