Could Balkan Nephropathy be a Disorder of Renal Embryogenesis?

Introduction The etiology of Balkan endemic nephropathy (BEN) remains unknown despite numerous investigations carried out during the last 50 years. The pathophysiology of this disease remains unclear too, and there is no pathognomonic finding, which can confirm or discard the diagnosis of Balkan nephropathy in any particular patient. The widely accepted concept, however, is that Balkan nephropathy is a form of chronic tubulo-interstitial nephritis or some other form of chronic tubular injury to the kidney, which leads to tubular atrophy and severe reduction in kidney size (1). As such, Balkan nephropathy could be due to the action of any kind of toxic or infectious agent, including heavy metals, fungal toxins, radioactive substances, aromatic compounds, bacteria or viruses. However, after 50 years of research, no such factor has been yet identified with certainty enough to discard all other hipotheses and to define the etiology of this disease. Alternatively, Balkan nephropathy could be due to a genetic disorder, which leads to progressive tubular atrophy and renal failure. If this were the case and there were no environmental factor acting to produce the clinical manifestations of the disease, however, we would observe a steady incidence and prevalence over the years, and not the decline, which is now evident by looking back at the years passed. The most recent large population study, which was performed by Tz. Dimitrov and coworkers in the very last few years, discovered only 131 alive patients among a screened population of 3634 inhabitants of the 13 most endemic villages in Bulgaria (2). Three very important observations of this study deserve special attention: first, the number of alive patients has decreased with almost 90% in comparison with the number of patients registered during the late fifties and early sixties of the 20-th century; second, the mean age of the alive patients has increased markedly up to between 60 and 80 years of age, while virtually no patients under the age of 51 were registered; and third, interestingly, among the discovered patients, 87% were females, a very peculiar finding, which is in contrast with the almost equal sex distribution found during the BEN epidemic in the 1960-ies. Because the patient population grows older and decreases in number, it is obvious that there are no new young patients, but we only see the last survivors from a “wave” of affected patients, which had a maximum during the 1960ies. Such observation cannot be attributed to a purely genetic disorder, without the action of an environmental factor, because a genetic disorder alone must produce a steady incidence and prevalence over many decades, as it is with the number of patients, for example, suffering from autosomal dominant polycystic kidney disease. There are two types of events, which can cause a “wave” of new patients with kidney disease to emerge: one is any type of environmental factor, which might cause kidney damage in an adult subject, while the other is an environmental factor, which might have disturbed the renal embryogenesis and thus resulted in a “wave” of newborns, destined to develop slowly progressive renal failure during their adult life. The latter hypothesis has not been yet explored, and here we present evidence, which supports it: