Increased blood pressure in adult offspring of families with Balkan Endemic Nephropathy: a prospective study

BACKGROUND: Previous studies have linked smaller kidney dimensions to increased blood pressure. However, patients with Balkan Endemic Nephropathy (BEN), whose kidneys shrink during the course of the disease, do not manifest increased blood pressure. The authors evaluated the relationship between kidney cortex width, kidney length, and blood pressure in the offspring of BEN patients and controls. METHODS: 102 offspring of BEN patients and 99 control offspring of non-BEN hospital patients in the Vratza District, Bulgaria, were enrolled in a prospective study and examined twice (2003/04 and 2004/05). Kidney dimensions were determined using ultrasound, blood pressure was measured, and medical information was collected. The parental disease of BEN was categorized into three groups: mother, father, or both parents. Repeated measurements were analyzed with mixed regression models. RESULTS: In all participants, a decrease in minimal kidney cortex width of 1 mm was related to an increase in systolic blood pressure of 1.4 mm Hg (p = 0.005). There was no association between kidney length and blood pressure. A maternal history of BEN was associated with an increase in systolic blood pressure of 6.7 mm Hg (p = 0.03); paternal BEN, +3.2 mm Hg (p = 0.35); or both parents affected, +9.9 mm Hg (p = 0.002). There was a similar relation of kidney cortex width and parental history of BEN with pulse pressure; however, no association with diastolic blood pressure was found. CONCLUSION: In BEN and control offspring, a smaller kidney cortex width predisposed to higher blood pressure. Unexpectedly, a maternal history of BEN was associated with average increased systolic blood pressure in offspring

Offspring of parents with Balkan Endemic Nephropathy have higher C-reactive protein levels suggestive of inflammatory processes: a longitudinal study

<p>Abstract</p> <p>Background</p> <p>Despite the characteristic extensive tubulointerstitial fibrosis, Balkan Endemic Nephropathy (BEN) is usually considered a non-inflammatory disease.</p> <p>Methods</p> <p>We examined a marker of inflammation, C-reactive protein (CRP), in the offspring of patients with BEN, a population at risk for BEN, prior to development of established disease to determine if an inflammatory process could be identified in the early stages of the disease. In 2003/04, 102 adult offspring whose parents had BEN and a control group of 99 adult offspring of non-BEN patients were enrolled in this prospective study. This cohort was re-examined yearly for four consecutive years. Levels of serum CRP were measured in years 3 and 4 and compared between groups. The data were analyzed with mixed models.</p> <p>Results</p> <p>Compared to controls, offspring of BEN parents had statistically higher CRP levels in two consecutive years, suggestive of early inflammatory reactivity. Whenever the mother was affected by BEN (both parents, or mother only), serum CRP was significantly increased, but not if only the father had BEN. CRP was inversely related to kidney cortex width but not to markers or renal function.</p> <p>Conclusion</p> <p>Early stages of BEN may involve inflammatory processes. The observation of a maternal involvement supports the concept of fetal programming, which has been implicated in the pathogenesis of other chronic kidney diseases.</p

Metals and kidney markers in adult offspring of endemic nephropathy patients and controls: a two-year follow-up study

Abstract Background The etiology of Balkan Endemic Nephropathy, (BEN), a tubulointerstitial kidney disease, is unknown. Although this disease is endemic in rural areas of Bosnia, Bulgaria, Croatia, Romania, and Serbia, similar manifestations are reported to occur in other regions, for instance Tunisia and Sri Lanka. A number of explanations have been stated including lignites, aristolochic acid, ochratoxin A, metals, and metalloids. Etiologic claims are often based on one or a few studies without sound scientific evidence. In this systematic study, we tested whether exposures to metals (cadmium and lead) and metalloids (arsenic and selenium) are related to Balkan Endemic Nephropathy. Methods In 2003/04 we recruited 102 adults whose parents had BEN and who resided in one of three communities (Vratza, Bistretz, or Beli Izvor, Bulgaria). A control group comprised of 99 adults having non-BEN hospitalized parents was enrolled in the study during the same time. We conducted face-to-face interviews, ultrasound kidney measurements, and determined kidney function in two consecutive investigations (2003/04 and 2004/05). Metals and metalloids were measured in urine and blood samples. To assess the agreement between these consecutive measurements, we calculated intraclass correlation coefficients. Repeated measurement data were analyzed using mixed models. Results We found that cadmium and arsenic were associated with neither kidney size nor function. Lead had a significant but negligible effect on creatinine clearance. Selenium showed a weak but significant negative association with two of the four kidney parameters, namely creatinine clearance and β2-microglobulin. It was positively related to kidney length. These associations were not restricted to the offspring of BEN patients. Adding credence to these findings are reports showing comparable kidney effects in animals exposed to selenium. Conclusion The findings of this 2-year follow-up study indicate that metals and metalloids do not play a role in the etiology of Balkan Endemic Nephropathy. Against the assumption in the literature, selenium was not protective but a risk factor. Since comparable associations were observed in animals, future studies are needed to explore whether selenium may have adverse renal effects in humans.</p

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity

Whole genome methylation array analysis reveals new aspects in Balkan endemic nephropathy etiology

Background Balkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries. DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood. Methods We performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions. Results Using specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles. SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders. Conclusion Our data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis. Keywords: Epigenetics; Whole genome array analysis; Balkan endemic nephropath

Multicentric survey of patient doses in fluoroscopy guided diagnostic and interventional cardiac procedures: comparison with Diagnostic Reference Levels and follow-up levels for patients at risk for radiation induced skin effects

Въведение. Интервенционалните кардиологични процедури, често са свързани с голямо облъчване на пациентите, поради което изискват специално внимание по отношение на защитата от появата на радиационно индуцирани ефекти при пациента.Материали и методи. Проучването на типичните стойности на дозата е проведено ретроспективно, в девет лечебни заведения, с общо четиринадесет ангиографски уредби. За две от най-често извършваните процедури - перкутанна коронарна интервенция (PCI) и коронарна артериография (CA) са изчислени типичните стойности на величините произведение керма-площ (КАП), кумулативна доза (КД) и време на скопия (ВС) и са сравнени с актуалните Национални диагностични референтни нива (НДРН) за България. Извършен е анализ на данните по отношение на риска от възникване на кожно индуцирани ефекти, вследствие на интервенционалните кардиологични процедури.Цел. 1) да се представят и анализират типичните стойности на величината КАП за най-често провежданите кардиологични процедури - перкутанна коронарна интервенция и коронарна артериография в кардиологични отделения с голяма работна натовареност и да се сравнят с НДРН; 2) да се сравнят дозите на пациентите с публикуваните в Наредба 2 нива за проследяване, за установяване на пациенти с риск за възникване на радиационно индуцирани ефекти.Резултати. Резултатите показват, че типични стойности на изследваните величини за PCI и CA при някои от уредбите, са по-високи от НДРН. Във всяко от разглежданите лечебни заведения има пациенти с поне едно превишено ниво за проследяване за процедура PCI.Изводи. Резултатите показват потенциал за оптимизиране, както на работата в отделенията с високи типични стойности на дозата, така и при уредбите с много ниски типични стойности на изследваните величини. При проследените пациенти не се наблюдават оплаквания и поява на радиационно индуциран ефект. Изготвянето и въвеждането в рутинната клинична практика на процедури за рутинно прилагане на „Инструкцията за пациента след проведена интервенционална/и процедура/и с по-голяма степен на сложност и дълго време на скопия“ ще позволи навременна диагностика и навременно лечение на кожните ефекти в следствие на проведените кардиологични процедури под рентгенов контрол. Introduction. Interventional cardiac procedures are often associated with high patient exposure and therefore require special care in protecting patients from radiation-induced effects.Materials and methods. A retrospective study of typical patients’doses was performed in nine hospitals, with a total number of fourteen angiography systems. The typical values for kerma-area product (KAP), cumulative dose (CD) and fluoroscopy time (FT) for two of the most commonly performed procedures - percutaneous coronary intervention (PCI) and coronary arteriography (CA), were calculated and compared with the Bulgarian National Diagnostic Reference Levels (NDRL). Data analysis, regarding the risk of radiation-induced skin effects due to interventional cardiac procedures, was performed.Aim. 1) to present and analyze the typical KAP values for PCI and CA procedures in cardiology departments with high workload and to compare them with the NDRL; 2) to compare the patient doses with the follow-up levels published in Ordinance 2, to identify patients at risk for radiation-induced effects.Results. The results show that typical values for PCI and CA procedures for some of the angiography systems are higher than the NDRL. In all investigated departments there are patients with at least one exceeded follow-up level for PCI.Conclusions. The results show a potential for optimization in the departments with both high or very low typical dose or FT values. No radiation-induced effect was observed in the followed-up group of patients. The introduction of procedure with "Instruction to the patient after an interventional cardiac procedure(s) with greater complexity and a long fluoroscopy time" for patient follow-up and its regular implementation into the routine clinical practice will help for timely diagnosis and treatment of radiation-induced skin effects after cardiac procedures under fluoroscopy control

Pseudorapidity densities of charged particles with transverse momentum thresholds in pp collisions at √ s = 5.02 and 13 TeV

The pseudorapidity density of charged particles with minimum transverse momentum (pT) thresholds of 0.15, 0.5, 1, and 2 GeV/c is measured in pp collisions at the center of mass energies of √s=5.02 and 13 TeV with the ALICE detector. The study is carried out for inelastic collisions with at least one primary charged particle having a pseudorapidity (η) within 0.8pT larger than the corresponding threshold. In addition, measurements without pT-thresholds are performed for inelastic and nonsingle-diffractive events as well as for inelastic events with at least one charged particle having |η|2GeV/c), highlighting the importance of such measurements for tuning event generators. The new measurements agree within uncertainties with results from the ATLAS and CMS experiments obtained at √s=13TeV.