Autosomal dominant polycystic kidney disease: Emerging concepts of pathogenesis and new treatments
ABSTRACTSome of the mystery of autosomal dominant polycystic kidney disease (ADPKD) is starting to clear. Basic research is shedding light on its pathogenesis, and new treatments are in clinical trials. This paper reviews some of these advances and what they mean to patients.
KEY POINTS
- In ADPKD the expanding cysts destroy normally functioning kidney tissue, causing hypertension, pain, and other complications, but renal function remains relatively stable until kidney volumes reach a critical size.
- Testing for genetic defects that cause ADPKD is available. The specific mutation involved (PKD1 or PKD2) affects the age of onset and therefore the rate of disease progression as well as the likelihood of cardiovascular complications. Other factors include somatic mutations (“second hits”) of the normal paired chromosome.
- Intracranial aneurysms are a key noncystic feature and may present with a very severe (“sentinel” or “thunderclap”) headache requiring immediate medical attention. Their occurrence is strongly influenced by family history.
- Basic research indicates that patients may be advised to increase their water intake, limit their sodium intake, and avoid caffeine and methylxanthine derivatives.
What does this mean for our patient?
Although these results were derived primarily from animal experiments, they do provide a substantial rationale for advising our patient to:
Drink approximately 3 L of water throughout the day right up to bedtime in order to suppress vasopressin secretion and the stimulation of cAMP. This should be done under a doctor’s direction and with regular monitoring.15,17,18,23
Avoid caffeine and methylxanthines because they block phosphodiesterase, thereby leaving more cAMP to stimulate cyst formation.19,20
Follow a low-sodium diet (< 2,300 mg/day), which, while helping to control hypertension and kidney stone formation, may also help to maintain smaller cysts and kidneys. Keith et al,24 in an experiment in rats, found that the greater the sodium content of the rats’ diet, the greater the cyst sizes and kidney volumes by the end of 3 months.
Consider participating in a study. Several clinical treatment studies in ADPKD are currently enrolling patients who qualify:
- The Halt Progression of Polycystic Kidney Disease (HALT PKD) study, funded by the National Institutes of Health, is comparing the combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) vs an ACE inhibitor plus placebo. Participating centers are Beth Israel Deaconess Medical Center, Cleveland Clinic, Emory University, Mayo Clinic, Tufts-New England Medical Center, University of Colorado Health Sciences Center, and University of Kansas Medical Center. This study involves approximately 1,020 patients nationwide.
- The Tolvaptan Efficacy and Safety in Management of Polycystic Disease and its Outcomes (TEMPO) study plans to enroll approximately 1,500 patients.
- Rapamycin is being studied in a pilot study at Cleveland Clinic and in another study in Zurich, Switzerland.
- A study of everolimus, a shorter-acting mTOR inhibitor, is beginning.
- A study of somatostatin is under way in Italy.
HYPERTENSION AND ADPKD
Uncontrolled hypertension is a key factor in the rate of progression of kidney disease in general and ADPKD in particular. It needs to be effectively treated. The target blood pressure should be in the range of 110 to 130 mm Hg systolic and 70 to 80 mm Hg diastolic.
Hypertension develops at least in part because the renin-angiotensin-aldosterone system (RAAS) is up-regulated in ADPKD due to renal cysts compressing and stretching blood vessels.25 Synthesis of immunoreactive renin, which normally takes place in the juxtaglomerular apparatus, shifts to the walls of the arterioles. There is also ectopic renin synthesis in the epithelium of dilated tubules and cysts. Greater renin production causes increases in angiotensin II and vasoconstriction, in aldosterone and sodium retention, and both angiotensin II and aldosterone can cause fibrosis and mitogenesis, which enhance cyst formation.
ACE inhibitors partially reverse the decrease in renal blood flow, renal vascular resistance, and the increase in filtration fraction. However, because some angiotensin II is also produced by an ACE-independent pathway via a chymase-like enzyme, ARBs may have a broader role in treating ADPKD.
In experimental rats with polycystic kidney disease, Keith et al24 found that blood pressure, kidney weight, plasma creatinine, and histology score (reflecting the volume of cysts as a percentage of the cortex) were all lower in animals receiving the ACE inhibitor enalapril (Vasotec) or the ARB losartan (Cozaar) than in controls or those receiving hydralazine. They also reported that the number of cysts and the size of the kidneys increased as the amount of sodium in the animals’ drinking water increased.
The potential benefits of giving ACE inhibitors or ARBs to interrupt the RAAS in polycystic disease include reduced intraglomerular pressure, reduced renal vasoconstriction (and consequently, increased renal blood flow), less proteinuria, and decreased production of transforming growth factor beta with less fibrosis. In addition, Schrier et al26 found that “rigorous blood pressure control” (goal < 120/80 mm Hg) led to a greater reduction in left ventricular mass index over time than did standard blood pressure control (goal 135–140/85–90 mm Hg) in patients with ADPKD, and that treatment with enalapril led to a greater reduction than with amlodipine (Norvasc), a calcium channel blocker.
The renal risks of ACE inhibitors include ischemia from further reduction in renal blood flow (which is already compromised by expanding cysts), hyperkalemia, and reversible renal failure that can typically be avoided by judicious dosing and monitoring.27 In addition, these drugs have the well-known side effects of cough and angioedema, and they should be avoided in pregnancy.
If diuretics are used, hypokalemia should be avoided because of both clinical and experimental evidence that it promotes cyst development. In patients who have hyperaldosteronism and hypokalemia, the degree of cyst formation in their kidneys is much greater than in other forms of hypertension. Hypokalemia has also been shown to increase cyst formation in rat models.
What does this mean for our patient?
When hypertension develops in an ADPKD patient, it would probably be best treated with an ACE inhibitor or an ARB. However, should our patient become pregnant, these drugs are to be avoided. Children of a parent with ADPKD have a 50:50 chance of having ADPKD. Genetic counseling may be advisable.
Chapman et al28 found that pregnant women with ADPKD have a significantly higher frequency of maternal complications (particularly hypertension, edema, and preeclampsia) than patients without ADPKD (35% vs 19%, P < .001). Normotensive women with ADPKD and serum creatinine levels of 1.2 mg/dL or less typically had successful, uncomplicated pregnancies. However, 16% of normotensive ADPKD women developed new-onset hypertension in pregnancy and 11% developed preeclampsia; these patients were more likely to develop chronic hypertension. Preeclampsia developed in 7 (54%) of 13 hypertensive women with ADPKD vs 13 (8%) of 157 normotensive ADPKD women. Moreover, 4 (80%) of 5 women with ADPKD who had prepregnancy serum creatinine levels higher than 1.2 mg/dL developed end-stage renal disease 15 years earlier than the general ADPKD population. Overall fetal complication rates were similar in those with or without ADPKD (32.6% vs 26.2%), but fetal prematurity due to preeclampsia was increased significantly (28% vs 10%, P < .01).28
The authors concluded that hypertensive ADPKD women are at high risk of fetal and maternal complications and measures should be taken to prevent the development of preeclampsia in these women.
In conclusion, the patient with ADPKD can present many therapeutic challenges. Fortunately, new treatment approaches combined with established ones should begin to have a favorable impact on outcomes.
