P SAGAR1,2, J ZHANG1,2, C MANNIX1,2, AT WONG1,2, G RANGAN1,2
1Centre for Transplant and Renal Research, Westmead Institute of Medical Research, University of Sydney, Sydney, Australia, 2Department of Renal Medicine, Westmead Hospital, Western Sydney Local Health District, Sydney, Australia
Aim: To determine the effect of paricalcitol (PC) on kidney cyst growth and hypertension in polycystic kidney disease (PKD).
Background: Vitamin D receptor agonists (VDRAs) reduce cell proliferation, hypertension and the renal activation of the renin-angiotensin system in chronic kidney diseases, but their role in PKD is not defined.
Methods: In Study 1, the preventative effects of monotherapy with PC on kidney cyst growth were assessed, and Lewis polycystic kidney disease (LPK) rats (a genetic ortholog of human nephronopthisis) received either PC (0.2 μg/kg/d by daily i.p.i) or vehicle (V) from weeks 3 to 10 (n=6 each). In Study 2, the therapeutic effects were assessed and LPK rats received either PC (0.8μg /kg by i.p.i. 3x/week), V, enalapril (E, 50 mg/L in drinking water) or a combination of E+PC from weeks 10 to 20 (n=5-7 each).
Results: In Study 1, PC did not reduce renal cyst growth or hypertension without adverse effects on serum calcium. In Study 2, the use of PC + E synergistically improved hypertension, more so than the effect of E alone, at both week 13 (LPK+V: 128+15; LPK+E: 103+17; LPK+PC: 137+11; LPK+PC+E: 100+6 mmHg, systolic blood pressure; P<0.01) and week 19 (LPK+V: 119+18; LPK+E: 117+12; LPK+P: 127+10; LPK+PC+E: 94+16 mmHg, systolic blood pressure, p<0.01). At week 20, this protective effect was associated with reduced cardiac enlargement (LPK+V: 0.45+0.03; LPK+E: 0.40+0.02; LPK+PC: 0.42+0.03; LPK+PC+E: 0.37+0.03; %cardiac:BW, p<0.01) but caused hypercalcaemia (LPK+V: 2.8+0.1; LPK+E: 2.8+0.0; LPK+PC: 3.6+0.03; LPK+PC+E: 3.4+0.3 mmol/L; p<0.01).
Conclusions: PC potentiates the anti-hypertensive action of ACE-inhibitors in experimental PKD but did not reduce renal cyst growth and resulted in significant hypercalcaemia. This cautions against further evaluation in clinical trials.
Priyanka is a nephrology advanced trainee at Westmead training network and is interested in experimental and clinical research in polycystic kidney diseases. She is currently completing a MPhil (medical research) at Westmead Institute of Medical Research, University of Sydney.