All you need to read in the other general journalsBMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e1248 (Published 22 February 2012) Cite this as: BMJ 2012;344:e1248
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PRIMO was a proof of concept study designed to test the hypothesis that vitamin D receptor activation improves left ventricular hypertrophy (LVH) in subjects with moderate LVH and chronic kidney disease, which is supported by several preclinical and clinical studies.(1-3) However, the results did not support a beneficial effect of paricalcitol on left ventricular mass index (LVMI).(4) Contrary to current understanding, the placebo group did not demonstrate any progression in LVMI. As expected, paricalcitol lowered iPTH levels, a currently approved indication in stages 3-5 CKD.
The results suggested a greater decline in estimated GFR (eGFR) based on creatinine and cystatin-C levels in the paricalcitol group. Consistent with previous data in subjects treated with other VDR activators,(5,6) a recent study in CKD subjects demonstrated increased creatinine production following paricalcitol administration without an affect on measured GFR determined by iothalamate clearance.(7) As subjects in the paricalcitol arm had a lower eGFR at baseline, a more rapid rate of decline is not unexpected, and perhaps explains the non-significant reduction of eGFR when calculated using cystatin C.
In the PRIMO study, there were a numerically (but not statistically) greater number of subjects in the paricalcitol arm that initiated long-term dialysis compared to controls (6 vs. 1). However, as described in the manuscript, an analysis of subjects initiating long-term dialysis during the study showed that subjects randomized to paricalcitol had worse renal function at baseline. Additional analysis of subjects who initiated dialysis revealed that even before randomization to paricalcitol, there was a much steeper slope of eGFR decline in these subjects compared to those who did not initiate dialysis in either the placebo or paricalcitol groups, suggesting this decline was independent of drug effect.
In summary, the PRIMO study was designed to evaluate the potential benefit of paricalcitol on cardiac structure as measured by LVMI. Although data did not support a beneficial effect on LVMI, improvement was of note with other parameters such as cardiovascular hospitalizations, levels of brain natriuretic peptide and left atrial volume index. The title of the summary article that “paricalcitol should not be given to people with CKD” is not supported by the PRIMO data, and is not reflective of the manuscript conclusions. Furthermore, the title contrasts the results of many previous studies which have shown a beneficial effect of paricalcitol in CKD subjects with secondary hyperparathyroidism including several studies demonstrating a significant beneficial effect of activated vitamin D and paricalcitol on secondary hyperparathyroidism and survival.(8-10)
1. Bodyak N, Ayus JC, Achinger S, Shivalingappa V, Ke Q, Chen YS, et al. Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci U S A 2007;104(43):16810-5.
2. Wu J, Garami M, Cheng T, Gardner DG. 1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes. J Clin Invest 1996;97(7):1577-88.
3. Park CW, Oh YS, Shin YS, Kim CM, Kim YS, Kim SY, et al. Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism. Am J Kidney Dis 1999;33(1):73-81.
4. Thadhani R, Appelbaum E, Pritchett Y, Chang Y, Wenger J, Tamez H, et al. Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial. Jama 2012;307(7):674-84.
5. Perez A, Chen TC, Turner A, Raab R, Bhawan J, Poche P, et al. Efficacy and safety of topical calcitriol (1,25-dihydroxyvitamin d3) for the treatment of psoriasis. Br J Dermatol 1996;134(2):238-46.
6. Bertoli M, Luisetto G, Ruffatti A, Urso M, Romagnoli G. Renal function during calcitriol therapy in chronic renal failure. Clin Nephrol 1990;33(2):98-102.
7. Agarwal R, Hynson JE, Hecht TJ, Light RP, Sinha AD. Short-term vitamin D receptor activation increases serum creatinine due to increased production with no effect on the glomerular filtration rate. Kidney Int 2011;80(10):1073-9.
8. Kalantar-Zadeh K, Kuwae N, Regidor DL, Kovesdy CP, Kilpatrick RD, Shinaberger CS, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int 2006;70(4):771-80.
9. Kovesdy CP, Ahmadzadeh S, Anderson JE, Kalantar-Zadeh K. Association of activated vitamin D treatment and mortality in chronic kidney disease. Arch Intern Med 2008;168(4):397-403.
10. Brancaccio D, Cozzolino M, Cannella G, Messa P, Bonomini M, Cancarini G, et al. Secondary hyperparathyroidism in chronic dialysis patients: results of the Italian FARO survey on treatment and mortality. Blood Purif 2011;32(2):124-32.
Competing interests: Mario Cozzolino has received honoraria from Abbott, Amgen, Shire, Genzyme and Roche. Samina Khan and Dennis Andress are employees of Abbott and may hold Abbott stock or options. Editorial support was provided by Matthew Mack on behalf of Abbott. The PRIMO study was funded by Abbott.