Pharmacological management of polycystic kidney disease.

Review

Pharmacological management of polycystic kidney disease Rudolf P Wu¨thrich† & Changlin Mei 1.

Autosomal-dominant polycystic kidney disease: a frequent genetic kidney

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Maastricht on 07/08/14 For personal use only.

disease causing end stage renal disease 2.

Development of therapies for ADPKD

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Conclusion

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Expert opinion

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University Hospital, Division of Nephrology, Zu¨rich, Switzerland

Introduction: Autosomal-dominant polycystic kidney disease (ADPKD) represents a therapeutic challenge as effective treatment to retard the growth of cysts in the kidneys and the liver has not been available despite decades of intense basic and clinical research. Areas covered: Several clinical trials have been performed in recent years to study the effect of diverse drugs on the growth of renal and hepatic cysts, and on functional deterioration of the glomerular filtration rate. The drug classes that have been tested in randomized clinical trials include the mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, the somatostatin analogues (octreotide, lanreotide, pasireotide), and most recently, the vasopressin V2 receptor antagonist, tolvaptan. The results with the mTOR inhibitors were disappointing, but more encouraging with the somatostatin analogues and with tolvaptan. Additional drugs are being tested, which include among others, the SRC-ABL tyrosine kinase inhibitor, bosutinib, and the traditional Chinese herbal medication, triptolide. Additional therapeutic strategies to retard cyst growth aim at blood pressure control via inhibition of the renin--angiotensin system and the sympathetic nervous system. Expert opinion: Given the accumulated knowledge, it is currently uncertain whether drugs will become available in the near future to significantly change the course of the relentlessly progressing polycystic kidney disease. Keywords: bosutinib, everolimus, lanreotide, mammalian target of rapamycin, octreotide, polycystic kidney disease, sirolimus, somatostatin, tolvaptan, triptolide Expert Opin. Pharmacother. (2014) 15(8):1085-1095

Autosomal-dominant polycystic kidney disease: a frequent genetic kidney disease causing end stage renal disease

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Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, which often leads to end-stage renal disease (ESRD) [1,2]. With an estimated incidence of 1:1000, it is one of the most frequent hereditary diseases of mankind. There are approximately 700,000 cases in Europe, and probably > 12,500,000 cases worldwide. ADPKD is characterized by the progressive development of innumerable cysts in both kidneys, which gradually replace the normal renal tissue [3]. The relentless growth of numerous cysts leads to an exponential increase in the total kidney volume (TKV) (Figure 1) [1,4]. Furthermore, there is a deterioration of renal function that occurs relatively late in the course of the disease, but leads to ESRD in approximately 50% of the patients in their sixth to seventh decade (Figure 2) [5]. ADPKD results from mutations in the PKD1 (85% of the cases) or PKD2 gene (15% of the cases). Patients with PKD1 gene mutation display a more severe course than patients with PKD2 mutations; in the former, ESRD occurs at a median age of 54, which is roughly 20 years earlier than in patients with a PKD2 gene mutation [5,6]. Thus, fewer patients with PKD2 mutations reach ESRD during their lifetime.

10.1517/14656566.2014.903923 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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Autosomal-dominant polycystic kidney disease (ADPKD) is the most frequent genetic renal disease, occurring in 1 per 1000 livebirths, and progressing to end stage renal disease in 50% of the cases. Standard management has largely been focused on following patients regularly, controlling their blood pressure and treating complications. A vast amount of data from basic science research has led to the development of drugs that inhibit cyst growth. These include mainly the mammalian target of rapamycin (mTOR) inhibitors sirolimus (rapamycin) and everolimus, the long-acting somatostatin analogues octreotide and lanreotide, and the vasopressin V2-receptor antagonist tolvaptan. Although promising in animal models, the mTOR inhibitors sirolimus and everolimus were not efficacious in randomized clinical studies, possibly because of underdosage and/or high dropout rate due to the narrow therapeutic window of these drugs. Octreotide and lanreotide were found to inhibit cyst growth in liver and kidney in the first year of treatment; however, the effect diminished with prolonged treatment, and no effect could be demonstrated on the decline of glomerular filtration rate (GFR). The aquaretic drug tolvaptan significantly decreases cyst volume growth and GFR decline at the expense of inducing massive polyuria. Prolonged treatment may result in decreased efficacy, and the overall effect on GFR preservation appears to be marginal. The requirements for future treatments for ADPKD include heightened efficacy, improved tolerance, and optimized safety for long-term use.

This box summarizes the key points contained in the article.

Several risk factors and markers for more severe disease progression have been identified, including presence of the PKD1 genotype, early onset (< 30 years of age) of hypertension or cyst hemorrhage, and presence of albuminuria. Because a disease-retarding treatment is not available, the therapeutic efforts have largely been limited to regular clinical controls and management of complications (hypertension, cyst hemorrhage and infection). When ESRD occurs in ADPKD patients, it is usually treated by renal replacement therapy (dialysis) or renal transplantation. Overall, the disease is causing an enormous socioeconomic burden, wherefore an effective treatment to retard disease progression is desperately needed [7,8]. Patients with ADPKD suffer mostly from the consequences of their cystic renal disease, which include cyst hemorrhage, pain, cyst and urinary tract infections (UTIs), early-onset hypertension, nephrolithiasis, polyuria, and renal failure (chronic kidney disease) that may progress to ESRD [2]. Cysts occur often in extrarenal locations, including, by decreasing order of importance, liver, pancreas, spleen and ovary. Polycystic liver disease (PLD) is rarely associated with liver failure, but may cause numerous problems when the extent of the 1086

liver cysts is important. A number of cardiac and vascular anomalies and diseases are associated with ADPKD, including left ventricular hypertrophy (LVH), mitral valve prolapse, mild aortic insufficiency due to dilatation of the aortic root and cerebral aneurysms [9-11]. Colonic diverticulosis and diverticulitis, as well as inguinal hernias, are also more frequent in ADPKD patients than in the general population [12]. In the present review, we will focus on the cystic renal disease and the possibilities of treatment to slow the rate of cyst growth and decline of renal function. In ADPKD, the glomerular filtration rate (GFR) remains stable for decades because of compensatory mechanisms (hyperfiltration). By the time the GFR starts to decline, cysts have replaced most of the normal kidney parenchyma (Figure 2). It is believed that early intervention in ADPKD would lead to greater therapeutic benefit than late treatment as cysts have not yet replaced the bulk of intact renal parenchyma and renal function is still maintained. Kidney volume growth is due to cyst expansion and precedes functional renal deterioration by decades. The rate of kidney volume growth is currently considered to be a valid progression marker of the disease. Noninvasive radiologic methods such as CT and MRI are used to assess and monitor the growth rate of kidney and cyst volume, and allow monitoring of the therapeutic response of an experimental drug [13-15]. Although CT scanning represents an accurate method to measure kidney volume [16,17], it involves ionizing radiation and -- if used -- nephrotoxic contrast medium. CT scanning is therefore not an ideal method in patients with impaired renal function, particularly if repetitive measurements are performed. Due to its high soft tissue contrast and the lack of ionizing radiation, MRI is most frequently used to monitor kidney volume changes over time in patients with ADPKD [18,19]. The progression rate of the renal disease has been analyzed in large cohorts in terms of annual growth of TKV and total cyst volume, and also in terms of decline of GFR. Thus, it was shown that relatively young patients with ADPKD that are felt to benefit the most from a drug treatment have an annual TKV growth rate of 5.4% and an annual decline of GFR of > 3 ml/min/1.73 m2. In patients selected for more rapid progression, the annual TKV growth rate may exceed 15%, and the decline in eGFR may be larger than 5 ml/min/1.73 m2 [13,14]. 2.

Development of therapies for ADPKD

Therapeutic aims and targets in ADPKD The goal of therapeutic drug development for patients with ADPKD aims to retard cyst growth primarily in the kidney, but also in the liver for those patients with extensive hepatic cyst growth [20]. The management of complications has not been in the focus of recent clinical trials; however, it is felt that certain symptoms and complications might also be ameliorated with a given drug treatment, for example, pain, hypertension, occurrence of UTI, or cyst hemorrhage [21]. 2.1

Expert Opin. Pharmacother. (2014) 15(8)

Pharmacological management of polycystic kidney disease

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Figure 1. Total kidney volume (TKV) as an important parameter of disease progression in autosomal-dominant polycystic kidney disease. The TKV is shown in 232 women (blue data points) and men (red data points) studied over a 3-year period (from [1]). Copyright 2008 Massachusetts Medical Society. All rights reserved.

There are certain principles that are common to all specific therapies for ADPKD [20]: i) late treatment initiation is unlikely to significantly improve the outcome; ii) specific treatment needs to be given over extended periods of time; iii) because of large interindividual disease variability, treatment decisions will need to be individualized; and iv) given its delayed decline, GFR is not a suitable measure of outcome, wherefore most clinical trials use TKV changes as a surrogate parameter. A number of nonspecific therapies have been recommended to slow renal disease progression, including certain lifestyle (smoking cessation, fitness) and dietary recommendations (ample fluid intake, low sodium diet, avoidance of tea and coffee) and optimal blood pressure (BP) control. Except for high fluid intake [22], BP control [23], and low sodium intake [24], most of these recommendations are opinion-based rather than evidence-based. Numerous ADPKD-specific pathophysiological alterations have been described at the cellular and molecular level [2,3,21,25]. Crucial information has been derived from an enormous number of studies to conceive possible drug treatment strategies that influence some of the major cellular alterations in ADPKD. Pharmaceutical companies unfortunately may not have a strong interest and a particular incentive to develop a drug treatment for ADPKD. This has the following reasons: i) because ADPKD is a frequent hereditary disease, it is not generally accepted that it fits into the category of orphan

diseases (defined as having a prevalence of < 1:2000) that usually benefit from specialized drug development programs in certain countries, which may include among others prolonged patent protection; ii) as ADPKD is a slowly progressing disease, it takes more time than usual and high costs to test and develop a drug for ADPKD; and iii) an improvement in GFR would be the most desirable effect a drug could have in ADPKD, but as significant GFR changes occur only late in the disease it is commonly felt that it may not be possible to prove a drug’s efficacy if it is tested late in the disease course when GFR is impaired and irreversible organ damage has already occurred. Thus, pharmaceutical companies may not want to invest in ADPKD as the development of an efficient treatment strategy carries a high risk. Given the large number of affected patients and the high cost of treatment with dialysis and transplantation, there is, on the other hand, a great need to develop a drug treatment that ameliorates or cures ADPKD [26,27]. Despite these limitations, there is a window of opportunity to treat the disease, that is, to retard the relentless cystic expansion. A major difficulty is the fact that ADPKD is a very heterogeneous disease. The extent and the speed of the cyst development is very different among patients. Although there are well-established predictors of disease progression, at the individual patient level there is a need for more subtle parameters or markers that reliably predict disease progression or response to a particular treatment. Furthermore, the choice of the primary end point in clinical trials has been difficult as ideally one would like to prevent the occurrence of ESRD, yet renal failure occurs relatively late in the course of the disease when the majority of the renal parenchyma has already been irreversibly altered by the massive development and expansion of renal cysts. The complex pathophysiology of ADPKD involves alterations of the mechanosensing ciliary functions of renal tubular epithelial cells, leading to enhanced tubular cell proliferation and fluid secretion and the formation of cysts along all segments of the nephron [2,3,28,29]. Numerous signaling cascades are distinctly altered in animal models of polycystic kidney disease (PKD) and human ADPKD, which have been associated with disrupted intracellular Ca2+ homeostasis (reduced resting intracellular Ca2+), vasopressin V2 receptor-mediated accumulation of cyclic AMP, and polycystin/tuberin-mediated activation of mammalian target of rapamycin (mTOR) and S6 kinase, which control growth and proliferation of kidney epithelial cells [30]. Interventions to inhibit these central pathways have been very successful at the level of animal studies and have triggered the initiation of clinical proof-of-concept studies to determine whether cyst volume growth and GFR decline can be inhibited. Several drugs have been recently evaluated in clinical trials, including mTOR inhibitors (rapamycin/sirolimus, everolimus), vasopressin V2 receptor antagonists (tolvaptan), and long-acting somatostatin analogues (octreotide, lanreotide, pasireotide). The most frequently chosen primary end point has been the change of TKV growth. This end point is easily


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Figure 2. In patients with autosomal-dominant polycystic kidney disease, the delayed but rapid deterioration of renal function glomerular filtration rate contrasts with steady cyst volume growth as depicted by the MRI scans in the center of the graph.

measured by repeated abdominal MRI without gadolinium contrast. We will now review the clinical trial information that has been derived from the most important recent studies. Sirolimus and everolimus Sirolimus (rapamycin) and everolimus are mTOR inhibitors that were tested in several animal models of PKD and were found to significantly inhibit cyst formation and decrease polycystic kidney size [31-38]. Both drugs have been recently tested in randomized controlled clinical trials [39-42]. These trials unfortunately failed to show a beneficial effect on change in kidney volume and renal function. The SUISSE ADPKD study was an 18-month, open-label, randomized controlled trial that sought to determine whether sirolimus halts the growth in kidney volume among patients with ADPKD [40]. Patients between the ages of 18 and 40 years (n = 100) and a creatinine clearance of > 70 ml/min were randomly assigned to receive either sirolimus (target dose 2 mg daily) or standard care. The median increase in TKV over the 18-month period was 99 cm3 (interquartile range, 43 -- 173) in the sirolimus group and 97 cm3 (interquartile range, 37 -- 181) in the control group. The GFR did not differ significantly between the two groups, but the urinary albumin excretion rate was higher in the sirolimus group. The short treatment time and the relatively low dose of sirolimus might partly explain the lack of an effect. The German Everolimus ADPKD study was a doubleblind trial, randomly assigning 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus (target dose 5 mg daily) for 2 years [41]. The primary outcome was the change in TKV, as measured by MRI, at 12 and 24 months. TKV increased between baseline and 2 years by 230 ml in the everolimus group versus 301 ml in the placebo group (p = 0.06). Cyst volume increased by 181 ml in the everolimus group and 215 ml in the placebo group after 2 years (p = 0.28). The mean decrement in the estimated GFR after 24 months was -8.9 ml/min/1.73 m2 in the 2.2

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everolimus group versus -7.7 ml/min/1.73 m2 in the placebo group (p = 0.15). Thus, everolimus slowed the increase in TKV of patients with ADPKD insignificantly and did not slow the progression of renal impairment. Proteinuria also increased in the everolimus group. The dropout rate was relatively large due to side effects of everolimus (mainly oral ulcerations). Two additional smaller trials have also reported unsatisfactory results [39,42]. A recent meta-analysis concluded that mTOR inhibitor therapy is relatively safe to slow down the increase in kidney volume in patients with early-stage ADPKD, but it has limited impact on slowing down the decrease in GFR [43]. Sirolimus and everolimus are drugs with a narrow therapeutic window. Due to their side effects, a higher dosage is therefore difficult, particularly for long-term treatment. In support of the marginal therapeutic effect of mTOR inhibitors is the history of a previously unknown ADPKD deceased renal transplant donor whose kidneys were engrafted in two different recipients [44]. One of the two received an immunosuppressive regimen based on sirolimus for 5 years whereas the other did not. After transplantation, both patients developed severe transplant cystic disease. This suggests that sirolimus when used at standard dosage is not able to retard cyst growth in ADPKD kidneys. It remains to be seen whether mTOR inhibition in combination with other therapies could be of value to decrease disease progression in ADPKD [31]. Somatostatins The natural hormone somatostatin is a cyclic peptide that has a very short half-life of 1 -- 3 min. Several synthetic analogues have been developed for clinical use in the treatment of acromegaly and gastroenteropancreatic neuroendocrine tumors, including the octapeptide octreotide (Sandostatin LAR, a long-acting release formulation of octreotide encapsulated in polymeric microspheres), lanreotide, and pasireotide. These analogues have been shown to decrease cAMP production 2.3




and cyst fluid secretion in renal tubular cells and cholangiocytes. Somatostatin analogues such as octreotide and lanreotide are promising, especially for PLD, and they have the convenience of monthly pulse injection. The initial data with somatostatin analogue treatment were obtained in small randomized, placebo-controlled trials with octreotide and lanreotide [45-48]. Two trials were extended open label [49,50]. Octreotide and lanreotide were found to be effective in slowing hepatic and renal volume expansion in ADPKD. Because of its broad receptor binding profile, pasireotide may be more potent than octreotide. A clinical trial is ongoing to study its effect in PLD (NCT01670110). Overall it seems that somatostatin analogues are more effective in reducing liver cyst volume than kidney cyst volume. However, the studies were underpowered and of too short duration to reach definitive conclusions, particularly regarding their possible renoprotective efficacy. Drug-related side effects of octreotide and lanreotide include abdominal cramps, loose stools, cholelithiasis, steatorrhea, and weight loss. The recently published ALADIN study aimed to assess the effect of 3 years of octreotide treatment on kidney and cyst growth and renal function decline in participants with ADPKD [51]. The study was a multicenter, randomized, single-blind, placebo-controlled, parallel-group trial randomizing 38 patients in the octreotide group and 37 patients in the placebo group. The mean TKV increase in the octreotide group (220 ml) was numerically smaller than in the placebo group (454 ml), but the difference was not significant (p = 0.25). Over the entire follow-up period, the yearly rate of GFR decline tended to be lower in the octreotide group than in the placebo group (-3.85 vs -4.95 ml/min/1.73 m2), but the difference was not significant. Participants with serious adverse events were similarly distributed in the two treatment groups, but four cases of cholelithiasis or acute cholecystitis occurred in the octreotide group and appeared to be treatment related. Overall the study failed to show a sustained beneficial effect on renal cyst growth and GFR decline. Somatostatin analogues could potentially be useful agents to retard kidney and liver cyst growth in ADPKD. However, studies with a larger patient number and of longer follow-up need to be performed. It is encouraging to see that several studies are currently ongoing and recruiting patients [52]. Tolvaptan Vasopressin is the major adenylyl cyclase agonist in the principal cells of the collecting duct, acting via V2 receptors. The V2 receptor antagonists mozavaptan (OPC-31260) and tolvaptan (OPC-41061) were found to lower renal cAMP levels and decrease the severity of cyst formation in various orthologous and nonorthologous mouse and rat models of PKD [53-56]. Furthermore, tolvaptan was found to block the vasopressin-mediated proliferation, fluid secretion and cyst formation in cultured ADPKD cells [57]. Given the large body of preclinical pathophysiological evidence that vasopressin-mediated cAMP generation might 2.4

play a major role in cystogenesis, several clinical studies have been initiated to test the effect of vasopressin V2 receptor antagonists on cyst growth and renal function in patients with ADPKD [58]. The lead drug is tolvaptan, an orally active small-molecule vasopressin V2 receptor antagonist, which is effective and marketed in several countries for the treatment of hypervolemic or euvolemic hyponatremia and congestive heart failure. Initial clinical studies with tolvaptan have indicated that the drug is safe and well tolerated in ADPKD, although adverse events were common, in particular a disturbing polyuria and nocturia, which may limit its long-term use [59]. The 3-year trial results from two Phase II studies of tolvaptan in 63 ADPKD subjects randomly matched 1:2 to historical controls by gender, hypertension, age, and baseline TKV or eGFR showed that control TKV increased 5.8 versus 1.7% per year for tolvaptan (p < 0.001), and that the corresponding annualized eGFR declined by -2.10 versus -0.71 ml/min/1.73 m2 per year. Thus, ADPKD cyst growth appeared to progress more slowly with tolvaptan than in historical controls. Additional shortterm studies have shown that tolvaptan has acute effects on decreasing GFR and TKV growth, which need to be distinguished from the long-term effects [60,61]. A large Phase III trial with tolvaptan (TEMPO 3:4 trial) has enrolled > 1400 patients, and results have been published in 2012 [62]. In this Phase III, multicenter, double-blind, placebo-controlled, 3-year trial, 1445 patients, 18 -- 50 years of age, who had ADPKD with a TKV of 750 ml or more and an estimated creatinine clearance of ‡ 60 ml/min, were randomly assigned in a 2:1 ratio to receive tolvaptan or placebo. At baseline, the mean age of the participating patients was 39 years. Kidney function was preserved, but nearly 80% of the patients had hypertension. Kidney size was increased by a factor of five, and half the patients had reported kidney pain. The study met its primary and secondary end points -tolvaptan, when given at an average dose of 95 mg/day over a 3-year period, slowed the usual increase in TKV by 50% (5.5% per year in the placebo group and 2.8% per year in the tolvaptan group) and reduced the decline in the GFR. The effect of tolvaptan on kidney volume was most pronounced during the first year of the study, probably owing to the early reduction in the secretion of cyst fluid. In contrast, the effect on GFR became apparent only after the first year of treatment. A considerable number of patients discontinued tolvaptan due to its aquaretic side effects (thirst, polydipsia, polyuria, and nocturia). Tolvaptan treatment was also associated with elevated liver enzyme levels, hypernatremia, an increased level of uric acid, and gout. However, compared with placebo, significantly fewer patients on tolvaptan had adverse events related to ADPKD, such as kidney and back pain, hematuria, and UTI [63]. The cost-effectiveness of tolvaptan has been recently examined using a decision-analytic model to determine the expected benefit from tolvaptan over the lifetime of patients with ADPKD [64]. Tolvaptan was predicted to prolong the


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median age at ESRD onset by 6.5 years and to increase life expectancy by 2.6 years. However, the cost of such a treatment would be huge: at US$ 5760 per month, tolvaptan would cost US$ 744,100 per quality-adjusted life-year gained compared with standard care. Thus, cost-effectiveness would not compare favorably with many other commonly accepted medical interventions. Thus, V2 receptor antagonists are promising, but may not provide a definitive solution to prevent long-lasting progression in patients with ADPKD. Bosutinib Bosutinib is an Src inhibitor in clinical use for the treatment of chronic myeloid leukemia in adult patients with resistance or intolerance to prior therapy [65,66]. It is also being developed for metastatic breast cancer [67]. In experimental PKD studies, the activity of the common signaling intermediate Src was found to correlate with cystic disease progression. Inhibition of Src activity with bosutinib (also termed SKI-606) resulted in amelioration of renal cyst formation and biliary ductal abnormalities, suggesting that Src inhibition may provide therapeutic benefit in PKD [68,69]. A Phase II clinical trial is currently underway (NCT0123 3869), examining whether treatment with bosutinib could be beneficial for cystic disease progression and renal functional deterioration in ADPKD [29]. A high incidence of drug-related gastrointestinal adverse events (diarrhea, nausea, vomiting) may limit its future clinical use.


2.5

Triptolide In China, the medicinal herb formulation Tripterygium wilfordii (TW) is widely used to treat immune-mediated proteinuric renal diseases [70]. Recently, the major TW extract triptolide demonstrated inhibitory effects in murine models of polycystic kidney disease [71-73]. It was shown that triptolide inhibits cell proliferation, thereby attenuating cyst formation by restoring Ca2+ signaling in cyst epithelial cells [71]. Recently, a first clinical study from China has reported beneficial effects of TW in proteinuric patients with ADPKD [74]. Nine ADPKD patients with persistent proteinuria > 1 g/day were treated with TW for at least 6 months. Triptolide-containing TW treatment was associated with a reduction of the 24-h urine protein excretion from 2.6 ± 1.4 to 0.7 ± 0.4 g/day, and the rate of cyst growth and the decline of renal function also appeared to improve. Gonadal inhibition (menstrual cycle disturbances) was a major side effect of TW treatment. Larger and randomized controlled trials of longer duration are required to confirm these data and to determine whether TW also has beneficial effects in nonproteinuric or mildly proteinuric ADPKD patients. 2.6

Treating hypertension Hypertension is the most frequent complication among ADPKD patients, occurring in approximately 60% of the patients although their GFR is still in the normal range. 2.7

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Compared with the general population, it occurs at a much earlier age in ADPKD patients. Hypertension relates to progressive kidney enlargement and is a significant independent risk factor for progression to ESRD. Controlling BP is important to prevent the development of complications in ADPKD, including LVH, ischemic heart disease and stroke [75-77]. The pathogenesis of hypertension in ADPKD is complex and dependent on many factors that influence each other [10]. As in other forms of hypertension, the renin--angiotensin-aldosterone system (RAAS) plays a major role [78]. In addition, the sympathetic nervous system is activated very early in patients with ADPKD at a stage when renal function (GFR) is still normal [79,80]. Thus, sympathetic hyperactivity contributes to the pathogenesis of hypertension in ADPKD in a major way. Several studies have shown that hypertension in ADPKD patients is associated with increased renal volumes and LVH [76,81]. Hypertension and LVH are important risk factors for cardiovascular disease, which is the most common cause of death in patients with ADPKD. Thus, it is of utmost importance to control BP adequately in patients with ADPKD in order to retard disease progression and improve cardiovascular morbidity and mortality [9]. Whether optimal treatment of hypertension can reduce progression of disease in patients with ADPKD is the subject of intense investigations. The so-called HALT-PKD study (Halt Progression of Polycystic Kidney Disease) is testing the efficacy of aggressive RAAS blockade in preventing or slowing renal function decline in ADPKD [82]. This ongoing multicenter study is sponsored by the National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), the National Institutes of Health (NIH), and the U.S. Department of Health and Human Services. The study is composed of two parts. In study A (NCT00283686), early-stage disease participants (n = 558) aged 15 -- 49 years with a GFR > 60 ml/min/1.73 m2 have been randomized to one of four conditions in a 2-by-2 design: combination (ACE-I; lisinopril) and angiotensin receptor blocker ([ARB]; telmisartan) therapy at two levels of BP control (standard, systolic 120 -- 130 and diastolic 70 -- 80 mmHg vs low, systolic 95 -- 110 and diastolic 60 -- 75 mmHg) or ACE-I monotherapy at the same two levels of BP control. The primary outcome of study A is the % change in TKV, as measured by MRI. In study B (NCT01885559), late-stage disease participants (n = 486) aged 18 -- 64 years with a GFR of 25 -- 60 ml/min/1.73 m2 have been randomized to assess the effects of intensive blockade of the RAAS through combination ACE-I/ARB (lisinopril/telmisartan) therapy compared with ACE-I monotherapy (lisinopril), with both groups treated to standard levels of BP control, on the time to 50% reduction in baseline eGFR, ESRD, or death. The HALT-PKD study will provide important information as to whether optimal control of BP with ACE-I and/or ARB




will retard disease progression in ADPKD. The study recruitment is finished, and final results are expected later in 2014 [83]. As sympathetic activation occurs in patients with ADPKD [80], a recent therapeutic strategy that has been proposed consists of renal denervation to treat hypertension in the context of ADPKD. In a rat model of PKD (Han:SPRD rats), the bilateral renal surgical denervation led to an improvement of hypertension and interestingly also to a slower cyst volume progression [79]. This suggests that the sympathetic axis could be targeted therapeutically to retard disease progression in PKD. Two recent case reports indicated the feasibility of such an approach and reported a significant effect on BP control and sympathetic nervous activity with renal denervation using a catheter-based approach [84,85]. A study has now been initiated in China to test in patients with ADPKD and hypertension the efficacy of bilateral renal artery sympathetic denervation by catheter-based radiofrequency ablation on BP control (NCT 01932450). 3.

Conclusion

In nephrological research, the field of the cystic kidney diseases has probably been one of the most rapidly advancing fields. Evidence from a large body of data from basic sciences has subsequently led to the initiation of preliminary and also more definitive clinical studies testing a number of different drugs for their efficacy and safety in patients with ADPKD. As renal function remains normal for decades, the development of drugs that could improve the deterioration of the GFR has been difficult. As a surrogate parameter that predicts the future decline in GFR, most studies have therefore used the TKV to follow the therapeutic effects of candidate drugs in clinical trials. TKV, and particularly the height-adjusted TKV, were found to increase exponentially over time, thus allowing monitoring the yearly change in cm3 or % in individual patients or patient populations. Therapies that diminish the TKV growth rate are believed to ultimately benefit the eGFR decline. This view is shared by the scientific community at large, but is unfortunately not accepted by all health authorities, in particular not by the US FDA. As TKV appears to be the only realistic surrogate marker, there is work ahead to convince health authorities to accept this imperfect but valid end point. Several well-performed studies have not been able to show a significant benefit of inhibiting mTOR [40,41]. The somatostatin analogues octreotide and lanreotide were found to inhibit liver cyst growth initially, but the effect seems to decrease over time. Kidney cyst growth is also reduced with octreotide and lanreotide, at least initially, but a sustained effect on GFR decline has so far not been demonstrated [49,51]. In terms of drug development, the most advanced substance is tolvaptan, an aquaretic drug that through its inhibition of vasopressin-mediated cAMP generation is inhibiting cyst growth. Otsuka, the maker of tolvaptan, has sponsored the

largest therapeutic trial ever in the field of ADPKD, enrolling 1445 patients. The results of this Phase III study have been recently published, showing a beneficial effect on TKV growth and renal functional decline [62]. Given the limited effect and the disturbing side effects, disease heterogeneity, and pharmacoeconomic issues, it is at present unclear which subset of patients with ADPKD will benefit from long-term treatment with tolvaptan [62-64]. The therapeutic development is ongoing for the somatostatin analogues and for tolvaptan. The latter has been denied approval by the FDA in 2013, and EMA decision is being awaited in 2014. Data from the upcoming HALT trial will become available in 2014 and will answer the important question whether ACE and/or ARB are beneficial for cyst growth, and whether a low or a moderately low BP target has to be aimed for. 4.

Expert opinion

A number of different drugs have been tested in ADPKD, targeting mainly kidney but also liver cyst growth. The clinical end points have most often included TKV growth and GFR decline, but other parameters have also been studied, including albuminuria, pain from cystic kidneys, and BP. Clinical trials examining the mTOR inhibitors sirolimus [40] and everolimus [41] failed to show a significant improvement in cyst growth and GFR decline. These drugs have a narrow therapeutic window, and a subtherapeutic dosage or a high dropout rate may have contributed to the insignificant results of these studies. Although somatostatin analogues may display a better tolerance than mTOR inhibitors, they also have significant side effects, and their efficacy is not convincing in the studies performed so far [51]. Larger studies of longer duration would be required, and some trials are ongoing, including the more broadly acting somatostatin analogue pasireotide. Tolvaptan was found to decrease the TKV growth rate from 5.5 to 2.8%, although the effect was most prominent during the first year of treatment because the acute effects of tolvaptan and decreased subsequently, pointing to an escape phenomenon that has also been suggested for the somatostatin analogues [63]. Despite the limitations of the TEMPO 3:4 study, tolvaptan might be the only drug that has a chance to be registered in the near future. Additional data with patients displaying a more advanced GFR loss are currently being gathered in multicenter, randomized trials. Whether optimal BP control -- either through the inhibition of the RAAS with ACE inhibitors or ARB, or perhaps through the sympathetic nervous system by catheter-based renal denervation -- will show efficacy in reducing cyst growth and renal functional deterioration will soon be known when the results of the large HALT PKD study [82] and other trials will become available in the near future. The quest for an efficacious therapy for patients with ADPKD is ongoing. Whereas on the one side a ‘magic bullet


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approach’ is still a possibility at the horizon, a multitargeted approach using optimization of lifestyle (large fluid and low sodium intake), BP control, combination therapy (e.g., with mTOR inhibitors and aquaretics), and genetic counseling will hopefully define the therapeutic future for patients with relentlessly progressing polycystic disease. As the disease is quite heterogeneous, it will be equally important to define the patients that are most likely to progress and to benefit the most from pharmacological therapy. These data are being gathered from various cohorts of patients with ADPKD, such as the CRISP [13], SUISSE ADPKD [14], and Shanghai cohorts [86]. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest The authors are supported by the Sino Swiss Science & Technology Cooperation (SSSTC) Program, the HartmannMu¨ller Foundation, the Swiss National Science Foundation (320030-144093 to RP Wu¨thrich), and the National Natural Science Foundation of China General Projects (30971368, 30871179 to C Mei). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation


Rudolf P Wu¨thrich†1 & Changlin Mei2 † Author for correspondence 1 Professor, University Hospital, Division of Nephrology, Ra¨mistrasse 100, 8091 Zu¨rich, Switzerland Tel: +41 44 255 33 84; Fax: +41 44 255 45 93; E-mail: [email protected] 2 Professor, Second Military Medical University, Kidney Institute, Shanghai Changzheng Hospital, Department of Nephrology, Shanghai, PR China


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