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

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited chronic kidney disorder (CKD) that is characterized by the development of numerous fluid-filled cysts in kidneys. It is caused either due to the mutations in the PKD1 or PKD2 gene that encodes polycystin-1 and polycystin-2, respectively. This condition progresses into end-stage renal disorder if the renal or extra-renal clinical manifestations remain untreated. Several clinical trials with a variety of drugs have failed, and the only Food and Drugs Administration (FDA) approved drug to treat ADPKD to date is tolvaptan that works by antagonizing the vasopressin-2 receptor (V2R). The pathology of ADPKD is complex and involves the malfunction of different signaling pathways like cAMP, Hedgehog, and MAPK/ERK pathway owing to the mutated product that is polycystin-1 or 2. A measured yet substantial number of preclinical studies have found pioglitazone to decrease the cystic burden and improve the renal function in ADPKD. The peroxisome proliferator-activated receptor-gamma is found on the epithelial cells of renal collecting tubule and when it gets agonized by pioglitazone, confers efficacy in ADPKD treatment through multiple mechanisms. There is only one clinical trial (ongoing) wherein it is being assessed for its benefits and risk in patients with ADPKD, and is expected to get approval from the regulatory body owing to its promising therapeutic effects. This article would encompass the updated information on the epidemiology, pathophysiology of ADPKD, different mechanisms of action of pioglitazone in the treatment of ADPKD with preclinical and clinical shreds of evidence, and related safety updates.

Inhibition of Centrosome Clustering Reduces Cystogenesis and Improves Kidney Function in Autosomal Dominant Polycystic Kidney Disease

“…Using a similar dosing scheme, mice were administered either vehicle or CCB02 beginning at 6 months of age every 2 days for a total of 5 months (Figure 5A). In parallel, Pkd1 RC/RC mice were given Tolvaptan, a selective vasopressin receptor 2 (V2) antagonist that is currently the only FDA approved drug for treatment of ADPKD ( 53, 54 ) and has a different mechanism of action than centrosome clustering inhibitors. Similar to the 2-month treatment plan, the mice showed no adverse effects to CCB02, whereas Tolvaptan-treated animals showed significant weight loss over that 5-month period (Figure 5B), which has been previously reported as a significant side effect of this compound ( 54, 55 ).…”

“…The copyright holder for this preprint this version posted November 17, 2022. ; https://doi.org/10.1101/2022.11.16.516801 doi: bioRxiv preprint receptor 2 (V2) antagonist that is currently the only FDA approved drug for treatment of ADPKD (53,54) and has a different mechanism of action than centrosome clustering inhibitors. Similar to the 2-month treatment plan, the mice showed no adverse effects to CCB02, whereas Tolvaptan-treated animals showed significant weight loss over that 5-month period (Figure 5B), which has been previously reported as a significant side effect of this compound (54,55).…”

Evidence of Risk Factors Associated with Autosomal Dominant Polycystic Kidney Disease in Newly Diagnosed Adult Hypertensive Patients in NAUTH Nnewi, Nigeria

“…The significant increase in mean Chloride can be as a result of chloride shift which usually happens when renal function and acid-base balance of the body are impaired. Cystic fibrosis transmembrane conductance regulator (CFTR)mediated chloride transport has been strongly implicated in progressive renal cyst development and as an important inducer of cAMP transmembrane fluid secretion in ADPKD [20]. It has been shown that the force of active chloride excretion in PKD is enhanced by the basolateral sodium-potassium ATPase producing a chemical gradient driving the influx of potassium and chloride through basolateral sodium, potassium and chloride (Na + -K + -2Cl -) co-transporters and the significant accumulation of sodium and chloride in lumen results in water secretion by osmotic forces in PKD [21].…”

Autosomal dominant polycystic kidney disease: A case report

“…60 mg.day) [14]. A study also showed that long-term administration of tolvaptan at a high dose is both safe and effective to reserve kidney function, though a gradual increase in total kidney volume was seen, particularly during the later phase [15].…”