Živka Dika

Consensus statement on screening, diagnosis, classification and treatment of endemic (Balkan) nephropathy

Currently used diagnostic criteria in different endemic (Balkan) nephropathy (EN) centers involve different combinations of parameters, various cut-off values and many of them are not in agreement with proposed international guidelines. Leaders of EN centers began to address these problems at scientific meetings, and this paper is the outgrowth of those discussions. The main aim is to provide recommendations for clinical work on current knowledge and expertise. This document is developed for use by general physicians, nephrologists, urologist, public health experts and epidemiologist, and it is hoped that it will be adopted by responsible institutions in countries harboring EN. National medical providers should cover costs of screening and diagnostic procedures and treatment of EN patients with or without upper urothelial cancers.

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.

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.

Reliability of CKD-EPI predictive equation in estimating chronic kidney disease prevalence in the Croatian endemic nephropathy area.

Introduction Chronic kidney disease (CKD) is a significant public health problem and it is not possible to precisely predict its progression to terminal renal failure. According to current guidelines, CKD stages are classified based on the estimated glomerular filtration rate (eGFR) and albuminuria. Aims of this study were to determine the reliability of predictive equation in estimation of CKD prevalence in Croatian areas with endemic nephropathy (EN), compare the results with non-endemic areas, and to determine if the prevalence of CKD stages 3-5 was increased in subjects with EN. Materials and methods A total of 1573 inhabitants of the Croatian Posavina rural area from 6 endemic and 3 non-endemic villages were enrolled. Participants were classified according to the modified criteria of the World Health Organization for EN. Estimated GFR was calculated using Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI). Results The results showed a very high CKD prevalence in the Croatian rural area (19%). CKD prevalence was significantly higher in EN then in non EN villages with the lowest eGFR value in diseased subgroup. Conclusions eGFR correlated significantly with the diagnosis of EN. Kidney function assessment using CKD-EPI predictive equation proved to be a good marker in differentiating the study subgroups, remained as one of the diagnostic criteria for EN.

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.

PS 14-88 BLOOD PRESSURE PREDICTS NEW-ONSET CHRONIC KIDNEY DISEASE INDEPENDENTLY OF METABOLIC SYNDROME – LONGITUDINAL DATA FROM THE CROATIAN RURAL STUDY (ENAH)

Objective: Chronic kidney disease (CKD) and metabolic syndrome (MetSy) are important predictors of mortality. Our objective was to assess the predictors of new onset CKD in rural population with and without MetSy. Design and Method: Out of 954 subjects enrolled in ENAH follow-up study, 521 (147 m, 374 w) were eligible for further analysis and followed up for total of 3333 person-years (median 7 (5–7) years). Exclusion criteria were pregnancy, CV or cerebrovascular incident and chronic terminal diseases. Blood pressure (BP) was measured using Omron M6. Fasting blood was analysed for glucose, lipids, serum creatinine and other parameters. MetSy was diagnosed according to NCEP-ATP III criteria. Results: Prevalence of MetSy at baseline was 24.0% being similar in men and women (24.6% vs. 22.4%, p = 0.35). The prevalence of individual MetSy components in subjects with MetSy were: high BP (88.9%), pathological WC (81.6%), high FBG (60.0%), high TG (48.8%) and low HDL-C (30.4%); women having pathological WC more frequently (98.9% vs. 87.9%, p = 0.017). The incidence rate of new onset MetSy was 3.7% per year. Prevalence of CKD at baseline in our group was 5.6%, being similar in subjects with MetSy and controls (8.1% vs 5.1%, p = 0.13). Contrary to this, 31 subjects developed new onset CKD for an incidence rate of 1.0% per year and an incidence almost 2.5-fold higher in subjects with MetSy (11.5% vs. 4.8%, p = 0.02). There was no difference in number of MetSy components or their individual prevalence between CKD and non-CKD subjects (p > 0.05). In whole group, BP (OR 3.0,95% CI 0.9,10.0) and older age (OR 1.2,95% CI 1.1,1.3) were predictors of new onset CKD. Conclusions: MetSy is highly prevalent in Croatian rural population and frequently associated with CKD. Beside age, BP is predictor of new-onset CKD. Dietary and BP lowering population-level strategies might show efficient in preventing not just MetSy, but to a certain extent CKD.

Endemic (Balkan) Nephropathy: A Disease Caused by Aristolochic Acid

Endemic (Balkan) nephropathy (EN) is a devastating chronic renal disease, affecting residents of rural villages situated near tributaries of the Danube river in Croatia, Bosnia and Herzegovina, Serbia, Bulgaria and Romania. The disease affects at least 25,000 men and women, while another 75,000 are estimated to be at risk. The prevalence of confirmed EN cases in the endemic regions of Croatia has fluctuated between 2% and 10% of the village population. Significant epidemiologic features of EN include its presence only in certain villages; a familial pattern of disease; occurrence in adults and never in children under 15 years of age; restriction to rural farming populations; and strong association (∼50%) with transitional urothelial cell carcinoma of the upper urinary tract. This epidemiologic evidence strongly suggests that an environmental toxin is involved in the etiology of EN and its associated cancers.

Prevalence, treatment and control of hypertension in a Croatian endemic nephropathy area.

Background: Hypertension is not considered to be a characteristic of endemic nephropathy (EN). Recent observations suggested that it might be more prevalent than it was reported before. Aim: The aim of our study was to analyze prevalence, treatment and control of hypertension in a Croatian endemic area. Methods: In the present cross-sectional study, 1,602 farmers were enrolled, 1,246 from EN and 356 from control villages. Epidemiological and medical histories were taken and clinical and laboratory examinations performed for kidney function. Blood pressure was measured following the ESH/ESC guidelines. Results: The prevalence of hypertension in EN villages was higher than in control (50.8 vs. 46.5%, p = 0.005). There was no difference in overall treatment, control of all and treated hypertensives between the villages. In all villages, women were treated more than men (EN 41.6 vs. 28.4%, p < 0.001; control 46.4 vs. 27.3%, p < 0.001), but better control of treated was achieved in men (EN 24.7 vs. 17.4%, p = 0.002; control 29.6 vs. 15.5%, p = 0.002). Women had lower income and level of education than men (p < 0.01). Conclusion: Hypertension is highly prevalent in endemic villages. In all villages, men had better blood pressure control despite being treated less. This finding could be explained by poorer education and income in women.

Angiotensin-converting enzyme gene polymorphism and N-Acetyl-β-D-glucosaminidase excretion in endemic nephropathy.

Background: Tubular proteinuria and enzymuria are hallmarks of endemic nephropathy (EN). The role of I/D angiotensin convertase (ACE) gene polymorphism has not yet been elucidated in this peculiar chronic tubulointerstitial nephritis, and our aim was to investigate the role of this polymorphism in EN focusing on the urinary N-acetyl-β-D-glucosaminidase (NAG) excretion, a biomarker of proximal tubular damage. Methods:ACE genotype and allele frequencies were determined in 229 farmers (147 women and 82 men) from an endemic Croatian village. The farmers were stratified according to the WHO criteria into the following subgroups: those ‘at risk’ for EN (n = 37), ‘suspected of having EN’ (n = 57), and ‘others’ (n = 135). Results: There were 74 (32.3%) subjects homozygous for the D allele, 99 (43.2%) heterozygous (ID genotype) and 56 (24.4%) homozygous for the I allele. No differences in allele frequency were found between the established WHO subgroups (p > 0.05). In the whole group, DD subjects had significantly higher values of diastolic blood pressure (p = 0.003) and urinary NAG than subjects with ID and II genotype (5.5 ± 1.2 vs. 4.0 ± 3.0 vs. 3.8 ± 4.2, respectively; p = 0.023). The highest values of serum creatinine (p = 0.02), proteinuria (p = 0.03) and urinary NAG (6.0 ± 3.7 vs. 3.7 ± 2.1 vs. 3.0 ± 1.6, respectively; p = 0.008) were observed in those suspected of having EN group with the DD genotype. Conclusion:ACE gene polymorphism is not a risk factor for EN. However, it might influence the clinical course of EN, and increased excretion of NAG might be a prognostic marker of this chronic tubulointerstitial nephritis.