By David N. Leff

Cysts of immense proportions are not at all unheard of on the kidneys of patients with polycystic kidney disease (PKD).

There are only two treatments for end-stage renal disease, both drastic. One is permanent dialysis; the other, organ transplant. About 10 percent of patients on dialysis in the U.S. are there because of polycystic kidney disease. There are half a million cases of PKD in the U.S. today, and 6,000 or 7,000 new ones are diagnosed each year.

With a one-in-1,000 incidence in the population, PKD is second only to diabetes as a cause of kidney failure.

Besides its clinical morbidity and mortality, dialysis and transplantation cost the U.S. economy at least $250 million a year, or $1 billion if all other ailments caused by PKD are added in.

Molecular biologist and geneticist Katherine Klinger said, " This is because PKD, despite its name, is a multi-organ disorder, with lots of extrarenal manifestations. Cysts are quite common in the liver, pancreas, spleen and other organs." Klinger is vice president of science at Genzyme Corp., in Framingham, Mass., and heads its division of genetics research and development.

"Polycystic kidneys," she told BioWorld Today, "can look like giant bubble wrap. "Their cysts range from under a millimeter to as large as a grapefruit. People with PKD can wind up with enormous abdominal enlargements because of huge kidneys. Some have their kidneys removed just for pain control, separate from the end-stage renal failure."

She added: "If one of your parents had PKD, you have a 50 percent chance that you will inherit the disease. It's an autosomal dominant disorder, which means it's inherited directly, generation to generation, with equal male/female frequency."

But there's more to PKD's complex inheritance pattern than that. "Perhaps half the people who come to diagnosis," Klinger continued, "don't know their own family history of PKD. One reason is clinical variability."

She explained: "Say the affected parent has a mild, late-blooming case, while his or her offspring is more seriously affected. So at the time the child presents with symptoms, its parent may not yet have had onset, if ever. Clinical variation is common in genetic diseases."

Another reason is the extreme mobility and frequent break-up of the American family. If one parent is lost to follow-up, that breaks the inheritance history and renders clinical diagnosis more dicey, and more dependent on symptoms.

Nowadays, ultrasound imaging provides visual confirmation of renal cysts. But the catch-22 is that there's no specific treatment for the disease, which is highly progressive. At best, efforts center on keeping blood pressure within or below normal limits, and countering with antibiotics the severe urinary tract infections that often mark PKD.

The latest step toward dispelling the uncertainty that surrounds the disorder and frustrates clinical countermeasures is a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated June 10, 1997. Its title: "Polycystin: In vitro synthesis, in vivo tissue expression, and subcellular localization identifies a large membrane-associated protein."

This feat of genetic mapping and sequencing, Klinger told BioWorld Today, "is the first, and to my knowledge, the only full-length cDNA that has been constructed for the PKD1 gene."

Compared to the 350,000 base pairs of the cystic fibrosis (CF) gene, she pointed out, "the PKD1 gene, with about 54,000 base pairs, is much more compact, but its messenger RNA is much larger, about 14 kilobases, compared with 4 kb for CF.

PKD1 sits on the extreme tip of human chromosome 16's short arm. It encodes a protein, polycystin, which encompasses 4,302 amino acids.

The PNAS paper's lead author is molecular geneticist Oxana Ibraghimov-Bezkrovnaya, who runs the functional genomics group in Klinger's division.

Oxana told BioWorld Today: "We are now looking into the mutation of the PKD1 gene and its product, polycystin, in patients. We hope to take certain steps, by which Genzyme may benefit, that can interfere with the progression of the disease.

"The first step one takes," she continued, "is to identify the primary localization of polycystin in normal tissues, and how it behaves in polycystic tissues. We believe the normal function of the protein is to ensure cell-cell contact; that it functions as an adhesion molecule. The kidney's tubular structures are lined with epithelial cells, where the polycystin resides, and this is where cysts arise."

Klinger observed that "cysts can arise in any one of these tubules, and get very large and pathologic. Even so, only a very small percentage of the gazillions of epithelial cells give rise to a cyst. Yet they all inherited the same germline mutation."

From this paradox, she and Oxana construed that PKD's weird inheritance pattern partakes of the "double-hit" phenomenon that explains many malignancies. "People," she explained, "inherit a germline mutation from a parent, and then secondary somatic mutations happen that inactivate the 'good' copy of the gene, leaving only the defective variant. It's like converting from heterozygosity to homozygosity. The PKD bubble," she went on, "is not giving rise to a tumor, of course. It's giving rise to a cyst instead."

On their plate right now is determining whether the mutated PKD1 gene causes loss of function of its product. If so, she pointed out, "then one can contemplate gene therapy to replace the defective gene and make good protein. But how can you access the kidney and deliver a gene that big?"

Answering that rhetorical question, Klinger observed: "Genzyme has a very large gene therapy program. One organ it probably doesn't extend to at the moment is the kidney, although that may change, now that we've got this data."

She concluded: "Genzyme also has a large component that provides clinical services, so in that respect we're very close to these patients, and the impact on them and the clinician. That probably colors the way we feel about researching these diseases. We look at these people and say: 'What can we do to help them, as opposed to just diagnosing them?'" *