Efficacy and Safety of Paricalcitol for Reduction of Proteinuria in Kidney Transplant Recipients
Efficacy and Safety of Paricalcitol for Reduction of Proteinuria in Kidney Transplant Recipients
The study 'Safety and Efficacy of Paricalcitol for Reduction of Proteinuria in Kidney
 Transplant Recipients' is designed to assess the effects of paricalcitol in kidney transplant
 recipients with proteinuria.

 It is a single centre, randomized, placebo-controlled, double-blind clinical trial that tests
 the hypothesis that 24 weeks' treatment with paricalcitol compared to placebo will result in
 a decrease in urinary protein excretion in recipients of a kidney transplant at least three
 months after transplantation. Additionally, the effects of paricalcitol on albuminuria,
 estimated glomerular filtration rate, and blood pressure will be investigated.
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.
Inclusion Criteria:

 -  Recipients of a deceased donor kidney transplant at least 3 months after
 transplantation

 -  Urinary protein to creatinine ratio (UPCR) > 200 mg/g (20 mg/mmol) as determined by
 the the mean of three second morning void urine specimens

 -  Subject is on stable immunosuppression for at least 3 months

 -  Subject is on stable doses of antihypertensive medications for at least 3 months

 -  Subject is not expected to begin dialysis for at least 6 months

 -  Estimated glomerular filtration rate > 15 ml/min/1.73 m2

 -  Corrected serum calcium level < 2.6 mmol/l

 -  Intact parathormone value > 30 pg/ml

 Exclusion Criteria:

 -  Subjects on vitamin D receptor activation therapy within 3 months prior to the first
 study visit

 -  Acute kidney injury within 3 months of the first study visit

 -  Subjects with poorly controlled hypertension