The Effect of Long-Term Intravenous Calcitriol Administration on Parathyroid Function in Hemodialysis

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1 The Effect of Long-Term Intravenous Calcitriol Administration on Parathyroid Function in Hemodialysis 12 Mariano Rodriguez,3 Arnold J. Felsenfeld, Carl Williams, James A. Pederson, and Francisco Liach M. Podriguez, A.J. Felsenfeld, F. Liach, Department of Medicine, Wadsworth Veterans Administration Medical Center and UCLA, Los Angeles, CA C. Williams, J.A. Pederson, Department of Medicine, Oklahoma City Veterans Administration Medical Center and the University of Oklahoma Health Sciences Center, Oklahoma City. OK (J. Am. Soc. Nephrol. 1991; 2: ) ABSTRACT Secondary hyperparathyroidism is common in dialysis patients. Intravenous calcitriol has proven to be an effective therapy for the reduction of parathyroid hormone (PTH) levels. However, the effect of i.v. calcitriol on parathyroid function, defined as the sigmoldal PTH-calcium curve developed during hypocalcemla and hypercalcemia, has not been evaluated during the prolonged administration of iv. calcitriol. Six hemodialysis patients with marked secondary hyperparathyroidism, PTH levels greater than 500 pg/mi (normal, 10 to 65 pg/mi), were treated for 42 wk with 2 g of i.v. calcitriol after each hemodialysis. Parathyroid function was evaluated before and after 10 and 42 wk of caicitriol therapy. Between baseline and 42 wk, the basal PTH level decreased from 890 ± 107 to 346 ± I 19 pg/mi (P < 0.02) and the maximally stimulated PTH level decreased from 1293 ± 188 to 600 ± 140 pg/mi (P< 0.0 1). In addition, calcitriol administration significantly decreased PTH levels throughout the hypocalcemic range of the PTH-calcium curve. Although the slope of the PTH-calcium curve (with maximal PTH, Received January 22, Accepted July Parts of this study hove been presented previously at the Joint Meeting of the 10th international Conference on Calcium Regulating Hormones and the I Ith Annual Meeting of the American Society for Bone and Mineral Research, Montreal, Canada, September 9-14, 1989, and the International Meeting on Renal Bone Disease. Parathyroid Hormone, and Vitamin D, Singapore, July Correspondence to Dr. M. Rodriguez, (WI I IL), Division of Nephrology, Wadsworth VA Medical Center, Wilshire and Sawtelle Boulevards, Los Angeles, CA / $03.00/0 Journal of the American Society of Nephroiogy Copyright C 1991 by the American Society of Nephroiogy as 100%) decreased between baseline and 42 wk (P < 0.05), the set point of calcium did not change. Two patients with a decrease in both basal and maximally stimulated PTH levels after 10 wk of calcitriol, developed marked hyperphosphatemia between 10 and 42 wk; this resulted in an exacerbation of hyperparathyroidism despite continued calcitriol therapy. In conclusion, prolonged iv. calcitriol administration is an effective treatment for secondary hyperparathyroidism in hemodialysis patients provided that reasonable control of the serum phosphate is achieved. In addition, the slope of the PTHcalcium curve may be a better indicator of parathyroid cell sensitivity than the set point of calcium. Key Words: Parathyroid hormone, secondary hyperparathyroidism, serum calcium, serum phosphate, set point of calcium S econdary hyperparathyroidism is common in maintenance hemodialysis patients (1-3). It is generally associated with a form of renal osteodystrophy (osteitis fibrosa), with bone histology characterized by increased cellular activity, with an increased bone formation rate, and with endosteal fibrosis (4-6). Treatment with oral or i.v. calcitniol has decreased parathyroid hormone (PTH) levels and improved bone histology (7-1 2). However, in studies with oral calcitriol, it is often difficult to determine whether the observed reduction in PTH levels was due to a direct suppressive effect of calcitniol or was secondary to the increase in serum calcium induced by calcitriol (7-9). Several studies have shown that i.v. calcitriol, administered thrice weekly at the end of each hemodialysis, reduced PTH levels independent of changes in the serum calcium concentration ( 1 0, 1 1). In a recently published study of hemodialysis patients, we showed that 2 g of i.v. calcitniol administered thrice weekly for 1 0 wk reduced basal PTH levels. In addition, an evaluation of parathyroid function, defined as the sigmoidal PTH-calcium curve developed during the induction of hypocalcemia and hypercalcemia, showed that treatment with calcitniol reduced PTH levels throughout the PTH-calcium curve. Despite a reduction in PTH levels, the set point of calcium (defined as the serum calcium concentration necessary to reduce the maximal PTH level by 1014 Volume 2. Number

2 Rodriguez et al 50%) did not change (13). However, long-term studies that evaluate the effect of i.v. calcitriol on parathyroid function are not available. In the study presented here, six hemodialysis patients with marked secondary hyperparathyroidism were treated with thrice weekly i.v. calcitriol for 42 wk. Parathyroid function was evaluated by the use of the sigmoidal PTH-calcium curve generated during hypocalcemia and hypercalcemia. Treatment with i.v. calcitriol for 42 wk decreased both basal and maximally stimulated PTH levels; the sensitivity of parathyroid cells (defined as the slope of the PTHcalcium curve) also decreased even though the set point of calcium for the PTH-calcium curve did not change. However, in two patients, the calcitriol-induced reduction of PTH appeared to be inhibited by the development of marked hyperphosphatemia. METHODS Six stable maintenance hemodialysis patients were studied. These six patients were part of a larger group of previously reported patients who had received i.v. calcitriol for 10 wk (13). Although the original study was completed after 1 0 wk, some of the patients continued to receive i.v. calcitriol as part of the their treatment. When it was learned that six patients had been treated with i.v. calcitriol for 37 to 45 wk, it was decided to reevaluate their parathyroid function. Before the current treatment with calcitriol, these patients had never received calcitriol or vitamin D analogs. Patients were selected for i.v. calcitriol therapy on the basis of a serum PTH level greater than 500 pg/ml and a serum aluminum level less than 50 ig/l. Patients were dialyzed for 3.5 to 4 h thrice weekly throughout the study period. At the start of the study, the six patients were taking aluminumcontaining antacids to bind phosphate. Between 10 and 42 wk, calcium carbonate was added as a phosphate binder. The amount of calcium prescribed was similar in the six patients. All patients were male. Their mean age was 55 ± 4 yr (range, 38 to 62 yr), and the mean duration of dialysis was 32 ± 9 months (range, 6 to 60 months). To evaluate parathyroid function, a low-calcium dialysis (dialysate calcium, 1 mecijl) was performed to induce hypocalcemia and maximally stimulate PTH secretion. The following week, a high-calcium dialysis (dialysate calcium, 4 meq/l) was performed to induce hypercalcemia and maximally inhibit PTH secretion. The methodology for these studies have been described in detail previously (13-15). Blood for PTH as well as total and ionized calcium was obtained at the start of the low-calcium and the high-calcium dialyses and every 30 mm throughout the hemodialysis treatment. Serum chemistries including total calcium, phosphate, and alkaline phosphatase were obtained immediately before the study and at regular intervals throughout the study. After the baseline studies, patients were treated with 2 ig of i.v. calcitriol at the end of each hemodialysis for a mean duration of 42 wk (range, 37 to 45 wk). Throughout the remainder of the text, the mean value of 42 wk will be used. During calcitriol therapy, the dialysate calcium was reduced to 2.5 meq/l to prevent the development of hypercalcemia. If the serum calcium exceeded 10.5 mg/dl, the calcitriol dosage was reduced. This was only necessary in one patient in whom, after 38 wk, the calcitriol dose was reduced to 1 g after each hemodialysis. In another patient, the calcitriol dose was increased after 3 wk, to 3 zg after each hemodialysis. During the period of the formal study (first 1 0 wk), the administration of i.v. calcitriol was based on both the total calcium concentration and a calcium times phosphate product less than 70. In one patient, i.v. calcitriol was withheld for 1 wk during the first 1 0 wk because of a high calcium times phosphate product. However, after completion of the formal study, the decision to administer i.v. calcitriol was based only on the total serum calcium concentration and, inadvertently, the calcium times phosphate product was not used as a criteria. After both 1 0 and 42 wk of calcitriol therapy, parathyroid function was again evaluated with a lowand high-calcium dialysis as previously described. From the data obtained during dialysis-induced hypocalcemia and hypercalcemia, individual PTHionized calcium curves were constructed for each patient at baseline (0 wk) and after 1 0 to 42 wk of i.v. calcitriol. As we have done in previous studies (13-15), composite PTH-calcium curves for each group were compiled from the individual curves. For the analysis of the PTH-calcium curve, the following terms are defined and illustrated in Figure 1 maximat PTH was the highest PTH level which was ob- Serum Pm (pg/mi) maximal PTH ionized calcium level at madmal PTH ionized calcium level at minimal PTH - set point minimal I PTH Ionized Calcium (mg/dl) Figure 1. A PTH-calcium curve from an individual patient is presented, and the terms used for the analysis the PTHcalcium curve are illustrated. Each of the terms is defined in Methods. Journal of the American Society of Nephrology 1015

3 Calcitriol and Parathyroid Function served in response to hypocalcemia and which add!- tional lowering of the serum-ionized calcium concentrat!on did not further increase; minimal PTH was the lowest PTH level during suppression by hypercalcemia and which an additional increase in serumionized calcium did not produce further inhibition; the slope of the sigmoidal PTH-ionized calcium curve was calculated as the PTH concentration at maximal PTH minus the PTH concentration at mmimal PTH divided by the difference between the serum-ionized calcium concentration at which maximal PTH and minimal PTH were observed; this slope, when the maximal PTH concentration is represented as 1 00% should indicate the sensitivity of parathyroid cells (defined as the change in PTH for the change in ionized calcium) and should thus provide an appropriate comparison of groups with different absolute PTH concentrations; the set point of calcium was the serum-ionized calcium concentration at which maximal PTH secretion was reduced by 50%; the ionized calcium concentration at maximal PTH was the serum-ionized calcium concentration at which maximal PTH was first observed; and the ionized calcium concentration at minimat PTH was the serum-ionized calcium concentration at which minimal PTH was first observed. In addition to the above-illustrated terms, in this study, the basat PTH was defined as the PTH level obtained immediately before the performance of the low-calcium dialysis and the basal ionized calcium was the serum-ionized calcium concentration obtained immediately before the low-calcium dialysis. In all six patients, the basal PTH and basal ionized calcium concentrations were similar before the low- and high-calcium dialyses. Intact parathyroid hormone was measured by the immunoradiometnic assay (Allegro, Nichols Institute, San Juan Capistrano, CA). Validation of this assay in dialysis patients has been shown in previous studies (9, ). Normal values are 1 0 to 65 pg/ml. Serum-ionized calcium was measured with an ICA1 ionized calcium analyzer (Radiometer A/S. Copenhagen, Denmark). Serum phosphate, alkaline phosphatase, and total calcium were measured with a Technicon SMA II autoanalyzer (Technicon, Tarrytown, NY). Serum aluminum was determined by flameless atomic absorption spectrophotometry as previously described ( 1 6). Informed consent was obtamed from each patient in a protocol approved by the Institutional Review Board. Data were analyzed by t test for paired comparisons and analysis of variance for repeated measures. Results are expressed as the mean ± SE. RESULTS In Table 1, the serum chemistries at 0, 1 0, and 42 wk are presented. The mean values provided represent the mean of three values before the start of calcitriol (0 wk), the mean of all values between 0 and 10 wk (10 wk), and the mean of all values between 10 and 42 wk (42 wk). Total serum calcium increased between 0 and 42 wk. The mean serum phosphate did not change during the course of the study. However, between 10 and 42 wk, two patients were notable because of poor control of their serum phosphate. During this interval in these two patients, the serum phosphate increased from 6.8 to and from 9.6 to mg/dl, respectively. Between 0 and 42 wk, the serum alkaline phosphatase decreased from 260 to 1 65 U/L, but this decrease was not significant despite a decline in five of the six patients. The exception was a patient who developed marked hyperphosphatemia. In Table 2, the maximal, basal, and minimal PTH values are presented before and after 1 0 and 42 wk of calcitniol. Significant decreases in maximal and basal PTH levels were observed between 0 and 1 0 wk and between 0 and 42 wk, but not between 1 0 and 42 wk. However, if the two patients who developed marked hyperphosphatemia between 1 0 and 42 wk are excluded, significant decreases in the maximal (P = 0.035) and basal PTH (P = 0.024) levels were observed between 10 and 42 wk. No significant differences in the basal ionized calcium concentration, the ionized calcium concentration at maximal PTH, and the ionized calcium concentration at minimal PTH were observed; this was true even if the two patients who developed marked hyperphosphatemia were excluded. Although the ratio of basal to max!- TABLE 1. Biochemical data before and after 10 and 42 wk of i.v. calcitriol#{176} 0 wk 10 wk 42 wk Normal Range Serum Calcium (mg/di) 8.78 ± ± ± 0.27b Serum Phosphate (mg/di) 7.23 ± ± ± Serum Alkaline Phosphatase (U/i) 260 ± ± ± Values are mean ± SE. b p< 0.05 versus 0 wk Volume 2 Number

4 Rodriguez et al TABLE 2. Parameters of the PTH-calcium curve before and after 10 and 42 wk of i.v. calcitriol Owk lowk 42wk Basal PTH (pg/mi) 890 ± ± 89b 346 ± I f9b Maximal PTH (pg/ml) 1293 ± ± 126b 600 ± 14Db Minimal PTH (pg/mi) 227 ± ± ± 27 Basal/Maximal PTH (%) 72 ± 9 55 ± 9 51 ± 8 Set Point of Calcium (mg/di) 4.58 ± ± ± 0.23 Slope of PTH-Calcium Curve (% change in PTH/mg -168 ± ± ± 17b of calcium) Ionized Calcium at Maximal PTH (mg/di) 4.27 ± ± ± 0.23 Ionized Calcium at Basal PTH (mg/di) 4.41 ± ± ± 0.29 Ionized Calcium at Minimal PTH (mg/di) 4.91 ± ± ± Values are mean ± SE. b p< 0.05 versus 0 wk. mal PTH declined during calcitriol treatment, this decrease was not significant. In Figure 2, the PTH-calcium curves are presented for each of the three time intervals. Between ionized calcium concentrations from 3.75 to 4.50 mg/dl, significant differences in PTH levels were observed between 0 and 10 wk and 0 and 42 wk; however, between 10 and 42 wk, differences approached but did not attain significance at ionized calcium concentrations of 4.0 mg/dl (P = 0.06) and 4.25 mg/dl (P = 0.07). If the two patients who developed marked hyperphosphatemia are excluded, significant differences were then observed at ionized calcium concentrations of 4.0 mg/dl (P = 0.049) and 4.25 mg/dl (P = 0.003). In Figure 3, the three PTH-calcium curves are presented with the maximal PTH level as 100%. This transformation of maximal PTH to 1 00% was performed to factor for differences in absolute PTH 1evels between the three PTH-calcium curves and should also provide an assessment of PTH production per parathyroid cell. The only significant difference present between the three PTH-calcium curves was between 1 0 and 42 wk at an ionized calcium concentration of 5.00 mg/dl (P = 0.034). The set point of calcium (Table 2) was not different for the three PTHcalcium curves. However, the slopes of the PTHcalcium curves (Table 2), which should indicate the sensitivity of parathyroid cells, decreased between 0 and 42 wk (P = 0.041) and 10 and 42 wk (P = ). These results were not altered by the exclusion of the two patients who developed marked hyperphosphatemia. The development of marked hyperphosphatemia in two patients appeared to negate the inhibitory effect of calcitriol on PTH secretion. This is illustrated in Figures 4A and B. Basal (Figure 4A) and maximal (Figure 4B) PTH levels decreased in all patients between 0 and 1 0 wk and continued to decrease in the four patients with reasonably controlled serum phos PTH (pg/mi) WEEKS..o. 1OWEEKS WEEKS Ionized Calcium (mg/dl) Figure 2. The effect of calcitriol treatment on the PTH-calcium curve is shown. The baseline (0 wk) PTH-calcium curve is before calcitriol therapy, and the other two PTH-calcium curves are after I 0 and 42 wk of i.v. calcitriol administration. Between 0 wk and both I 0 and 42 wk, significant differences were present in the hypocalcemic segment of the PTHcalcium curves. The points on each PTH-calcium curve were connected by a curve fitting program. The values are the mean ± SE. P < 0.05 versus 42 wk. phate levels. However, in the two patients who developed marked hyperphosphatemia, patients 5 and 6, basal and maximal PTH levels increased between 10 and 42 wk. The mean serum phosphate and calcium values during this time period are shown for the six patients in Table 3. The serum phosphate levels ranged from 5.32 to mg/dl and were considerably higher in patients 5 and 6. Similarly, the serum calcium levels were lower in patients 5 and 6. DISCUSSION The results of this study demonstrate that longterm administration of i.v. calcitriol effectively reduced PTH levels in hemodialysis patients with Journal of the American Society of Nephrology 1017

5 Calcitriol and Parathyroid Function Perceni Maximal PTH Serum PTh (pg/me WEEKS 0 IOWEEK WEEKS -. -a ooo WEEKS 10 WEEKS 42 WEEKS 0 I I I Ionized Calcium (mg/dl).-e- i -#{149}- PatsrS 2 -a x #{149} #{149}.+. Paknt6 Figure 3. The PTH-calcium curve is shown with maximal PTH transformed to 100%. This transformation was performed to factor for differences in absolute PTH levels. The only signiflcant difference between the three PTH-calcium curves was at an Ionized calcium concentration of 5.0 mg/di at which the PTH value was greater in the 42-wk PTH-calcium curve than in the other two (P < 0.05). Although not shown in this figure, the slope of the PTH-calcium curve at 42 wk was significantly less than the slopes of the other two curves. A 2000 Serum Pm (pg/mr 1600 marked secondary hyperparathyroidism. Both basal and maximal PTH levels were reduced after 1 0 and 42 wk of calcitriol. In addition, calcitriol administration reduced PTH levels throughout the hypocalcemic range of the PTH-calcium curves. Calcitniol administration reduced the slope of the PTH-calcium curve even though the set point of calcium did not change. However, the results of this study also indicate that control of the serum phosphate is essential for calcitriol administration to effectively reduce PTH 1evels. Although treatment with calcitriol for 42 wk did increase the total serum calcium concentration, the reduction of the dialysate calcium concentration to 2.5 meq/l at the commencement of calcitriol therapy effectively prevented marked increases in serum calcium. At the end of the study, only one patient had a serum calcium concentration greater than mg/ dl; in this patient, the calcitriol dose was reduced after 38 wk to 1 g after each hemodialysis. Optimal control of the serum phosphate was difficult to achieve in two patients. It is possible that through its effect on gut absorption of phosphate, calcitriol contributed to the elevation of serum phosphate (17). However, before the start of this study, these two patients had very high serum phosphate levels. Because lowering of the serum phosphate was achieved during the first 1 0 wk at a time when PTH was highest, it is likely that noncompliance was an important factor in these two patients, especially because control of the serum phosphate was not a problem in the other patients. Treatment with i.v. calcitriol reduced basal and B -9- Pswt I -e- 0 WEEKS -.- Pak1 2..x. 10 WEEKS 42 WEEKS Pss.n16 Figure 4. The basal (A) and maximal (B) PTH level of each patient is shown at baseline (0 wk) and after 10 and 42 wk of i.v. calcitriol administration. Patients 5 and 6 are the two patients who developed marked hyperphosphatemia between 10 and 42 wk. As opposed to the other patients who had a progressive decrease in basal and maximal PTH levels between 10 and 42 wk, these two patients had an exacerbation of their secondary hyperparathyroidism despite continued calcitriol administration. maximally stimulated PTH levels as well as PTH levels throughout the hypocalcemic range of the PTHcalcium curve. We and others have shown that i.v. calcitriol for up to 1 0 wk decreased hypocalcemiastimulated PTH secretion (1 0, 1 1, 1 3). Longer studies have shown that both oral and i.v. calcitriol reduced basal PTH levels (8,9, 1 2). However, in these studies, it is often difficult to separate the effect of calcitriol from that produced by the increase in the serum calcium concentrations. In the study presented here, 1018 Volume 2 Number

6 Rodriguez et al TABLE 3. Mean serum calcium and phosphate levels between 10 and 42 wk of caicitrioi treatment Patient No. Serum Calcium Serum Phosphate (mg/di) I ± 0.26 (N= 13) 6.76 ± 0.35 (N= 12) ±0.13(N= 15) 7.83±0.31 (N= 15) ± 0.10 (N= 20) 6.76 ± 0.44 (N= 20) ± 0.07 (N= 20) 5.32 ± 0.20 (N= 20) ± 0.09 (N= 22) ± 0.77 (N= 17) ±0.15(N= 12) 11.28±0.48(N= 12) 0 Values are mean ± SE. N, number of determinations. calcitriol treatment did not significantly reduce basal and maximally stimulated PTH levels between 10 and 42 wk. However, in Figure 4, it can be ascertamed that the two patients (patients 5 and 6) who developed marked hyperphosphatemia during this interval had increases in their basal and maximally stimulated PTH levels that affected the comparisons. If these two patients are excluded, then significant reductions in basal and maximally stimulated PTH levels were observed in the remaining patients. Similarly, between 1 0 and 42 wk, PTH values in the hypocalcemic range of the two PTH-calcium curves were significantly lower with the exclusion of these two patients. Studies in renal failure have established that hyperphosphatemia exacerbates the magnitude of secondany hyperparathyroidism (18-20). One mechanism is that hyperphosphatemia produced skeletal resistance to the calcemic action of PTH (21,22). Little information is available about whether marked hyperphosphatemia directly affects PTH secretion. Despite the presumed presence of high circulating levels of calcitniol, basal and maximal PTH levels increased between 1 0 and 42 wk in the two patients with marked hyperphosphatemia. The mean serum phosphate levels in these two patients exceeded 10 mg/dl and were more than 2 mg/dl greater than those of any of the other patients. Thus, even though calcitniol is known to directly inhibit PTH production (23-25) and may also improve the calcemic response to PTH (26,27), it did not counteract the stimulus for hyperparathyroidism induced by marked hyperphosphatemia. An important finding in the study presented here was that the slope of the PTH-calcium curve decreased between 0 to 42 wk, whereas the set point of calcium for the three PTH-calcium curves did not change. The set point is often presented as a marker of the sensitivity of the parathyroid gland to calcium (1 1,28,29). However, it is our belief as well as that of others (30) that the slope of the PTH-calcium curve (with maximal PTH represented as 100% to provide an assessment of PTH production per parathyroid cell) is a better indicator of the sensitivity of the parathyroid cell. Thus, sensitivity would represent the change in PTH production for the change in serum calcium concentration. We believe the set point may be a better indicator of the serum calcium level at which PTH secretion is stimulated. The results of the study presented here serve to support these concepts. Although treatment with calcitriol for 42 wk decreased maximally stimulated PTH from 1,293 to 600 pg/ml, the set point increased minimally. However, during the same time, the slope of the PTH-calcium curve significantly decreased. Our interpretation of these findings is that the sensitivity of parathyroid cells (PTH production for the change in serum calcium) decreased, whereas the serum calcium concentration at which PTH was stimulated did not change. In summary, six hemodialysis patients with marked secondary hyperparathyroidism were treated after each hemodialysis with high-dose i.v. calcitniol for 42 wk. Both basal and maximal PTH levels, in addition to PTH levels throughout the hypocalcemic range of the PTH-calcium curve decreased significantly. Calcitniol treatment decreased the slope of the PTH-calcium curve but did not alter the set point. Finally, two patients who developed marked hyperphosphatemia after an initial response to calcitriol had exacerbation of their hyperparathyroidism despite continued calcitriol therapy. In conclusion, i.v. calcitriol is an effective treatment of secondary hyperparathyroidism in hemodialysis patients provided that reasonable control of the serum phosphate is achieved. In addition, the slope of the PTH-calcium curve may be a better indicator of parathyroid sensitivity than is the set point of calcium. ACKNOWLEDGMENTS The authors thank Ms Jan Myers for technical assistance. REFERENCES 1. Massry SG, Coburn JW, Popovtzer MM, Shinaberger JH, Maxwell MH, Kleeman CR: Secondary hyperparathyroidism in chronic renal failure: The clinical spectrum in uremia, during hemodialysis, and after renal transplantation. Arch Intern Med 1969;124: Fournier AE, Arnaud CD, Johnson WJ, Taylor WF, Goldsmith RS: Etiology of hyperparathyroidism and bone disease during chronic hemodialysis. II. Factors affecting serum immunoreactive parathyroid hormone. J Clin Invest 1971;50: Fuss M, DeBacker M, Bauman J, et at.: Parathyroid hormone plasma level in untreated chronic renal failure and hemodialyzed patients. Journal of the American Society of Nephrology 1019

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