The Best American Travel Writing 2014 (4 page)

P
AUL
T
HEROUX

FROM
The New Yorker

 

L
AST SEPTEMBER
, at a hospital in eastern Croatia, my father and I visited a collection of some 400 human kidneys. Most had belonged to the victims of a mysterious, fatal kidney disease, which occurs in agrarian communities on the Danube River and its tributaries. Some villages have it; others, seemingly identical in every way, do not. The onset of the disease, which is known as Balkan endemic nephropathy (often abbreviated as
BEN
), takes place in middle to later life, after the patient has lived in an affected village for 15 or 20 years. The first symptoms include weakness, anemia, and a coppery skin discoloration. The kidneys begin to atrophy, and about half of patients also develop a rare cancer of the upper urinary tract. Without a kidney transplant or treatment by dialysis, death usually occurs within a year.

At the kidney collection, a pathologist took several formalin-filled jars out of a cabinet and lined them up on the counter. Inside were kidneys riddled with holes, misshapen kidneys with visible tumors, biopsied kidneys sliced in half, and atrophied kidneys, ghostly pale, some as small as walnuts. My father, a nephrologist, says that he has never seen kidneys as tiny as those removed from
BEN
patients.

BEN
was first described in the 1950s. Over the years, many theories have been proposed to explain the disease, from cadmium poisoning and hantaviruses to toxic molds and chromosomal mutation. Uncertainty and controversy surround the most basic data, such as the number of people with the disease. One doctor I spoke to puts the figure at a hundred thousand. A recent Croatian study found that the incidence of the disease is declining, while a Serbian study found that it isn't.

Because
BEN
takes decades to develop, investigators are always following a cold trail, and this makes the disease a particularly intractable puzzle. Animals don't live long enough to get it, and respond to toxic substances differently from humans, which limits the possibilities of experimental research. The villages affected are in a demographically fragmented region, fraught with wars, revolutions, genocides, and totalitarianism—all of which have hampered research and medical record-keeping. Today,
BEN
is a budget-straitened side project for most scientists who study it. A disease that affects only middle-aged Balkan farmers isn't exactly a magnet for international funding.

 

My father began studying
BEN
in the 1980s, but his work was interrupted by the Yugoslav wars. Last fall, he returned to the Balkans for the first time in years, and I went with him. We began our trip in Timişoara, the largest city in western Romania, where we met Calin Tatu, a researcher who has been studying the disease with the U.S. Geological Survey for more than a decade. Tatu, who is in his 40s, and has a buzzcut and a close-trimmed beard, holds a medical degree in immunology but prefers working in the lab to seeing patients. He was wearing tinted glasses and a cargo vest, and had spent the previous week climbing Mont Blanc. At lunch, over two double espressos and two Coke Zeros, he told us about his research.

For the past 10 years, Tatu has been investigating the Pliocene lignite hypothesis—a theory developed by a geologist who noticed that the map of the endemic villages closely shadows the locations of Pliocene-era coal deposits. It isn't clear exactly how the coal would make people sick, but Tatu believes that toxic compounds may be leaching from the coal into the groundwater. At his lab, he showed us a machine capable of reducing 20 gallons of groundwater to a few teaspoons of brown sludge. He says that he has found unique organic compounds in water samples from the region, but he doesn't yet know whether they contribute to
BEN
.

In recent years, Tatu has been testing another theory as well: poisoning by aristolochic acid, a toxin found in plants of the
Aristolochia
genus. This theory, which has recently gained wide acceptance, was formulated thanks to one of those grievous human misfortunes described by scientists as “a natural experiment.” In Brussels, in the 1990s, a number of otherwise healthy young women suffered end-stage kidney failure, requiring dialysis or transplants. It turned out that they all belonged to the same diet clinic, where they had taken a Chinese herbal slimming blend containing aristolochic acid. About half of them later developed the same rare upper-urinary-tract cancer found in
BEN
patients. Researchers soon made the connection with
BEN
, particularly since a species of aristolochia—
Aristolochia clematitis,
or European birthwort—is common throughout the Balkans.

In 2007, an American pharmacologist named Arthur Grollman analyzed kidneys from
BEN
patients and found molecules derived from aristolochic acid bound to the patients' DNA. In further studies, he identified aristolochic acid's mutational signature in DNA from patients' tumors. According to Grollman, these findings prove that the cancers were caused by aristolochic acid, which he suspects was ingested after seeds from the plant got mixed with wheat and ended up in the villagers' bread. Other researchers have built on these findings, and many now favor the term “aristolochic-acid nephropathy” over “Balkan endemic nephropathy.” Grollman believes that the mystery has been solved.

Yet questions remain. Some researchers have been unable to find the same molecules, either in the Belgian women or in
BEN
patients. Others have drawn attention to the differences between the Belgian women's disease and
BEN
; notably, the Belgian women tended to become sick within 12 to 18 months, rather than 20 years. Perhaps the biggest puzzle is why aristolochic acid would make people sick only in certain areas, given that it grows throughout the Balkans, as well as in much of the rest of Europe and the Middle East.

The aristolochia theory is strong precisely where the Pliocene theory is weak, and vice versa. Pliocene coal is found throughout the endemic regions, but it has no known causal link to
BEN
symptoms. Aristolochia has been linked to the symptoms, but it grows all over the place. Tatu suggested that aristolochic acid and coal compounds might be working in combination. He agrees that aristolochic acid is a cause of
BEN
, and thinks that the biggest remaining question is how exposure to aristolochic acid occurs. He is skeptical about the idea that aristolochia seeds get ground into flour, having found no traces of the poison when he analyzed flour from mills in endemic regions of Romania.

We had met Tatu in downtown Timişoara, in the lobby of a vast rectangular Soviet-style hotel, and were joined by his collaborator, Nikola Pavlović, a Serbian nephrologist in his 60s, with mild blue eyes. Pavlović's speech was soft, hesitant yet relentless, each claim accompanied by a stream of qualifications. When the conversation turned to research, he spoke approvingly of almost all the hypotheses. He didn't seem bothered by the fact that a given risk factor could also be found in non-endemic regions, because maybe those regions weren't really non-endemic. “How do you know there aren't two or three cases there?” he asked. He even thought that a
BEN
-like disease might exist wherever there are lignite coal deposits. Showing us a lignite map of the United Kingdom, he observed that the areas with the most lignites also had the highest rates of undiagnosable renal disease. In the U.S., states with lignite deposits also have some of the highest death rates from certain kidney cancers.

My father objected that in 40 years of medical practice he had never seen an illness with quite the same profile as
BEN
, with kidneys so shrunken, fibrosis so severe, and such an advanced state of disease with no hypertension. His own hunch is that radiation is involved. He notes that the pattern of
BEN
distribution resembles that of radon distribution in the United States, and that radiation causes acute fibrosis in kidneys. If radioactive material were leaching into drinking water in the Balkans, the kidneys would process it in small amounts over the years. There is no hard evidence to support this theory, however. Two Michigan-based environmental scientists working on
BEN
told me that they think radiation is worth looking into—elevated levels of uranium have been found in the endemic regions—but they haven't raised the necessary funds.

Tatu, Pavlović, and my father exchanged news of
BEN
researchers past and present: who favored the aristolochic-acid theory and who didn't, who had retired, who had died, who was now producing minerals for laundry detergent. My father had last seen Pavlović in 1988. “I remember him a young man,” he told me later. “I guess he thought the same thing about me.”

 

That afternoon, we drove to the endemic region in Mehedinţi County, 150 miles southeast of Timişoara. The trolley lines and the churches soon gave way to rolling countryside. Large haystacks stood in groups. Shaggy, hulking, almost shamanistic, they resembled animate huts. There was something mutable and alive about them, the way they absorbed the light. The leaves were starting to change, and the air was exceptionally clear. Tiny horses stood out against a distant hillside.

Along the way, Tatu pulled his car over next to a cornfield. It was overrun with aristolochia. In the golden afternoon light, I saw the famous plant for the first time, recognizing its heart-shaped leaves, narrow yellow tubular flowers, and the round brown pods that have given rise to one of its local names: priest's balls. Tatu broke open a pod. Inside, hundreds of seeds were lined up in two rows, like pupils in a schoolhouse.

I picked a leaf and smelled it. “If you taste it, it's very bitter,” Tatu said, chewing on a leaf and immediately spitting it out. “Pah! This is actually not a good idea.”

In Romania, as in many parts of the world, aristolochia leaves have been used in folk medicine for centuries. The leaves also contain aristolochic acid, but in a far lower concentration than the seeds. Tatu picked up a pod off the ground. “If you ate this, you would get really sick,” he said. “You would have acute renal failure.”

“If you want to eat it, go ahead,” my father offered. “There are two nephrologists here.” Nobody ate the pod.

As we drove through the Romanian countryside, Tatu frequently stopped to collect water and soil samples. Many villagers still don't have plumbing and get their water from natural springs. At one spring, two older women sat placidly on a bench. When Tatu asked them about nephropathy, their faces grew hard. Tatu told me that the villagers generally didn't like to be asked about the disease. They would say the other village had it, the one across the hill.

At an abandoned coal mine nearby, runoff water rushed noisily out of a pipe into a ditch. Tatu said that villagers collected the runoff and drank it. He pointed out where pieces of Pliocene coal lay scattered on the ground: 3-million-year-old chips of cypress. They still looked like wood. Being so young, the coal was of a terrible quality and hardly burned at all, especially since the mines were so waterlogged. “It was pretty much the worst coal you could get ever,” Tatu said. Opened in the 1970s, the mine had been closed for some 20 years. A concrete barrier blocked the entrance. It had been erected after a boy and a cow wandered inside and drowned.

Two women came by with some cows. The women seemed excited to see us. It turned out that they thought we had come to reopen the mine and create jobs. The cows lowered their massive, beautiful heads to the water and drank.

“It's amazing how much you can observe just by watching,” my father said, paraphrasing Yogi Berra. I was more amazed by how much you
couldn't
observe—how the things you saw seemed to withhold their meaning. The culprit wouldn't be the mold you saw in a granary today but the mold in a granary that had been torn down 20 years ago.

A drunk man arrived. He said that the mine was actually a tomb, and that you could tell this from the configuration of stones. He had been a miner for three years, and had seen many deaths, though from collapsing shafts and suffocation rather than from kidney disease. Twenty meters in, he said, the shaft was all water. The miners used to drink it. There had been a study of those miners. They didn't seem to get nephropathy any more frequently than anyone else.

The biggest dialysis clinic in Mehedinţi County is housed in an old villa, with irregularly shaped rooms branching off a central staircase. Under the stairs stood several rows of 10-liter jugs of dialysate, a fluid that flows through the dialysis machine, separated from the patient's blood by a membrane.

The clinic serves 168 patients, more than half of whom have
BEN
. The
BEN
patients were instantly recognizable: frail, coppery-skinned peasants with haunted eyes, reclining on white chaises, as blood was pumped into and out of their bodies through tubes. The place where the two catheters punctured the forearm was marked on each patient by an irregular, discolored potato-size fistula, surgically created by connecting a vein and an artery. The fistula made me think for the first time about how much blood has to leave the body during dialysis: not a liter or two but
all
of it, several times over, to the extent that the blood vessels have to be hot-wired in order to get it in and out. Each patient's blood passed through a long plastic tube and around a slowly turning wheel, which pumped the blood through the machine. The machines turned slowly in unison, like mill wheels. A dialysis unit looks precise and powerful, but it can only approximate the intricate function of a human kidney. For patients with atrophying diseases like
BEN
, dialysis rarely buys more than 5 to 10 years.

“Dialysis creates essentially a new kind of human,” Pavlović whispered.