Effects of Oral Paricalcitol on Secondary Hyperparathyroidism and Residual Proteinuria of Kidney Transplant Patients

Secondary hyperparathyroidism (SHPT) persists up to 15% to 50% of patients at 1 year of kidney transplantation (1). This persistent SHPT contributes to bone mass loss, a higher risk of fracture, hypercalcemia, hypophosphoremia, and vascular calcifications in transplanted patients. On the contrary, the magnitude of proteinuria is a factor of paramount importance for the rate of progression in many kidney diseases (2, 3). Several studies have clearly indicated that the same correlation can be observed in kidney transplant patients and that the sensitivity of transplanted kidney to the level of proteinuria could be even higher than that of native kidneys (4–7). Paricalcitol is a selective activator of vitamin D receptor that has demonstrated a significant improvement of SHPT in patients with chronic kidney disease while inducing less hypercalcemia and hyperphosphoremia than other vitamin D analogues (8). Recent experimental and clinical studies have demonstrated a reduction in proteinuria and less structural damage after paricalcitol treatment in diabetic and nondiabetic nephropathies (9, 10). These renoprotective influences have been corroborated by the Vitamin D activation with Paricalcitol for Reduction of Albuminuria in Patients with Type 2 Diabetes Trial study, which demonstrated a significant reduction in albuminuria in type 2 diabetic patients treated with paricalcitol (11). Information about paricalcitol treatment for SHPT after kidney transplantation is remarkably scarce. The aim of this study was to analyze our experience with paricalcitol in the treatment of transplanted patients with SHPT. We included all the transplanted patients who had received paricalcitol treatment in the period 2009–2010. Criteria for paricalcitol treatment were the presence of a SHPT, with serum intact parathyroid hormone (iPTH) ≥150 pg/mL along with serum calcium ≤10 mg/mL and serum phosphorus ≤4.5 mg/dL. Oral paricalcitol at a dose of 1 μg on alternate days was prescribed. When serum calcium increased to 10.5 to 10.9 mg/dL and serum phosphorus increased to ≥5 mg/dL, paricalcitol was reduced to two thirds of previous dose; when serum calcium increased above 11 mg/dL, paricalcitol was stopped. No patient received vitamin D supplements. The main outcomes of the study were the reduction of serum iPTH ≥30% and changes in serum iPTH during follow-up. Secondary outcomes were the reduction in proteinuria ≥50% of the baseline values and changes in proteinuria during follow-up. Tertiary outcomes were changes in renal function, blood pressure, and changes in serum C-reactive protein (CRP) during follow-up. Mean and median of follow-up was 20.1 and 18 months, respectively. Data are expressed as the mean±1 standard deviation. Remission ≥30% of iPTH and ≥50% of 24 hr proteinuria was calculated by univariate and multivariable logistic regression. We reported adjusted odds ratio (OR) with 95% confidence intervals (CI). For all tests, P values<0.05 were considered to be statistically significant. Fifty-eight patients were included in the study. The mean age was 55.7±12.7 years and time since kidney transplantation was 74.2±45.4 months. A combination of corticosteroids, tacrolimus, and mycophenolate was the most commonly used immunosuppressive regimen. Mean serum creatinine at baseline was 2.1±0.7 mg/dL, and estimated glomerular filtration rate (eGFR) was 34.9±14.1 mL/min/1.73 m2. Angiotensin-converting enzyme inhibitors (ACEI) were used in 28 (48.3%) patients and no patient received treatment with angiotensin II receptor antagonist. ACEI doses were not changed after paricalcitol introduction. The levels of iPTH showed a rapid and sustained significant decrease after paricalcitol treatment, as shown in Table 1 and Figure 1. The percentage of patients who achieved a reduction of baseline PTH ≥30% increased gradually from 55% at month 3 up to 76% at the end of follow-up. By multivariable logistic regression, a baseline iPTH ≥500 pg/mL was the only clinical factor significantly associated with an iPTH reduction ≥30% (OR, 5.6; 95% CI, 1.3–24.6; P=0.022).TABLE 1: Evolution of mineral metabolism, blood pressure, and renal function parameters with paricalcitol therapyFIGURE 1: Evolution of serum iPTH (A), proteinuria (B), and eGFR (C) after paricalcitol treatment. *P<0.05, with respect to baseline. eGFR, estimated glomerular filtration rate; iPTH, intact parathyroid hormone.Changes in serum calcium, phosphorus, and 25(OH)D after paricalcitol treatment are shown in Table 1. A mild but significant increase in serum calcium and serum phosphorus was observed. Paricalcitol doses were reduced since the third month of treatment until the end of the follow-up (4.1±1.8–3.3±1.2 μg/week; P<0.05) to avoid higher increases in serum calcium and serum phosphorus. Proteinuria showed a significant decrease after the introduction of paricalcitol, ranging from 29.2% to 42.1% (mean, 35.6%), as shown in Table 1 and Figure 1. This reduction was significant since the third month of treatment until the end of the follow-up (1.1±0.7 g/24 hr at baseline vs. 0.7±0.7 g/24 hr at last visit; P<0.05). No associations were found between the reduction in proteinuria and changes in renal function or blood pressure. The number of patients who achieved a reduction of proteinuria ≥50% increased gradually from 10.3% (6 of 58 patients) at month 3 up to 44.8% (26 of 58 patients) at the last visit (Table 1). Patients with or without ACEI treatment showed a similar proteinuria reduction after paricalcitol treatment. By multivariable logistic regression, the only baseline clinical factor independently associated to a proteinuria decrease ≥50% was a serum CRP <1.2 mg/dL (OR, 13.8; 95% CI, 2.0–95.1; P=0.008). As shown in Table 1 and Figure 1, renal function remained stable after the onset of paricalcitol treatment. By contrast, eGFR had significantly decreased during the 2 years previous to paricalcitol treatment, from 39.9±14.7 mL/min/1.73 m2 at −2 years to 34.9±14.1 mL/min/1.73 m2 at baseline (P<0.01). A significant difference was found between the change in eGFR during the −2 year pre-paricalcitol period (−2.51 mL/min/1.73 m2/yr) and the change after paricalcitol treatment (−1.21 mL/min/1.73 m2/yr; P<0.001; Fig. 1). Systemic inflammation, measured by CRP serum levels, showed a significant decline after paricalcitol therapy (Table 1). No significant changes in blood pressure were observed (Table 1). There were no changes in the number of antihypertensive drugs or in the percentage of patients treated with ACEI. No clinical side effects attributable to paricalcitol were observed. Mild increases of serum calcium (10–10.5 mg/dL) or phosphorus (4–4.5 mg/dL) were detected in 4 (6.9%) and 7 (12.1%) patients, respectively, and they responded to reduction in paricalcitol doses. No episodes of more severe hypercalcemia (serum calcium >10.5 mg/dL) or hyperphosphoremia (serum phosphorus >5 mg/dL) were detected. No episodes of acute rejection or clinically significant worsening or renal function were observed during paricalcitol treatment. No patient required withdrawal, even temporary, of paricalcitol. Our study is the first to report the effects of paricalcitol on SHPT in a cohort of kidney transplant patients with chronic kidney disease and vitamin D insufficiency several years after kidney transplantation. The rapid and significant decline of serum iPTH (76% of the patients had achieved >30% baseline iPTH decrease at the last visit) was accompanied by only a mild increase in the levels of serum calcium and phosphorus that, although statistically significant, maintained these parameters within normal limits in a majority of patients throughout paricalcitol therapy. Another finding of our study worth remarking is that these beneficial effects were achieved with relatively low paricalcitol doses (1 μg three to four times per week). It should be considered, however, that iPTH tends to decline over time after kidney transplantation and that dual-energy X-ray absorptiometry scans were not performed in our patients, thus precluding the demonstration of a beneficial effect of paricalcitol on bone disease. There is a cumulative number of studies showing a close correlation between the presence of proteinuria in kidney transplant recipients patients and graft survival. The risk of graft loss is directly correlated with the amount of proteinuria and recent studies have shown that the presence of proteinuria >0.150 g per 24 hour at 1 year after transplantation significantly decreases graft survival (4–7). In this context, our finding that paricalcitol significantly decreases proteinuria in kidney transplant patients is novel and important. Mean proteinuria reduction from baseline was 36% and almost a half of the patients showed >50% baseline proteinuria decrease. Another interesting finding of our study was the remarkable stability of eGFR throughout paricalcitol treatment, as shown in Table 1 and Figure 1. This eGFR stability contrasted with the −2 year period preceding paricalcitol treatment, in which a significant eGFR decline had been observed. Hypothetically, both the reduction in proteinuria and a possible immunomodulatory effect of paricalcitol (12) could have played a protective role in our patients. In a recent experimental study, paricalcitol attenuated cyclosporine-induced kidney damage by suppressing inflammatory, fibrotic, and apoptotic factors (13). Nevertheless, it should be considered that our patients were stable kidney transplant recipients several years after the kidney graft and that renal function was evaluated by means of creatinine-based estimating equations, without a precise measurement of GFR. Finally, and confirming the anti-inflammatory properties of paricalcitol and other vitamin D analogues reported in previous studies (14), we found a significant decrease in serum CRP levels after paricalcitol treatment. In conclusion, oral paricalcitol at relatively low doses (1 μg three to four times per week) is a safe and efficacious treatment of SHPT in long-term kidney transplant patients. Paricalcitol treatment was accompanied by a significant and sustained reduction in proteinuria and stable renal function. In addition, a significant reduction in serum CRP was observed. These renoprotective and systemic beneficial effects of paricalcitol in the setting of kidney transplantation should be confirmed by means of randomized controlled trials. Esther Gonzalez 1 Jorge Rojas-Rivera2 Natalia Polanco1 Enrique Morales1 José María Morales1 Jesus Egido2 Andres Amado1 Manuel Praga1 1 Division of Nephrology Instituto de Investigación Hospital 12 de Octubre Universidad Complutense de Madrid Madrid, Spain 2 Division of Nephrology and Hypertension IIS-Fundación Jiménez Díaz Madrid, Spain