Efficacy and Safety of Paricalcitol for Reduction of Proteinuria in Kidney Transplant Recipients

Kidney transplantation is the treatment of choice for end-stage renal disease patients. In comparison to dialysis it offers longer survival and better quality of life to certain patients with end stage renal disease. In the last two decades, short-term (i.e. 1- and 3-year) kidney transplant survival has increased significantly and is currently exceeding 90% in state-of-the-art transplant centers. This is considered to be due to the safe and effective immunosuppressive therapy in the early post-transplant period, and to the careful management of patients with chronic renal disease (CRD) before and after the transplantation. In spite of the progress described above, long-term (i.e. 5- and 10-year) transplant survival has not significantly improved over the recent decades. Two main causes for long-term loss of transplanted kidneys are the development of the transplant chronic kidney disease (CKD) (i.e. chronic allograft nephropathy) and patient death with a functioning transplant due to cardiovascular events.

Proteinuria (> 150 mg of proteins in urine per day) is a manifestation of kidney disease and is an important risk factor for CKD progression. This applies also to kidney transplant recipients. Studies have shown that proteinuria is present in 20-40% of transplanted patients. According to observational studies, proteinuria is an independent predictor for CKD progression and transplant failure, as well as of increased risk for cardiovascular events. In CKD patients, treatment with renin-angiotensin-aldosterone system inhibitors (RAAS - angiotensin converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor blockers) reduces proteinuria and thus slows the renal disease progression. In spite of the demonstrated renoprotective effect of RAAS inhibitors, the risk for CKD progression remains high. Furthermore, large epidemiological studies have not shown clinically significant effect of RAAS inhibitor therapy on the reduction of cardiovascular risk. In spite of an optimal RAAS inhibitor therapy, renal and cardiovascular diseases continue to progress, which is also associated with persistent proteinuria. Therefore, new treatment modalities to reduce proteinuria with consequent delay in the progression of CKD and cardiovascular disease are being sought.

Calcitriol is an active form of vitamin D produced in the kidneys. It is important for calcium and phosphate metabolism, as well as for bone mineralization. Decreasing blood calcitriol levels are associated with declining renal function. Decreased calcitriol levels in patients with CKD contribute to the development of secondary hyperparathyroidism. Furthermore, calcitriol deficiency is associated with increased proteinuria and further progression of renal impairment. Vitamin D deficiency in patients with end stage renal disease is also related to higher cardiovascular mortality. The pleiotropic effects of calcitriol probably reflect the presence of vitamin D receptors in different tissues; it is via these receptors that calcitriol exerts its pharmacological effects. Vitamin D receptors have been found not only in kidneys and bones, but also in the cells of the myocardium, in the vascular endothelium, the endocrine part of the pancreas, the intestine and the prostate.

Treatment with an analogue of the active vitamin D form, paricalcitol, significantly reduced proteinuria and slowed progression of renal disease in animal models as well as in patients with CKD, particularly in patients diabetes and diabetic nephropathy. This is considered to be due to the positive effect of paricalcitol on RAAS inhibition in the kidneys, which is independent of calcium and parathormone metabolism. Reduced proteinuria leads to a reduced inflammatory response, preservation of the glomerular basement membrane structure and slowing of glomerulosclerosis.

The positive effects of paricalcitol on the reduction of proteinuria observed in patients with CKD may also be important for kidney transplant recipients: by reducing the proteinuria, progression of CKD in the transplanted kidney might be delayed and the risk for cardiovascular events reduced. This might contribute to the improvement of long-term kidney transplant survival, which has not changed significantly in the last two decades.

This study tests the hypothesis whether paricalcitol persistently reduces proteinuria in kidney transplant recipients.