Renal cyst growth is attenuated by a combination treatment of tolvaptan and pioglitazone, while pioglitazone treatment alone is not effective

Abstract

Autosomal Dominant polycystic Kidney Disease (ADpKD) is one of the most common monogenic disorders, characterized by the progressive formation of fluid-filled cysts. Tolvaptan is an approved drug for ADPKD patients, but is also associated with multiple side effects. The peroxisome proliferatoractivator receptor gamma (ppARγ) agonist pioglitazone slows disease progression in the pcK rat model for pKD. Here, we tested whether a combination treatment of relevant doses of tolvaptan and pioglitazone leads to improved efficacy in an adult-onset PKD mouse model. Tolvaptan indeed slowed PKD progression, but the combination treatment was not more effective than tolvaptan alone. In addition, although pioglitazone raised plasma levels of its surrogate drug marker adiponectin, the drug unexpectedly failed to slow PKD progression. The pioglitazone target PPARγ was expressed at surprisingly low levels in mouse, rat and human kidneys. other pioglitazone targets were more abundantly expressed, but this pattern was comparable across various species. The data suggest that several potential pharmacokinetic and pharmacodynamic (PK/PD) differences between different species may underlie whether or not pioglitazone is able to slow pKD progression. the ongoing phase ii clinical trial with low-dose pioglitazone treatment (NCT02697617) will show whether pioglitazone is a suitable drug candidate for ADpKD treatment. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders, affecting 1 in 2500 individuals 1. The most prominent disease feature is the progressive formation of fluid-filled cysts, mainly in the kidneys and less frequent in liver and pancreas 2. In the majority of patients, the cause of disease is a mutation in the PKD1 (±85%) or PKD2 (±15%) gene, encoding for either polycystin-1 or polycystin-2 3,4. Although the exact mechanisms are not yet completely understood, both PKD1 and PKD2 mutations have been shown to dysregulate many intracellular signalling pathways including mammalian target of rapamycin (mTOR), 5' adenosine monophosphate-activated protein kinase (AMPK), transforming growth factor-beta (TGF-β) and extracellular signal-related kinase (ERK) 5-12. Also, altered fluid secretion involving the cystic fibrosis transmembrane conductance regulator (CFTR) and metabolic alterations (increased glycolysis and reduced fatty acid oxidation) have been reported to contribute to disease progression 13-16. Over the recent years, various interventions based on correcting dysregulated intracellular signalling have been tested in clinical trials 17-21. So far, only the vasopressin V2 receptor antagonist tolvaptan (Jinarc ®), which lowers intracellular cyclic AMP (cAMP) levels in the collecting duct segment of the kidney, was convincingly shown to slow disease progression in patients and is currently available in multiple countries as a treatment option 22-24. While tolvaptan is effective in delaying the loss of renal function, the drug is accompanied by side effects, including polyuria and liver ...

Insights Into the Molecular Mechanisms of Polycystic Kidney Diseases

“…In rodent models, treatment with vasopressin aggravated the development of ADPKD, while antagonism of its receptor helped preserve renal function ( Hopp et al, 2015 ; Wang et al, 2019a ). Blocking the V2R with tolvaptan can affect the extracellular signal-regulated kinase (ERK) pathway, cAMP production, and Cl − secretion ( Reif et al, 2011 ; Aihara et al, 2014 ; Kanhai et al, 2020 ). The central signaling pathways affected by tolvaptan are mediated by cAMP, which is increased at different stages in ADPKD ( Cantero Mdel et al, 2015 ; Menezes and Germino, 2019 ; Sherpa et al, 2019 ): The elevated cAMP levels in PKD have been associated with the activation of V2R ( Sherpa et al, 2019 ).…”

Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects

“…Surprisingly, pioglitazone alone did not have a beneficial effect on these parameters, but the combinational therapy of tolvaptan and pioglitazone did show a better renal survival efficiency; though this difference was not statistically significant (P = 0.1325). The above-mentioned parameters were similar between the tolvaptan, and combination group (Kanhai et al 2020 ).…”

“…Nevertheless, the efficacy and safety of pioglitazone have not been yet verified in the patients with ADPKD as the only clinical trial (ClinicalTrials.gov number, NCT02697617) assessing the efficacy and safety parameters of pioglitazone in ADPKD patients is still ongoing Clinicaltrials 2020 and in the literature, there are only the preclinical studies (Blazer-Yost et al 2010 ; Yoshihara et al 2012 ; Flaig et al 2016 ; Raphael et al 2009b ; Kanhai et al 2020 ; Muto et al 2002 ) based on which we can validate its exceptional, and beneficial effects in ADPKD that certainly makes it an outstanding contender among the drugs that are currently being tested under the clinical trials for the treatment of ADPKD. At last, all eyes are on the regulatory body (USFDA) which will base its decision on the data that will come after the completion of the above-mentioned trial after which the rationality behind the pioglitazone treatment in ADPKD patients will get more strengthened and apparent.…”

Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

“…High-dose pioglitazone improved renal survival in Pkd1 negative mouse models. In a PKD mouse model, combination of pioglitazon and tolvaptan reduced renal polycystosis more than pioglitazon alone [ 64 ]. A phase 2 clinical trial with low-dose pioglitazon in ADPKD patient has been recently finished ( (accessed on 1 February 2022)).…”