The Quest for Renal Disease Proteomic Signatures: Where Should We Look?

Renal diseases are prevalent and important. However, despite significant strides in medicine, clinical nephrology still relies on nonspecific and inadequate markers such as serum creatinine and total urine protein for monitoring and diagnosis of renal disease. In case of glomerular renal diseases, biopsy is often necessary to establish the diagnosis. With new developments in proteomics technology, numerous studies have emerged, searching for better markers of kidney disease diagnosis and/or prognosis. Blood, urine, and renal biopsy tissue have been explored as potential sources of biomarkers. Some interesting individual or multiparametric biomarkers have been found; however, none have yet been validated or entered clinical practice. This review focuses on some studies of biomarkers of glomerular renal diseases, as well as addresses the question of which sample type(s) might be most promising in preliminary discovery phases of candidate proteins.     

Should We Still Focus That Much on Cardiovascular Mortality in End Stage Renal Disease Patients? The CONvective TRAnsport STudy

Background

We studied the distribution of causes of death in the CONTRAST cohort and compared the proportion of cardiovascular deaths with other populations to answer the question whether cardiovascular mortality is still the principal cause of death in end stage renal disease. In addition, we compared patients who died from the three most common death causes. Finally, we aimed to study factors related to dialysis withdrawal.

Methods

We used data from CONTRAST, a randomized controlled trial in 714 chronic hemodialysis patients comparing the effects of online hemodiafiltration versus low-flux hemodialysis. Causes of death were adjudicated. The distribution of causes of death was compared to that of the Dutch dialysis registry and of the Dutch general population.

Results

In CONTRAST, 231 patients died on treatment. 32% died from cardiovascular disease, 22% due to infection and 23% because of dialysis withdrawal. These proportions were similar to those in the Dutch dialysis registry and the proportional cardiovascular mortality was similar to that of the Dutch general population. cardiovascular death was more common in patients <60 years. Patients who withdrew were older, had more co-morbidity and a lower mental quality of life at baseline. Patients who withdrew had much co-morbidity. 46% died within 5 days after the last dialysis session.

Conclusions

Although the absolute risk of death is much higher, the proportion of cardiovascular deaths in a prevalent end stage renal disease population is similar to that of the general population. In older hemodialysis patients cardiovascular and non-cardiovascular death risk are equally important. Particularly the registration of dialysis withdrawal deserves attention. These findings may be partly limited to the Dutch population.     

Homocysteine and Alzheimer's disease: a modifiable risk?

A hypothesis is proposed that reconciles the epidemiological observation of elevated homocysteine in Alzheimer's disease (AD) with clinical features of the disease, particularly evidence of increased oxidative stress. We propose homocysteine is involved in an iron dysregulation/oxidative stress cycle that has a central role in the pathogenesis of AD. The implications of the hypothesis and some strategies for testing it are discussed.     

What Is Cold Adaptation and How Should We Measure It?

Cold adaptation encompasses all those aspects of an organism'sphysiology that allow it to live in polar regions. With theexception of the special case of the need to avoid freezing,it is therefore merely a specific example of the more generaltemperature compensation needed by all marine organisms. Temperaturecompensation is a form of homeostasis; the extent to which agiven organism has achieved this can only be assessed in thoseprocesses which can be studied at the molecular level. Recentstudies of polar organisms, primarily fish, have indicated thatcompensation is not always perfect. Studies of complex integratedprocesses such as growth or respiration do not necessarily giveuseful information concerning cold adaptation. Growth, for example,may show compensation at the molecular level but still be slowfor other reasons (for example, resource limitation). Respirationis a particularly misleading indicator of temperature compensation,primarily because it represents the summation of many processeseach of which may react differently to temperature. The useof respiration rate to assess temperature compensation shouldbe abandoned forthwith.     

Can Genetic Pleiotropy Replicate Common Clinical Constellations of Cardiovascular Disease and Risk?

The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD) is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions from the NHGRI genome-wide association study (GWAS) catalog, in an attempt to replicate the established notion of shared pathophysiology and risk. We used pathway-based analyses to detect subsets of pleiotropic genes involved in similar biological processes. We identified 107 eligible GWAS studies related to CVD and its established comorbidities and risk factors and assigned genes that correspond to the associated signals based on their position. We found 44 positional genes shared across at least two CVD-related phenotypes that independently recreated the established relationship between the six phenotypes, but only if studies representing non-European populations were included. Seven genes revealed pleiotropy across three or more phenotypes, mostly related to lipid transport and metabolism. Yet, many genes had no relationship to each other or to genes with established functional connection. Whilst we successfully reproduced established relationships between CVD risk factors using GWAS findings, interpretation of biological pathways involved in the observed pleiotropy was limited. Further studies linking genetic variation to gene expression, as well as describing novel biological pathways will be needed to take full advantage of GWAS results.     

Plant Breeding and Drought in C3 Cereals: What Should We Breed For?

Drought is the main abiotic constraint on cereal yield. Analysingphysiological determinants of yield responses to water may helpin breeding for higher yield and stability under drought conditions.The traits to select (either for stress escape, avoidance ortolerance) and the framework where breeding for drought stressis addressed will depend on the level and timing of stress inthe targeted area. If the stress is severe, breeding under stress-freeconditions may be unsuccessful and traits that confer survivalmay become a priority. However, selecting for yield itself understress-alleviated conditions appears to produce superior cultivars,not only for optimum environments, but also for those characterizedby frequent mild and moderate stress conditions. This impliesthat broad avoidance/tolerance to mild–moderate stressesis given by constitutive traits also expressed under stress-freeconditions. In this paper, we focus on physiological traitsthat contribute to improved productivity under mild–moderatedrought. Increased crop performance may be achieved throughimprovements in water use, water-use efficiency and harvestindex. The first factor is relevant when soil water remainsavailable at maturity or when deep-rooted genotypes access waterin the soil profile that is not normally available; the twolatter conditions become more important when all available wateris exhausted by the end of the crop cycle. Independent of themechanism operating, a canopy able to use more water than anotherwould have more open stomata and therefore higher canopy temperaturedepression, and ¹³C discrimination (¹³C) in plant matter. Thesame traits would also seem to be relevant when breeding forhot, irrigated environments. Where additional water is not availableto the crop, higher water-use efficiency (WUE) appears to bean alternative strategy to improve crop performance. In thiscontext ¹³C constitutes a simple but reliable measure of WUE.However, in contrast to lines performing better because of increasedaccess to water, lines producing greater biomass due to superiorWUE will have lower ¹³C values. WUE may be modified not onlythrough a decrease in stomatal conductance, but also throughan increase in photosynthetic capacity. Harvest index is stronglyreduced by terminal drought (i.e. drought during grain filling).Thus, phenological traits increasing the relative amount ofwater used during grain filling, or adjusting the crop cycleto the seasonal pattern of rainfall may be useful. Augmentingthe contribution of carbohydrate reserves accumulated duringvegetative growth to grain filling may also be worthwhile inharsh environments. Alternatively, extending the duration ofstem elongation without changing the timing of anthesis wouldincrease the number of grains per spike and the harvest indexwithout changing the amount of water utilized by the crop.     

Measurement of Visceral Fat: Should We Include Retroperitoneal Fat?

Objective

Whether retroperitoneal fat should be included in the measurement of visceral fat remains controversial. We compared the relationships of fat areas in peritoneal, retroperitoneal, and subcutaneous compartments to metabolic syndrome, adipokines, and incident hypertension and diabetes.

Methods

We enrolled 432 adult participants (153 men and 279 women) in a community-based cohort study. Computed tomography at the umbilicus level was used to measure the fat areas.

Results

Retroperitoneal fat correlated significantly with metabolic syndrome (adjusted odds ratio (OR), 5.651, p<0.05) and the number of metabolic abnormalities (p<0.05). Retroperitoneal fat area was significantly associated with blood pressure, plasma glycemic indices, lipid profile, C-reactive protein, adiponectin (r = −0.244, P<0.05), and leptin (r = 0.323, p<0.05), but not plasma renin or aldosterone concentrations. During the 2.94±0.84 years of follow-up, 32 participants developed incident hypertension. Retroperitoneal fat area (hazard ration (HR) 1.62, p = 0.003) and peritoneal fat area (HR 1.62, p = 0.009), but not subcutaneous fat area (p = 0.14) were associated with incident hypertension. Neither retroperitoneal fat area, peritoneal fat area, nor subcutaneous fat areas was associated with incident diabetes after adjustment.

Conclusions

Retroperitoneal fat is similar to peritoneal fat, but differs from subcutaneous fat, in terms of its relationship with metabolic syndrome and incident hypertension. Retroperitoneal fat area should be included in the measurement of visceral fat for cardio-metabolic studies in human.     

Infectious Disease: Can We Avert a Lethal Flu Pandemic?

If avian flu becomes directly transmissible among humans, could we prevent a pandemic by using prophylactic antivirals? Possibly, if the virus is not too transmissible, and we react fast and efficiently.