Volume 46, Issue 3 , Pages 557-559, September 2005
Hypertension in Individuals at Risk for Autosomal Dominant Polycystic Kidney Disease: To Screen or Not to Screen?
Article Outline
AUTOSOMAL DOMINANT polycystic kidney disease (ADPKD) is one of the most common genetic disorders. Recent advances in the understanding of the molecular and cell biology of cystic kidney disease, including discoveries of the likely participation of the primary cilium in the pathogenesis of cystogenesis and the role of cyclic adenosine monophosphate in the enhancement of growth and fluid secretion of cystic epithelium, provide a basis for great excitement and hope regarding prospects for the development of therapeutic interventions. The recent demonstration of the marked inhibition of cyst growth in multiple animal models of cystic kidney disease by the vasopressin V2 receptor antagonists OPC31260 and OPC41061 has led to substantial interest in the use of these agents in clinical investigations of human ADPKD.1 Pending proof of efficacy to delay the progression of cystic kidney disease by these agents or others (ie, angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers), it is reasonable to ask whether the at-risk individual in an ADPKD family should undergo diagnostic testing in the absence of signs or symptoms of illness.
Taylor et al2 report in the present issue of the American Journal of Kidney Diseases that individuals born between 1951 and 1974 were diagnosed with ADPKD at an earlier age than a cohort born before 1951. It is unclear whether earlier diagnosis in the younger cohort reflects greater understanding of the genetic nature of ADPKD or the more widespread use of kidney ultrasound. The benefits of making an earlier diagnosis need to be considered, along with the potential for anxiety and discrimination that may accompany the knowledge that one carries a chronic and, ultimately, fatal disease.
The many advantages of knowing one’s disease status at an early and asymptomatic stage include: (1) the ability to institute specific therapy targeted at delaying the progression of kidney disease (although, at present, a specific therapy to reduce cystogenesis does not exist); (2) earlier detection and management of hypertension, progressive kidney failure, and its complications; (3) provision of more detailed and specific information regarding prognosis and risk for complications; (4) the ability to make more informed reproductive choices; (5) motivation for enhanced compliance and medical follow-up; and (6) the ability to share otherwise blood-group–incompatible kidneys across extended ADPKD families to maximize the number of living donor kidney transplantations. Unfortunately, at this time, specific therapy with proven efficacy targeted at renal progression is not available.
The overall and cardiovascular benefits of treating hypertension in patients with ADPKD are well summarized in the article by Taylor et al.2 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Blood Pressure recommends a lower-than-usual blood pressure goal of less than 130/80 mm Hg for individuals with proteinuria (atypical of ADPKD) and/or those with a glomerular filtration rate less than 60 mL/min/1.73 m2 (<1.00 mL/s),3 in recognition of the high cardiovascular risk of this population. There are several compelling reasons why individuals with ADPKD, even with normal kidney function, also should be treated to this lower blood pressure goal. Specifically, hypertension occurs earlier in the course of disease than with other forms of CKD, and cardiovascular disease also has been shown to be prevalent at relatively early stages of the disease. In addition, the progressive loss of kidney function, which further increases the risk for cardiovascular disease, is a predictable outcome of ADPKD. An analysis of long-term follow-up of the Modification of Diet in Renal Disease Study cohort showed that a relatively short interval (median treatment time, 2.2 years) of low target blood pressure control (mean arterial pressure, <92 mm Hg) decreased the relative risk for kidney failure after a median of approximately 6 years by one third compared with that in individuals treated with usual target blood pressure control (mean arterial pressure, <107 mm Hg).4 This effect was similar irrespective of the cause of kidney disease, including ADPKD. Whether aggressive blood pressure lowering has even greater benefits if applied at an early stage of disease (glomerular filtration rate > 60 mL/min/1.73 m2 [>1.00 mL/s/1.73 m2]) will be assessed as part of the National Institutes of Health–sponsored Halt Progression in Autosomal Dominant Polycystic Kidney Disease (HALT-PKD) Study, scheduled to start in the fall of 2005. In terms of an earlier diagnosis affecting the choice of antihypertensive agent, angiotensin blockade already is used commonly for treatment of hypertension in patients with ADPKD.5 Recent guidelines6 suggest no preference for an agent in the absence of proteinuria, so early diagnosis would not alter this aspect of hypertension management.
Given the actual or potential medical benefit of making a diagnosis of ADPKD, what is the downside of testing asymptomatic members of an ADPKD family? For some individuals, the emotional burden and anxiety of knowing their disease status prevents them from seeking testing for ADPKD. However, for others, the major concerns about presymptomatic testing relate to concerns about insurance- or employment-based discrimination because of their risk for needing expensive medical care for kidney failure and the need for dialysis or transplantation. The extent to which this is a realistic concern has not been defined. In 1996, Golin et al7 surveyed individuals with ADPKD and found that 57% made employment choices based on the availability of employer-provided health insurance, 37% stayed on the job because of health insurance, and 30% had previously been denied health insurance. A recent commentary suggests that genetic discrimination is increasingly common.8 Concerns about this issue have risen to the federal level. The Senate has unanimously passed legislation addressing genetic discrimination (S. 306, the Genetic Information Nondiscrimination Act of 2005). A similar version of the legislation (HR 1227) awaits action in the House of Representatives.
Few would disagree that the presence of such signs or symptoms as hematuria, urinary tract infection, nephrolithiasis, or pain in an at-risk individual should mandate diagnostic testing with kidney imaging. In addition, manifestation of any of the extrarenal complications of ADPKD should be investigated fully with all appropriate diagnostic modalities. The earlier detection of hypertension, given the young age of onset and high cardiovascular risk of this population, argues in favor of making an earlier diagnosis. The choice of antihypertensive agents is not necessarily affected by precise knowledge of ADPKD, but the level of blood pressure targeted possibly should be lower for an individual with ADPKD, even with normal kidney function, than for treatment of patients with essential hypertension.
Increased awareness of ADPKD as an inherited disorder has led to the possibility of earlier diagnostic screening and potentially earlier implementation of medical interventions that could impact on disease progression and extrarenal manifestations. We believe that the potential medical benefits of screening for ADPKD are evident. However, concerns about establishing a “preexisting condition” for insurance purposes may rightfully raise concerns about testing for ADPKD and thereby prevent initiation of intensive antihypertensive therapy and other appropriate interventions. It also is possible that some family members in ADPKD families avoid medical encounters entirely because of such concerns, but there is only anecdotal information regarding this possibility. Access to clinical research trials for individuals at earlier stages of disease, especially those with well-preserved kidney function, would be precluded should such individuals remain undiagnosed. Therefore, it is unfortunate and potentially tragic that some individuals affected by ADPKD may not avail themselves of appropriate medical interventions or access to therapeutic clinical trials because of concerns about health insurance or other discrimination. Genetic nondiscrimination should be the law of the land.
References
- . Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat . J Am Soc Nephrol . 2005;16:846–851
- . Earlier diagnosis of autosomal dominant polycystic kidney disease (Importance of family history and implications for cardiovascular and renal complications) . Am J Kidney Dis . 2005;46:415–423
- Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (The JNC 7 Report) . JAMA . 2003;289:2560–2572 (erratum in JAMA 290:197, 2003)
- The effect of a lower target blood pressure on the progression of kidney disease (Long-term follow-up of the Modification of Diet in Renal Disease Study) . Ann Intern Med . 2005;142:342–351
- Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD) (The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) cohort) . Kidney Int . 2003;64:1035–1045
- . K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease . Am J Kidney Dis . 2004;43(suppl 1):S1–S290
- . Insurance for autosomal dominant polycystic kidney disease patients prior to end-stage renal disease . Am J Kidney Dis . 1996;27:220–223
- . Genetic nondiscrimination . Nat Genet . 2005;37:559–560
PII: S0272-6386(05)00919-4
doi:10.1053/j.ajkd.2005.07.016
© 2005 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
Refers to article:
- Earlier Diagnosis of Autosomal Dominant Polycystic Kidney Disease: Importance of Family History and Implications for Cardiovascular and Renal Complications , 22 July 2005
Volume 46, Issue 3 , Pages 557-559, September 2005
