A kalcium reguláló hormonok és a csontanyagcsere klinikai és kísérletes vizsgálata fiziológiás és patológiás állapotokban = Clinical and experimental investigations of calcium regulating hormones and bone metabolisms in physiologic and pathologic conditions

A veseelégtelenség progressziója és az ezzel járó kardiovasculáris, gastroenterologiai és hormonális betegségek a betegek életminőségének jelentős korlátjai. Projektünk célja volt a veseelégtenségben szenvedő betegek közül megtalálni azokat, akik fokozottan veszélyeztetettek a szövődmények kialakulására. Az volt a célunk, hogy jellemző mintákat találjunk, melyek alkalmasak a betegek szűrésére és monitorozására. Kutatásaink a proteinszintézis, a metabolizmus és az immunválasz genetikai hátterének kimutatására koncentrált, melyek jobban jelzik a betegség klinikai lefolyását, a szövődmények rizikóját vagy az alkalmazott hatóanyagok hatásosságát és mellékhatását. Kutatásaink legfontosabb eredményei új gén variánsok azonosítására volt, amit in silico technikákkal, a fehérjék háromdimenziós struktúrájának computerizált modellezésével, és az in vitro expressziós rendszerek funkcionális konzekvenciájának jellemzésével igazoltunk. Kifejlesztettünk olyan prognosztikai technikát, amely genetikai információk kimutatásával jellemzi ezt a betegcsoportot. Ezekkel a vizsgálatokkal különösen a több éves hosszú távú kezelésben részesülő betegeknél a betegség kezdetén kell elvégezni. Az eredményeinket nemzetközi folyóiratban publikáltuk. | The progression of kidney failure bone and the associated cardiovascular, gastroenterological and hormonal disorders have a major burden on patients' quality of life. Our project targeted patients with end stage renal disease in order to identify those individuals who are at increased risk for these complications. Our aims were to find characteristic patterns that are suitable for screening and monitoring purposes. Our research focused on variants of genes implicated in protein biosynthesis, metabolism and immune response and that may predict more precisely the clinical course, risk of complications, or the efficacy and/or side-effects of agents used for therapy. The main achievements of research include identification of novel gene variants using in silico techniques, computerized modelling of their effects on three-dimensional protein structure, and characterization of their functional consequences using in vitro expression systems. We developed prognostic techniques, that is featuring to this group of patients by using the genetic information of the examinations. By these methods the risk-factors that must be more focused on during the more-year-long treatment, can be identified at the beginning of the disease. The results were published in international scientific papers

Prescription of reninâ angiotensinâ aldosterone system inhibitors (RAASi) and its determinants in patients with advanced CKD under nephrologist care

Reninâ angiotensinâ aldosterone system inhibitors (RAASi) are recommended for chronic kidney disease (CKD) patients. In this study, we describe RAASi prescription patterns in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, Germany, France, and the United States (US). 5870 patients (mean age 66â 72 years; congestive heart failure [CHF] in 11%â 19%; diabetes in 43%â 54%; serum potassium â ¥5 in 20%â 35%) were included. RAASi prescription was more common in Germany (80%) and France (77%) than Brazil (66%) and the United States (52%), where the prevalence of prescription decreases particularly in patients with CKD stage 5. In the multivariable regression model, RAASi prescription was least common in the United States and more common in patients who were younger, had diabetes, hypertension, or less advanced CKD. In conclusion, RAASi prescription patterns vary by country, and by demographic and clinical characteristics. RAASi appear to be underused, even among patients with strong classâ specific recommendations. Although the reasons for this variation could not be fully identified in this crossâ sectional observation, our data indicate that the risk of hyperkalemia may contribute to the underuse of this class of agents in moderate to advanced CKD.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150590/1/jch13563.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150590/2/jch13563_am.pd

Considerable international variation exists in blood pressure control and antihypertensive prescription patterns in chronic kidney disease

Although blood pressure control is a major goal in chronic kidney disease, no worldwide overview of either its achievement or antihypertensive prescriptions is currently available. To evaluate this we compared crude prevalence of uncontrolled blood pressure among 17 cohort studies, including 34 602 individuals with estimated glomerular filtration rate under 60 ml/min/1.73 m2 and treated hypertension across four continents, and estimated observed to expected prevalence ratios, adjusted for potential confounders. Crude prevalence of blood pressure of 140/90 mm Hg or more varied from 28% to 61% and of blood pressure of 130/80 or more from 54% to 84%. Adjusted prevalence ratios indicated poorer hypertension control than expected in cohorts from European countries, India, and Uruguay, and better control in patients from North American and high-income Asian countries. Four antihypertensive drug classes or more were prescribed to more than 30% of participants in North American and some European cohorts, but this practice was less common elsewhere. Renin angiotensin-aldosterone system inhibitors were the most common antihypertensive drugs, prescribed for 54% to 91% of cohort participants. Differences for other drug classes were much stronger, ranging from 11% to 79% for diuretics, 22% to 70% for beta-blockers, and 27% to 75% for calcium-channel blockers. The confounders studied explain only a part of the international variation in blood pressure control among individuals with chronic kidney disease. Thus, considerable heterogeneity in prescription patterns worldwide calls for further investigation into the impact of different approaches on patient outcomes

Regional variation in hemoglobin distribution among individuals with chronic kidney disease: the ISN International Network of Chronic Kidney Disease (iNET-CKD) Cohorts

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin.Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model.Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17–49 ml/min) and 3 pediatric cohorts (median eGFR range of 26–45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7–6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R2 7%–44% across cohorts).Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations.</p

Beziehung des Grundumsatzes zu Kreislauf symptomen bei Thyreotoxikose und Myxödem.

Gecorrigeerd via dispenserDiss. München.OPLADEN-RUG0

Timely Referral to Outpatient Nephrology Care Slows Progression and Reduces Treatment Costs of Chronic Kidney Diseases

IntroductionWe present a new approach to evaluate the importance of ambulatory nephrology care in patients with chronic kidney disease (CKD).MethodsAn anonymized health claims database of German insurance companies was searched in a retrospective analysis for patients with CKD using the codes of the International Classification of Diseases, 10th German modification. A total of 105,219 patients with CKD were identified. Patients were assigned to the group “timely referral,” when nephrology care was present in the starting year 2009, or initiated during the following 3 years in CKD1–4. Using frequency matching for age and gender, 21,024 of the late referral group were matched with the equal number of patients in the timely referral group. Hospital admission rates, total treatment costs, and kidney function (change in CKD stages, start of dialysis, mortality) were documented each year during the 4-year follow-up.ResultsHospital admission rates (110%–186%) and total treatment costs (119%–160%) were significantly higher (P < 0.03) in late referral compared with timely referral. In the timely referral group, significantly more patients did not change their CKD stage (65%–72.9% vs. 52%–64.6%, P < 0.05) compared with late referral. Starting in CKD3 more patients tended to start dialysis in 1 year in timely referral (1.9 ± 0.6 vs. 1.0 ± 0.4, P = 0.1). In contrast, death rates were significantly higher in the late referral group (18.8 ± 1.8% vs. 6.7 ± 0.4%, P = 0.0001).DiscussionTimely referral to outpatient nephrology care is associated with slowed disease progression, less hospital admissions, reduced total treatment costs, and improved survival in patients with CKD

International study of health care organization and financing: development of renal replacement therapy in Germany

End-stage renal disease, Dialysis, Health care financing, Incentives, Medical costs, Reimbursement, Germany, I10, I11, I12, 118,

Muscarinic receptor subtypes - search for selective agonists and antagonists

Since the late eighties five muscarinic receptor subtypes (m1 - m5) have been cloned and four of them (M1 - M4) have also been pharmacologically characterized. However, there is still a lack of potent muscarinic agonists and antagonists, which are highly selective for one muscarinic receptor subtype over all other subtypes. For the treatment of Alzheimer's disease, M1-selective agonists capable of penetrating into the CNS are needed. It is hypothezised that such substances would not only improve memory and cognitive ability, but also delay the progression of the disease. In our laboratory, the functionally M1-selective quaternary ammonium compound McN-A-343 has been used as a starting point for the design of such CNS active muscarinic ligands. Structure-activity relationship studies led to the tertiary amine 4-(4-fluorophenylcarbamoyloxy)-2-butynylpyrrolidine (4-F-PyMcN), which was found to stimulate M1 receptors with some functional selectivity. In order to increase the potency and selectivity of 4-F-PyMcN several new derivatives were synthezised and pharmacologically characterized in different functional assays as well as in binding and biochemical (PI turnover) studies. The most promising results were obtained with (S)-4-(4-fluorophenylcarbamoyloxy)-1-methyl-2-butynylpyrrolidine (4-F-MePyMcN). Due to its potent partial agonistic activity at M1 receptors and its M2-antagonistic properties leading to an increase of acetylcholine release by blockade of M2 autoreceptors, this compound may be considered as an important tool for future drug research of cognitive disorders. M2 receptor antagonists may also be used for the treatment of Alzheimer's disease, furthermore in the therapy of supraventricular bradycardia and for quantifying M2 receptors in the CNS with PET imaging. In the search for antagonists which clearly differentiate M2 from other muscarinic receptors, we investigated the two enantiomers of the widely used H1-antihistaminic drug dimethindene. (S)-Dimethindene proved to be a potent M2-selective antagonist with lower affinities for the M1, M3 and M4 receptors. In addition, the (S)-enantiomer was more potent than the (R)-enantiomer in all muscarinic assays. Interestingly, the stereoselectivity was inverse at histamine H1 receptors, the (R)-enantiomer being the eutomer. M3 receptor antagonists may be useful in the treatment of spastic disorders of the gastrointestinal, urogenital and respiratory tract as well as for the relief of glandular hypersecretion. In previous studies, hexahydro-difenidol (HHD) and its sila-analogue, hexahydro-sila-difenidol (HHSiD), as well as the antiparkinsonian drug trihexyphenidyl (THP) were found to be valuable tools for the discrimination of M3 and M2 receptors. In order to further assess the structural requirements (including stereochemical aspects) of the above-mentioned compounds for potency and selectivity, a series of HHD and THP analogues as well as of the corresponding silicon and germanium derivatives (sila- and germa-substitution) were studied. The (R)-enantiomers displayed higher affinities and selectivities than the corresponding (S)-isomers. The enantioselectivity of some of these analogues is best explained by the concept of the four-binding-subsite model suggesting that the differences in affinity of the (R)- and (S)-enantiomers at muscarinic receptors are due to opposite binding of the phenyl and the cyclohexyl ring to the preferring subsites. Surprisingly, there was no significant difference between the Si and Ge analogues indicating a strongly pronounced Si/Ge bioisosterism in this series of compounds. The related carbon derivatives, however, showed higher receptor affinities as well as greater stereoselectivities at all muscarinic receptors studied compared with the silicon and germanium analogues. © 1996 Elsevier B.V. All rights reserved.SCOPUS: ar.kinfo:eu-repo/semantics/publishe