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

This study has been completed.
Sponsor:
Collaborator:
Ural Institute of Cardiology
Information provided by:
Ural State Medical Academy
ClinicalTrials.gov Identifier:
NCT01265615
First received: December 22, 2010
Last updated: May 23, 2011
Last verified: November 2010
  Purpose

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.


Condition Intervention Phase
Cardiorenal Syndrome
Chronic Allograft Nephropathy
Drug: Paricalcitol
Drug: Calcitriol
Drug: Cholecalciferol
Dietary Supplement: Supplemental
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Phase 4 Study of Paricalcitol and Calcitriol for Reparative Management of Chronic Allograft Dysfunction and Renocardiac Syndrome in Vitamin D Insufficient Renal Transplant Recipients

Resource links provided by NLM:


Further study details as provided by Ural State Medical Academy:

Primary Outcome Measures:
  • CAD (Chronic Allograft Dysfunction) Degree [ Time Frame: day 180 after Tx (transplantation) ] [ Designated as safety issue: Yes ]

    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)



Secondary Outcome Measures:
  • Heart Failure (HF) [ Time Frame: on day 180 after Tx (transplantation) ] [ Designated as safety issue: Yes ]

    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.


  • GFR (Glomerular Filtration Rate) [ Time Frame: on day 180 ] [ Designated as safety issue: No ]
    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.

  • CAD (Chronic Allograft Dysfunction) Degree [ Time Frame: on day 90 ] [ Designated as safety issue: Yes ]

    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)


  • Serum Creatinine [ Time Frame: on day 180 after Tx ] [ Designated as safety issue: No ]
    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)

  • Number of Circulating SP (Side Population) Stem-Progenitor Cells [ Time Frame: on day 180 ] [ Designated as safety issue: No ]
    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).

  • VDR (Vitamin D Receptor) Expression in Myocardium [ Time Frame: on day 180 ] [ Designated as safety issue: No ]
    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.

  • VDR (Vitamin D Receptor) Expression in Kidney [ Time Frame: on day 180 ] [ Designated as safety issue: No ]
    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.

  • Systolic Blood Pressure [ Time Frame: on day 180 ] [ Designated as safety issue: No ]
    SBP measured by routine method

  • Coronary Calcium Score [ Time Frame: on day 180 ] [ Designated as safety issue: No ]
    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.


Enrollment: 109
Study Start Date: October 2009
Study Completion Date: September 2010
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: Fosamax
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 Name: Diet, sun, multivitamin drugs, food

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.

  Eligibility

Ages Eligible for Study:   40 Years to 75 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01265615

Locations
Russian Federation
Ural Institute of Cardiology
Yekaterinburg, Russian Federation, 620144
Sponsors and Collaborators
Ural State Medical Academy
Ural Institute of Cardiology
Investigators
Principal Investigator: Alexander Kharlamov, M.D. Ural Institute of Cardiology
Principal Investigator: Alexander Perrish, M.D. Ural State Medical Academy
  More Information

Additional Information:
No publications provided

Responsible Party: Jan Gabinsky/ Prof. Dr., C.E.O., Ural Institute of Cardiology
ClinicalTrials.gov Identifier: NCT01265615     History of Changes
Other Study ID Numbers: VDCRS03
Study First Received: December 22, 2010
Results First Received: December 27, 2010
Last Updated: May 23, 2011
Health Authority: Russia: Ethics Committee

Keywords provided by Ural State Medical Academy:
chronic allograft nephropathy
stem-progenitor cells
cardiorenal syndrome
calcitriol
paricalcitol
cholecalciferol
cardiac repair
renal repair

Additional relevant MeSH terms:
Cardio-Renal Syndrome
Kidney Diseases
Syndrome
Cardiovascular Diseases
Disease
Heart Diseases
Heart Failure
Pathologic Processes
Renal Insufficiency
Urologic Diseases
Calcitriol
Cholecalciferol
Ergocalciferols
Bone Density Conservation Agents
Calcium Channel Agonists
Cardiovascular Agents
Growth Substances
Membrane Transport Modulators
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Vasoconstrictor Agents
Vitamins

ClinicalTrials.gov processed this record on October 23, 2014