Cardiorenal Syndrome, Chronic Allograft Nephropathy
Conditions
Keywords
chronic allograft nephropathy, stem-progenitor cells, cardiorenal syndrome, calcitriol, paricalcitol, cholecalciferol, cardiac repair, renal repair
Brief summary
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.
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.
Interventions
DRUGParicalcitol
paricalcitol group (6-8 μg daily per os - orally - without special diet)
DRUGCalcitriol
calcitriol group (2-4 μg daily orally under with dietary restrictions of vitamin D)
DRUGCholecalciferol
cholecalciferol group (intake of cholecalciferol with recommended daily allowance equals 1200-2400 IU per day)
DIETARY_SUPPLEMENTSupplemental
intake of cholecalciferol in food and multivitamins, less than 400-900 IU per day
Sponsors
Ural Institute of Cardiology
De Haar Research Foundation
Ural State Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
40 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CAD (Chronic Allograft Dysfunction) Degree | day 180 after Tx (transplantation) | 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
| Measure | Time frame | Description |
|---|---|---|
| GFR (Glomerular Filtration Rate) | on day 180 | 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 | on day 90 | 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 | on day 180 after Tx | 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 | on day 180 | 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). |
| Heart Failure (HF) | on day 180 after Tx (transplantation) | 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. |
| VDR (Vitamin D Receptor) Expression in Kidney | on day 180 | 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 | on day 180 | SBP measured by routine method |
| Coronary Calcium Score | on day 180 | 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. |
| VDR (Vitamin D Receptor) Expression in Myocardium | on day 180 | 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. |
Countries
Netherlands, Russia
Participant flow
Recruitment details
A total of 120 patients (Russian and dutch caucasian, kidney recipients with vitamin D deficiency defined as 25(OH)D \< 30 ng/mL) were assigned on the basis of Ural Institute of Cardiology. Nine of the 120 patients were subsequently excluded due to protocol violation. All the patients had given their written informed consents.
Participants by arm
| Arm | Count |
|---|---|
| Paricalcitol Treatment 6-8 μg daily per os without special diet | 30 |
| Calcitriol Treatment 2-4 μg daily orally under with dietary restrictions of vitamin D | 30 |
| Cholecalciferol alendronate sodium/ cholecalciferol capsules with recommended daily allowance equals 1200-2400 IU per day | 30 |
| Supplemental intake of cholecalciferol in food and multivitamins, less than 400-900 IU per day | 30 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 2 | 2 | 4 | 3 |
Baseline characteristics
| Characteristic | Calcitriol Treatment | Cholecalciferol | Paricalcitol Treatment | Supplemental | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 4 Participants | 2 Participants | 3 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants | 26 Participants | 28 Participants | 27 Participants | 109 Participants |
| Age, Continuous | 59 years STANDARD_DEVIATION 4 | 58 years STANDARD_DEVIATION 5 | 56 years STANDARD_DEVIATION 4 | 57 years STANDARD_DEVIATION 4 | 58 years STANDARD_DEVIATION 9 |
| Region of Enrollment Russian Federation | 30 participants | 30 participants | 30 participants | 30 participants | 120 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 30 Participants | 30 Participants | 30 Participants | 30 Participants | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 30 | 15 / 30 | 9 / 30 | 9 / 30 |
| serious Total, serious adverse events | 9 / 30 | 21 / 30 | 6 / 30 | 8 / 30 |
Outcome results
Primary
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)
Time frame: day 180 after Tx (transplantation)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | CAD (Chronic Allograft Dysfunction) Degree | 1.24 Scores on a Banff scale | Standard Deviation 0.14 |
| Calcitriol Treatment | CAD (Chronic Allograft Dysfunction) Degree | 1.22 Scores on a Banff scale | Standard Deviation 0.42 |
| Cholecalciferol | CAD (Chronic Allograft Dysfunction) Degree | 1.43 Scores on a Banff scale | Standard Deviation 0.22 |
| Supplemental | CAD (Chronic Allograft Dysfunction) Degree | 1.68 Scores on a Banff scale | Standard Deviation 0.36 |
p-value: <0.05ANOVA
Secondary
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)
Time frame: on day 90
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | CAD (Chronic Allograft Dysfunction) Degree | 1.24 Scores on a Banff scale | Standard Deviation 0.14 |
| Calcitriol Treatment | CAD (Chronic Allograft Dysfunction) Degree | 1.22 Scores on a Banff scale | Standard Deviation 0.42 |
| Cholecalciferol | CAD (Chronic Allograft Dysfunction) Degree | 1.43 Scores on a Banff scale | Standard Deviation 0.22 |
| Supplemental | CAD (Chronic Allograft Dysfunction) Degree | 1.68 Scores on a Banff scale | Standard Deviation 0.36 |
p-value: <0.05ANOVA
Secondary
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.
Time frame: on day 180
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | Coronary Calcium Score | 530 units on a scale | Standard Deviation 423 |
| Calcitriol Treatment | Coronary Calcium Score | 611 units on a scale | Standard Deviation 502 |
| Cholecalciferol | Coronary Calcium Score | 524 units on a scale | Standard Deviation 122 |
| Supplemental | Coronary Calcium Score | 990 units on a scale | Standard Deviation 120 |
p-value: <0.05ANOVA
Secondary
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.
Time frame: on day 180
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | GFR (Glomerular Filtration Rate) | 84 ml/min/1.73 m^2 | Standard Deviation 11 |
| Calcitriol Treatment | GFR (Glomerular Filtration Rate) | 81 ml/min/1.73 m^2 | Standard Deviation 9 |
| Cholecalciferol | GFR (Glomerular Filtration Rate) | 76 ml/min/1.73 m^2 | Standard Deviation 10 |
| Supplemental | GFR (Glomerular Filtration Rate) | 54 ml/min/1.73 m^2 | Standard Deviation 9 |
p-value: <0.05ANOVA
Secondary
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.
Time frame: on day 180 after Tx (transplantation)
Population: A total of 120 patients (Russian and dutch caucasian, kidney recipients with vitamin D deficiency defined as 25(OH)D \< 40 nmol/l) were assigned. Analysis was per protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | Heart Failure (HF) | 1.8 NYHA functional class of HF | Standard Deviation 0.2 |
| Calcitriol Treatment | Heart Failure (HF) | 1.9 NYHA functional class of HF | Standard Deviation 0.3 |
| Cholecalciferol | Heart Failure (HF) | 1.9 NYHA functional class of HF | Standard Deviation 0.1 |
| Supplemental | Heart Failure (HF) | 2.5 NYHA functional class of HF | Standard Deviation 0.2 |
p-value: <0.05ANOVA
Secondary
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).
Time frame: on day 180
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | Number of Circulating SP (Side Population) Stem-Progenitor Cells | 7.6 per cent of SP cells | Standard Deviation 0.9 |
| Calcitriol Treatment | Number of Circulating SP (Side Population) Stem-Progenitor Cells | 6.5 per cent of SP cells | Standard Deviation 1 |
| Cholecalciferol | Number of Circulating SP (Side Population) Stem-Progenitor Cells | 5.7 per cent of SP cells | Standard Deviation 0.8 |
| Supplemental | Number of Circulating SP (Side Population) Stem-Progenitor Cells | 4.2 per cent of SP cells | Standard Deviation 0.7 |
p-value: <0.05ANOVA
Secondary
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)
Time frame: on day 180 after Tx
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | Serum Creatinine | 2.5 mg/dL | Standard Deviation 0.9 |
| Calcitriol Treatment | Serum Creatinine | 2.5 mg/dL | Standard Deviation 0.7 |
| Cholecalciferol | Serum Creatinine | 2.8 mg/dL | Standard Deviation 0.7 |
| Supplemental | Serum Creatinine | 4.1 mg/dL | Standard Deviation 1.1 |
p-value: <0.05ANOVA
Secondary
Systolic Blood Pressure
SBP measured by routine method
Time frame: on day 180
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | Systolic Blood Pressure | 143 mmHg | Standard Deviation 22 |
| Calcitriol Treatment | Systolic Blood Pressure | 141 mmHg | Standard Deviation 9 |
| Cholecalciferol | Systolic Blood Pressure | 147 mmHg | Standard Deviation 13 |
| Supplemental | Systolic Blood Pressure | 165 mmHg | Standard Deviation 19 |
p-value: <0.05ANOVA
Secondary
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.
Time frame: on day 180
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | VDR (Vitamin D Receptor) Expression in Kidney | 584 fmol VDR/ mg protein | Standard Deviation 103 |
| Calcitriol Treatment | VDR (Vitamin D Receptor) Expression in Kidney | 599 fmol VDR/ mg protein | Standard Deviation 102 |
| Cholecalciferol | VDR (Vitamin D Receptor) Expression in Kidney | 478 fmol VDR/ mg protein | Standard Deviation 79 |
| Supplemental | VDR (Vitamin D Receptor) Expression in Kidney | 333 fmol VDR/ mg protein | Standard Deviation 62 |
p-value: <0.05ANOVA
Secondary
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.
Time frame: on day 180
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paricalcitol Treatment | VDR (Vitamin D Receptor) Expression in Myocardium | 801 fmol VDR/ mg protein | Standard Deviation 112 |
| Calcitriol Treatment | VDR (Vitamin D Receptor) Expression in Myocardium | 715 fmol VDR/ mg protein | Standard Deviation 96 |
| Cholecalciferol | VDR (Vitamin D Receptor) Expression in Myocardium | 654 fmol VDR/ mg protein | Standard Deviation 88 |
| Supplemental | VDR (Vitamin D Receptor) Expression in Myocardium | 389 fmol VDR/ mg protein | Standard Deviation 77 |
p-value: <0.05ANOVA