Effect of Early and Delayed Commencement of Paricalcitol in Combination with Enalapril on the Progression of Experimental Polycystic Kidney Disease.

Priyanka S Sagar,Gopala K Rangan,Annette T Y Wong,Sayanthooran Saravanabavan,Alexandra Munt

doi:10.3390/jcdd8110144

Abstract

Vitamin D secosteroids are intranuclear regulators of cellular growth and suppress the renin-angiotensin system. The aim of this study was to test the hypothesis that the vitamin D receptor agonist, paricalcitol (PC), either alone or with enalapril (E) (an angiotensin-converting enzyme inhibitor), reduces the progression of polycystic kidney disease. Preventative treatment of Lewis polycystic kidney (LPK) and Lewis control rats with PC (0.2 μg/kg i.p. 5 days/week) or vehicle from postnatal weeks 3 to 10 did not alter kidney enlargement. To evaluate the efficacy in established disease, LPK rats received either PC (0.8 μg/kg i.p; 3 days/week), vehicle, E (50 mg/L in water) or the combination of PC + E from weeks 10 to 20. In established disease, PC also did not alter the progression of kidney enlargement, kidney cyst growth or decline in renal function in LPK rats. Moreover, the higher dose of PC was associated with increased serum calcium and weight loss. However, in established disease, the combination of PC + E reduced systolic blood pressure and heart-body weight ratio compared to vehicle and E alone (p < 0.05). In conclusion, the combination of PC + E attenuated cardiovascular disease but caused hypercalcaemia and did not alter kidney cyst growth in LPK rats.

Highlights

Polycystic kidney diseases (PKD) are a group of inherited conditions associated with the development of numerous enlarging renal cysts that lead to life-threatening end-stage kidney disease (ESKD) [1]
At Week 10, Lewis polycystic kidney (LPK) + V rats developed increased proteinuria and urine volume, and impairment of endogenous creatinine clearance without significantly increased serum creatinine compared to the Lewis + V rats, and this was not affected by treatment with PC (Table 1)
There was a significant reduction in 25, hydroxy-vitamin D in both LPK rat groups compared with Lewis rats, as expected with early kidney disease (p < 0.01, Table 1)

Summary

Introduction

Polycystic kidney diseases (PKD) are a group of inherited conditions associated with the development of numerous enlarging renal cysts that lead to life-threatening end-stage kidney disease (ESKD) [1]. Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent form of PKD in adults and affects 6.5 million people worldwide [1]. Early-onset hypertension occurs prior to the onset of renal impairment and, in addition to left ventricular hypertrophy, contributes to increased mortality, with cardiovascular disease as the most common cause of death for ADPKD patients [2,3,4,5]. In ADPKD patients, hypertension presents on average in their mid-thirties, and they have a greater prevalence of cardiovascular risk factors compared to the general CKD population [5]. The vasopressin receptor-2 antagonist, tolvaptan, was introduced as the only disease modifying drug for ADPKD, but its universal implementation is limited by off-target adverse effects that include polyuria and idiosyncratic hepatotoxicity. Additional pharmacological approaches for PKD that have minimal adverse effects and utilise re-purposed medicines are needed [1,6,7]

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