Paricalcitol Versus Calcitriol for the Management of Renocardiac Syndrome in Renal Transplant Patients

Phase 4 Study of Paricalcitol and Calcitriol for Reparative Management of Chronic Allograft Dysfunction and Renocardiac Syndrome in Vitamin D Insufficient Renal Transplant Recipients

We hypothesize that paricalcitol and calcitriol in dose-dependent manner are effective for the management of chronic allograft dysfunction (CAD), protection and repair of kidney and heart, management of chronic renocardiac syndrome (CRS). We assume that paricalcitol can have some advantages if compare with calcitriol or cholecalciferol due to absence of calcemic and phosphatemic complications alongside with great beneficial potential.

Study Overview

• Status: Completed
• Conditions: Cardiorenal Syndrome; Chronic Allograft Nephropathy
• Intervention / Treatment: Drug: Paricalcitol; Drug: Calcitriol; Drug: Cholecalciferol; Dietary supplement: Supplemental

Detailed Description

Paricalcitol and calcitriol are identically effective for the management of chronic allograft dysfunction (CAD), protection and repair of kidney and heart, management of chronic renocardiac syndrome (CRS). Vitamin D can reduce progression of CAD. Activation of VDR in proximal part of nephron leads to rapid non-genomic beneficial effects with urgent multilevel protection of the most functionally important portion of kidney. Rising expression of VDR in distal portions of nephron stimulates slows genomic effects with some local repair responses.

Hormone D may stimulate recruitment and activity of the different origin stem-progenitor cells (SPCs) with beneficial effects on different stages of regeneration by force of para- and autocrine activity. SPCs are revealing mostly in interstitium and among fibroblast-like cells. Vitamin D did not confirm efficacy as a tool for management of mesenchymal stem cells (MSCs) in human however it needs more research experimental evidences due to multifactorial influence on SPCs in human being including immunosuppressive and bone-marrow-related effects of cyclosporine in kidney transplant (Tx) patients. Paricalcitol and calcitriol can slow down migration and infiltration of MSC into interstitium and vessel wall. The side population of mature and SPCs (first of all, with bone-marrow and mesenchymal phenotype) is the most metabolically and functionally active portion of cells with high sensitivity to vitamin D receptor (VDR) activation that responsible for repair of tissue.

The most optimal scheme of treatment with vitamin D in patients with CAD and CRS is an administration of paricalcitol with dose 2-4 μg daily and supplemental intake of vitamin D including special diet, multivitamins, and others with optimal dose until 1800 international units (IU) but excluding insolation as a factor of skin carcinoma. High-dose medicinal intake of calcitriol (until 6 mcg and higher) showed relatively high efficacy but rather excessive level of complications mediated with mineral metabolism.

Paricalcitol and calcitriol may significantly improve contractility of myocardium and reduce cardiovascular risk, heart failure (HF) and hypertension with some beneficial effects on cardiorenal axis and renin-angiotensin-aldosterone system.

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3071PR
      • De Haar Research Foundation
• Russian Federation
  • Yekaterinburg, Russian Federation, 620144
    • Ural Institute of Cardiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 36 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Age 40-75
• Male
• History of chronic kidney disease and cardiorenal syndrome
• Written informed consent

Exclusion Criteria:

• Female
• Acute illness
• Life-threat competitive illness
• Mental disorders
• Endocrinologic diseases (including diabetes mellitus, hyperparathyroidism, and other thyroid disorders)
• Need for dialyses
• Hypercalcemia
• Concomitant use of hormone or cytokine medication
• Participation to any drug-investigation during the previous 60 days as checked with VIP check

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Paricalcitol treatment; 6-8 μg daily per os (orally) without special diet	Drug: Paricalcitol; paricalcitol group (6-8 μg daily per os - orally - without special diet); Other Names: Zemplar
Active Comparator: Calcitriol treatment; 2-4 μg daily orally under with dietary restrictions of vitamin D	Drug: Calcitriol; calcitriol group (2-4 μg daily orally under with dietary restrictions of vitamin D); Other Names: Rocaltrol
Active Comparator: Cholecalciferol; alendronate sodium/ cholecalciferol capsules with recommended daily allowance equals 1200-2400 IU per day	Drug: Cholecalciferol; cholecalciferol group (intake of cholecalciferol with recommended daily allowance equals 1200-2400 IU per day); Other Names: Fosamax
Other: Supplemental; intake of cholecalciferol in food and multivitamins, less than 400-900 IU per day	Dietary supplement: Supplemental; intake of cholecalciferol in food and multivitamins, less than 400-900 IU per day; Other Names: Diet, sun, multivitamin drugs, food

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CAD (Chronic Allograft Dysfunction) Degree	Beyond 180 days, chronic allograft dysfunction (CAD) was characterized by mean Banff degree (revised 2005/2007 criteria) with the data of renal biopsy material. Renal tissue was recovered during routined biopsy. We assessed antibody-mediated rejection, borderline changes, T-cell-mediated rejection, interstitial fibrosis and tubular atropthy, and other changes. Grades: Grade I. Mild interstitial fibrosis and tubular atrophy (<25% of cortical area) II. Moderate (26-50%) III. Severe (>50%) (may include non-specific vascular and glomerular sclerosis)	day 180 after Tx (transplantation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart Failure (HF)	NYHA (New York Heart Association) functional class verified with veloergometry probe and by NYHA clinical classification NYHA Class Symptoms I No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc. II Mild symptoms and slight limitation during ordinary activity. III Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest. IV Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.	on day 180 after Tx (transplantation)
GFR (Glomerular Filtration Rate)	Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated form of the Modification of Diet in Renal Disease (MDRD) study equation: eGFR = exp (5.228 - 1.154 × ln (serum creatinine) - 0.203 × ln (age). Concerning of GFR with Tc99m DTPA renography was used for the complex analysis of renal function. Camera based GFR estimated from Tc99m DTPA renography was named Gates GFR.	on day 180
CAD (Chronic Allograft Dysfunction) Degree	CAD degree measured by Banff score after routine renal biopsy (revised 2005/2007 criteria). We assessed antibody-mediated rejection, borderline changes, T-cell-mediated rejection, interstitial fibrosis and tubular atropthy, and other changes. Grades: Grade I. Mild interstitial fibrosis and tubular atrophy (<25% of cortical area) II. Moderate (26-50%) III. Severe (>50%) (may include non-specific vascular and glomerular sclerosis)	on day 90
Serum Creatinine	After an overnight fast, plasma concentrations of hemoglobin, creatinine, cholesterol, glucose, total calcium, and phosphate were measured using an autoanalyzer as described by Adorini L. (2005)	on day 180 after Tx
Number of Circulating SP (Side Population) Stem-Progenitor Cells	Renal cells and solid tissue were obtained from the normal portion of cortex obtained from surgically removed kidneys or by standart biopsy on day 180. Cytofluorimetric analysis and immunofluorescence were performed as described by Oliver J.A. (2004). Sorting and analysis of different cells was done on a FACS (fluorescent activated cell sorting) and by flow cytometry. Cells were analyzed with EPICS systems (Beckman Coulter). Quantification of mRNA expression was achieved using Assays-on-Demand gene expression kits and the ABI PRISM 7000 Sequence Detection System (Applied Biosystem).	on day 180
VDR (Vitamin D Receptor) Expression in Myocardium	VDR content was determined by using an ELISA developed in this laboratory. The protein concentration of the homogenates was determined by the method of Bradford (1976), using BSA as a standard.	on day 180
VDR (Vitamin D Receptor) Expression in Kidney	VDR content was determined by using an ELISA developed in this laboratory. The protein concentration of the homogenates was determined by the method of Bradford (1976), using BSA as a standard.	on day 180
Systolic Blood Pressure	SBP measured by routine method	on day 180
Coronary Calcium Score	Bone mineral density assessed by dual-energy X-ray absorptiometry (DXA) of the whole body, lumbar spine and hip was performed using Hologic scanners (QDR 1000W or QDR 2000). The total Agatston coronary calcium score (CCS) was measured as the sum of calcified plaque scores of all the coronary arteries. The amount of calcium present in the coronary arteries is scored according to the Agatson scale, as follows: 0 - no identifiable disease; 1 to 99 - mild disease; 100 to 399 - moderate disease; 400 or higher - severe disease.	on day 180

Collaborators and Investigators

• Sponsor: Ural State Medical University
• Collaborators: Ural Institute of Cardiology; De Haar Research Foundation
• Investigators: Principal Investigator: Alexander Kharlamov, M.D., Ural Institute of Cardiology; Principal Investigator: Alexander Perrish, M.D., Ural State Medical University

Publications and helpful links

General Publications

• Kharlamov AN, Perrish AN, Gabiskii IaL, Ronne Kh, Ivanova EIu. [Vitamin D in the treatment of cardiorenal syndrome in patients with chronic nephropathy]. Kardiologiia. 2012;52(3):33-44. Russian.

Helpful Links

• Ural Institute of Cardiology
• Ural State Medical Academy

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: December 22, 2010
• First Submitted That Met QC Criteria: December 22, 2010
• First Posted (Estimate): December 23, 2010

Study Record Updates

• Last Update Posted (Estimate): June 9, 2015
• Last Update Submitted That Met QC Criteria: May 14, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: cardiorenal syndrome; cholecalciferol; paricalcitol; calcitriol; chronic allograft nephropathy; stem-progenitor cells; cardiac repair; renal repair
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Urologic Diseases; Disease; Renal Insufficiency; Heart Failure; Syndrome; Kidney Diseases; Cardio-Renal Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Micronutrients; Membrane Transport Modulators; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vasoconstrictor Agents; Calcium Channel Agonists; Vitamin D; Cholecalciferol; Calcitriol
• Other Study ID Numbers: VDCRS03