Most functional and metabolic abnormalities of uremia that are only marginally affected by chronic dialysis therapy may substantially improve with successful kidney transplantation. However, there are exceptions. CKD mineral and bone disorders (MBDs) may even worsen post-transplant, despite restoring near-normal renal function.1,2 Bone mineral density (BMD) rapidly decreases in the early post-transplant period, and bone demineralization may eventually progress over years, albeit at a lower rate. This result largely explains why, in recipients of kidney transplants, the incidence of fractures is 4-fold higher than in the general population and even exceeds the incidence observed in patients on hemodialysis.3–5
Several factors involved in the pathogenesis of post-transplant CKD-MBD include immunosuppressive therapy, especially corticosteroids,6 hormonal disturbances, and progressive deterioration of graft function.7 Secondary hyperparathyroidism (SHPT) has been consistently reported to play a central role in post-transplant CKD-MBD.8–11 Most of the clinical and laboratory abnormalities of SHPT seem to be largely explained by enhanced intact parathyroid hormone (iPTH) production.12 Thus, reducing iPTH levels by, for instance, supplementation of calcitriol, the active metabolite of vitamin D, has been explored as a rational approach to prevent or ameliorate SHPT.13 However, in patients with preterminal CKD,13 calcitriol therapy was found to increase serum calcium and phosphate concentrations, an effect that, in the long term, translated into accelerated vascular calcification and increased cardiovascular mortality.14 Because of these major side effects, the idea to test the expected benefits of supplementation for post-transplant CKD-MBD with natural or active forms of vitamin D on mineral metabolism was progressively abandoned.
The enthusiasm for this line of research was revived by the availability for clinical use of paricalcitol, a selective activator of vitamin D receptor, that, in patients on hemodialysis, was found to achieve a faster reduction in serum iPTH levels with less hypercalcemia compared with calcitriol,15 an effect that even associated with improved patient survival.16 Moreover, in patients with diabetic and nondiabetic chronic nephropathies, treatment with oral paricalcitol, in addition to improving mineral metabolism, was found to significantly reduce urinary protein excretion, an effect that, in the long term, is expected to translate into slower progression toward ESRD and need for RRT.17,18
Thus, in this prospective, randomized, crossover study, we aimed to assess whether paricalcitol treatment may reduce iPTH levels and ameliorate the clinical and laboratory features of SHPT in recipients of renal transplant. Secondarily, we evaluated whether and to what extent this effect associated with reduced protein excretion in this population.
Results
Baseline Clinical Characteristics
Of 60 screened participants, 13 participants were excluded because of iPTH<80 pg/ml, 1 participant was excluded for hypercalcemia, and three participants were excluded when they withdrew consent before randomization. Thus, 43 participants (30 men) were randomized from September of 2009 to June of 2011 (Figure 1): 22 patients to paricalcitol followed by nonparicalcitol therapy and 21 patients to nonparicalcitol therapy followed by paricalcitol treatment. Baseline characteristics of the two sequence groups were similar (Table 1). All participants were on cyclosporin-based immunosuppression that included mycophenolate mofetil or azathioprine. Of them, 25 participants were also on steroid therapy and similarly distributed between the two treatment arms (Table 1). No change in the immunosuppressive regimen was introduced throughout the whole study period. Sixteen patients were on renin-angiotensin system inhibitor therapy at baseline and continued their treatment without changes during the whole study period; 10 participants were receiving statins, 3 participants were on polyunsaturated fatty acids, and 17 participants were on a combination of both medications. Lipid-lowering therapy was not modified during the study. Two of seven patients who were being treated with phosphate oral supplementations at the time of screening reduced the drug dose to target serum phosphorous levels after randomization. No patient stopped or was given calcium- or noncalcium-based phosphate binders ex novo during the study. Two patients per sequence group withdrew from the study, all of them during the paricalcitol treatment period: two patients because of consent withdrawal and two patients because of adverse events (pulmonary carcinoma and severe anemia) considered as not related to paricalcitol treatment (Figure 1). Thus, 39 patients completed both treatment periods.
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Figure 1:
Study flow chart. Sixty kidney transplant recipients with secondary hyperparathyroidism and stable renal function were assessed for eligibility. Forty-three of the 60 participants were randomly assigned to paricalcitol (n=22) or nonparicalcitol (n=21) therapy.
Table 1:
Baseline patient characteristics in the study group as a whole (overall) and according to treatment sequence
Serum PTH Concentrations
Serum iPTH levels significantly declined during the first 3-month treatment with 1 µg/d paricalcitol (P<0.001 versus baseline) and further decreased after drug dose uptitration to 2 µg/d during the next 3 months (P<0.001 versus baseline) (Table 2). By contrast, iPTH concentrations did not change appreciably over 6 months of nonparicalcitol therapy. Serum iPTH levels were significantly lower on paricalcitol compared with nonparicalcitol therapy at both 3 (P<0.001) and 6 (P<0.001) months of follow-up (Figure 2). Three- and six-month differences between paricalcitol and nonparicalcitol therapies (P=0.03 and P<0.001, respectively) were confirmed by analysis of covariance restricted to the first treatment period before patient crossover. Serum iPTH levels decreased in 36 (95%) and 19 (46%) patients during 6-month paricalcitol and nonparicalcitol therapies, respectively (P<0.001). Twenty-nine patients had their serum iPTH levels reduced to <80 pg/ml at the end of the paricalcitol treatment period, and nine patients had their serum iPTH levels reduced to <80 pg/ml at the end of the nonparicalcitol treatment period (P<0.001).
Table 2:
Clinical and laboratory parameters of study patients at baseline and 3 and 6 months of treatment with paricalcitol or nonparicalcitol therapy
Figure 2:
iPTH levels significantly decreased at 3 and 6 months of treatment with paricalcitol compared with baseline but did not change appreciably during nonparicalcitol therapy. At 3 and 6 months, PTH levels were significantly lower on paricalcitol than nonparicalcitol therapy. Data are means±SEMs. conc., Concentration.
Mineral Metabolism Biomarkers and Bone Remodeling
Bone Formation
As shown in Table 2, bone alkaline phosphatase (BAP) and osteocalcin serum levels significantly decreased during the first 3-month paricalcitol treatment and further declined over the next 3 months (P<0.05 and P<0.001 versus baseline for both parameters, respectively). Conversely, during the nonparicalcitol treatment period, BAP serum levels gradually increased, and the increase approached statistical significance at 6 months (P=0.06) versus baseline, whereas osteocalcin levels did not change appreciably. Serum BAP and osteocalcin levels decreased in 34 (89%) and 32 (82%) patients during 6-month paricalcitol therapy and 13 (33%) and 16 (39%) patients during 6-month nonparicalcitol therapy, respectively (P<0.001 and P<0.001, respectively). Both BAP and osteocalcin concentrations were significantly lower on paricalcitol than nonparicalcitol therapy both at 3 (BAP: P<0.005; osteocalcin: P<0.05) and 6 (P<0.001 for both parameters) months.
Bone Reabsorption
Urine deoxypyridinoline-to-creatinine ratio progressively declined during paricalcitol treatment, and the ratio was significantly lower (P<0.05) at both 3 and 6 months than at baseline, whereas it did not change appreciably over the nonparicalcitol treatment period (Table 2).
Serum Concentrations of 25-Hydroxy Vitamin D, Calcium, and Phosphate
Serum levels of these parameters did not change appreciably during both treatment periods and were all comparable between treatment periods at both 3 and 6 months (Table 2).
BMD
Compared with baseline, BMD of L3 vertebra increased on paricalcitol, and the increase approximated the statistical significance (P=0.06) at the end of the 6-month treatment period. At variance, it did not appreciably change during nonparicalcitol therapy. Thus, at 6 months, BMD values were significantly higher on paricalcitol than nonparicalcitol therapy (1.054±0.225 versus 1.010±0.185 g/cm2, respectively; P=0.04). At 6 months, L4 vertebra BMD showed a nonsignificant trend to increase during paricalcitol (1.046±0.222 g/cm2) and decrease during nonparicalcitol therapy (1.004±0.177 g/cm2) compared with baseline (1.016±0.2082 g/cm2). Thus, at 6 months, BMD was significantly different between paricalcitol and nonparicalcitol treatment periods (P=0.05). Consistently, BMD of L2 vertebra and femoral neck also showed a significant trend to increase on paricalcitol and decrease during nonparicalcitol therapy (data not shown).
BP, Serum Creatinine, and Proteinuria
Systolic BP showed a trend to decrease during paricalcitol therapy. However, no significant changes in systolic and diastolic BPs were observed throughout both treatment periods (Table 2). Serum creatinine slightly but significantly increased and creatinine clearance decreased over the 6-month treatment with paricalcitol compared with baseline, whereas both parameters did not change appreciably during the nonparicalcitol treatment period (Table 2).
Compared with baseline, proteinuria showed a trend to decrease at month 3 of paricalcitol treatment versus baseline, and the reduction achieved nominal significance at 6 months (Figure 3, Table 2). Urinary protein did not change appreciably during the nonparicalcitol treatment period. Among 38 patients with available data throughout both 6-month treatment periods, proteinuria decreased in 25 (65.8%) and 20 (52.6%) patients and increased in 13 (34.2%) and 18 (47.4%) patients during paricalcitol and nonparicalcitol therapy, respectively (Supplemental Figure 1).
Figure 3:
Effect of paricalcitol on urinary protein excretion. Proteinuria significantly decreased at 6 months of treatment with paricalcitol compared with baseline but did not change appreciably during nonparicalcitol therapy. Data are means±SEMs.
Safety
Twenty-seven (62.8%) participants had at least one adverse event during paricalcitol. Twenty-one (48.8%) participants had at least one adverse event during nonparicalcitol treatment (Table 3). Most side effects were nonserious during both periods. No serious adverse event was considered to be treatment-related. Despite the trend to more events on paricalcitol, there was no significant difference between treatments in the incidence of total, serious (including cardiovascular), and nonserious events considered as a whole or according to the involved apparatus. Hypercalcemia was observed at one single occasion in two patients on paricalcitol dose uptitration to 2 μg/d and no patients on nonparicalcitol therapy. Both events recovered with dose backtitration to 1 μg/d. Hyperphosphatemia was never observed over both treatment periods. Lung carcinoma and bilateral renal carcinoma were diagnosed in two participants during paricalcitol treatment. No acute rejection episode or pathologic bone fracture was observed throughout the study.
Table 3:
Serious and nonserious adverse events with paricalcitol or nonparicalcitol therapy during each treatment period considered separately
Discussion
In this prospective, randomized, controlled clinical trial, we found that 6-month treatment with oral paricalcitol achieved a prompt and significant reduction in serum iPTH levels in recipients of renal transplants with persistent SHPT and normal or slightly reduced renal function. Treatment effect was already apparent after 3 months of treatment with 1 µg/d paricalcitol and further increased during the subsequent 3-month treatment period after uptitration to the target dose of 2 µg/d. Amelioration of SHPT was associated with biologic evidence of slower bone remodeling, radiologic findings suggestive for prevented bone mass loss, and reduced urinary protein excretion. Overall, treatment was well tolerated. Despite the trend to more serious and nonserious adverse events during paricalcitol therapy (Table 3), all treatment-related adverse events were nonserious and generally mild, and patients fully recovered after treatment withdrawal.
To the best of our knowledge, this study is the first formal demonstration in the context of a prospective trial that paricalcitol therapy may ameliorate already established SHPT—and related mineral and bone abnormalities—in patients with a long-term functioning kidney graft. The idea of the trial germinated from a retrospective, uncontrolled observation that paricalcitol therapy associated with amelioration of SHPT in recipients of long-term renal allografts19 and prospective data that paricalcitol supplementation started early post-transplant reduced the 1-year prevalence of hyperparathyroidism compared with no additional therapy.20 Of interest, our data extend previous evidence that paricalcitol may effectively suppress PTH production in patients with diabetic renal disease to recipients of renal transplants.21
Finding that controlled PTH production associated with reduced serum levels of biomarkers of bone formation, such as osteocalcin and BAP, and at the same time, reduced urinary excretion of a biomarker of osteoclastic-mediated bone reabsorption, such as deoxypyridinoline,22 provides consistent evidence that paricalcitol therapy may effectively suppress the high-turnover bone disease that characterizes SHPT. This effect could explain the improved BMD, particularly of lumbar vertebras, documented by dual-energy x-ray absorptiometry at the end of the paricalcitol treatment period compared with nonparicalcitol therapy period. Although a confounding effect of concomitant changes in abdominal vessels calcifications on lumbar vertebral mineral density cannot be definitely excluded, particularly without evidence of concomitant improvement of femoral neck calcification, altogether, the above findings can be taken to suggest that, in the long term, paricalcitol supplementation might help prevent progressive bone mass loss and excess risk of pathologic bone fractures that invariably associate with SHPT, particularly in recipients of kidney transplants.3–5 Moreover, experimental data suggest that reduced osteocalcin and BAP production could help prevent vascular calcifications in this population. Indeed, osteocalcin modulates osteochondrogenic differentiation of pathologically mineralizing vascular smooth muscle cells, a crucial process in the progression of vascular calcification,23 and in mice with arterial calcifications, BAP activity of aortic tissue correlated with the area of calcified lesion.24 These findings may have clinical implications, because elevated BAP levels have been associated with increased cardiovascular morbidity and mortality in patients with preterminal or terminal CKD.25,26
An ancillary finding was that amelioration of hyperparathyroidism and mineral bone metabolism was already apparent with 1-μg daily doses of paricalcitol. This result may have clinical implications, because patients who fail to tolerate the target 2-μg daily dose might be safely maintained on the lower dose to avoid renouncing to the potential benefit of long-term paricalcitol exposure.
Another message of our study is that paricalcitol supplementation may reduce urinary protein excretion in recipients of renal transplants with SHPT, whereas nonparicalcitol therapy is devoid of any specific antiproteinuric effect in this context. Although the relatively small sample size and the inclusion of patients with no or subclinical, proteinuria reduced the power to detect significant differences in urinary protein excretion between the two treatment periods, this finding seems to reflect a genuine effect of treatment for at least three reasons. (1) Solid experimental evidence shows that defective vitamin D receptor associates with albuminuria and glomerulosclerosis,27 whereas receptor activation by paricalcitol supplementation is antiproteinuric and nephroprotective28 through several mechanisms29 that include suppressed renin transcription,30,31 antiproliferative and antifibrotic effects, inhibited transforming growth factor production,32 nephrin upregulation, and reduced NF-κB activity.33 (2) There is evidence of a specific antiproteinuric effect of paricalcitol supplementation in subjects with stage 3 or 4 CKD18 or diabetes and albuminuria.17 (3) The extent of proteinuria reduction prospectively observed in our series is consistent with that retrospectively observed in a previous uncontrolled series of recipients of renal transplants with SHPT.19 Altogether, the above findings converge to indicate that paricalcitol may have a specific antiproteinuric effect, even in human transplantation. This effect seems to be clinically relevant, because even low-protein excretion rates ranging from 150 to 500 mg/d predict poor long-term graft survival in recipients of kidney transplants.34–36 Long-term controlled clinical trials are needed to assess whether paricalcitol-induced reductions in proteinuria as well as serum iPTH and BAP25 levels may translate into a protective effect against renal and cardiovascular events in the long term.
Safety
Six-month treatment with oral paricalcitol was well tolerated. Although the treatment period was too short to definitely establish the safety of chronic paricalcitol therapy, finding that treatment-related adverse events were mild in nature and always reversible was reassuring. Finding that only two transient and reversible episodes of hypercalcemia were observed in two patients on paricalcitol dose uptitration to 2 μg/d was consistent with evidence from randomized trials that, unlike supplementation with nonselective vitamin D receptor activators, such as calcitriol,14 paricalcitol therapy did not associate with an excess risk of hypercalcemia15,37,38 in patients on hemodialysis with SHPT. These findings are most likely explained by less stimulation of intestinal calcium (and phosphate) absorption with paricalcitol compared with calcitriol supplementation,39 an effect that, in the long term, might contribute to reduced risk for coronary artery calcification,40 an independent cardiovascular risk factor in the kidney transplant population.41
Consistent with previous investigations in patients with CKD,17,42 we found that paricalcitol treatment was associated with a slight increase in serum creatinine. This finding was most likely explained by decreased creatinine tubular secretion, increased creatinine generation, or both. Worsening of kidney function was unlikely, because comparative analyses showed that activators of vitamin D receptors do not affect inulin clearance—the gold standard for the measurement of GFR.42–44 Thus, on the basis of the above findings, paricalcitol should not be misperceived as a potentially nephrotoxic drug, and changes in serum creatinine levels or creatinine clearance should not be taken as an indication to stop paricalcitol supplementation.
A fully unexpected finding was the diagnosis of lung carcinoma and native kidney cancer in two patients during paricalcitol therapy. We are prone to consider these findings as casual findings, because cancer has never been described as a possible paricalcitol-related side effect, and actually, experimental and epidemiologic evidence is available that vitamin D and even paricalcitol may exert specific anticancer effects.45 Moreover, it is extremely unlikely that paricalcitol might have independently induced these neoplasms and sustained their growth to the point of becoming clinically apparent over only 6 months of exposure.
Limitations and Strengths
Major limitations of the study were the small sample size and the short-term follow-up, which do not allow us to draw definite conclusions on the risk/benefit profile of paricalcitol therapy in this clinical context. These limitations reflect the explorative nature of the trial and in part, were dictated by the resource restriction that almost invariably stifles the finalization of academic internally funded studies. Given the proof-of-concept nature of the study, paricalcitol treatment was not tested against the active metabolite of vitamin D calcitriol. Data, however, were robust enough to suggest that previous benefits of paricalcitol therapy observed in patients on chronic dialysis16 or with diabetes and albuminuria17 can be extended to recipients of renal transplants with SHPT. However, adequately powered long-term randomized clinical trials are needed to assess whether chronic paricalcitol therapy may improve the outcome of CKD-MBD in this population and is safe.
Major strengths were the prospective randomized design, the rigorous monitoring of study participants, and the generalizability of the results to a large part of the renal transplant population.
Conclusions
In recipients of renal transplants with SHPT, 6-month paricalcitol supplementation reduced PTH levels and proteinuria, attenuated bone remodeling and mineral loss, and also, reduced eGFR. Long-term studies are needed to monitor directly measured GFR,46 ensure that the bone remodeling and mineral effects are sustained, and determine if the reduction in proteinuria improves renal and cardiovascular outcomes.
Concise Methods
Study participants were identified among >18-year-old recipients of kidney transplants referred to the Outpatient Clinic of the Unit of Nephrology at the Azienda Ospedaliera Papa Giovanni XXIII who, at baseline evaluation, fulfilled the following selection criteria: serum iPTH levels>80 pg/ml (after at least a 1-month washout period in those with previous treatment with natural vitamin D or analogs), serum calcium≤10.2 mg/dl, serum creatinine<2 mg/dl, maintenance immunosuppressive therapy with calcineurin inhibitors and mycophenolate mofetil or azathioprine, no ongoing therapy with vitamin D analogs, and no evidence of active hepatitis C or B virus or HIV infection or drug or alcohol abuse. Patients on previous treatment with natural vitamin D or analogs were eligible if, at 1 month after treatment withdrawal and at baseline evaluation, their serum iPTH levels were >80 pg/ml (a prospective, pilot, crossover study to assess the efficacy of paricalcitol in reducing parathyroid hormone levels and ameliorating markers of bone remodeling in renal transplant recipients with secondary hyperparathyroidism [APPLE Study], ClinicalTrials.gov identifier NCT01220050, date of registration October 11, 2010). Patients with previous history of hypersensitivity, allergy, or intolerance to the study drug; changes in serum creatinine>30% or acute rejection episodes over the last 6 months; or chronic clinical conditions expected to affect completion of the study or jeopardize data interpretation as well as pregnant, lactating, or fertile women without adequate contraception were excluded. The study conformed to the principles of the Declaration of Helsinki and the Declaration of Istanbul as outlined in the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism.” The hospital’s Ethics Committee approved the protocol, and all participants provided a written informed consent. The study was coordinated and monitored by the Department of Renal Medicine of the Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Istituto di Ricerche Farmacologiche Mario Negri.
Baseline Evaluations
BP was recorded after a 5-minute rest in the sitting position as the mean of three readings 2 minutes apart. Blood was sampled in the morning after overnight fast for laboratory measurements, including routine hematochemistry, renal and liver function tests, and serum levels of iPTH, 25-hydroxy vitamin D, calcium, phosphate, and bone remodeling biomarkers osteocalcin and BAP. Twenty-four–hour urine collections were sampled for protein excretion, whereas spot morning urine samples were analyzed for the level of the index of bone reabsorption deoxypyridinoline. BMDs of lumbar spine and femoral neck were determined by dual-energy x-ray absorptiometry.
Treatment and Monitoring
Patients off therapy with any form of vitamin D for at least 1 month who fulfilled the selection criteria were randomized on a 1:1 basis to two treatment sequences by an independent investigator (A.P.) at the coordinating center according to a computer-generated randomization list: 6-month treatment with oral paricalcitol (Zemplar; Abbvie) followed by 6 months of nonparicalcitol therapy, or 6 months of nonparicalcitol therapy followed by 6 months of paricalcitol therapy. Paricalcitol was started at 1 µg/d and if tolerated (calcium≤10.2 and phosphate≤5.1 mg/dl) for 3 months, uptitrated to the target dose of 2 µg/d. To prevent the risk of adynamic bone disease, the dosage had to be backtitrated or treatment was withdrawn in case of iPTH level reduction to <50 pg/ml.47 If serum calcium or phosphate levels exceeded 10.2 or 5.1 mg/dl, respectively, paricalcitol was reduced or withdrawn until level normalization and then restarted at 1 µg/d. Participants on oral calcium-based phosphate binders or calcium and phosphate supplementation during the screening period were maintained on their treatment without systematic changes throughout the study period. However, adjustments were allowed to maintain serum calcium and phosphorous within predefined normal range (8.7–10.2 and 2.3–5.1 mg/dl, respectively). Serum calcium and phosphate levels were also measured at 1 week after the administration of the first paricalcitol dose and after paricalcitol dose uptitration. The same clinical and laboratory parameters evaluated at baseline were assessed every 3 months during both treatment periods up to study end, and any intercurrent adverse event was recorded at the same time points. BMD measurement was repeated at 6 months and the end of the study. All serious and nonserious adverse events observed during the whole study period were reported and described in detail by the investigators in patient case report forms. Data were obtained by direct interview of the patient at each study visit and revision of the clinical records. All adverse events were monitored up to their complete resolution, even after study conclusion, by the Data Monitoring Group of the Clinical Research Center, and specific queries had to be adequately addressed by the investigators whenever causes, treatments, and outcomes of any observed event were not exhaustively reported.
Measurements
Serum iPTH concentrations were measured by Immulite 2000 Intact PTH Assay (Siemens Healthcare Diagnostics), serum BAP and osteocalcin were measured by Liaison BAP Ostase and Liaison Osteocalcin assays, respectively (CLIA Assay, Saluggia, Italy), and urinary deoxypyridinoline was measured by a CLIA immunoassay and normalized to urinary creatinine concentration. BMD was measured from L2 to L4 vertebral bodies and the femoral neck and expressed in grams per square centimeter.
Sample Size Estimation
The main prespecified efficacy variable of the study was the change in iPTH levels during the 6-month paricalcitol therapy compared with the change observed during the 6-month nonparicalcitol therapy. By analogy, with patients on chronic hemodialysis, we predicted a mean 20% (±42.8%) reduction in serum iPTH levels during the 6-month paricalcitol therapy and no change on nonparicalcitol therapy. To show a significant difference (α=0.05, paired t test, two-sided test) in serum iPTH changes during the two treatment periods with 80% power, 38 patients were needed for comparative analysis. To account, conservatively, for a 10% dropout rate before study completion, we planned to include 42 patients.
Statistical Analyses
Normally and not normally distributed data are reported as means±SDs or medians and interquartile ranges, respectively. Binary data are summarized by counts and percentages. Primary and secondary efficacy outcomes were evaluated in the modified intention-to-treat population consisting of all randomly assigned patients who took at least one dose of study drug and had at least one efficacy measurement after the first dose of study drug, irrespective of protocol violations. The differences between treatments were assessed by repeated measures ANOVA. A mixed model ANOVA with treatment and period as fixed factors and participant as a random factor was also performed. This model had no baseline covariates, because we assumed that baseline variation was accounted for by adjustment for period and participant effects and that all effects of carryover had disappeared by the time of baseline for the second treatment period. Carryover effects were assessed by visual inspection. The robustness of the results was assessed by analysis of covariance (which included baseline values) of the primary efficacy variable restricted to the first period only before treatment crossover. Safety data were assessed in all randomly assigned patients who took at least one dose of study drug. Categorical variables were compared by McNemar test. P<0.05 was considered statistically significant. All statistical analyses were performed using SAS (version 9.1).
Disclosures
None.
We thank Dr. Anna Maria Costanzo (Abbvie) for continuous support to the study and major contributions to all of the administrative and operational aspects concerning the supply and distribution of the study drug. The authors also thank the Fondazione ART (Association for Research on Transplantation) per la Ricerca sui Trapianti for the continuous support.
Abbvie freely supplied Paricalcitol and partially supported the study by an unconditioned grant.
The abstract of this manuscript was selected for a poster presentation at the Annual Scientific Meeting of the American Society of Nephrology (November 5–10, 2013) in Atlanta, GA.
Published online ahead of print. Publication date available at www.jasn.org.
This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2013111185/-/DCSupplemental.
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