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.
THE ROLE OF VASOPRESSIN AND ACTIVATION OF cAMP
In classic experiments, Wang et al36 cross-bred rats having genetically inherited polycystic kidney disease (actually, autosomal recessive polycystic kidney disease) with Brattleboro rats that completely lack vasopressin. At 10 and 20 weeks of age, the offspring had virtually complete inhibition of cystogenesis because of the absence of vasopressin. However, when vasopressin was restored by exogenous administration continuously for 8 weeks, the animals formed massive renal cysts.
Vasopressin activates cAMP, which then functions as a second messenger in cell signaling. cAMP increases the activation of the protein kinase A (PKA) pathway, which in turn increases downstream activity of the B-raf/ERK pathway. Up-regulation of cAMP and PKA appears to perpetuate activation of canonical Wnt signaling, down-regulate non-canonical Wnt/planar cell polarity signaling, and lead to loss of tubular diameter control, resulting in cyst formation.31 Normally, cAMP is degraded by phosphodiesterase. However, because of the primary cilium calcium transport defect in ADPKD, phosphodiesterase is reduced and cAMP persists.37 In conjunction with the defective primary cilial calcium transport, cAMP exerts a proliferative effect on renal tubular epithelial cells that is opposite to its effect in normal kidneys.31,32 cAMP also up-regulates the cystic fibrosis transmembrane conductance regulator (CFTR) that promotes chloride ion transport. Sodium ions follow the chloride ions, leading to fluid accumulation and cyst enlargement.31
Inhibiting vasopressin by increasing water intake
A simple key mechanism for limiting vasopressin secretion is by sufficient water ingestion. Nagao et al38 found that rats with polycystic kidney disease given water with 5% glucose (resulting in 3.5-fold increased fluid intake compared with rats given tap water) had a 68% reduction in urinary vasopressin and a urine osmolality less than 290 mOsm/kg. The high-water-intake rats had dramatically reduced cystic areas in the kidney and a 28% reduction of kidney-to-body weight ratio vs controls.
In an obvious oversimplification, these findings raised the question of whether a sufficient increase in water intake could be an effective therapy for polycystic kidney disease.39 A pilot clinical study evaluated changes in urine osmolality in eight patients with ADPKD who had normal renal function.40 At baseline, 24-hour urine osmolality was typically elevated to approximately 753 mOsm/kg compared to the plasma at 285 mOsm/kg, indicating that antidiuresis is the usual state. During the 2-week study, urine volume and osmolality were measured, and additional water intake was adjusted in order to achieve a urine osmolality goal of 285 ± 45 mOsm/kg. These adjustments resulted in water intake that appeared to be in the range of 2,400 to 3,000 mL per 24 hours. The major limitations of the study were that it was very short term, and there was no opportunity to measure changes in total kidney volume or estimated GFR.
In a recent preliminary report from Japan, high water intake (2,500–3,000 mL daily) in 18 ADPKD patients was compared over 12 months with ad libitum water intake in 14 ADPKD controls (clinicaltrials.gov NCT 01348505). There was no statistically significant change in total kidney volume or cystatin-estimated GFR in those on high water intake, but serious defects in study design (patients in the high water intake group were allowed to decrease their intake if it was causing them difficulty, and patients in the ad libitum water intake group had no measurement of their actual water intake) prevent any conclusions because there was no evidence that the groups were different from one another with respect to the key element of the study, namely, water intake.
Blocking the vasopressin receptor slows disease progression
Using another approach, Gattone et al41 inhibited the effect of vasopressin by blocking the vasopressin 2 receptor (V2R) in mouse and rat models of polycystic kidney disease, using an experimental drug, OPC31260. The drug halted disease progression and, in one situation, appeared to cause regression of established disease. As noted by Torres and Harris,31 even though both increased water intake and V2R antagonists decrease cAMP in the distal tubules and collecting ducts, circulating levels of vasopressin are decreased by increased water intake but increased by V2R antagonists.
After these remarkable results in animal models, clinical trials of the V2R antagonist tolvaptan were conducted in patients with ADPKD. In the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes 3:4 study,42 1,445 adults (ages 18 to 50) with ADPKD in 133 centers worldwide were randomized to receive either tolvaptan or placebo for 3 years. Key inclusion criteria included good renal function (estimated GFR ≥ 60 mL/min) and total kidney volume of at least 750 mL (mean 1,700 mL) as measured by MRI. Tolvaptan was titrated to the highest tolerated twice-daily dose (average total of 95 mg/day). All patients were advised to maintain good hydration and to avoid thirst by drinking a glass of water after each urination. Unfortunately, neither water intake nor urine output was measured.
The primary end point was the annual rate of change in total kidney volume, with secondary end points of clinical progression (worsening kidney function, pain, hypertension, albuminuria), and rate of decline in kidney function as measured by the slope of the reciprocal of serum creatinine.42
Patients in the tolvaptan arm had a slower annual increase in total kidney volume than controls (2.8% vs 5.5%, respectively, P < .001) and a slower annual decline in renal function (−2.61 vs −3.81 mg/mL−1, respectively, P < .001).42 More participants in the treatment group withdrew than in the placebo group (23% vs 14%, respectively).
Adverse events occurred more frequently with tolvaptan.42 Liver enzyme elevations of greater than three times the upper limit of normal occurred in 4.4% of patients in the treatment group, leading to a drug warning issued in January 2013. As expected, side effects related to diuresis (urinary frequency, nocturia, polyuria, and thirst) were more frequent in the treatment group, occurring in up to 55% of participants.
The authors noted, “Although maintaining hydration helped ensure that the blinding in the study was maintained, the suppression of vasopressin release in the placebo group may have led to an underestimation of the beneficial effect of tolvaptan and may account for the lower rates of kidney growth observed in the placebo group.”42
In 2013, the US Food and Drug Administration (FDA) denied a new drug application for tolvaptan as a treatment for ADPKD.
THE mTOR PATHWAY IS UP-REGULATED
The mTOR pathway that plays a major role in cell growth and proliferation includes interaction of the cytoplasmic tail of polycystin 1 with tuberin.43 Activation products of mTOR, including phospho-S6K, have been found in tubular epithelial cells lining cysts of ADPKD kidneys but not in normal kidneys.43 Mutant mice with polycystic disease had phospho-S6K in tubular epithelial cells of cysts, whereas those treated with the mTOR inhibitor rapamycin did not.43 But subsequent studies have shown that only a low level of mTOR activation is present in 65% to 70% of ADPKD cysts.44
Two major studies of the treatment of ADPKD with rapamycin that were published contemporaneously in 2010 failed to demonstrate any significant benefit with mTOR inhibitor treatment.45,46
Serra et al45 conducted an 18-month, open-label trial of 100 ADPKD patients ages 18 to 40 with an estimated GFR (eGFR) of at least 70 mL/min. Patients were randomized to receive rapamycin, given as sirolimus 2 mg per day, or standard care. The primary end point was the reduction in the growth rate of total kidney volume, measured by MRI. Secondary end points were eGFR and protein excretion (albumin-creatinine ratio). No significant difference was found in total kidney volume, but a nonsignificant stabilization of eGFR was noted.
Walz et al46 in a 2-year, multicenter, double-blind trial, randomized 433 patients (mean age 44; mean eGFR 54.5 mL/min) to treatment with either the short-acting mTOR inhibitor everolimus (2.5 mg twice daily) or placebo. Although patients in the treatment group had less of an increase in total kidney volume (significant at 1 year but not at 2 years), they tended to show a decline in eGFR. But further analysis showed that the only patients who had a reduction in eGFR were males who already had impaired kidney function at baseline.47
In a pilot study, 30 patients with ADPKD (mean age 49) were randomized to one of three therapies:
- Low-dose rapamycin (trough blood level 2–5 ng/mL)
- Standard-dose rapamycin (trough blood level > 5–8 ng/mL)
- Standard care without rapamycin.48
In contrast to other studies, the primary end point was the change in iothalamate GFR at 12 months, with change in total kidney volume being a secondary end point.
At 12 months, with 26 patients completing the study, the low-dose rapamycin group (n = 9) had a significant increase in iothalamate GFR of 7.7 ± 12.5 mL/min/1.73 m2, whereas the standard-dose rapamycin group (n = 8) had a nonsignificant increase of 1.6 ± 12.1 mL/min/1.73 m2, and the no-rapamycin group (n = 9) had a fall in iothalamate GFR of 11.2 ± 9.1 mL/min/1.73 m2 (P = .005 for low-dose vs no rapamycin; P = .07 for standard-dose vs no rapamycin; P = .52 for low-dose vs standard-dose rapamycin; and P = .002 for combined low-dose and standard-dose rapamycin vs no rapamycin.).48 These differences were observed despite there being no significant change in total kidney volume in any of the groups. Patients on low-dose rapamycin had fewer adverse effects than those on standard dose and were more often able to continue therapy for the entire study. This, and the use of iothalamate GFR rather than eGFR to measure GFR, are believed to be the main reasons that low-dose effects were more pronounced than those with standard doses. One may speculate that rapamycin may have its effect on microcysts and cystogenic cells, resulting in stabilization of or improvement in renal function without detectable slowing in total kidney volume enlargement. Mechanisms for this possibility involve new concepts, as discussed below.
