88 research outputs found
A prospective cohort study in patients with type 2 diabetes mellitus for validation of biomarkers (PROVALID) –study design and baseline characteristics
Background/Aims: The prevalence of diabetes mellitus type 2 and kidney disease in these
patients varies widely between European countries. Methods: In addition to store biosamples
the “Prospective cohort study in patients with type 2 diabetes mellitus for validation
of biomarkers” collects information on history, physical status, laboratory measurements
and medication in 4000 patients with diabetes mellitus type 2, being taken care of at the
primary level of healthcare in 5 European countries (Austria, Hungary, Netherlands, Poland
and Scotland). Next to comparing the rate of loss of eGFR between the countries, a further
objective of the PROVALID study is to determine the 5-year cumulative incidence of renal and
cardiovascular outcomes. Results: The mean age of the population recruited is 62.9±10 years,
54.6% are male and the mean BMI is 30.9±5.4 kg/m2
. Metabolic control (median HBA1c 6.8
% (6.2;7.5)) is achieved via administration of metformin in 67.4% of the patients and insulin in 30.3%. Median systolic and diastolic blood pressure at recruitment is 135 (125;146) and 80
(72;85) mmHg, 65.4% of subjects received RAAS blocking agents. Mean eGFR is 80.7±29.2
ml/min/1.73m2
and median baseline albumin/creatinine ratio 8.3 mg (IQR: 3.8 and 25.1).
Conclusion: PROVALID will provide information on incidence and progression of renal and
cardiovascular disease and therapy in patients with type 2 diabetes mellitus in different
European countries. Thus, in contrast to many other cohort studies we will be able to associate
national clinical practise pattern with outcome in this highly vulnerable patient population
Apoptosis induction and inhibition of cellular proliferation by angiotensin II: possible implication and perspectives
The
renin-angiotensin
system
plays
a
pivotal
role
in
the
regulation
of
fluid,
electrolyte
metabolism
and
blood
pressure.
Molecular
cloning
and
pharmacological
studies
have
defined
two
major
classes
of
Angiotensin
II
(Ang
II)
receptors,
designated
AT1
and
AT2.
Recently,
it
has
been
well
recognized
that
Ang
II,
beside
its
classical
physiological
actions,
is
a
profibrogenic
peptide
and
displays
characteristics
of
a
growth
factor.
The
emerging
picture
suggests
that
angiotensin
receptor
subtypes
exert
opposing
features
in
many
aspects
of
their
biological
function,
most
importantly
in
cellular
growth
and
proliferation.
Accordingly,
the
proliferative
and/or
growth-promoting
effects
of
Ang
II
are
thought
to
be
mediated
by
AT1
receptor,
whereas
the
AT2
receptor
subtype
may
have
growth-inhibitory
properties.
The
novel
finding
that
Ang
II
is
able
to
induce
apoptosis
by
AT
2
receptors
in
diverse
cell
types
is
of
great
scientific
interest,
as
recent
studies
revealed
a
role
for
apoptosis
as
a
deliberate
form
of
cell
death
in
the
pathogenesis
of
various
cardiovascular
diseases
such
as
heart
failure
and
vascular
remodeling.
Furthermore
apoptotic
cell
death
might
occur
during
the
development
of
progressive
glomerulosclerosis.
It
is
tempting
to
speculate
that
autocrine-paracrine
vasoactive
substances
such
as
Ang
II
might
regulate
these
apoptotic
processes
during
pathogenic
conditions
Determinants of distribution and prevalence of avian malaria in blue tit populations across Europe : separating host and parasite effects
Although avian malarial parasites are globally distributed, the factors that affect the geographical distribution and local prevalence of different parasite lineages across host populations or species are still poorly understood. Based on the intense screening of avian malarial parasites in nine European blue tit populations, we studied whether distribution ranges as well as local adaptation, host specialization and phylogenetic relationships can determine the observed prevalences within populations. We found that prevalence differed consistently between parasite lineages and host populations, indicating that the transmission success of parasites is lineage specific but is partly shaped by locality-specific effects. We also found that the lineage-specific estimate of prevalence was related to the distribution range of parasites: lineages found in more host populations were generally more prevalent within these populations. Additionally, parasites with high prevalence that were also widely distributed among blue tit populations were also found to infect more host species. These findings suggest that parasites reaching high local prevalence can also realize wide distribution at a global scale that can have further consequences for host specialization. Although phylogenetic relationships among parasites did not predict prevalence, we detected a close match between a tree based on the geographic distance of the host populations and the parasite phylogenetic tree, implying that neighbouring host populations shared a related parasite fauna
Validation of plasma biomarker candidates for the prediction of eGFR decline in patients with type 2 diabetes
Objective:
The decline of estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes is variable and early interventions would likely be cost effective. We elucidated the contribution of 17 plasma biomarkers to the prediction of eGFR loss on top of clinical risk factors.
Research Design and Methods:
We studied participants in PROVALID, a prospective multinational cohort study of patients with type 2 diabetes and a follow up of more than 24 months (n = 2560; baseline median eGFR 84 mL/min/1.73m2, UACR 8.1 mg/g). The 17 biomarkers were measured at baseline in 481 samples using Luminex technology and ELISA. The prediction of eGFR decline was evaluated by linear mixed modeling.
Results:
In univariable analyses nine of the 17 markers showed significant differences in median concentration between the two groups. A linear mixed model for eGFR obtained by variable selection exhibited an adjusted R2 of 62%. A panel of twelve biomarkers was selected by the procedure and accounted for 34% of the total explained variability, of which 32% were due to five markers. Each biomarker’s individual contribution to the prediction of eGFR decline on top of clinical predictors was generally low. When included into the model, baseline eGFR exhibited the largest explained variability of eGFR decline (R2 of 79%) and the contribution of each biomarker dropped below 1%.
Conclusions:
In this longitudinal study of patients with type 2 diabetes and maintained eGFR at baseline, 12 of the 17 candidate biomarkers were associated with eGFR decline, but their predictive power was low
Intra-individual variability of eGFR trajectories in early diabetic kidney disease and lack of performance of prognostic biomarkers
Studies reporting on biomarkers aiming to predict adverse renal outcomes in patients with type 2 diabetes and kidney disease (DKD) conventionally define a surrogate endpoint either as a percentage of decrease of eGFR (e.g. ≥ 30%) or an absolute decline (e.g. ≥ 5 ml/min/year). The application of those study results in clinical practise however relies on the assumption of a linear and intra-individually stable progression of DKD. We studied 860 patients of the PROVALID study and 178 of an independent population with a relatively preserved eGFR at baseline and at least 5 years of follow up. Individuals with a detrimental prognosis were identified using various thresholds of a percentage or absolute decline of eGFR after each year of follow up. Next, we determined how many of the patients met the same criteria at other points in time. Interindividual eGFR decline was highly variable but in addition intra-individual eGFR trajectories also were frequently non-linear. For example, of all subjects reaching an endpoint defined as a decrease of eGFR by ≥ 30% between baseline and 3 years of follow up, only 60.3 and 45.2% lost at least the same amount between baseline and year 4 or 5. The results were similar when only patients on stable medication or subpopulations based on baseline eGFR or albuminuria status were analyzed or an eGFR decline of ≥ 5 ml/min/1.73m2/year was used. Identification of reliable biomarkers predicting adverse prognosis is a strong clinical need given the large interindividual variability of DKD progression. However, it is conceptually challenging in early DKD because of non-linear intra-individual eGFR trajectories. As a result, the performance of a prognostic biomarker may be accurate after a specific time of follow-up in a single population only
Non-adherence to cardiometabolic medication as assessed by LC-MS/MS in urine and its association with kidney and cardiovascular outcomes in type 2 diabetes mellitus
Aims/hypothesis
Non-adherence to medication is a frequent barrier in the treatment of patients with type 2 diabetes mellitus, potentially limiting the effectiveness of evidence-based treatments. Previous studies have mostly relied on indirect adherence measures to analyse outcomes based on adherence. The aim of this study was to use LC-MS/MS in urine—a non-invasive, direct and objective measure—to assess non-adherence to cardiometabolic drugs and analyse its association with kidney and cardiovascular outcomes.
Methods
This cohort study includes 1125 participants from the PROVALID study, which follows patients with type 2 diabetes mellitus at the primary care level. Baseline urine samples were tested for 79 cardiometabolic drugs and metabolites thereof via LC-MS/MS. An individual was classified as totally adherent if markers for all drugs were detected, partially non-adherent when at least one marker for one drug was detected, and totally non-adherent if no markers for any drugs were detected. Non-adherence was then analysed in the context of cardiovascular (composite of myocardial infarction, stroke and cardiovascular death) and kidney (composite of sustained 40% decline in eGFR, sustained progression of albuminuria, kidney replacement therapy and death from kidney failure) outcomes.
Results
Of the participants, 56.3% were totally adherent, 42.0% were partially non-adherent, and 1.7% were totally non-adherent to screened cardiometabolic drugs. Adherence was highest to antiplatelet and glucose-lowering agents and lowest to lipid-lowering agents. Over a median (IQR) follow-up time of 5.10 (4.12–6.12) years, worse cardiovascular outcomes were observed with non-adherence to antiplatelet drugs (HR 10.13 [95% CI 3.06, 33.56]) and worse kidney outcomes were observed with non-adherence to antihypertensive drugs (HR 1.98 [95% CI 1.37, 2.86]).
Conclusions/interpretation
This analysis shows that non-adherence to cardiometabolic drug regimens is common in type 2 diabetes mellitus and negatively affects kidney and cardiovascular outcomes
Sustained hyperosmolarity increses TGF-beta1 and Egr-1 expression in the rat renal medulla.
BACKGROUND: Although TGF-ss and the transcription factor Egr-1 play an important role in both kidney fibrosis and in response to acute changes of renal medullary osmolarity, their role under sustained hypo- or hyperosmolar conditions has not been elucidated. We investigated the effects of chronic hypertonicity and hypotonicity on the renal medullary TGF-ss and Egr-1 expression. METHODS: Male adult Sprague Dawley rats (n = 6/group) were treated with 15 mg/day furosemide, or the rats were water restricted to 15 ml/200 g body weight per day. Control rats had free access to water and rodent chow. Kidneys were harvested after 5 days of treament. In cultured inner medullary collecting duct (IMCD) cells, osmolarity was increased from 330 mOsm to 900 mOsm over 6 days. Analyses were performed at 330, 600 and 900 mOsm. RESULTS: Urine osmolarity has not changed due to furosemide treatment but increased 2-fold after water restriction (p < 0.05). Gene expression of TGF-ss and Egr-1 increased by 1.9-fold and 7-fold in the hypertonic medulla, respectively (p < 0.05), accompanied by 6-fold and 2-fold increased c-Fos and TIMP-1 expression, respectively (p < 0.05) and positive immunostaining for TGF-ss and Egr-1 (p < 0.05). Similarly, hyperosmolarity led to overexpression of TGF-ss and Egr-1 mRNA in IMCD cells (2.5-fold and 3.5-fold increase from 330 to 900 mOsm, respectively (p < 0.05)) accompanied by significant c-Fos and c-Jun overexpressions (p < 0.01), and increased Col3a1 and Col4a1 mRNA expression. CONCLUSION: We conclude that both TGF-ss and Egr-1 are upregulated by sustained hyperosmolarity in the rat renal medulla, and it favors the expression of extracellular matrix components
Breeding Experience and the Heritability of Female Mate Choice in Collared Flycatchers
Heritability in mate preferences is assumed by models of sexual selection, and preference evolution may contribute to adaptation to changing environments. However, mate preference is difficult to measure in natural populations as detailed data on mate availability and mate sampling are usually missing. Often the only available information is the ornamentation of the actual mate. The single long-term quantitative genetic study of a wild population found low heritability in female mate ornamentation in Swedish collared flycatchers. One potentially important cause of low heritability in mate ornamentation at the population level is reduced mate preference expression among inexperienced individuals.Applying animal model analyses to 21 years of data from a Hungarian collared flycatcher population, we found that additive genetic variance was 50 percent and significant for ornament expression in males, but less than 5 percent and non-significant for mate ornamentation treated as a female trait. Female breeding experience predicted breeding date and clutch size, but mate ornamentation and its variance components were unrelated to experience. Although we detected significant area and year effects on mate ornamentation, more than 85 percent of variance in this trait remained unexplained. Moreover, the effects of area and year on mate ornamentation were also highly positively correlated between inexperienced and experienced females, thereby acting to remove difference between the two groups.The low heritability of mate ornamentation was apparently not explained by the presence of inexperienced individuals. Our results further indicate that the expression of mate ornamentation is dominated by temporal and spatial constraints and unmeasured background factors. Future studies should reduce unexplained variance or use alternative measures of mate preference. The heritability of mate preference in the wild remains a principal but unresolved question in evolutionary ecology
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