Nephrology Dialysis Transplantation

NDT Advance Access originally published online on May 16, 2006
Nephrology Dialysis Transplantation 2006 21(7):1752-1757; doi:10.1093/ndt/gfl246

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Editorial Comment

Therapeutic approaches in autosomal dominant polycystic kidney disease (ADPKD): is there light at the end of the tunnel?

Gerd Walz

Renal Division, Freiburg, Germany

Correspondence and offprint requests to: Gerd Walz, Renal Division, University Hospital Freiburg, Hugstetter Street. 55, 79106 Freiburg, Germany. Email: gerd.walz{at}uniklinik-freiburg.de

Keywords: mTOR inhibitors; polycystic kidney disease; tacrolimus; vasopressin-2 receptor antagonist

	The new kids on the block

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For more than three decades, autosomal dominant polycytic kidney disease (ADPKD) researchers around the globe, spurned by millions of affected patients, have tried to elucidate the mechanisms that lead to cyst formation and progression of renal failure in this heterogenetic disease. It was not until recently that realistic therapeutic interventions have come within reach. This editorial will briefly summarize the key findings that led the researchers to test vasopressin-2-receptor antagonists (V2RA) and mammalian targets of rapamycin (mTOR) inhibitors in animal models of polycystic kidney disease, and will highlight why these therapeutic avenues might be more promising and fortunate than their predecessors (Table 1).

View this table: [in this window] [in a new window]   Table 1. Reagents that have been successfully tested in different model systems (name of known genes and proteins in parenthesis) of polycystic kidney disease.

 

	Vasopressin-2-receptor antagonists (V2RA)

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Modern ADPKD research started when epithelial cells lining the cysts in kidneys of ADPKD patients were successfully isolated and maintained in ex vivo cultures [1]. Multiple observations led to the hypothesis that cyst cells are less-than-terminally differentiated, continue to proliferate, secrete fluid and destroy the surrounding normal tissue by expansion (reviewed in [2,3]). The cyst fluid was found to contain many hormonal activities, including antidiuretic hormone (ADH) and epidermal growth fator (EGF), as well as a lipophilic substance, capable of stimulating the accumulation of cyclic adenosine monophosphate (cAMP) [4–6]. In epithelial cells of the distal tubules and collecting ducts, ADH activates the vasopressin-2-receptor (V2R), a G_s-coupled seven-membrane spanning receptor linked to adenylate cyclase. Accumulation of cAMP mediates the insertion of aquaporin channels into the plasma membrane, allowing water to diffuse back into the interstitium. With the advent of selective V2RA, it seemed almost mandatory to test their effects on cyst formation and disease progression in mouse models of ADPKD. In milestone articles, Gattone [7], Torres [8] and coworkers probed this concept, and found that V2RA are effective agents to reduce cyst and kidney volumes. Initially tested in the pck (PKHD1, fibrocystin) rat model of autosomal recessive PKD, and the pcy (NPHP3, nephrocystin-3) mouse model of nephronophthisis, this therapeutic intervention was subsequently tested in a PKD2-deficient mouse model, confirming the striking results. OPC-31260 preferentially binds the rodent V2R. Therefore, tolvaptan® (OPC-41061), a similar substance with higher affinity for the human V2R, was tested in the pck rat model, and proved equally effective [9]. Tolvaptan®, currently the only V2RA that has been evaluated more extensively, was recently studied in patients with heart failure [10,11]. As expected, V2RA increased diuresis to 3–4 l/day, but was otherwise well-tolerated. Thirst and polyuria were the only significant side effects. Otsuka Pharmaceutical, the manufacturer of Tolvaptan®, will therefore proceed with a world-wide phase III clinical trail to examine the efficacy of Tolvaptan® in ADPKD. Approximately 1500 patients, randomized to either Tolvaptan® or placebo, will be observed for a period of 5 years. Although generally the compliance to take a drug that causes nocturnal polyuria would typically be low, ADPKD patients, having awaited therapy for so many years, are highly motivated to accommodate a drug that avoids the almost inevitable fate of dialysis. In contrast to many other therapeutic interventions, heralded with much ado in the past, Tolvaptan® promises safety in a disease that likely requires life-long therapy. Yet, there are some caveats that will need future attention. The V2R promoter contains a cAMP-responsive element, and is up-regulated in cystic epithelial cells of distal origin. However, ectopic expression in more proximal segments has not been observed. Thus, the effect of V2RA could be limited to V2R-expressing cystic cells. In autosomal recessive PKD and nephronopthisis, cysts appear to originate from distal nephron segments, while cysts are uniformly spread over all nephron segments in ADPKD. Interestingly, the inhibition of cyst formation and/or progession in the PKD2 mouse model of ADPKD was not confined to distal nephron segments, raising doubt that the postulated mechanisms, responsible for the benefical effects of V2RA, are completely understood. Other important issues are antagonist-mediated V2R down-regulation, desensibilization and compensatory up-regulation of other vasopressin receptors potentially associated with undesirable side effects.

	(mTOR) inhibitors

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The mammalian target of rapamycin (mTOR) enters the center stage for the second time. Known for its central role in proliferation of activated T-lymphocytes, the inhibitor of mTOR has become an integral part of immunosuppressive therapy after organ transplantation. TOR is a member of the phosphoinositide kinase-related kinases, and phosphorylates target proteins, such as S6 kinase (S6K) and 4E binding protein (4EBP1) on serine/threonine residues (reviewed in [12–14]) (Figure 1). Phosphorylation of 4EBP1 releases EIF4E, which facilitates the translation of mRNAs with pyrimidine motifs, and increases the protein levels of cyclin D1, c-myc and vascular endothelial growth factor (VEGF). TOR requires activation of the small GTPase Rheb, which binds directly to the kinase domain in mTOR and activates mTOR in a GTP-dependent manner. The GTPase-activating protein (GAP) TSC2 facilitates the release of GTP from Rheb, returning it to the inactive, GDP-bound form. Stimulation of phosphoinositol-3 kinase (PI3K) (for example by growth factors and their cognate receptors) activates AKT, which in turn phosphorylates and inactivates the TSC1–TSC2 complex, allowing Rheb to activate mTOR (Figure 1). To exert its function on protein synthesis and metabolism, mTOR forms a complex (termed TORC1) with Raptor, a large adaptor protein thought to recruit the substrates of mTOR. In contrast, the interaction of mTOR with Rictor (TORC2) renders the complex insensible to rapamycin, and mediates reorganization of the actin cytoskeleton. TOR controls multiple aspects of cellular nutrient homeostasis, including fat metabolism. Rapamycin treatment prevents adipocyte differentiation and lipid accumulation, potentially through inhibition of PPAR activity. Three recent papers have now demonstrated that inhibition of mTOR by rapamycin slows disease progression in the Han:SPRD rat model of PKD [15,16]. Subsequent work by Weimbs and colleagues revealed that activated mTOR and S6k can be detected in epithelial cells lining the cysts of polycystic kidneys [17]. Treatment with rapamycin was effective in reducing cyst and kidney volume in two models of recessive PKD, the orpk (Tg737/polaris) and the bpk (Bicaudal) mouse, suggesting that dysregulation of mTOR activity, which was also present in a PKD1-knockout model, might represent a common final pathway in cystogenesis. Although the mechanism responsible for mTOR activation remains largely elusive, the carboxy-terminal cytoplasmic domain of polycystin-1 was shown to interact with TSC2. Whether aberrant expression of polycystin-1, or sequestration of the TSC complex cause mTOR activation, remains to be examined. Alternatively, growth factors detectable in the cyst fluid could contribute to mTOR activation by stimulating the PI3K/AKT pathway. In any case, most of the inputs to mTOR signalling are funnelled through the TSC complex, which represents an important node of signal integration. Rapamycin-induced apoptosis of epithelial cells surrounding the cysts may explain the decrease in cyst and kidney volumes of the treated animals. Interestingly, rapamycin was effective in the pcy mouse model even when started at a later time point, suggesting that initiation of therapy at later stages might still ameliorate the clinical course of ADPKD. In a small retrospective analysis, Shillingford et al. [17] found that the size of ADPKD kidneys significantly decreased in patients who incidentally received rapamycin after renal transplantation in comparison to the ADPKD patients treated with calcineurin inhibitors. Further encouragement for a rapamycin-based therapy in ADPKD comes from several small studies, treating tuberous sclerosis patients with rapamycin. Significant benefits have been reported for several symptoms, including regression of angiomyolipoma by more than 50%, and improvement of lymphangioleiomyomatosis. The Cincinnati Rapamycin trial as well as the ongoing multicentre trials in the UK and the US (Dana-Farber Cancer Institute in Collaboration with the National Cancer Institute) will provide further insight into the efficacy of mTOR inhibition in tuberous sclerosis. Taken together, the animal results in combination with the emerging clinical data strongly support the hypothesis that rapamycin has the potential to ameliorate the progression of disease in patients with ADPKD.

View larger version (43K): [in this window] [in a new window]   Fig. 1. The TSC1/TSC2 (TSC) complex functions as a Ras homology enriched brain (Rheb) GTPase activating protein (GAP), and inhibits the function of Rheb. The TSC complex integrates three important inputs, growth factor-medited activation of AKT, nutrients (amino acids), and energy homeostatsis (AMP/ATP ratio). Rheb activates mTOR. In contrast to yeast, higher eukaryotes possess only a single TOR gene. The rapamycin-sensitive TOR complex (TORC1) contains the large HEAT/WD40 repeats-containing adaptor protein Raptor, while the rapamycin-insensitive TOR complex (TORC2) contains the 200 kDa protein Rictor. Knockout of Rictor, but not Raptor, results in loss of actin polymerization and cell spreading, implying a role of the TORC2 in organization of the actin cytoskeleton. Rapamycin inhibits TORC1, and requires the peptidyl-prolyl cis/trans-isomerase FKBP12 for its action. Ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E binding protein (4EBP1) are key regulators of protein translation. Phosphorylation of S6 protein by S6K increases the translation of mRNAs containing pyrimidine tracts, including cyclin D1, c-Myc, and VEGF. 4EBP1 acts as a translational repressor by binding and inhibiting the eurkaryotic translation initiation factor 4E (EIF4E), which recognizes the 5' end cap of eukaryotic mRNAs. Phosphorylation of 4EBP1 results in dissociation of 4EBP1 from EIF4E (modified from [12–14]).

 

	Other therapeutic approaches in ADPKD

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Keeping in mind the necessity for a life-long therapy, few drugs with efficacy in animal models of PKD have the potential to translate into clinical trials (Table 1); toxicity, safety profiles, or the application modus often preclude their utilization in humans. In addition, several agents are effective in inhibiting cyst progression only in select animal models [18–21], shedding doubt on their efficacy in ADPKD. There are perhaps three exceptions that deserve a closer look. Recently, kidney volumes were reported to have a significantly slower increase in 12 patients treated with the long-acting stomatostatin octreotide-LAR [22]. Somatostatin markedly inhibits chloride secretion in the shark rectal gland, suggesting inhibition of adenylcyclase and cAMP-dependent fluid secretion. Increased apoptosis may be responsible for cyst formation and demise of normal renal parenchyma, and was first described in kidneys from ADPKD patients [23]. Multiple observations in animal [24,25] and in vitro models [26–28] have since then linked apoptosis to ADPKD. Capitalizing on this hypothesis, Edelstein and coworkers have now found that the caspase inhibitor IDN-8050 is effective in decreasing apoptosis and ameliorating cyst progression in the Han:SPRD rat model of PKD [26–28]. PPAR agonists also hold promise for the future. Tested in the Han:SRPD rat model of PKD, the drugs efficiently suppress cyst growth (B. Dai and C. Mei, personal communication). The precise mechanism of the beneficial action of PPAR agonists remains to be determined, but may also hint at novel and unexplored signal transduction pathways in cyst formation.

	How to monitor the therapeutic efficacy in ADPKD?

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Although cystogenesis may start well before birth, ADPKD patients remain asymptomatic for several decades, during which their renal functions measured by creatinine or glomerular filtration rate (GFR) remain virtually stable. Although hyperfiltration in unaffected nephrons may preserve renal function, secondary focal segmental glomerulosclerosis is not a typical feature of ADPKD. Once the patients experience a rise in creatinine, the subsequent course of the disease can be predicted more accurately. Typically, a patient at this stage has massively enlarged kidneys, and has probably lost half of the renal function. The subsequent decline approximates 5 ml/min/year, leading to end-stage renal disease (ESRD) within the subsequent 10 years; however, the individual variability is substantial. Thus, treating patients at early stages of their disease (GFR 90 ml/min/1.73 m²) may not reveal any measurable outcome for many years. On the other hand, therapy for patients with advanced disease may come too late to rescue enough preserved tissue to have an impact on long-term renal function. To find surrogate markers of disease severity and progression, the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease followed 241 ADPKD patients by sequential magnetic resonance imaging (MRI) measurements. Renal and cyst volumes correlated inversely with the GFR, and were directly related to hypertension and urinary albumin excretion. The average yearly increase in total kidney volume was 5.3%; cyst growth is more aggressive in patients with large kidneys and/or young age at diagnosis [29,30]. Although MR imaging (MRI) is costly and needs to be performed in a highly standardized fashion, volumetric kidney measurements by MRI will likely remain the gold standard to determine disease progression until better surrogate parameters are established.

	Is it too early to start clinical trials in ADPKD?

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In January 2006, the National Institute of Diabetes and Digestive and Kidney Diseases supported by Boehringer Ingelheim Pharmaceuticals, Merck, and the Polycystic Kidney Disease Foundation started the multicentre HALT progression of PKD (HALT PKD) trail. This randomized, placebo-controlled study will determine the efficacy of angiotensin-converting enzymes inhibitors (ACE-I) and ACE-I/angiotensin receptor blocker (ARB) combination therapy on the progression of ADPKD. A total of 1018 patients with an estimated GFR 30 ml/min/1.73 m² will be followed by serial abdominal MRI and GFR measurements over the course of 4–6 years, and hopefully settle the controversy regarding the optimal blood pressure treatment in patients with ADPKD.

It is legitimate to ask whether further animal experiments are needed, before committing ADPKD patients to either V2RA or mTOR-inhibitor therapy. Clearly, more research is needed to determine the optimal dosage for either V2RA or mTOR inhibitors. For example, both rapamycin levels and dosing intervals required to prevent cyst formation or progression may significantly differ from the protocols currently used in organ transplantation. Furthermore, animal studies need to demonstrate the long-term effect on kidney function and survival in chronic progressive models. However, patients with PKD have waited for a long time to find a cure for their disease—on an average, every patient hopes for 50–60 years before he or she finally experiences ESRD. There is certainly no easy answer as to how to balance the benefits of further research against the destructive potential of a relentlessly progressive disease. Furthermore, no authentic animal model truly mimics ADPKD, and in the end, it will be a leap of faith to translate the experimental data into clinical trials.

In addition to the described tolvaptan study, two phase I/II trials are on their way to test the efficacy of rapamycin in ADPKD. One phase I/II study initiated by The Cleveland Clinic will enrol a total of 45 ADPKD patients and monitor the changes in iothalamate GFR and total kidney volume measured by computer tomography (CT) over the course of 12 months. The patients will be divided into three groups, control (n = 15), low-dose rapamycin (trough blood levels at 2–5 ng/ml) or high-dose rapamycin (trough blood levels greater than 5–8 ng/ml). A second mTOR-inhibitor trail will treat 300 ADPKD patients with everolimus (Certican®). This placebo-controlled phase II study will start in the second half of 2006 in Germany and Austria, and will follow ADPKD patients with an estimated GFR between 30 and 89 ml/min/1.73 m² for 2 years by repeated MRI. The drug regimen in these trails adopts the dosages and drug concentrations used in the organ transplantation. The Mario Negri Institute of Pharmacological Research in Italy will enrol 66 ADPKD patients to test the efficacy of long-acting somatostatin in a phase III, placebo-controlled clinical trail. This study will treat patients with an estimated GFR >40 ml/min/1.73 m², and follow their response to therapy by serial MRI over three years.

	Outlook

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Clearly, future research must determine the most effective ADPKD therapy, which could likely entail combining or alternating different drug classes. Despite all progress in the last decade, the pathogenesis of cystogenesis, cyst progression and the cause of renal failure in ADPKD has continued to elude us. Thus, empirical studies will have to optimize the drug regimen, find the correct dosage and mode of application, and most importantly, determine the optimal time point when the therapy needs to be started or abandoned. Adjuvant therapies with ACE-I, ARB and HMG-CoA reductase inhibitors have the potential to increase the efficacy of ADPKD-specific therapies. As always when there is light at the end of the tunnel, there are more tunnels to trespass. Nevertheless, the coming years will be exciting for both ADPKD patients and their doctors.

Conflict of interest statement. None declared.

	References

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