26 research outputs found
Inverse correlation of intact PTH, oxidized PTH as well as non-oxidized PTH with 25-hydroxyvitamin D3 in kidney transplant recipients
Background
25-hydroxyvitamin D (25(OH)D) and potentially also 1,25-dihydroxyvitamin D (1,25(OH)2D) inhibits the synthesis of parathyroid hormone (PTH) in the chief cells of the parathyroid gland. Clinical studies showing a negative correlation between (25(OH)D and PTH are in good agreement with these findings in basic science studies. However, PTH was measured in these studies with the currently clinically used 2nd or 3rd generation intact PTH (iPTH) assay systems. iPTH assays cannot distinguish between oxidized forms of PTH and non-oxidized PTH. Oxidized forms of PTH are the by far most abundant form of PTH in the circulation of patients with impaired kidney function. Oxidation of PTH causes a loss of function of PTH. Given that the clinical studies done so far were performed with an PTH assay systems that mainly detect oxidized forms of PTH, the real relationship between bioactive non-oxidized PTH and 25(OH)D as well as 1,25(OH)2D is still unknown.
Methods
To address this topic, we compared for the first time the relationship between 25(OH)D as well as 1,25(OH)2D and iPTH, oxPTH as well as fully bioactive n-oxPTH in 531 stable kidney transplant recipients in the central clinical laboratories of the Charité. Samples were assessed either directly (iPTH) or after oxPTH (n-oxPTH) was removed using a column that used anti-human oxPTH monoclonal antibodies, a monoclonal rat/mouse parathyroid hormone antibody (MAB) was immobilized onto a column with 500 liters of plasma samples. Spearman correlation analysis and Multivariate linear regression were used to evaluate the correlations between the variables.
Results
There was an inverse correlation between 25(OH)D and all forms of PTH, including oxPTH (iPTH: r=-0.197, p<0.0001; oxPTH: r=-0.203, p<0.0001; n-oxPTH: r=-0.146, p=0.001). No significant correlation was observed between 1,25(OH)2D and all forms of PTH. Multiple linear regression analysis considering age, PTH (iPTH, oxPTH and n-oxPTH), serum calcium, serum phosphor, serum creatinine, fibroblast growth factor 23 (FGF23), osteoprotegerin (OPG), albumin, and sclerostin as confounding factors confirmed these findings. Subgroup analysis showed that our results are not affected by sex and age.
Conclusion
In our study, all forms of PTH are inversely correlated with 25-hydroxyvitamin D (25(OH)D). This finding would be in line with an inhibition of the synthesis of all forms of PTH (bioactive n-oxPTH and oxidized forms of PTH with minor or no bioactivity) in the chief cells of the parathyroid glad
Cardio-renal protection of riociguat (BAY 63-2521) in low- and high-renin models of hypertension
Renal Effects of the Novel Selective Adenosine A1 Receptor Blocker SLV329 in Experimental Liver Cirrhosis in Rats
Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A1 receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A1 receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (â36.5%, p<0.05), especially in those receiving furosemide (â41.9%, p<0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17% vs. 54%, p<0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A1 receptor antagonists are clinically beneficial at different stages of liver cirrhosis
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Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner
ABSTRACT Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood
Pathophysiology of vasoactive mediators Endothelin-1 and NO and their interaction in animal models
In dieser kumulativen Arbeit werden insgesamt 7 Studien des Autors zum Thema
âPathophysiologie der vasoaktiven Mediatoren Endothelin-1 und NO sowie ihrer
Interaktion am Tiermodellâ vorgestellt. Beide Systeme sind im GefĂ€Ăendothel
aktiv und bekanntermaĂen beteiligt am Vasotonus, sowie an Inflammations- und
FibrosevorgĂ€ngen. Sie wirken als Antagonisten und man nimmt an, dass sie ĂŒber
einen Regelkreis mit negativer RĂŒckkoppelung verbunden sind, wobei Endothelin
via ETB-Rezeptor die Bildung von NO fördert, welches dann die Expression von
Endothelin inhibiert. Ziel der vorliegenden Arbeit ist es, die
pathophysiologische Bedeutung der Systeme, sowie die ihrer Interaktion in vivo
in verschiedenen Tiermodellen zu untersuchen: Wir konnten im Schweinemodell
des akuten Lungenversagens durch inhalative Applikation eines ETA âRezeptors-
Antagonisten den Gasaustausch verbessern, die MortalitÀt senken und die
pulmonale Inflammationsreaktion supprimieren. Wir konnten keinen Effekt einer
Defizienz des ETB âRezeptors im Tiermodell der Peritonealfibrose bei
Peritonealdialyse nachweisen. Wir konnten durch orale Applikation eines sGC-
Aktivators im hypertensiven, niereninsuffizienten Tiermodell (5/6
Nephrektomie) den Blutdruck signifikant senken, den histologisch
nachgewiesenen kardiorenalen Endorganschaden und die weitere Progression der
Niereninsuffizienz verlangsamen. Wir zeigten an einem eigens zu diesem Zweck
etablierten und validierten Tiermodell, dass eine Blockade der NO-Synthethasen
in der Tat zu einer deutlichen Hochregulation der renalen ET-Expression fĂŒhrt,
welche interessanterweise gewebespezifisch unterschiedlich moduliert war. Mit
dieser Studie ist eine Interaktion ET-NO-Interaktion im Sinne des
beschriebenen Regelkreises in der Niere in vivo bewiesen. Wir konnten an zwei
zu diesem Zweck etablierten transgenen Mausmodellen (ET+/+iNOS-/- und
ET+/+eNOS-/-) zeigen, dass die fĂŒr den ET-NO-Regelkreis pathophysiologisch
relevante RĂŒckkoppelung ĂŒber die eNOS mediiert wird, da das diesbezĂŒgliche
Tiermodell im Sinne der Hypothese den erwarteten PhĂ€notyp âgekennzeichnet
durch Hypertension, histologische GefĂ€ĂverĂ€nderungen und eine deutliche
vaskulÀre Hochregulation des Endothelinsystems- zeigt. Jedoch ist auch die
Interaktion von ET und iNOS pathophysiologisch relevant, da ein Fehlen der
iNOS beim ET-ĂŒberexprimierenden Tier zu einer AbschwĂ€chung der ET-induzierten
HerzverĂ€nderungen fĂŒhrt. Wir demonstrierten weiterhin, dass eine Blockade des
NO-Systems bei Endothelin-ĂŒberexprimierenden MĂ€usen zu einem inflammatorischen
und fibrotischen PhĂ€notyp der Lunge fĂŒhrt. Dieser Effekt tritt weder beim
Wildtyp, noch bei ET-ĂŒberexprimierenden MĂ€usen mit gleichzeitiger ET-
Rezeptorblockade auf. Dies verweist auf die ET-NO-Imbalance als wesentlichsten
pathophysiologischen Auslöser des pulmonalen Gewebeschadens in unserem Modell.
Zusammenfassend lÀsst sich festhalten, dass das Endothelinsystem im Tiermodell
des Lungenversagens eine wesentliche Rolle spielt, eine therapeutische
Nutzbarkeit ist naheliegend und sollte in klinischen Studien evaluiert werden.
Die Abwesenheit eines nachweisbaren Effektes einer ETB âRezeptordefizienz auf
die Peritonealfibrose bei Peritonealdialyse in unserer Arbeit verlangt nach
analogen Studien mit ETA âAntagonisten, bevor ein endgĂŒltiges Urteil ĂŒber die
pathophysiologische Bedeutung des ET-Systems in diesem Krankheitsbild gefÀllt
werden kann. Mit Blick auf das NO/cGMP-System legen unsere Ergebnisse einen
Nutzen von sGC-agonistischen Wirkprinzipien in hypertensiologisch-
kardiovaskulÀren Indikationsgebieten nahe; dies ist bereits Gegenstand
aktueller klinischer Studien. Wir konnten in vivo fĂŒr das renale Gewebe die
ET-NO-Interaktion im Sinne eines negativ rĂŒckgekoppelten Systems beweisen.
Dass dieser Interaktion pathophysiologisch mehr Bedeutung zukommt als der
AktivitÀt des Einzelsystems konnten wir an der Modulation des pulmonalen
PhĂ€notyps der ET-ĂŒberexprimierenden MĂ€use demonstrieren. Zwei Mausmodelle mit
einer fixierten Dysbalance zwischen ET und NO-System wurden daraufhin
beschrieben (ET+/+iNOS-/- und ET+/+eNOS-/-), wobei dem ET+/+eNOS-/- Modell im
Sinne des beschriebenen ET-NO-Regelkreises die gröĂere pathophysiologische
Bedeutung zukommt.This work contains a summary of 7 studies that the author has conducted in
order to elucidate the pathophysiological impact of the endothelin- and NO
/cGMP-system and their interaction in vivo. Both systems are known to be
located in vascular endothelium, to regulate vasotonus and contribute to
inflammatory/fibrotic tissue damage. They act as antagonists and it is
generally assumed that they form a negatively coupled feedback loop thereby
endothelin stimulating NO-release and in turn NO inhibiting ET-1 expression.
The objective of this work is to investigate the pathophysiological impact of
both systems and their interaction in various animal models: We demonstrated
in a pig model of acute lung injury better gas exchange, lower mortality and
suppression of pulmonary inflammation after inhalative application of an ETA-
receptor-antagonist. We failed to detect any effect of ETB-receptor-deficiency
in an animal model of peritoneal fibrosis in peritoneal dialysis. We showed a
significant reduction of blood pressure and cardiorenal target organ damage in
a rat model of hypertension and chronic renal failure (5/6 nephrectomy) by
treatment with an sGC-activator. We created a mouse model for facilitating
investigation of ET-1 Expression in vivo and using this model we demonstrated
that inhibition of NO-production indeed leads to increased ET-1 expression in
the kidney in a cell-type specific manner, thereby providing evidence for the
existence of the ET-NO-feedback loop in vivo in the kidney. We demonstrated
via creation of 2 transgenic mouse models (ET+/+iNOS-/- und ET+/+eNOS-/-) that
the pathophysiologically relevant ET-NO-Interaction seems to be mediated via
eNOS as the respective mouse model indeed displayed the phenotype-
hypertension, vascular remodelling and significant upregulation of the
vascular ET-system-which is expected in ET-NO-Imbalance. However, the iNOS-ET-
interaction also bears pathophysiological impact, as the concomitant lack of
iNOS in ET-overexpressing mice leads to a significant alleviation of ET-
induced cardiac tissue damage. We further showed that inhibition of NO
production in ET-overexpressing mice leads to an inflammatory and fibrotic
pulmonary phenotype. This effect was absent both in wildtype animals and in
ET-overexpressing mice if a dual ET-receptor-blocker was given at the same
time. These findings indicate a pivotal role for ET-NO-imbalance as the main
cause for pulmonary tissue damage in our model. As a conclusion we state that
the ET-system is a major player in acute lung injury. Inhalative ETA âblockade
should be evaluated in clinical trials as a treatment option. The absence of
any effect of ETB âdeficiency in a rat model of peritoneal fibrosis in
peritoneal dialysis urges the need for corresponding studies using
ETAâantagonists before a final judgement regarding the pathophysiological
impact of ET in this disease can be made. Our results indicate beneficial
effects of sGC-agonistic compounds in cardiovascular diseases; this is
currently investigated in clinical trials. We give evidence for renal ET-NO-
interaction in vivo and demonstrated in pulmonary tissue of ET-overexpressing
mice that this interaction bears more pathophysiological impact on pulmonary
tissue scarring than isolated intervention in one of the systems. Two mouse
models (ET+/+iNOS-/- und ET+/+eNOS-/-) with genetically determined imbalance
between ET and NO were described in order to study the pathophysiological
impact of ET-NO-Imbalance in vivo thereby identifying the ET+/+eNOS-/- mouse
as the model with greater pathophysiological relevance concerning vascular ET-
NO-Imbalance
Analysis of a nurse-provided on-call peritoneal dialysis support in an outpatient reference care centre
Abstract Background To analyse the nature of medical or technical emergency issues of ambulatory peritoneal dialysis (PD) patients calling a nurse-provided emergency PD support service of a reference centre that is provided all year in the after-hours. Methods We retrospectively analysed patientsâ chief complaint, urgency, resolution of and association to current PD treatment and modality directed to an on-call nurse-provided PD support service from 2015â2021 based on routinely collected health data. Calls were systematically categorized being technical/procedural-, medical-, material-related or type of correspondence. Call urgency was categorized to have âimmediate consequenceâ, inquiry was eligible for âprocessing next working dayâ or whether there was âno need for further actionâ. Call outcomes were classified according to whether patients were able to initiate, resume or finalize their treatments or whether additional interventions were required. Unexpected adverse events such as patientsâ acute hospitalization or need for nursesâ home visits were evaluated and quantified. Results In total 753 calls were documented. Most calls were made around 7:30 a.m. (5:00â9:00; median, 25-75th CI) and 6:30 p.m. (5:00â8:15). 645 calls were assigned to continuous ambulatory- (CAPD) or automated PD (APD). Of those, 430 calls (66.7%) had an âimmediate consequenceâ. Of those 77% (Nâ=â331) were technical/procedural-, 12.8% (Nâ=â55) medical- and 6.3% (Nâ=â27) material related issues. 4% (Nâ=â17) were categorized as other correspondence. Issues disrupting the course of PD were identified in 413 cases. In 77.5% (Nâ=â320) patients were able to initiate, resume or finalize their treatment after phone consultation. Last-bag exchange was used in 6.1% enabling continued therapy in 83.6%. In 35 cases a nurse visit at patientsâ home or patients' visit to the practice at the earliest possible date were required, while hospitalization was required in seven medical category cases (5.4% and 1.09% of total assessed calls, respectively). Conclusion The on-call PD-nurse provides patient support for acute and imminent issues enabling them to successfully initiate, resume or finalize their prescribed treatment. Nurses triage of acute conditions facilitated rapid diagnostics and therapy. Maintaining quality PD homecare, the provision of trained personnel is indispensable. The information gathered in this study may therefore be used as a foundation to tailor educational programs for nephrology nurses and doctors to further develop their competencies in PD
Maternal PCaaC38:6 is Associated With Preterm Birth - a Risk Factor for Early and Late Adverse Outcome of the Offspring
Background/Aims: Preterm birth (PTB) and low birth weight (LBW) significantly influence mortality and morbidity of the offspring in early life and also have long-term consequences in later life. A better understanding of the molecular mechanisms of preterm birth could provide new insights regarding putative preventive strategies. Metabolomics provides a powerful analytic tool to readout complex interactions between genetics, environment and health and may serve to identify relevant biomarkers. In this study, the association between 163 targeted maternal blood metabolites and gestational age was investigated in order to find candidate biomarkers for PTB. Methods: Five hundred twenty-three women were included into this observational study. Maternal blood was obtained before delivery. The concentration of 163 maternal serum metabolites was measured by flow injection tandem mass spectrometry. To find putative biomarkers for preterm birth, a three-step analysis was designed: bivariate correlation analysis followed by multivariable regression analysis and a comparison of mean values among gestational age groups. Results: Bivariate correlation analysis showed that 2 acylcarnitines (C16:2, C2), 1 amino acids (xLeu), 8 diacyl-PCs (PCaaC36:4, PCaaC38:4, PCaaC38:5, PCaaC38:6, PCaaC40:4, PCaaC40:5, PCaaC40:6, PCaaC42:4), and 1 Acylalkyl-PCs (PCaeC40:5) were inversely correlated with gestational age. Multivariable regression analysis confounded for PTB history, maternal body mass index (BMI) before pregnancy, systolic blood pressure at the third trimester, and maternal body weight at the third trimester, showed that the diacyl-PC PCaaC38:6 was the only metabolite inversely correlated with gestational age. Conclusions: Maternal blood concentrations of PCaaC38:6 are independently associated with gestational age
Additional file 1 of Analysis of a nurse-provided on-call peritoneal dialysis support in an outpatient reference care centre
Supplementary Material 1. Figures S1-S3, Tables S1-S5
Entwicklung einer sicheren Methode zur Bioabfallhygienisierung mit Kalk Abschlussbericht
Available from TIB Hannover: RO 1718(2003,1) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEArbeitsgemeinschaft Industrieller Forschungsvereinigungen e.V., Koeln (Germany)DEGerman