One of the world's most mysterious diseases

June 3, 2016 7:02 AM

In the late 1950s, Serbian authorities closed grain milling wheels made of lead used by a handful of villages in the Balkans. They were aiming to eliminate Balkan endemic nephropathy (BEN), a kidney disease limited to certain spots along the Danube and some of its tributaries. They failed, but they weren't the last to fail. Perhaps no other human disease has generated so many different hypotheses and ideas in an attempt to explain its causal factors. In 2013, Elif Batuman traveled to the Balkans with her father, a nephrologist who had studied the disease before the region was ripped apart by war. She found medical records destroyed by the fighting, balkanized health services, skeptical villagers, and a handful of scientists who think that the most important clue was discovered in 1992, when two women in a clinic waiting room in Belgium nodded ‘Hello’ to each other.

Balkan endemic nephropathy, also known as Danubian endemic familial nephropathy (DEFN), was first described in Bulgaria in the mid-1950s. From the start, curious clusters of patients were noted in villages, families and even houses. The spatial distribution has remained astonishingly unchanged with time: The disease affects the same endemic clusters as 50 years ago.

An experiment of sorts was conducted in the 1950s when Bulgarian authorities decided to move an entire village affected by the disease away from the area. Children who had spent a short time in the village never got the disease, while those who had spent 15-20 years there did - but only after they were 40-60 years old.

Attempted explanations have included lead intoxication, genetic predisposition, metals and metalloids (both deficiencies and poisoning), lecithin cholesterol acyl transferase deficiency, intoxication with A. clematitis, genetic polymorphism, ochratoxin A, chromosomal aberrations, pliocene lignite, viral disease, immunological factors, and organic substances from coal. Among others.

In the early 1990s, as the Soviet world was falling apart, BBC documentarian Tessa Livingstone traveled to the area to film The Curse of Karash (on dailymotion or veoh). At the time, there were two leading hypothesis. One scientist said he had found inherited chromosomal abnormalities, while other scientists had noted that the most affected villages and houses were damp and low-lying, and were confident that ochratoxin A, a nasty fungal toxin associated with damp grains, was the most likely culprit.

There are now two completely different leading hypotheses.

Also noting how often the affected houses were low-lying - and the opinion of many local residents that water is the cause - scientists from Romania and the U.S. Geological Survey tested well water and found that it was leaching toxic organic compounds from exceptionally young coal. They noted that similar coal - along with a rural population that often uses well water - is also found in the Dakotas, which also have higher rates of kidney cancer than the American average.

And now, back to the women in the Belgian waiting room. They had been taking a mislabeled herbal diet remedy which contained a member of the birthwort family (a plant whose womb-like flowers gave it its name - and made it a clear choice to give to women during labour, obviously), and ended up with a kidney disease resembling BEN. Taiwanese herbalists who work with birthwort also have high rates of kidney disease, and Taiwan has banned its use.

Birthworts are common in the Balkans, and recent scientific reviews have settled on aristolochic acid, a compound produced by the birthworts, as the most likely cause of BEN. They're pretty sure this time.

posted by clawsoon (12 comments total)

This is fascinating (and an incredible post). Clawsoon - how did you learn so much about this?
posted by blahblahblah at 7:39 AM on June 3, 2016 [3 favorites]

I wonder if there is any connection to the kidney disease prevalent in Central America?
posted by Bee'sWing at 7:52 AM on June 3, 2016 [3 favorites]

Great post, thank you.
posted by vignettist at 7:56 AM on June 3, 2016 [1 favorite]

Bee'sWing: I wonder if there is any connection to the kidney disease prevalent in Central America?

Fascinating article, thanks! Poor farmers in northern Sri Lanka also have an unsolved kidney disease. In all three cases, it seems to be a) poor farmers who b) have seen recent lifespan improvements and who c) ...live in a specific area? ...have chronic exposure to something? But is that something the same thing in all three cases, or different somethings in each case? (Or combinations of different somethings?)

blahblahblah, I saw the documentary and then started Googling and reading. It was too fascinating to stop! :-)
posted by clawsoon at 8:45 AM on June 3, 2016 [3 favorites]

balkanized health services

Couldn't resist, could you?
posted by Halloween Jack at 9:13 AM on June 3, 2016 [11 favorites]

I just emailed my mom about this (she lives in Serbia) and I'm very curious to see what she says since she went to med school there (when it was Yugoslavia); she works for a pharmaceutical company now; but, she is nevertheless quite "woo" about a lot of things that the prior two points should have discouraged (homeopathy, folk medicine, crystals, etc.). Perhaps uncharitably, I partly expect her to blame the disease on some nefarious Western influence and uphold the salubrious properties inherent to all plants (because they're natural, of course).
posted by Aubergine at 9:38 AM on June 3, 2016 [2 favorites]

Thanks for posting, clawsoon. I ran across the name of this disease a couple weeks ago while doing some health records research on nephropathy related to diabetes. Never would have given it a second thought, until this post. As someone who dabbles in epidemiology, this looks like some fascinating reading.
posted by mean square error at 10:16 AM on June 3, 2016 [1 favorite]

Unless all of the affected people were regularly fed the herbal, I'll go with the coal theory. Coal tar derivatives have been strongly associated with bladder cancer since the 1890s.
posted by Twang at 2:46 PM on June 3, 2016 [1 favorite]

I'm interested in the Ochratoxin A theory, because I have read about that before in relation to the genetic disease PKU. Inheriting two PKU genetic mutations can cause serious neurological problems, but having a single mutation is protective against miscarriage caused by Ochratoxin A, which is believed to be the reason why these mutations are relatively common despite the potentially very negative effects of inheriting two such mutations without treatment.

I wonder if there is a higher incidence of PKU mutations the same populations prone to BEN.... Or if BEN might be related to some similar genetic adaptation to an environmental threat, and thys more complicated than just genes OR environment...
posted by OnceUponATime at 7:26 PM on June 3, 2016

Fantastic post, thank you.
posted by Darmok and Jalad at Tanagra at 12:08 AM on June 4, 2016

Okay, I read more of the links and I guess they really are pretty sure this time, and it probably has nothing to do with Ochratoxin A. Though I still wonder if what genes are out there which are common in specific populations because they offer protection against some specific environmental threat, but without downsides as obvious as sickle cell or PKU. Maybe just increased susceptibility to some other disease...

The aristolochic acid explanation seems pretty sound but would seem to imply the association with low-lying areas is just a coincidence? No fair, nature. Respectable mystery authors avoid them, because they lead people off in the wrong direction and make mysteries much harder to solve...
posted by OnceUponATime at 2:12 AM on June 4, 2016

So for those of you waiting with bated breath for my mom's response* (in translation):

"Yes, it's a very interesting theory, so to speak - and as you can see, endemic nephropathy, as it was called when I studied it, is still unexplained. Now, if I recall correctly from what was discussed in that very long [New Yorker] article about radiation being one of the possible causes, you can only imagine what the 1999 [NATO] bombing with the depleted uranium did... It scares me to even think about it."

As for my powers of prediction, I was off by degree but not kind, in my opinion; Western malfeasance was invoked although not blamed for this particular malady.

*I only sent her the New Yorker article
posted by Aubergine at 8:36 AM on June 6, 2016 [2 favorites]