Date of Award


Document Type

Campus Access Dissertation


Epidemiology and Biostatistics



First Advisor

Wilfried Karmaus


Background: Balkan endemic nephropathy (BEN) is a chronic kidney disease that progresses slowly affecting only persons residing in Balkan countries, Europe. Despite the unique geographical specificity of this disease, genetic and environment factors have been reported as risk factors for BEN but its etiology remained unclear. Although some studies have used parental history of BEN as diagnostic criterion for BEN, it is not known how the disease develops in affected offspring. In addition, there are no known clinical markers capable to identify an early disease development. Therefore, the first aim of our study was to evaluate the relationship between parental history of BEN and clinical markers such as kidney length and cortex width, creatinine clearance, and &brkbar;Â2-microglobulin as predictors of new occurrences of BEN. Second, we tested whether these clinical markers were intervening variables between parental history of BEN and the incidence of BEN in offspring. The third aim was to investigate the relationships between hypertension and the incidence of BEN. Methods: Of 219 total participants, 122 were offspring of BEN with a parental history of BEN and 97 were offspring without a parental history of BEN, frequency- matched by age and gender. We conducted a five year prospective study, using the parental status and clinical markers in years 1 and 3 to predict new cases of BEN in year 5. Questionnaire data, clinical markers, and physical examination were collected five times between 2003 and 2009. New cases of BEN were defined based on three criteria: parental history,

reduced kidney size, and reduced kidney function. Incident cases were divided into (1) probable BEN, (2) definite BEN, and (3) both combined as total incidence of BEN. A parental history of BEN was either classified as ¡°yes/no¡± or as a specific status of parental BEN: maternal, paternal, biparental and non-BEN. Two methods were used to analyze the data, Cox regression models and path analysis, both controlling for age and gender.

Results: Approximately 80% of the participants remained in study until the last year of follow up. The incidence of BEN was 17.4% in both offspring groups combined. The results of the survival analyses demonstrated that paternal history of BEN was associated with all three incidence groups (hazard ratio: 33 to 86, P <0.05). A kidney cortex width reduction of 1 millimeter increased the incidence of definite BEN by 23 %; a reduction of kidney length of 1 millimeter resulted in a 5% increase of hazard ratio of probable BEN. However, after parental history of BEN was taken into account, the associations of the clinical markers lost their significance.

Findings of the path analyses suggested that a parental history of BEN had both direct and indirect effects on the occurrence of BEN. Participants with a parental history of BEN had a 57 times higher odds ratio for onset of BEN than those without a parental history. Similar findings were found for biparental, paternal, and maternal history of BEN. Several intervening variables between the parental status and onset of BEN were identified. A maternal history of BEN acted through kidney length and creatinine clearance. Biparental BEN was mediated by 1) creatinine clearance and 2) kidney length and creatinine clearance. Paternal history of BEN had three indirect effects; 1) through kidney length and creatinine clearance, 2) through kidney cortex width and creatinine clearance, and 3) through kidney cortex width alone.

Finally, we found that systolic blood pressure was indirectly related to the occurrence of BEN through a reduction of kidney cortex width and a decline of creatinine clearance. Systolic blood pressure ¡Ý140 mmHg without treatment affected the incidence of BEN through decreased kidney cortex width alone or decreased kidney cortex width with decreased creatinine clearance. With treatment, systolic blood pressure ¡Ý140 mmHg or ¡Ü140 mmHg groups were not associated with new cases of BEN.

Conclusions: A parental history of BEN is more important than any clinical markers for predicting the incidence of BEN. However, without a parental history of BEN, a diminished kidney cortex width predicted definite BEN. A positive family history of BEN also led to reduced kidney length and cortex width, and a decline in creatinine clearance, which in turn was related to the onset of BEN. High blood pressure without treatment was indirectly associated with the new cases of BEN through kidney cortex width and creatinine clearance. It seems that creatinine clearance is an important intervening variable in the relationship between the new cases of BEN and a parental history of BEN as well as kidney size, and high untreated blood pressure. Our results have the following implications. First, a family predisposition for BEN might be an important component in the development of the disease. Second, it is important to early diagnose and treat hypertension in the high risk group of BEN offspring. Third, BEN offspring should be educated about their family predisposition. Fourth, it is important to educate the high risk group to minimize other risk factors that may contribute to a reduction of creatinine clearance such as smoking and obesity. Finally, more studies need to explore the pathogenesis of Balkan Endemic Nephropathy.