The aim of this Concerted Action was to relieve the burden on patients, their families, and society of one of the most frequent and expensive genetic diseases of man.
Many research groups from all over Europe have taken part in genetic and clinical studies of polycystic kidney disease (PKD). The following clinical studies have been set up:
Two groups of patients have been selected to determine whether early treatment of hypertension in PKD is beneficial. One group with mild hypertension is being treated with a beta blocker (atenolol) or with an angiotensin coverting enzyme inhibitor (ACEI, enalapril) and the other group with incipient or border line hypertension is being treated with placebo or an ACEI. Follow up data will be analyzed over several years.
Aneurysm of intracranial arteries:
Data has been collected on aneurysmal rupture in PKD and patients surviving a cerebrovascular accident are at high risk of developing more aneurysms prone to bleeding.
A study has shown that removal of one kidney does not cause acceleration of loss of kidney function (ie kidney failure does not occur due to hyperperfusion and hyperfiltration of undamaged nephrons).
The first limited results from the twin studies show that in some monozygous pairs a clear difference in the course of PKD was apparent suggesting that, at least in some cases, the progression toward kidney failure is determined by environmental factors.
Dominantly inherited PKD in childhood:
In children with early symptoms of PKD the mutation was found to be inherited more frequently from the mother (41 times) than from the father (23 times).
With recombinants obtained during family studies the PKD1 gene was localized to pGGG1 (D16S259) distal, and 26-6 (D16S125) proximal, a region of 750 kb on chromosome 16. Almost the entire region of 750 kb has been cloned in overlapping cosmids and yeast artificial chromosomes (YAC).
The genetic heterogeneity of PKD was studied in a total of 328 families from all over Europe and the proportion of unlinked families was found to be 15%. The progression of PKD in p atients with unlinked PKD was slower indicating an intrinsic factor that is of influence on the age at which end stage renal failure is reached.
The Countries of the EEC spend roughly 4 billion ECU each year on renal replacement therapy, dialysis and transplantation. Throughout Europe around 5%, but in the Ferrara region of Italy, up to 20% of the patients with end stage renal failure have polycystic kidneys. Since the disease is caused by an autosomal dominant mutation, each child of a patient has a 50% risk to develop the disease. Cysts are present in the kidneys from the 12th week of gestation. Very slowly these cysts grow in size, thereby destroying the functional tissue. End stage renal failure usually occurs between 40 and 60, but in fact varies considerably between patients, even between members of the same family.
Which factors influence the progression of the disease towards kidney failure?
This is the basic question tackled by the Concerted Action (C.A.). Ultimately, when these factors have been identified, we wish to modify them in order to postpone the moment at which the patient has to start renal replacement therapy.
Adult polycystic kidney disease (PKD) is most frequently not detected until after the age of 30. Many patients have already passed on the mutation to their offspring when the disease becomes symptomatic. In theory, the birth of affected individuals can now be prevented by presymptomatic diagnosis of family members at risk for the mutation, followed by genetic counselling, and prenatal diagnosis of polycystic kidney disease with the intention to abort an affected foetus is very small. Prospective parents, although well informed by genetic counselling, in the majority of cases do not consider this acceptable for a treatable disease with late onset. This means that in the coming generations the number of patients with polycystic kidney disease is not going to decline.
Therefore, ways to slow down the progression of this disease have to be found if we wish to improve the outlook for individual patients, their families, and society.