Short-term vitamin D receptor activation increases serum creatinine due to increased production with no effect on the glomerular filtration rate
2011; Elsevier BV; Volume: 80; Issue: 10 Linguagem: Inglês
10.1038/ki.2011.207
ISSN1523-1755
AutoresRajiv Agarwal, Jennifer E. Hynson, Tyler J.W. Hecht, Robert P. Light, Arjun Sinha,
Tópico(s)Parathyroid Disorders and Treatments
ResumoVitamin D receptor activation has been associated with increased serum creatinine and reduced estimated glomerular filtration rates, raising concerns that its use may be detrimental to kidney function. Here we studied the effect of vitamin D receptor activation on serum creatinine, creatinine generation, and its clearance. We measured baseline serum creatinine and 24-h urine creatinine in 16 patients with chronic kidney disease. The measurements were repeated every day for 7 days, during which time the patients received 2μg paricalcitol, an orally active vitamin D receptor activator, every morning. At 4 days after stopping the vitamin analog, measurements were continued for 3 days. Geometric mean parathyroid hormone levels decreased from 77pg/ml at baseline to 43pg/ml at the end of treatment and significantly rebounded to 87pg/ml following paricalcitol withdrawal, thereby supporting the biological efficacy of the analog dose used. With this therapy, the serum creatinine significantly increased at a rate of 0.010mg/dl/day and urine creatinine at a rate of 17.6mg/day. Creatinine and iothalamate clearances did not change, whereas urine albumin decreased insignificantly. Thus, short-term vitamin D receptor activation increases creatinine generation and serum creatinine, but it does not influence the glomerular filtration rate. Vitamin D receptor activation has been associated with increased serum creatinine and reduced estimated glomerular filtration rates, raising concerns that its use may be detrimental to kidney function. Here we studied the effect of vitamin D receptor activation on serum creatinine, creatinine generation, and its clearance. We measured baseline serum creatinine and 24-h urine creatinine in 16 patients with chronic kidney disease. The measurements were repeated every day for 7 days, during which time the patients received 2μg paricalcitol, an orally active vitamin D receptor activator, every morning. At 4 days after stopping the vitamin analog, measurements were continued for 3 days. Geometric mean parathyroid hormone levels decreased from 77pg/ml at baseline to 43pg/ml at the end of treatment and significantly rebounded to 87pg/ml following paricalcitol withdrawal, thereby supporting the biological efficacy of the analog dose used. With this therapy, the serum creatinine significantly increased at a rate of 0.010mg/dl/day and urine creatinine at a rate of 17.6mg/day. Creatinine and iothalamate clearances did not change, whereas urine albumin decreased insignificantly. Thus, short-term vitamin D receptor activation increases creatinine generation and serum creatinine, but it does not influence the glomerular filtration rate. For vitamin D to exert its endocrine effects, it is critically important for the kidney to activate both nutritional and sunlight-derived vitamin D.1.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (9711) Google Scholar In the course of kidney disease, the activation of vitamin D is abrogated; this occurs early in the course of kidney disease, leads to reduction in calcium absorption from the gut, increase in parathyroid hormone (PTH) levels from the parathyroid gland, and culminates in secondary hyperparathyroidism. To countervail these effects, calcitriol, a vitamin D receptor (VDR) activator, has been synthesized and administered to treat secondary hyperparathyroidism among patients with chronic kidney disease (CKD). Among patients with CKD, some unexpected benefits have been observed. These relate to the antiproteinuric effects of VDR activators that raise the possibility of renoprotection in the long term.2.Agarwal R. Acharya M. Tian J. et al.Antiproteinuric effect of oral paricalcitol in chronic kidney disease.Kidney Int. 2005; 68: 2823-2828Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 3.Alborzi P. Patel N.A. Peterson C. et al.Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial.Hypertension. 2008; 52: 249-255Crossref PubMed Scopus (293) Google Scholar, 4.Fishbane S. Chittineni H. Packman M. et al.Oral paricalcitol in the treatment of patients with CKD and proteinuria: a randomized trial.Am J Kidney Dis. 2009; 54: 647-652Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar The best evidence for this derives from the recently reported VITAL (Selective Vitamin D Receptor Activator for Albuminuria Lowering) study in which 281 patients were studied and had measurements of estimated glomerular filtration rate (eGFR) at baseline and periodically over 6 months.5.Lambers Heerspink H.J. Agarwal R. Coyne D.W. et al.The selective vitamin D receptor activator for albuminuria lowering (VITAL) study: study design and baseline characteristics.Am J Nephrol. 2009; 30: 280-286Crossref PubMed Scopus (36) Google Scholar The study demonstrated that the VDR activator, paricalcitol, reduces albuminuria in patients with CKD with diabetic nephropathy.6.de Zeeuw D. Agarwal R. Amdahl M. et al.Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial.Lancet. 2010; 376: 1543-1551Abstract Full Text Full Text PDF PubMed Scopus (559) Google Scholar Among these patients, those randomized to high-dose (2μg) paricalcitol experienced a decline in eGFR.6.de Zeeuw D. Agarwal R. Amdahl M. et al.Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial.Lancet. 2010; 376: 1543-1551Abstract Full Text Full Text PDF PubMed Scopus (559) Google Scholar Although this decline in eGFR reversed after stopping the drug, it raises concerns of nephrotoxicity. If reduction in albuminuria was to be accompanied by a true decline in GFR, then it can be debated whether this drug would be useful in retarding the progression of kidney disease. There is some evidence that VDR activators may increase serum creatinine and, consequently, the appearance of a decline in eGFR.7.Christiansen C. Rodbro P. Christensen M.S. et al.Deterioration of renal function during treatment of chronic renal failure with 1,25-dihydroxycholecalciferol.Lancet. 1978; 2: 700-703Abstract PubMed Scopus (129) Google Scholar It is unclear whether the rise in serum creatinine is because of a true decline in GFR or because of alteration in creatinine handling, either through reduction in secretion of creatinine or via increased creatinine generation.8.Perez A. Raab R. Chen T.C. et al.Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis.Br J Dermatol. 1996; 134: 1070-1078Crossref PubMed Scopus (135) Google Scholar,9.Bertoli M. Luisetto G. Ruffatti A. et al.Renal function during calcitriol therapy in chronic renal failure.Clin Nephrol. 1990; 33: 98-102PubMed Google Scholar Two studies report conflicting mechanisms. One study suggests that VDR activators may reduce the tubular secretion of creatinine.8.Perez A. Raab R. Chen T.C. et al.Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis.Br J Dermatol. 1996; 134: 1070-1078Crossref PubMed Scopus (135) Google Scholar Another study suggests an increase in creatinine production rates.9.Bertoli M. Luisetto G. Ruffatti A. et al.Renal function during calcitriol therapy in chronic renal failure.Clin Nephrol. 1990; 33: 98-102PubMed Google Scholar Both these studies evaluated patients with a wide range of GFR. Moreover, they were not designed to directly examine creatinine generation and excretion over a period of time when no change in true GFR is expected. Neither of these studies examined the reversibility of GFR change by stopping the VDR activator. The results of these studies are unlikely to fully explain the VITAL study results because in the VITAL study, patients had moderate CKD and received a newer VDR activator, paricalcitol. In this study, we examined the notion that the VDR activator, paricalcitol, alters creatinine metabolism and has no effect on GFR. Furthermore, we evaluated whether these effects were reversed upon stopping the drug. A total of 93 patients were assessed for eligibility, out of which 32 were excluded (Figure 1). Of the 61 eligible patients, 45 did not consent. Of the 16 patients who consented, all were enrolled and of the 224 possible visits, 221 (98.6%) were completed. Iothalamate GFR measurements were available for all patients except one patient. In this patient, on day 7, because of technical problems with the insulin pump, only approximately two-thirds of the iothalamate dose was delivered. This was discovered on examining the log of the infused amount. Accordingly, this data point was censored. Two subjects missed three visits because of winter weather, but even these patients received the study medication, and hence no doses of medications were missed. The baseline characteristics of the patients are listed in Table 1. As may be expected of a veteran population, all patients were older men. Although 12 patients had diabetes mellitus, the etiology of kidney disease was thought to be diabetic nephropathy in only five patients. Baseline eGFR was 36.9ml/min per 1.73m2, whereas measured iothalamate clearance was 47.8ml/min per 1.73m2. Stage 3 CKD was present in 12 patients and stage 4 in four patients. Median PTH-intact was 90.3pg/ml (interquartile range 45.7–101.7).Table 1Characteristics of the study populationClinical characteristicn (%) or mean (s.d.)N16 (100%)Male16 (100%)Race White12 (75%) Black3 (19%) American Indian1 (6%)Age (years)69.6±9.8Weight (kg)97.6±35.6Height (cm)166.7±26.5BMI (kg/m2)29.9±3.3Etiology of CKD Adult autosomal polycystic kidney disease1 (6%) Diabetes mellitus5 (31%) Hypertensive nephrosclerosis6 (38%) Ischemic nephropathy1 (6%) Unknown3 (19%)Stage of CKD Stage III12 (75%) Stage IV4 (25%)History of smoking Never2 (13%) Past11 (69%) Current3 (19%)History of Myocardial infarction6 (38%) Heart failure2 (13%) Stroke4 (25%) Diabetes mellitus12 (75%) Revascularization8 (50%)Albumin (g/dl)3.6±0.4Creatinine (mg/dl)1.9±0.4Hemoglobin (g/dl)12.9±1.7Estimated GFR (ml/min per 1.73m2)36.9±10.3Measured GFR (ml/min per 1.73m2)47.8±17.1Calcium (mg/dl)9.0±0.3Phosphorous (mg/dl)3.3±0.5PTH-intact (pg/dl)90.3 (45.7, 101.7)Abbreviations: BMI, body mass index; CKD, chronic kidney disease; GFR, glomerular filtration rate; PTH, parathyroid hormone. Open table in a new tab Abbreviations: BMI, body mass index; CKD, chronic kidney disease; GFR, glomerular filtration rate; PTH, parathyroid hormone. Figure 2 shows the decline in PTH-intact. The geometric least square mean PTH declined from 77.2 to 43.2pg/ml at 1 week after taking 2μg paricalcitol. At 1 week after stopping the drug, the PTH-intact level increased to 87.2pg/ml or near-baseline level. Each patient showed a decline in PTH with a rebound in PTH after stopping the drug, making this effect highly significant (P<0.0001). Least square mean iothalamate GFR (right panel, Figure 2) was 49.1ml/min per 1.73m2, which was unchanged at 47.7ml/min per 1.73m2 after taking 2μg paricalcitol for 7 days. After washout, the GFR was unchanged at 47.0ml/min per 1.73m2. Figure 3 shows the changes in serum and urine calcium and phosphorus. For both calcium and phosphorus, the urinary excretions and serum concentrations showed a significant upward trend during exposure to the study drug, followed by a return to baseline after a week-long washout period. Linear increases were significant and were as follows: serum calcium 0.055mg/dl/day, serum phosphorus 0.05mg/dl/day, urine calcium 10.2mg/day, and urine phosphorus 23.3mg/day (all P 6mg/dl), hypercalcemia (>10mg/dl), vitamin D use (>400units/day), VDR activator use, use of drugs that block creatinine secretion (cimetidine, triamterene, or trimethoprim), or allergy to radiocontrast dye. The study protocol was approved by the Institutional Review Boards and the VA Research and Development Committee, and all patients provided written informed consent. The trial was registered at clinicaltrials.gov (NCT01163162). At baseline, we collected three consecutive 24h urine specimens to measure creatinine, urea, calcium, phosphorus, and albumin. Each urine collection was bracketed by a blood draw for measurement of creatinine, urea, calcium, phosphorus, and other analytes. The patients were asked not to consume meat before the blood draw. Following these collections we measured GFR by a continuous infusion of iothalamate as reported below. PTH-intact was measured once. After these baseline measurements, each patient received 2μg of paricalcitol once a day for 7 consecutive days. This was witnessed daily by the study coordinator. On each one of these days, the patient collected 24h urine, and blood was collected in the fasting state. Seated blood pressure was measured at each visit in triplicate using a validated oscillometric device (HEM 907, Omron Healthcare, Bannockburn, IL). After 7 days, GFR and PTH-intact was again measured and paricalcitol stopped. At 4 days after stopping the drug, 24h urine specimen and blood were collected again for 3 consecutive days. GFR and PTH-intact were then measured for the final time. An outpatient continuous infusion of iothalamate was used to measure GFR.23.Agarwal R. Ambulatory GFR measurement with cold iothalamate in adults with chronic kidney disease.Am J Kidney Dis. 2003; 41: 752-759Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar On the first visit, a baseline plasma sample was drawn. Further, a 1ml bolus of iothalamate (Conray 60; Mallinckrodt Medical, St Louis, MO) was injected intravenously. A subcutaneous catheter for infusion of iothalamate was inserted in the abdominal subcutaneous tissue. Iothalamate was infused at a constant rate of 125μl/h through an insulin pump (MiniMed model 506 or 507; Medtronic, Northridge, CA). Approximately 24h after the start of the infusion, the subjects returned to the research laboratory. The insulin pump was refilled with iothalamate if needed. An intravenous catheter was placed in the forearm and three blood samples were obtained at 30min intervals for measurements of plasma iothalamate by high-performance liquid chromatography.24.Agarwal R. Vasavada N. Chase S.D. Liquid chromatography for iothalamate in biological samples.J Chromatogr B Analyt Technol Biomed Life Sci. 2003; 785: 345-352Crossref PubMed Scopus (21) Google Scholar,25.Agarwal R. Chromatographic estimation of iothalamate and p-aminohippuric acid to measure glomerular filtration rate and effective renal plasma flow in humans.J Chromatogr B Biomed Sci Appl. 1998; 705: 3-9Crossref PubMed Google Scholar Plasma clearance of iothalamate was calculated by dividing the infusion rate by plasma iothalamate concentration. Plasma iothalamate clearances have a coefficient of variation of 7.7% when measured 4 months apart.23.Agarwal R. Ambulatory GFR measurement with cold iothalamate in adults with chronic kidney disease.Am J Kidney Dis. 2003; 41: 752-759Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Biochemical assays were performed in our hospital laboratory. Serum creatinine was calibrated to the isotope dilution mass spectroscopic standard. Urine albumin was measured with a particle-enhanced turbidimetric inhibition immunoassay adapted to the Dimension clinical chemistry system that allows direct quantification of albumin in urine samples (Siemens Healthcare Diagnostics, Deerfield, IL). Sample size estimation was based on the following considerations. Two previous studies that have investigated the effect of VDR activators on renal function measured inulin clearances in 8 and 10 patients, respectively.8.Perez A. Raab R. Chen T.C. et al.Safety and efficacy of oral calcitriol (1,25-dihydroxyvitamin D3) for the treatment of psoriasis.Br J Dermatol. 1996; 134: 1070-1078Crossref PubMed Scopus (135) Google Scholar,9.Bertoli M. Luisetto G. Ruffatti A. et al.Renal function during calcitriol therapy in chronic renal failure.Clin Nephrol. 1990; 33: 98-102PubMed Google Scholar Each of these studies could detect changes in creatinine metabolism even when assessments were made using single 24-h urine collections. Neither of the studies stopped VDR activators; thus, they did not explicitly test the reversibility of creatinine metabolism. The duration of those studies were long. Long duration of the study could result in deterioration in renal function that could obscure the effect of the drug from the effect of time on creatinine metabolism. Using a more intense protocol with repeated measurements, we reasoned that 16 patients would be sufficient to detect an effect size similar to, or smaller than, that seen with previous studies. A short term was chosen to obviate changes in GFR due to disease progression. The primary method of data analysis was by mixed models.26.Holden J.E. Kelley K. Agarwal R. Analyzing change: a primer on multilevel models with applications to nephrology.Am J Nephrol. 2008; 28: 792-801Crossref PubMed Scopus (64) Google Scholar The hypothesis being tested was that paricalcitol alters creatinine generation and increases serum creatinine, and that these changes in creatinine metabolism are reversible and unaccompanied by a reduction in GFR or creatinine clearance. We had 13 measurements of creatinine clearance per patient: three at baseline, seven during paricalcitol therapy, and three after washout. All these data were analyzed using a composite model. In this model, we specified fixed intercept effects for baseline, treatment, and washout. In addition, we specified a fixed slope effect for treatment. The random effects included in the model were subject and visits. Covariance was modeled as unstructured that allows the intercepts and slopes to change independently of each other. Maximal likelihood estimations were used to model the data. Statistical analysis was performed using Stata 11.0 (Stata, College Station, TX). Significance was set at two-sided P-value of <0.05. We dedicate this work in general to all veterans who selflessly participate in clinical research and in particular to the 16 participants of this arduous study. This study was supported by a grant from Abbott. Figure S1. Serum urea nitrogen and 24-h urine urea nitrogen at baseline, during drug treatment, and after washout. Figure S2. Seated systolic and diastolic blood pressure (BP) and 24-hour urine albumin excretion rate over the study. 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