Mario Laganović

Reduced telomere length is not associated with early signs of vascular aging in young men born after intrauterine growth restriction: a paradox?

Objective: The mechanisms that increase cardiovascular risk in individuals born small for gestational age (SGA) are not well understood. Telomere shortening has been suggested to be a predictor of disease onset. Our aim was to determine whether impaired intrauterine growth is associated with early signs of vascular aging and whether telomere length could be a biomarker of this pathway. Methods: One hundred and fourteen healthy young men born SGA or after normal pregnancy [appropriate for gestational age (AGA)] were enrolled. Patient data were gathered from questionnaires and clinical exams, including blood pressure (BP) measurement routine laboratory analyses, and carotid intima–media thickness (cIMT). Leukocyte telomere length (LTL) was assessed by quantitative PCR. Birth data were obtained from medical records. Results: The SGA group had significantly higher pulse pressure and cIMT, and a trend to increased SBP and heart rate in comparison to the AGA group. Interestingly, SGA men exhibited a 42% longer LTL than the AGA group. LTL was inversely associated with age, BMI, BP and birth parameters. In multiple regression analysis, BMI was the key determinant of SBP and cIMT. Conclusion: Young men born SGA show early signs of vascular aging. Unexpectedly, in our cohort, the SGA group had longer telomeres than the normal controls. Although longer telomeres are predictive of better health in the future, our findings could indicate a faster telomere attrition rate and probable early onset of cardiovascular risk in SGA participants. Follow-up of this cohort will clarify hypothesis and validate telomere dynamics as indicators of future health risks.

Kidney volume and albuminuria as markers of birth weight-blood pressure relationship in essential hypertension.

Our aim was to analyze whether birth weight contributes to future hypertension through reduced kidney volume, and whether albuminuria could be a marker of this pathway. We included 103 patients with newly diagnosed essential hypertension and 92 normotensive controls. Blood pressure (BP) was measured using a mercury sphygmomanometer and a ABP monitor. Kidney volume was determined by ultrasound. Data on birth weight were obtained from mothers. Albuminuria was determined in 24-hour urine samples. Hypertensive patients had lower birth weight and higher albuminuria than normotensives. There was no difference in kidney volume between the two groups. We found a negative correlation between birth weight and systolic BP in the hypertensive group. BP was significantly correlated with BMI and albuminuria in the hypertensive group. Multiple regression analysis had shown the greatest impact of BMI on BP and had also demonstrated that 24-hour systolic BP showed the greatest risk for developing albuminuria in hypertensive patients. In conclusion, birth weight influences BP values in adult age, but it is not mediated by a reduced kidney volume. A strong correlation, independent of birth weight, was observed between albuminuria and BP values. Increased BMI is the most important independent risk factor responsible for BP increase, even in an early phase of essential hypertension.

[OP.2B.03] GLOMERULAR HYPERFILTRATION AS A RISK FACTOR FOR RENAL IMPAIRMENT AND HYPERTENSION IN APPARENTLY HEALTHY SUBJECTS.

Objective: Chronic kidney disease(CKD) is established CV risk factor, and already early renal impairment(RI) increases risk for hypertension(HT) and loss of renal function. It was reported that blood pressure (BP) and metabolic derangements are associated with glomerular hyperfiltration(GHF), and GHF increases risk of developing microalbuminuria (MA) in HT stage 1. Our aim was to analyze whether GHF predicts progression to HT and RI in apparently healthy subjects. Design and method: Out of 954 subjects enrolled in ENAH follow-up study, 371 (137 m, 234 w; mean age = 46 years) were eligible for further analysis:100 with optimal, 72 with normal BP, 70 with PHT (high normal BP), and 129 with newly diagnosed untreated HT. Follow-up period was 77 ± 12 months. Exclusion criteria were treatment with antihypertensive drugs, diabetes, pregnancy, eGFR<60 ml/min, CV or cerebrovascular incident, chronic terminal diseases, dementia, immobility and missing data. BP and heart rate were measured using Omron 6 device following the ESH guidelines. Uric acid, glucose, lipids, serum creatinine, hsCRP, leptin and adiponektin were determined; HOMA index was used to calculate insulin resistance and MDRD formula to estimate GFR. Albumin to creatinine ratio (ACR) was determined from the first morning spot urine. GHF was defined as eGFR above the cut off value of the 5th quintile of the whole group. Results: In the GHF group eGFR(ml/min/year) decreased significantly more than in others (−3.4 (IQ−5.8 to −1.76 vs. −1.5 (IQ−2.6 to −0.3); total decrease −17.7% vs. −9.8%; per year −2.8% vs. −1.5%; all p < 0.001). ACR was non-significantly higher in GHF group at enter and at the end of follow-up (5.73 (IQ3.35–8.6) vs. 4.5 (IQ3.31–7.25); p = 0.06, 5.93 (IQ4.26–8.64) vs. 5.7 (IQ4.08–9.82; NS, respectively). In the GHF group, at the end of follow-up ACR did not increase significantly. At enter and at the end of follow-up BP was significantly lower in GHF group (p < 0.001). At the end of study we failed to observe difference in increase of BP and new-onset HT between GHF and others. Conclusions: In our group of healthy subjects GHF was associated only with more rapid decrease of GFR. No impact of GHF on ACR increase and development of new-onset HT in healthy subjects was observed. GHF has less prominent effect on HT and kidney function in apparently healthy subjects than in those with HT and metabolic disorder.

4D.11: ARTERIAL STIFFNESS IN PATIENTS WITH ENDEMIC NEPHROPATHY UNDERGOING HEMODIALYSIS.

Objective: Arterial stiffness (AS) is an independent risk factor of cardiovascular mortality in general and haemodialysis (HD) population. Endemic (Balkan) nephropathy (EN) is a chronic tubulointerstitial salt wasting nephropathy characterized with later onset of arterial hypertension (AH) which could also affect AS. Thus our aim was to analyse AS in EN patients compared with other end-stage renal disease patients undergoing HD. Design and method: A total of 186 HD patients (90 m, 96 w; 67.35 + 13.07 years) from 3 dialytic units and 2 endemic areas were enrolled. The exclusion criteria were: duration of dialysis < 3 months, atrium fibrillation, myocardial infarction or stroke in last 3 months, heart failure, arteriovenous anastomosis besides functional arteriovenous fistula. EN was diagnosed by modified WHO criteria. All patients were dialysed by European and KDIGO guidelines. Brachial blood pressure (BP) was measured with Omron M6 device and AS markers; pulse wave velocity (PWV) and aortic augmentation index (AIx) were measured by Arteriograph before mid-week dialysis. Results: There were no differences in sex, smoking status, type of vascular access, phosphate binder doses, vitamin D, hypertension and brachial BP between two groups. Non-EN patients had more antihypertensives drugs (p < 0.001), higher body mass index, waist circumference and diabetes. There were no differences in dialysis modalities except lower ultrafiltration in EN patients (p < 0.001). EN were significantly older (p < 0.001) with later start of dialysis. EN had lower values of phosphates (p < 0.001), CaxP (p < 0.001) and iPTH (p < 0.001), and significantly lower PWV (9.2 ± 1.6 vs.10.5 ± 1.9; p < 0.001). Using multiple linear regression models EN was the most significant independent negative predictor for PWV (p < 0.001) and AIx (p = 0.002). Using logistic regression non-EN patients had odds ratio for increased AS (PWV > 10 m/s OR 3.12; 1.72–5.82; p < 0.00001). Conclusions: EN patients despite being older had lower PWV and AIx values. Even more, EN is an independent predictor of lower arterial stiffness. This could be explained with later onset of AH in pre-dialytic clinical course and probably with lower phosphate values due to tubulopathy. Better control of Ca and P during dialysis also contributes to observed lower AS in EN patients undergoing HD.

Chronic Dietary Exposure to Aristolochic Acid and Kidney Function in Native Farmers from a Croatian Endemic Area and Bosnian Immigrants

BACKGROUND AND OBJECTIVES Improvements in agricultural practices in Croatia have reduced exposure to consumption of aristolochic acid-contaminated flour and development of endemic (Balkan) nephropathy. Therefore, it was hypothesized that Bosnian immigrants who settled in an endemic area in Croatia 15-30 years ago would be at lower risk of developing endemic nephropathy because of reduced exposure to aristolochic acid. To test this hypothesis, past and present exposure to aristolochic acid, proximal tubule damage as a hallmark of endemic nephropathy, and prevalence of CKD in Bosnian immigrants were analyzed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this cross-sectional observational study from 2005 to 2010, 2161 farmers were divided into groups: indigenous inhabitants from endemic nephropathy and nonendemic nephropathy villages and Bosnian immigrants; α-1 microglobulin-to-creatinine ratio >31.5 mg/g and eGFR<60 ml/min per 1.73 m(2) were considered to be abnormal. RESULTS CKD and proximal tubule damage prevalence was significantly lower in Bosnian immigrants than inhabitants of endemic nephropathy villages (6.9% versus 16.6%; P<0.001; 1.3% versus 7.3%; P=0.003, respectively); 20 years ago, Bosnian immigrants observed fewer Aristolochia clematitis in cultivated fields (41.9% versus 67.8%) and fewer seeds among wheat seeds (6.1% versus 35.6%) and ate more purchased than homemade bread compared with Croatian farmers from endemic nephropathy villages (38.5% versus 14.8%, P<0.001). Both Croatian farmers and Bosnian immigrants observe significantly fewer Aristolochia plants growing in their fields compared with 15-30 years ago. Prior aristolochic acid exposure was associated with proximal tubule damage (odds ratio, 1.64; 95% confidence interval, 1.04 to 2.58; P=0.02), whereas present exposure was not (odds ratio, 1.31; 95% confidence interval, 0.75 to 2.30; P=0.33). Furthermore, immigrant status was an independent negative predictor of proximal tubule damage (odds ratio, 0.40; 95% confidence interval, 0.19 to 0.86; P=0.02). CONCLUSIONS Bosnian immigrants and autochthonous Croats residing in endemic areas are exposed significantly less to ingestion of aristolochic acid than in the past. The prevalence of endemic nephropathy and its associated urothelial cancers is predicted to decrease over time.

Arterial stiffness in atherosclerotic renovascular hypertension.

Objective: Arterial stiffness is an independent cardiovascular risk factor. Aging, high blood pressure and increased renin-angiotensin system activity contribute to increased arterial stiffness in patients with atherosclerotic renovascular hypertension (aRVH). A literature search failed to identify any study related to this topic. Therefore, our aim was to determine the arterial stiffness in patients with aRVH and analyze whether stenting in addition to multifactorial drug therapy has beneficial effects on markers of stiffness and the clinical course. Methods: In this 6-month longitudinal study, 37 patients with refractory hypertension and unilateral aRVH were enrolled. After stenting, all patients received multifactorial dug therapy including 80 mg of telmisartan. Arterial stiffness indices were determined using Arteriograph. The control group consisted of 44 patients with essential hypertension. Results: There were no differences in brachial blood pressure values between the two groups (P > 0.05). At baseline, adjusted pulse wave velocity (PWV) was higher in aRVH patients than that of essential hypertensive patients (12.8 ± 0.4 vs. 11.6 ± 0.3 m/s; P = 0.029). In the aRVH group, at the end of the follow-up, a significant decrease in the aortic augmentation index (37.7 ± 9.9 vs. 33.7 ± 11.4; P = 0.02) without changes in PWV was observed (P > 0.05). Conclusion: This study is the first to show that arterial stiffness is higher in patients with refractory aRVH than in those with essential hypertension. Multifactorial therapy based on stenting and intensive medical treatment reduced central blood pressure and augmentation index. Failure to obtain PWV reduction is likely a consequence of the present irreversible structural vessel changes. Longer follow-up might enable us to resolve whether arterial stiffness indices have better predictive ability in patients with aRVH than brachial blood pressure.

Is herbal tea consumption a factor in endemic nephropathy

Endemic (Balkan) nephropathy (EN) is a chronic tubulointerstitial nephropathy frequently associated with upper urothelial cancer exclusively affecting farming villagers [1–3]. Based on our results, EN is considered to be an environmental form of aristolochic acid nephropathy (AAN) [1–3]. AAN was first reported in 1993 in Belgium and subsequently more AAN cases were reported worldwide as AA has been an integral part of traditional herbal medicines [4]. The extent of this problem was recently documented in Taiwan where precise data on prescriptions of herbal products containing AA is available [5]. Aristolochia spp. has been used for more than 2,000 years in the practice of traditional medicine and European physicians were familiar with the use of this plant as well. After its intrinsic toxicity became known, importing Aristolochia herbs was banned in many countries, including Croatia. Nevertheless, products containing AA remain a part of traditional medicine and are sold in many countries that do not have strict control protocols. Recently we reported that AA DNA adducts were present in 95 % of patients with EN who underwent surgery for upper urothelial cancers [2] and affirmed the idea that bread contaminated with AA might be the cause of EN [6, 7]. However, the causative relationship between AA and EN again raised the question whether bread intake is the only route of ingestion or whether AA was ingested also in EN as a part of folkloric medicine. Gluhovschi et al. [8] reported that although therapeutic remedies based on AA products are used in the EN affected area in Romania, no relationship between these remedies and the development of EN or of tumors was observed. However, they used HPLC for detection of AA in plasma, which is less sensitive than the mass spectrometry we recently used in tissue samples [1, 2]. In addition, when re-analyzing their data, it does appear that AA was used more frequently in the endemic area. In our opinion, this leaves the question whether herbal tea may play a role in EN still unanswered. In our preliminary study we failed to find any evidence in the group of 1,041 Croatian farmers that herbal tea or traditional medicine use is related to EN [9]. The observed differences between

Erectile Dysfunction in Chronic Kidney Disease

Chronic kidney disease (CKD) is a growing health problem worldwide affecting approximately 15 % of the adult population. The risk of dying is severalfolds higher than the risk of starting with renal replacement therapy (RRT), CVDs being the main cause of death. Among various risk factors and mechanisms, nitric oxide (NO) deficiency is particularly interesting. Currently with advances in medical care, the survival of CKD patients has been prolonged, and physical functioning and quality of life (QoL) became more important. CKD patients are likely to reveal various sexual dysfunctions prior to dialysis. Symptoms of this disturbing disability are reported with increasing frequency as renal function declines. Approximately 75 % of men undergoing dialysis have erectile dysfunction (ED) which is much higher than in other chronic diseases. ED is the main sexual problem associated with mental QoL in CKD men. The causes of such high prevalence are multifactorial and include physiological, psychological and iatrogenic factors. The pathogenesis of sexual and ED in CKD has been attributed to several risk factors, but to none of them conclusively. Importantly, ED as a serious handicap for normal life should be considered as a marker of endothelial dysfunction and atherosclerosis as well as an indicator of possible silent coronary heart disease.

Adiponectin is Not Associated With Blood Pressure in Normotensives and Untreated Hypertensives With Normal Kidney Function

AbstractThe role of adiponectin in hypertension is still a matter of debate. Obtained conflicting results could be mostly explained with diversity of subjects included in different studies. Our aim was to analyze association of adiponectin with blood pressure (BP) in a group of normotensive and untreated hypertensive subjects.Participants (N = 257) were selected from a random sample of 2487 subjects enrolled in an observational cross-sectional study. Subjects with diabetes and chronic kidney diseases were excluded. BP was measured using Omron M6 device following ESH/ESC guidelines. Adiponectin concentration was determined by ELISA.There were no differences in adiponectin values (mg/L) between hypertensives and normotensives (median 9.75; iqr: 7.44–17.88 vs 11.35; iqr: 7.43–12.63; P = 0.17). On univariate linear regression adiponectin was not associated with systolic or diastolic BP (P > 0.05). Furthermore, multivariate analysis did not show significant contribution of log-transformed adiponectin either to systolic (&bgr; = −0.040; P = 0.43) or diastolic BP (&bgr; = 0.066; P = 0.33).In our group of normotensives and untreated hypertensives with normal kidney function adiponectin was not associated with BP even after adjustment for other risk factors. Our results and conclusions should not be extrapolated to subjects with other characteristics.

HYPERTENSION IN PRIMARY GLOMERULONEPHRITIS - REPORT FROM THE CROATIAN REFERRAL CENTRE FOR GLOMERULAR DISEASES

Objective: Hypertension (HT) is an important prognostic factor for renal impairment and it accelerates progression of chronic kidney disease (CKD) and vice versa CKD increases blood pressure (BP) and HT prevalence. There are scarce data on prevalence and characteristics of HT in patients with primary glomerulonephritis (PGN) and our aim was to analyse data on HT in this heterogeneous group of patients with renal impairment. Design and method: In these analyses we included 708 subjects with PGN from the Croatian referral centre registry: 195 membranous glomerulopathy (MGN), 136 mesangioproliferative GN (MSGN), 167 IgAnephropathy (IgAN), 154 focal-segmental-glomerolosclerosis (FSGS) and 56 membranoproliferative GN (MPGN). Data were collected from medical records. Results: Prevalence of HT was 44.1%, 60.5%, 63.5%, 66.2% and 81.2% in MSGN, IgAN, MGN, FSGS and MPGN, respectively (p < 0.001). MSGN were the youngest, had less CKD > 3, and had the shortest duration of HT and kidney impairment before the kidney biopsy. MPGN had the highest prevalence of CKD > 3, and the longest duration of HT before the kidney biopsy. In all PGN HT were older, had more CKD > 3 and longer duration of HT before the kidney biopsy. There was no difference between HT and normotension (NT) in prevalence of obesity and duration of kidney impairment before the kidney biopsy. Significant difference in HT prevalence between patients with CKD < 3 and > 3 was observed in MGN, MSGN, IgAN, FSGS and MPGN (54.8% vs.72.2%; 38.6% vs.65.5%; 43% vs.82.2%; 54.7% vs.77.3%;66.6% vs.82.8%). We failed to find differences in HT prevalence among PGN when we analyzed only PGN with CKD > 3 (p > 0.05). However, in the subgroup with CKD < 3 HT prevalence was significantly lower in IgAN an MSGN compared to MGN, FSGS and MPGN (p = 0.01). Conclusions: Age, CKD > 3 and duration of HT before kidney biopsy are the most important determinants of HT in PGN at the time of kidney biopsy. In the subgroup of patients with CKD < 3 observed higher prevalence of HT in MGN, FSGS and MPGN vs. IgAN and MSGN could be explained with differences in pathology and pathophysiology.