Drugs in Clinical Development to Treat Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation that ultimately leads to kidney failure in most patients. Approximately 10% of patients who receive kidney replacement therapy suffer from ADPKD. To date, a vasopressin V2 receptor antagonist (V2RA) is the only drug that has been proven to attenuate disease progression. However, aquaresis-related adverse events limit its widespread use. Data on the renoprotective effects of somatostatin analogues differ largely between studies and medications. This review discusses new drugs that are investigated in clinical trials to treat ADPKD, such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators and micro RNA inhibitors, and drugs already marketed for other indications that are being investigated for off-label use in ADPKD, such as metformin. In addition, potential methods to improve the tolerability of V2RAs are discussed, as well as methods to select patients with (likely) rapid disease progression and issues regarding the translation of preclinical data into clinical practice. Since ADPKD is a complex disease with a high degree of interindividual heterogeneity, and the mechanisms involved in cyst growth also have important functions in various physiological processes, it may prove difficult to develop drugs that target cyst growth without causing major adverse events. This is especially important since long-standing treatment is necessary in this chronic disease. This review therefore also discusses approaches to targeted therapy to minimize systemic side effects. Hopefully, these developments will advance the treatment of ADPKD.

Fig. 1

MRI scan of a 33-year-old female with autosomal dominant polycystic kidney disease (ADPKD). Innumerable cysts are present throughout both kidneys (depicted in orange), and a few cysts are present in the liver (depicted in green). The total kidney volume (TKV) of this patient is 1800 mL; roughly eight times larger than normal. Two normal sized kidneys are shown on the right for reference (normal MRI-measured TKV in females: approximately 260–300 mL [4])

Fig. 2

Treatment effect of tolvaptan on annual rate of estimated glomerular filtration rate (eGFR) decline in the TEMPO 3:4 and REPRISE trials [25, 26]. Tolvaptan reduced the annual eGFR decline by 26% and 35% in the TEMPO 3:4 and REPRISE studies, respectively

Fig. 3

Illustration of the principal mechanisms of autosomal dominant polycystic kidney disease (ADPKD) pathogenesis and main targets of potential treatments. Dysfunction of polycystin 1 and 2 leads to abnormal ciliary function and a decrease in the intracellular calcium concentration, resulting in increased cAMP generation and mTOR activity which subsequently promote protein transcription and cell proliferation. Current and potential treatment options are depicted in green. AC adenylyl cyclase, ARE antioxidant response element, ATP adenosine triphosphate, AMPK 5’ AMP-activated protein kinase, B-raf serine/threonine-protein kinase B-Raf, cAMP cyclic adenosine monophosphate, CFTR cystic fibrosis transmembrane conductance regulator, EGFR epidermal growth factor receptor, ER endoplasmatic reticulum, ERK extracellular signal-regulated kinase, GCS glucosylceramide synthase, Gi inhibitory G protein of adenylyl cyclase, Gs stimulatory G protein of adenylyl cyclase, IKKβ I-kappa-B kinase unit beta, Keap1 Kelch-like ECH-associated protein 1, MEK mitogen-activated protein kinase kinase, miRNA 17 micro RNA 17, mTOR mammalian target of rapamycin, NF-κB nuclear factor kappa B, Nrf2 nuclear factor erythroid 2-related factor 2, PC1 polycystin 1, PC2 polycystin 2, PKA protein kinase A, pIgR polymeric immunoglobulin receptor, SSTR somatostatin receptor, TSC1/TSC2 tuberous sclerosis complex subunit 1/2, V2R vasopressin receptor 2