Paricalcitol and Endothelial Function in Chronic Kidney Disease Patients (the PENNY Study)
Paricalcitol and Endothelial Function in Chronic Kidney Disease Patients (the PENNY Study)
The primary aim of this study was to test the hypothesis that Paricalcitol, an active form of
 vitamin D, improved endothelial function in stage 3-4 chronic kidney disease (CKD) patients.
 A secondary aim of this trial was to study the relationship between endothelial function and
 plasma/serum and genetic biomarkers of bone mineral disorders in CKD (BMD-CKD) and renin
 angiotensin-aldosteron system (RAS) (angiotensin II and plasma renin activity).
Primary objective: Test the hypothesis that Paricalcitol, an active form of vitamin D
 improves endothelial function in stage 3-4 chronic kidney disease (CKD) patients.

 Secondary analysis: Study the relationship between endothelial function and plasma/serum and
 genetic biomarkers of bone mineral disorders in CKD (BMD-CKD) and renin
 angiotensin-aldosteron system (RAS) (angiotensin II and plasma renin activity).

 Background:

 Endothelial function is altered in patients with CKD. Factors responsible for disturbed
 endothelium-dependent vasodilatation in CKD include reduced bioactivity of the nitric oxide
 (NO) pathway with decreased endothelial NO synthase (NOS) activity or inhibition via
 accumulation of endogenous inhibitors. In patients with CKD and in those on dialysis serum
 25(OH)D3 and 1,25(OH)2D3 levels are associated with FMD. Vitamin D receptors and 1
 -hydroxylase activity are present in endothelial and vascular smooth muscle cells and
 1,25(OH)2D3 stimulates vascular endothelial growth factor and prostacyclin production by
 vascular smooth muscle cells. These biological observations may have clinical implications
 because paricalcitol treatment predicts longer survival in ESRD patients and very recent data
 link vitamin D to progression to ESRD in patients with stage 3-5 CKD. Furthermore, a previous
 study by us has shown that the BMSI polymorphism of the vitamin D receptor gene is associated
 with LVH and LVH progression in ESRD patients.

 Study population: Patients with stage 3-4 CKD of both sexes in the age range 18-80 years.
 Patients taking vitamin D supplements, with abnormal liver function tests, symptomatic
 cardiovascular disease, diabetes or cancer and those whose medications changed during the
 study were excluded.

 Design and Methods: The study was a double-blind, randomized, parallel groups trial. After
 baseline measurements, patients with iPTH level > 65 pg/ml; Ca between 8.4- 10.00 mg/dL and P
 between 2.9-4.5 were randomized to receive 2 micrograms Paricalcitol capsules (or matching
 placebo) daily, for 12 weeks. This doses was adjusted based on clinical laboratory parameters
 and the maximum dose was 2 micrograms daily.

 During the study if a subject experienced over suppression of serum iPTH (defined as a serum
 iPTH <15 pg/mL), or hypercalcemia (defined as Ca > 11.0 mg/dL), the subject continued to take
 study drug at reduced dosage 1 mcg any other day and returned in 2 weeks for an unscheduled
 visit. If the values from the unscheduled visit serum iPTH and/or Ca did not returned to > 15
 pg/mL and/or <11.0 mg/dL, respectively, the drug was discontinued.

 Flow mediated vasodilatation was measured according to a validated protocol developed at the
 coordinating center of a national (Italian)working group of vascular function testing.

 Primary end-point: Change in Flow Mediated Dilatation (FMD) induced by Paricalcitol in
 comparison to Placebo.

 Study power: To detect a 2% difference (standard deviation: ± 3.0%) in the change in FMD
 between Paracalcitol treated and untreated patients with a power of 80 %, a confidence level
 using a two-tailed test of 5% and a potential attrition rate of 15%, at least 44 patients per
 group were required (88 patients in total).

 Statistical analysis: Data will be summarized as mean ± standard deviation (normally
 distributed data), median and inter-quartile range (non normally distributed data) or as
 percent frequency, and comparison between groups will be made by independent T-Test,
 Mann-Whitney Test, or Chi Square test, as appropriate. Within patients comparisons will be
 done by statistical tests for paired observations. Data analysis of the primary outcome will
 be performed by comparing the changes in FMD in Paracalcitol treated and untreated patients
 by using the T-Test for independent observations. Possible differences in risk factors at
 baseline not controlled by randomization (i.e. differences due to chance) will be accounted
 for by using multivariate regression analyses.
Inclusion Criteria:

 -  Patients with iPTH level > 65 pg/ml; Ca between 8.4- 10.00 mg/dL and P between 2.9-4.5

 -  Negative serum pregnancy test for female subjects of childbering potential.

 -  Informed consent.

 Exclusion Criteria:

 -  Use vitamin D supplements.

 -  Altered liver function tests (bilirubin, aminotransferases and total alkaline
 phosphatase > 3 times the upper limit of normal ranges).

 -  Sympthomatic cardiovascular disease on the basis of clinical history. Cancer.