ADPKD and the clinical and ethical challenges of predictive medicine

Prof.Dr.med. Rita Kielstein
Clinic of Nephrology, Faculty of Medicine, Otto-von-Guericke University,
39112 Magdeburg, GERMANY

ABSTRACT

Progress in human genetics allows for information on severe human disorders such as Cystic Fibrosis, Huntington's chorea, Duchenne's disease, and ADPKD.

As only limited therapeutic and preventive measures are available in most cases, genetic information calls for developing carrier ethics, including health risk competence and a redefinition of the concept of responsible parenthood.

Pre-implementation diagnosis and early abortion, wherever clinically available and ethically acceptable, will become an instrument of new reproductive ethics. Human ADPKD disorder will be used as an exemplary case study for the impact of the Human Genome Project on medical ethics and carrier ethics in a transcultural perspective.

A MULTIGENERATIONAL FAMILY STORY
I met Mrs Winter, 55, in 1981, when she became a dialysis patient in our dialysis unit. As a carrier of Autosomal Dominant Polycystic Kidney Disease (ADPKD), she had developed renal insufficiency. In 1977 large cysts in both kidneys and in the liver were confirmed by ultrasound diagnosis. After Mrs Winter became a dialysis patient her four sons underwent ultrasound screening which showed, that all sons were presymptomatic carriers of ADPKD, living healthy lives. These were the reactions of the sons after they learned about their carrier status: First of all, the sons accused their mother for having as many as four children, even though she knew that this severe disease was running in the family. Mrs Winter's father and his two brothers had also died with renal insufficiency caused by ADPKD. Albert, 32, married, and father of a 6 year old son, committed suicide when he developed the first symptoms of pain and renal dysfunction three years later. Otto, 30, married, sold a house, which was half completed, when he learned about the diagnosis. He did not want to make long term plans for his life and burden his family with a mortgage. Karl, 25, and his fiancé dissolved their engagement because Karl did not want to have children, nor burden his fiancé with his own genetic predisposition. Paul, 21, the youngest, a student, did not complete his studies and took a job in order to make money and enjoy life while it lasted.

The Winter family story demonstrates very clearly different ways of translating DNA prediction into real life situations. This is in short the clinical and ethical challenge of DNA testing for severe human hereditary disorders. We are not just talking about genes and DNA, but about fellow humans, brothers and sisters, mothers, families with their hopes, fears, pain, satisfaction and enjoyment for life and suffering in life, discrimination and denial.

1. DNA-BASED PREDICTION OF SEVERE GENETIC DISORDERS
Molecular genetics has identified over 400 factors for hereditary diseases, and every day new factors are described and identified. Two percent of new-borns have genetic disorders of highest severity, which are life-threatening, or reduce the quality of life or span of life. Severe genetic disorders occur among four groups of disorders : (BLUM, 1993)
(1) HEMOGLOBINOPATHY : sickle cell anaemia, beta-thalassemia
(2) ENZYMOPATHY :
a) Carbohydrate meta-bolism ; galactosemia
b) Amino acid metabolism ; phenylketonuria
c) Lipid metabolism ; Gaucher's disease, Tay-Sachs disease
d) Mucopolysaccharid metabolism ; Hunter syndrome, Hurler syndrome
(3) OTHER DISEASES IN METABOLISM : lack of alpha-trypsin, Lesch-Nyhan disease,
Xeroderma pigmentosum, Duchenne's disease, Cystic Fibrosis
(4) ONCOLOGICAL AND OTHER DISEASES :
Retinoblastoma, Leukaemia, Lymphoma, Huntington's chorea, Alzheimer's disease, Haemophilia A and B, Neuro-fibromatosis von Recklinghausen, Friedreich's Ataxie, ADPKD.

Not all hereditary diseases are of the severest form. Among the most severe is Cystic Fibrosis (autosomal recessive), a multisystem disorder which is characterised by an abnormality in exocrine gland function. Nearly all patients develop chronic progressive disease of the respiratory system. Pulmonary disease is the most common cause of death and morbidity. Multiple clinical features include disturbances of the gastro-intestinal tract, reproductive system and skeletal system. Currently the median survival is about 20 years. The majority of Cystic Fibrosis patients are diagnosed in infancy or childhood. One of the most brutal disorders is Huntington's Chorea, (autosomal dominant) characterised by a combination of involuntary choreoathetotic movements and progressive dementia, usually beginning in mid-adult life. Younger patients, with an onset of symptoms in the age group of 15-40 years suffer a more severe form of disorder than older patients with an onset in the 50's and 60's. Lesch-Nyhan disease is an X-chromosomal-linked disorder of purin-metabolism. Affected patients have hyperuricemia and overproduction of uric acid with uric acid stones. In addition they have bizarre neurologic disorders, characterised by self-mutilation, hyperreflexia, choreoathetosis, spasticity and retardation of growth and mental function. The onset of symptoms begins at a young age between 15 and 30 years.

DNA factors inform about predictability of disorders, not about their severity, time of onset, severity of symptoms, span of life, quality of life and preventive options. Therefore genetic knowledge has to be translated into real life situations and predictions of families and individuals. Genetic risk factors alone do not predetermine the individual quality and the personal fate of human life. This is the clinical and ethical challenge to carriers, physicians, and society.

2. RISK AND RESPONSIBILITY OF PATIENTS WITH ADPKD
Individual, professional and societal challenges can be highlighted by ADPKD. This is a systemic disorder producing innumerable cysts of varying size in both kidneys, in liver, pancreas and ovaries. There are also structural abnormalities in the gastro-intestinal tract, e.g. colonic diverticulae, and in the cardio-vascular system, e.g. cardiac valvular abnormalities, thoracic aortic aneurysm, berry aneurysm of brain vessels.

About 5-10 percent of all patients on dialysis treatment suffer from cystic kidney disease. The countries of the EEC spend roughly 4 billion ECUs each year on renal replacement therapy, dialysis and transplantation. The frequency of ADPKD is 1:1000, which is more frequent than Cystic Fibrosis and Huntington's Chorea. An estimated half a million people have the disease in the United States. It is inherited as a autosomal-dominant trait with 100 percent penetrance. Hence each child of a carrier has a 50 percent risk to become a carrier her/himself. No sex preference is noted.

2.1. Genetics and Prognosis
Careful studies of patterns of DNA fragments have revealed consistent differences in the structure of DNA in the short arm of human chromosome 16 in association with ADPKD (BREUNING, 1990). Recent observations (KIMBERLING, 1988) indicate, that at least two different defects can be responsible for a very similar clinical picture, which cannot be distinguished in a single patient. These PKD-2 carriers live into their 7th to 9th decades and often die of nonrenal causes. PKD-1 carriers have symptoms and signs of the disease in their 4th and 5th decade. It is the usual experience that knowledge about the nature of ADPKD even in affected families, is poor.

Cysts are present in the kidneys from the 12th week of gestation. Very slowly these cysts grow in size and number, thereby destroying the functional tissue of the kidneys. End-stage renal failure usually occurs between the age of 40 and 60, but in fact varies considerably between patients, even between members of the same family. Autosomal dominant disorders are in general characterised by variability in age of onset and in phenotypic expression. Clinical age of onset is defined by the age at which symptoms appear or cysts can be found. The ages differ, depending upon the circumstances of inquiry (GABOW, 1993). Age of onset is also influenced by the technique used for screening.

The diagnosis of late stage ADPKD is easy: hypertension, abdominal pain, bilateral flank masses, hematuria or azotemia contribute to the typical clinical picture. Presymptomatic diagnosis can be done by ultrasonography, Computed-Tomography, or Magnetic Resonance Imaging. Since only about 60 percent of the patients will report a family history of this disease (GARDNER, 1989), presymptomatic, even prenatal and pre-implantation diagnosis can be done by methods of molecular genetics. DNA-based diagnosis is superior to ultrasound or X-ray based diagnosis as it can be done much, much earlier, either by analysing morula cells prior to implantation (HANDYSIDE, 1992) or by analysing fetal cells collected from maternal peripheral blood by non-invasive methods (KÜRTEN, 1993, LO Y- M, 1993) or by amniocentesis or chorionic villus biopsy.

2.2. Symptoms and Signs
Pain, caused by expanding and large kidneys, is the most common clinical symptoms of ADPKD in adults. Usually the pain is dull and constant, localised in the flank or lateral abdomen. Acute pain may arise from haemorrhage into a cyst or passage of a blood clot or stone. Sometimes inflammations, spreading to the renal bed from an infected cyst causes discomfort, usually in association with fever. Pain gradually increases over a patient's lifetime ultimately affecting more than 50 percent of the individuals.

Fifty percent of adult subjects with ADPKD experience hematuria at some time prior to diagnosis. Rupture of the cyst wall is blamed for the episodic hematuria in some patients. Episodes of gross hematuria can occur with strenuous physical activity and may last from days to weeks.

Gastro-intestinal complaints of nausea, vomiting, and diarrhoea are less common than renal symptoms, but can pose significant problems for occasional patients.

Headaches, often severe and recurrent, are a common occurrence unrelated to hypertension. Headaches may be caused by berry aneurysms of the brain vessels. They occur in 10-40 percent of affected persons and can rupture and cause sudden death.

Palpable hepatomegaly can be found in approximately one-half of individuals with ADPKD. This rarely causes symptoms or hepatic dysfunction or pain.

Hypertension is a common finding in otherwise healthy patients and occurs in approximately 60 percent of non-azotemic patients.

There are no typical changes in blood chemistry (anaemia, serum-creatinine and urea levels) until the onset of renal insufficiency (GRANTHAM, 1984).

We consider ADPKD to be a systemic disorder in which the phenotypic manifestation of the abnormal gene spans an array of organ systems. Not every affected individual manifests all the possible aspects. Both, inter-familial and intra-familial, variabilities occur in the extrarenal manifestation of ADPKD. Intra-family variability is illustrated by differing manifestations and severities of structural defects despite similar ages. Such intra-familial variability may reflect the influence of the non-ADPKD allele, of other genes, or environmental factors.

2.3. RISKS AND RESPONSIBILITIES OF PATIENTS
As the Winter family story shows, clinical manifestation as well as pre-symptomatic knowledge about the ADPKD disorder translates into very different individual life stories. To be informed about one's own carrier status is important for good hypertension prevention and for avoidance of work-related or sports-related rupture of cysts; ways and responses in coping will be different individually.

Pre-symptomatic knowledge also seems to be important for making life plan decisions which take the specifics of the probability of dialysis treatment or kidney transplantation into account. Decisions include career planning, occupational, professional, and recreational activities, family planning, social and cultural interactions. Each individual will translate her/his carrier status and symptoms into different parameters of individual life, its qualities, goals and limitations Knowledge is important for a preventive life style, for example: most essential hypertension control. Some recreational activities are not recommended as they might cause hematuria, such as jogging, horseback riding, wrestling, soccer or heavy physical work. It is also important to know about one's carrier status when making reproductive choices.

This is an issue of self-determination for each carrier to have adequate information, knowledge and counselling in career planning, life style and family planning. My clinical experience is, that there is a duty to know about carrier status of ADPKD on behalf of the carrier and there is a responsibility for clinicians, geneticists and families to consult with the carrier on medical and non-medical risks and decisions.

A very special responsibility is associated with family planning decisions of carriers. Because the best 'prevention' of ADPKD might be the 'prevention' of the future carriers, which can be done by :
a) not having procreative sex or using contraceptives,
b) selective abortion following early prenatal diagnosis
c) selective non-implantation following pre-implantation diagnosis.

3. RISKS AND RESPONSIBILITIES OF PARENTS

3.1. THE CASE OF ANITA M.
The ethical parameters of responsible parenthood of carriers of severe genetic diseases are well illustrated in the case of Anita M. Anita had been diagnosed as a carrier of ADPKD at the age of 16 when she was a subject in a research project which studied the family history of patients with this disease. Five years later she is 21 years old and pregnant. Her mother, 45, divorced, is a RDT-patient, her grandmother has just died due to liver complications after being in dialysis treatment for 14 years. Anita requests prenatal testing which now can be done by genetic screening. She expresses an obligation not to give birth to a baby with definite diagnosis and prognosis of ADPKD, as this means dialysis dependency in later years, and the certainty of decreased quality of life, such as renal complications, pain and hypertension allowing only for limited quality of life and a way of suffering and dying she had just witnessed in her grandmother's last years. The test identifies the fetus positively as a carrier. Anita schedules a counselling session prior to setting a date for selective abortion, but she misses this appointment, never calls back, and probably had moved somewhere else and had given birth to her child.

3.2. VALUES AT CONFLICT
In Anita's case there are at least four different values in conflict: first of all respect for life, secondly self-determination, further-more responsible parenthood, and family planning.

As in most cases of reproductive ethics Anita faces a special challenge in balancing the respect for unborn life and responsible parenthood. This is a different situation from normal conflicts between the right to choose (self-determination of the mother) and the right to live (respecting potential interests of the fetus). Anita's fetus carries a severe genetic disorder which forecasts, if nothing else happens, an uncomfortable dialysis treatment reducing the quality of life, or transplantation plus all the other associated burdens and symptoms of ADPKD (KIELSTEIN, 1993). Aborting the fetus might be an ethical option of responsible parenthood and indeed, it was the predetermined choice of Anita. The fact that she did not have the abortion might be caused by:
a) emotional stress,
b) actual situational ethical uncertainty,
c) expecting to become a mother and having a baby, no matter what the carrier status is,
d) avoiding making any decisions, further more it could have been
e) putting trust in the progress of ADPKD treatment for the next 30 years, until the onset of her fetus's symptoms (KIELSTEIN/SASS, 1992).

3.3. MEDICAL MORAL SCENARIOS FOR RESPONSIBLE PARENTHOOD
I see at least 8 scenarios of decision making in reproductive ethics for severe genetic disorders in cases similar to Anita's situation :
1.) GIVING BIRTH and establishiNG a family by having children is a very normal individual and cultural goal in a woman's life. An ADPKD carrier most likely will be 'healthy' and happy for a long period of life and might even die of other causes a long time before the onset of severe symptoms. The offspring might have a families of their own and over the next few decades progress in medicine might develop new methods of prevention, healing, or treatment of kidney cysts. On the other hand, the mother knowingly gives life to a carrier of a very severe genetic disorder. Can she responsibly do that, being aware of many future risks and uncertainties, including expensive and uncomfortable dialysis treatment or transplantation ? Also accusations of "irresponsible parenthood" may come from the offspring, the spouse, the family at large, the society and the insurance companies.
2.) ABORTION, Anita could have chosen abortion as her preferred means of contraception because she did not want to give birth to a child having the same disease as her mother, grandmother and herself. But other family planning methods would be of higher moral acceptance such as sterilisation, the use of contraceptives, or selective abortion after prenatal diagnosis only.
3.) ABORTION AFTER PRENATAL DIAGNOSIS would value the principle of responsible parenthood higher than the principle of respect for life or giving birth in general. If parents have responsibilities for the children then there is a prime parental duty not to harm the unborn by an unhealthy life style, such as smoking cigarettes or drinking alcohol excessively and consequently there might be a duty not to give birth to a child 'harmed' by one's own severe genetic disorder.
4.) PRE-IMPLANTATION DIAGNOSIS Carriers of severe hereditary diseases might, for medical, ethical and emotional reasons prefer pre-implantation diagnosis over elective abortion. Pre-implantation diagnosis has been reported to be successful in Cystic Fibrosis (HANDYSIDE, 1992) and might become the ethical instrument of first choice in responsible parenthood decisions.
5.) NOT HAVING CHILDREN might be a choice for those who, for religious or ethical reasons, do not accept diagnosis or selection of unborn human life.
6.) NOT GETTING MARRIED, or having no heterosexual partners, most likely will be based on other than reproductive decisions, but will have the side effect that carriers will not implant their own severe disorder into other (new) people. In the modern world the carrier status also could be used as an excuse for a responsibility-free singles life-style.
7.) ADOPTION of a non-carrier would allow for having a child of one's own who would not be a carrier, but family planning by adoption would come within the well known parameters of ethical and emotional 'pros and cons' of adoption.
8.) TO GIVE BIRTH TO A CARRIER and let the carrier be adopted by others would be the worst case scenario for responsible parenthood. There are never uniform medical or ethical cases. Each case will be different medically and ethically, so will the family situation and the enframing culture. I recommend that we avoid the inflexible legal or medical standards for handling reproductive choices of ADPKD carriers or any other carriers of severe genetic disorders. Rather, I feel non-directive counselling would be the best ethical approach of clinicians and geneticists. In my opinion severe genetic disorders are part of the family history heritage and should be dealt with, within the family and not by governmental or medical authorities. In order to assist the patient in making responsible decisions for her/himself and for reproductive choices, a four step approach in medical and ethical counselling can be used. This four step method helps the carrier, pre-symptomatic or symptomatic, to make decisions for her/himself, or in family planning.
The first step identifies the problem by :
a) collecting DNA-based data and
b) human data and
c) identifying value elements.

In a second step the consultant:
a) establishes the medical prognosis for different future scenarios,
b) identifies the ethical principles and problems for each scenario, and
c) discusses medical, ethical and personal issues within each scenario with the patient.

A third step addresses risks and risk management by:
a) discussing medical and moral uncertainties,
b) identifying moral agents, and
c) assisting the patient to define 'the best solution'.

In a final step the consultant assists the patient in reviewing the patient's decision by:
a) asking her/him to clearly specify her /his reasoning,
b) to address uncertainties and risks associated with the patient's reasoning, and
c) to defend her/his decision.

3.4. IDENTIFYING RISK TAKERS AND MORAL AGENTS
Moral agents for making decisions, exclusively or jointly, could be governed by law, insurance companies or health care systems, religious or societal groups, consulting professional (clinician and/or geneticists, ethicists, or team), families, spouses, women. In this and the following scenarios my personal choice would be to make the woman the prime moral agent for reproductive choice and responsible parenthood. She is the nucleus, as she carries the future person in her, it is a part of her body, and none has access to it.
Subsequent responsibilities are in the wider circles of spousal responsibility, thereafter family, physician (primarily clinicians rather than geneticists) and ethicists have consulting but no deciding authority (non-directive counselling !). I see some reasons for moral input on behalf of the payment system (however that is organised ), but very minimal rights of the state to intervene in very private family matters. There might be a difference between post-enlightenment European individualism and traditional Confucian and Asian thinking in the framework of family network and solidarity, which I hope we will address in detail in our discussions on multicentral and cross cultural factors of moral decision making in reproductive ethics.

4. CONCLUSION

Let me conclude with questions rather than answers. Answers are not easy in modern pluralistic societies based on individual self-determination; they are even more complicated in the global multicultural world. Predictive medicine presents new scenarios for the physician-patient interaction and will change priorities among traditional principles, maxims and models of medical ethics.

Progress in DNA testing and in predictive medicine is more a challenge to the ethics of the legal decision makers than to the medical profession. Acute crisis-style intervention, step by step, will have to be replaced by non-acute predictive or preventive discourse. New methods of assessing technical and ethical risks and probabilities will have to be developed in order to translate the certainty of hereditary facts into uncertainty of prognosis and health risks, quality of life parameters, health literacy and self determination of the citizen/patient, and the design of prevention and therapy. The clinical and ethical challenges of DNA based predictive medicine can be summarised around five questions:
(1) Who is the prime moral agent?
(2) Is there a duty to know or a right not to know?
(3) How will predictive medicine influence future medicine?
(4) How will predictive medicine influence future medical ethics?
(5) How will the 'global village' deal with moral issues?

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