Advances in autosomal dominant polycystic kidney disease—2014 and beyond
ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD), which frequently leads to end-stage renal disease, currently has no specific drug therapies. Better understanding of its pathogenesis and recent clinical trials have led to more accurate diagnosis of the disease and its manifestations, as well as to promising new approaches to treatment.
KEY POINTS
- For at-risk patients in the previously difficult diagnostic group from 30 to 39 years of age, newer ultrasonographic criteria for diagnosing PKD1 and PKD2 now require a minimum total of three renal cysts.
- An intracranial aneurysm occurs in approximately 16% of ADPKD patients who have a family member with ADPKD plus an intracranial aneurysm or subarachnoid hemorrhage. Appropriate screening is warranted.
- Combined positron-emission and computed tomography helps identify infected renal or liver cysts and may uncover other unsuspected abdominal or pelvic infections.
- Cyst expansion and increasing total kidney volume might be slowed by increasing water intake to 2,500 to 3,000 mL per day, although formal documentation of this is not published. However, this must be done under a physician’s supervision because of possible adverse effects.
- Tolvaptan, a promising new drug for treating ADPKD, failed to receive US approval. Rapamycin is another potentially effective agent but has had mixed results in clinical trials.
NEW CONCEPTS
Specialized cells also promote renal cyst formation
Specialized cells that promote cyst formation have been identified by Karihaloo et al49 in a mouse model of polycystic kidney disease. In this model, alternatively activated macrophages homed to cystic areas and promoted cyst growth. These findings suggested that interrupting the homing and proliferative signals of macrophages could be a therapeutic target for ADPKD. Although rapamycin can suppress macrophage proliferation by macrophage colony-stimulating factor and inhibit macrophage function,50 alternatively activated macrophages have not been specifically studied for rapamycin responsiveness.
More promising is evidence that CD133+ progenitor cells from human ADPKD kidneys—but not from normal human kidneys—form cysts in vitro and in severe combined immunodeficient mouse models.51 Treatment with rapamycin decreased proliferation of the de-differentiated CD133+ cells from ADPKD patients and reduced cystogenesis.51
Visible cysts are the tip of the iceberg
Using ADPKD nephrectomy specimens from eight patients, Grantham et al52 compared cyst counts by MRI and by histology and found that for every renal cyst detected by MRI, about 62 smaller cysts (< 0.9 mm) are present in the kidney. For a typical patient having an average of 587 cysts in both kidneys that are detectable by MRI, this means that more than 36,000 cysts are actually present, and MRI detects less than 2% of the total cysts present.
Although microcysts are too small to contribute much to total kidney volume, they can interfere with kidney function. Microcysts can reduce GFR in two major ways: by compressing microvasculature, tubules, and glomeruli in the cortex; or by blocking the drainage of multiple upstream nephrons when they form in or block medullary collecting ducts.52 Although the growth rates of microcysts less than 1 mm in size have not yet been measured, the adult combined growth rates of the renal cyst component is approximately 12% per year, with yearly individual cyst growth rates up to 71%, and with fetal cyst growth rates even higher for cysts larger than 7.0 mm.53 Before and during an accelerated growth period, microcysts may be susceptible to certain therapies that could first improve GFR and only later change measurable total kidney volume by slowing microcyst progression to macrocysts either directly or through specialized cells that may be sensitive to rapamycin.
CURRENT MANAGEMENT OF ADPKD
Blood pressure control is essential—but too low is not good. For adult patients with hypertension caused by ADPKD, an acceptable blood pressure range is 120–130/70–80 mm Hg. However, further information from recently published blood pressure guidelines54 and the results of the Halt Progression of Polycystic Kidney Disease (HALT-PKD) study to be reported in late 201455 may provide more precise ranges for blood pressure control in ADPKD.
Although substantial experimental evidence exists for the benefits of inhibiting the up-regulation of the renin-angiotensin-aldosterone system in ADPKD, clinical proof is not yet available to confirm that angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are preferred therapy.55 This may be determined by results of the HALT-PKD study, due for release in late 2014.55
Controlling blood pressure should be done with caution. Patients with low GFRs whose blood pressure is too low tend to have a more rapid decline of GFR, as suggested in the Modification of Diet in Renal Disease (MDRD) study in 1995.56
Experimental evidence suggests that avoiding calcium channel blockers may be advisable. Yamaguchi et al34 found that calcium channel blockers worsen the calcium transport defect and convert tubular epithelial cells to a proliferative phenotype.34
High fluid intake (2,500–3,000 mL/day), because it suppresses vasopressin, may be useful if permitted by several factors such as the patient’s cardiopulmonary and renal and electrolyte status, other medications, and diet.31 The reader is referred to a detailed description of the precautions necessary when prescribing high water intake.31 Patients should have their fluid intake managed by a physician and their renal function and serum sodium and electrolytes monitored regularly in order to avoid hyponatremia. Severe hyponatremia has occurred in patients with ADPKD and impaired kidney function who drank excessive quantities of water. Cardiac and pulmonary complications from excessive fluid intake are also possible, especially with a low GFR and compromised cardiac function.
A low-sodium diet, if not a contributing factor in hyponatremia, can be used under physician direction in the management of hypertension as well as in the prevention of calcium oxalate kidney stones.
Caffeine should be avoided because it may interfere with the activity of the phosphodiesterase that is necessary for the catabolism of cAMP to 5′AMP.
A low-protein diet is of unproven benefit,56 but it is prudent to avoid high protein intake.57
Complications such as bleeding (into or from cysts), infection (urinary tract, kidney cysts, and liver cysts), kidney stones, and urinary tract obstruction should be treated promptly and may require hospitalization.
Regular symptom reviews and physical examinations need to be performed with nonrenal concerns also in mind, such as intracranial aneurysms and cardiac valve lesions.11,58
Formal genetic counseling and molecular testing are becoming more frequently indicated as more complex inheritance patterns arise.6–8,59
Renal replacement therapy in the form of dialysis or transplantation is usually available for the patient when end-stage renal disease occurs. In the largest study thus far, ADPKD patient survival with a kidney transplant was similar to that of patients without ADPKD (about 93% at 5 years), and from 5 years to 15 years death-censored graft survival was actually better.60 Thromboembolic events are more frequent after transplantation,27,60 but they may also occur before transplantation from a massive right kidney compressing the iliac vein or the inferior vena cava, or both, leading to thrombus formation.26
Investigational as well as standard drug studies have intensified. Results from a large randomized study in approximately 1,000 adult ADPKD patients that evaluated over 6 to 8 years the effects of ACE inhibition with or without ARB treatment of hypertension, at both usual and lower blood pressure ranges in those with good renal function, are expected in late 2014.55 Outcomes from a few small clinical studies, eg, one with long-acting somatostatin31,61 and one using low-dose rapamycin48 in adults with ADPKD, will require confirmation in large randomized placebo-controlled clinical studies. In a new 3-year randomized placebo-controlled study of 91 children and young adults (ages 8 to 22) with ADPKD and essentially normal renal function who continued treatment with lisinopril, the addition of pravastatin (20 mg or 40 mg daily based on age) resulted in a significant reduction in the number of patients (46% vs 68%, respectively, P = .03) experiencing a greater than 20% change (increase) in height-adjusted total kidney volume.62 Change in GFR was not reported,62 but an earlier 4-week study in 10 patients treated with simvastatin did show an increase in renal blood flow and GFR.63 Numerous other agents that lack human studies include some described in older experimental work (eg, amiloride,31,64 citrate31,65) and many others from a growing list of potential therapeutic targets.31,66–73 It must be emphasized that there is no FDA-approved medication specifically for the treatment of ADPKD.
Future specific treatments of ADPKD may also involve minimally toxic doses of combination or sequential therapy directed at precystic and then both micro- and macrocystic/cystic fluid expansion aspects of ADPKD.48,74 Unfortunately, at the present time there is no specific FDA-approved therapy for ADPKD.
