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

• 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)

  
  

• 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.
  
  

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.