original article http://www.kidney-international.org & 2008 International Society of Nephrology

Secondary is associated with higher mortality in men with moderate to severe CP Kovesdy1,2, S Ahmadzadeh1,2, JE Anderson3 and K Kalantar-Zadeh4,5

1Division of Nephrology, Salem Veterans Affairs Medical Center, Salem, Virginia, USA; 2Department of Medicine, University of Virginia, Charlottesville, Virginia, USA; 3Division of Nephrology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA; 4Harold Simmons Center for Kidney Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center, Torrance, California, USA and 5David Geffen School of Medicine at UCLA, Los Angeles, California, USA

Secondary hyperparathyroidism is associated with mortality Secondary hyperparathyroidism (SHPT) is a common in patients undergoing maintenance dialysis treatment. We complication of chronic kidney disease (CKD)1 and has been studied 515 male US veterans with chronic kidney disease, linked to higher cardiovascular morbidity2,3 and mortality4–6 who were not yet on dialysis, to see what outcomes were in patients on maintenance hemodialysis. SHPT develops associated with secondary hyperparathyroidism in this gradually as kidney function deteriorates.1 Patients with population. Relationships between intact parathyroid earlier stages of CKD by far outnumber those undergoing hormone levels and all-cause mortality along with the maintenance dialysis treatment,7 but the impact on mortality composite of mortality or incidence of dialysis were associated with SHPT in this group is unknown. It is also measured in unadjusted and adjusted Cox models for case- unclear to what extent the outcomes linked to SHPT could be mix and laboratory variables. Elevated confounded by other factors associated with higher para- levels above the upper limit compared to the lower limit of thyroid hormone (PTH) levels, such as hyperphosphatemia the normal range were significantly associated with mortality (associated with higher mortality8 and more severe progres- after adjustments. Higher intact parathyroid hormone levels sion of kidney disease9,10 in CKD) and the use of activated in the upper limit of normal were significantly associated vitamin D (associated with better survival in dialysis with higher mortality overall and showed similar trends in patients5,11). We examined outcomes (all-cause mortality subgroups of patients with stage 3 and stage 4–5 chronic and the composite of predialysis mortality or initiation of kidney disease and with higher and lower serum calcium and maintenance dialysis) as a function of PTH level in 515 male phosphorus levels. Similar associations were found with the US veterans with predialysis CKD stages 3–5, with special composite outcome of mortality or dialysis. Our study shows attention to the confounding effect of hyperphosphatemia, that secondary hyperparathyroidism is independently hypocalcemia, and treatment with activated vitamin D. associated with higher mortality in patients with chronic kidney disease but not yet on dialysis. RESULTS Kidney International (2008) 73, 1296–1302; doi:10.1038/ki.2008.64; The patient cohort had a mean age of 69.4±10.2 years and published online 12 March 2008 included 24% black patients. The mean estimated glomerular 2 KEYWORDS: chronic kidney disease; parathyroid hormone; mortality filtration rate (GFR) was 31.1±10.9 ml per min per 1.73 m and the median PTH level was 103 pg ml1 (interquartile range: 65–179pg ml1). Baseline characteristics by categories of PTH level are shown in Table 1. Patients with higher PTH levels had higher blood pressure; lower estimated GFR, serum albumin, bicarbonate, calcium, and blood hemoglobin; and higher serum phosphorus and 24-h urine protein, and they were more likely to use phosphate binders and activated vitamin D. Overall, 127 patients died before starting dialysis (mortality rate: 104/1000 patient-years, 95% confidence interval (CI): 88–124) and 130 patients initiated dialysis Correspondence: CP Kovesdy, Division of Nephrology, Salem Veterans Affairs Medical Center, 1970 Roanoke Blvd, Salem, Virginia 24153, USA. (dialysis initiation rate: 107/1000 patient-years, 95% CI: E-mail: [email protected] 90–127) during a median follow-up of 2.3 years. Six patients Received 6 September 2007; revised 25 November 2007; accepted 28 were lost to follow-up and their characteristics were not December 2007; published online 12 March 2008 significantly different (data not shown).

1296 Kidney International (2008) 73, 1296–1302 CP Kovesdy et al.: PTH and outcomes in CKD original article

Table 1 | Baseline characteristics of individuals stratified by categories of intact PTH level PTH (pg ml1) o65 (N=128) 65–110 (N=146) 111–179 (N=113) 4179 (N=128) P-value Age (years) 68.4±10.3 70.1±9.9 71.1±9.1 68.1±11.2 0.06 Race (% Black) 26 (20) 29 (20) 29 (26) 38 (30) 0.18 DM 76 (59) 84 (58) 60 (53) 70 (55) 0.7 ASCVD 77 (60) 80 (55) 75 (66) 68 (53) 0.14 Smoking 29 (24) 30 (21) 22 (21) 39 (31) 0.2 Comorbidity index 2.3±1.6 2.6±1.9 2.4±1.4 2.7±1.7 0.2 Vitamin D analog use 16 (12) 64 (44) 87 (77) 89 (70) o0.001 Calcium-containing medication use 25 (20) 29 (20) 34 (30) 80 (62) o0.001 Sevelamer HCl use 9 (7) 19 (13) 21 (19) 43 (34) o0.001 ACEI/ARB use 100 (78) 113 (77) 78 (69) 99 (77) 0.3 Statin use 94 (73) 105 (72) 81 (72) 85 (66) 0.6 BMI (kg m2) 28.7±5.2 29.4±6.0 29.2±5.7 29.0±6.1 0.8 SBP (mm Hg) 143±26 145±24 148±27 152±25 0.02 DBP (mm Hg) 72±15 70±15 69±16 75±14 0.01 eGFR (ml per min per 1.73 m2) 35.7±10.0 34.7±10.4 30.9±8.7 22.5±9.1 o0.0001 CKD stage 3/4/5 91 (71)/33 (26)/4 (3) 96 (66)/46 (32)/4 (3) 60 (53)/49 (43)/4 (4) 23 (18)/76 (59)/29 (23) o0.0001 Serum albumin (g per 100 ml) 3.6±0.4 3.6±0.5 3.6±0.4 3.4±0.5 0.005 Serum cholesterol (mg per 100 ml) 181±46 186±49 179±49 190±53 0.23 Serum bicarbonate (mg per 100 ml) 26.0±3.1 26.3±3.0 26.0±3.6 24.0±3.9 o0.0001 Serum calcium (mg per 100 ml) 9.4±0.6 9.2±0.5 9.2±0.5 8.8±0.7 o0.0001 Serum phosphorus (mg per 100 ml) 3.9±0.7 3.8±0.6 4.0±0.7 4.4±0.9 o0.0001 Blood Hgb (g per 100 ml) 12.7±1.8 12.8±1.6 12.4±1.7 11.8±1.7 o0.0001 Blood WBC (1000 mm3) 7.4±2.4 7.5±2.5 7.4±2.0 7.2±2.2 0.7 Blood lymphocytes (% WBC) 24.3±8.4 21.8±7.9 22.5±7.8 22.4±8.4 0.08 Proteinuria (g per 24 h) 613 (476–790) 526 (418–660) 488 (381–627) 1404 (1094–1801) o0.0001 ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; Hgb, hemoglobin; SBP, systolic blood pressure; WBC, white blood cell count. Data are presented as means±s.d., number (% of total), or geometric means (95% CI). Comparisons are made by ANOVA or w2 test.

SHPT and all-cause mortality 1 PTH level was not associated with mortality in unadjusted analyses (unadjusted hazard ratios (95% CI) for PTH 65–110, 0.5 110–179, and 4179 versus o65 pg ml1: 0.90 (0.58–1.42), 0.89 (0.54–1.46), and 0.89 (0.53–1.48); P ¼ 0.6 for trend), but higher PTH levels were associated with higher mortality after 0 adjustment for age, race, body mass index (BMI), smoking,

comorbidities, estimated GFR, serum calcium, phosphorus, hazard Log relative –0.5 albumin and cholesterol levels, and the use of activated vitamin D and calcium-containing medications (adjusted –1 hazard ratios (95% CI) for PTH 65–110, 110–179, and 4179 30 80 130 180 230 280 330 380 1 versus o65 pg ml : 1.49 (0.91–2.43), 1.67 (0.95–2.94), and PTH (pg ml–1) 2.00 (1.06–3.80); P ¼ 0.028 for trend). Adjustment for Figure 1 | Estimated log relative hazards of all-cause mortality for treatment with activated vitamin D had the largest impact continuous PTH in a multivariable regression spline model on the association between PTH and mortality (P ¼ 0.4 for adjusted for age, race, BMI, smoking status, Charlson linear trend before and P ¼ 0.028 for linear trend after comorbidity index, diabetes mellitus, use of activated vitamin D and calcium-containing medications, estimated GFR, and serum inclusion of variable for activated vitamin D use in the levels of calcium, phosphorus, albumin and cholesterol. Dashed multivariable model). lines, 95% pointwise CIs. Figure 1 shows the multivariable-adjusted estimated log relative hazard of mortality associated with continuous PTH, indicating a monotonic increase in mortality with higher levels of serum PTH. Table 2 shows the mortality hazard ratio log-transformed PTH level was associated with a fully (95% CI) associated with PTH when examined as a adjusted death hazard ratio of 1.28 (95% CI: 1.04–1.58; continuous variable, along with mortality hazard ratios P ¼ 0.021). (95% CI) associated with the other components included Figure 2 shows hazard ratios of mortality associated with a in the multivariable Cox model. A 1 s.d. higher natural PTH level of 465 pg ml1 compared to a level of

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p65 pg ml1, overall and in selected subgroups. A PTH level status. Patients with CKD stages 4 and 5 showed a stronger of 465 pg ml1 was associated with higher mortality overall, association between PTH 465 pg ml1 and mortality and similar trends were present in the studied subgroups, (adjusted hazard ratio: 2.10 (95% CI: 0.99–4.45)) compared albeit without reaching statistical significance in most; this to patients with CKD stage 3 (adjusted hazard ratio: 1.32 association was less pronounced in diabetic patients, but the (95% CI: 0.72–2.44)), but no statistically significant inter- interaction with diabetes mellitus was not statistically action with CKD stage was present. Figure 3 shows the significant. A PTH level of 465 pg ml1 tended to be multivariable-adjusted estimated log relative hazard of associated with higher mortality in both patients who never mortality associated with continuous PTH in subgroups received an activated vitamin D product (adjusted hazard of patients with CKD stage 3 and stages 4 and 5, indicating an ratio: 1.47 (95% CI: 0.89–2.41)) and in patients who received increase in mortality with higher levels of serum PTH level in such treatment (adjusted hazard ratio: 2.40 (95% CI: both subgroups. 0.55–10.47)), although none of these associations reached The composite end point of predialysis mortality or statistical significance; there was also no statistically end-stage renal disease also showed an association with significant interaction with activated vitamin D treatment higher PTH, with adjusted hazard ratios of the composite end point (95% CI) for PTH 65–110, 110–179, and 4179 versus o65 pg ml1 being 1.30 (0.88–1.90), 1.69 (1.11–2.58), Table 2 | Hazard ratios of all-cause mortality for variables and 1.83 (1.17–2.85), P ¼ 0.004 for trend. Figure 4 shows the included in the multivariable Cox model multivariable-adjusted estimated log relative hazard of the Hazard ratio 95% CI combined end point associated with continuous PTH, indicating a monotonic increase in mortality with higher PTH 1.28 1.04–1.58 levels of serum PTH level. Age 1.80 1.39–2.31 Black race (referent: white race) 0.97 0.62–1.51 BMI 0.78 0.62–0.98 DISCUSSION Active smoking (referent: non-smoking) 1.92 1.21–3.05 SHPT develops early and shows a progressive worsening Comorbidity index 1.31 1.08–1.59 during the course of CKD.1 Higher PTH levels have been DM (referent: no DM) 1.37 0.90–2.06 Activated vitamin D use (referent: no 0.28 0.18–0.42 associated with multiple complications, including bone 12,13 14 activated vitamin D use) disease, uremic pruritus, cognitive and sexual dysfunc- Calcium use (referent: no calcium use) 0.31 0.18–0.52 tion,15,16 and higher cardiovascular morbidity2,3,17 and eGFR 0.88 0.69–1.13 mortality.4–6 The higher morbidity and mortality associated Serum calcium 1.10 0.89–1.35 Serum phosphorus 1.65 1.30–2.09 with SHPT has been described in patients receiving Serum albumin 0.61 0.49–0.75 maintenance hemodialysis, but it is unclear if the same Serum cholesterol 0.81 0.66–0.99 associations hold true in patients with earlier stages of CKD. BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; eGFR, We described outcomes associated with higher PTH levels in estimated glomerular filtration rate; PTH, parathyroid hormone. Shown for all continuous variables are hazard ratios (95% CIs) associated with a 1 s.d. a cohort of male patients with CKD stages 3–5 who were not higher level of the variable. yet on dialysis, and found that once we accounted for the

Adjusted hazard ratio 95% CI

All Age -70 years Age >70 years White race Black race

DM No DM

ASCVD No ASCVD eGFR -30 ml per min per 1.73 m2 eGFR >30 ml per min per 1.73 m2

Calcium -9.2 mg per 100 ml Calcium >9.2 mg per 100 ml Phosphours -4.0 mg per 100 ml Phosphours > 4.0 mg per 100 ml Calcitriol No calcitriol

0.5 1.0 1.5 2.0 2.5 3.0 Figure 2 | Multivariable adjusted hazard ratios (95% CIs) of all-cause mortality associated with an intact PTH level 465 pg ml1 compared to o65 pg ml1, overall and in selected subgroups. Models were adjusted for age, race, BMI, smoking status, Charlson comorbidity index, diabetes mellitus, use of activated vitamin D and calcium-containing medications, estimated GFR, and serum levels of calcium, phosphorus, albumin and cholesterol.

1298 Kidney International (2008) 73, 1296–1302 CP Kovesdy et al.: PTH and outcomes in CKD original article

2 2 CKD stage 3 CKD stage 4–5

1 1

0 0 Log relative hazard Log relative Log relative hazard Log relative

–1 –1 30 55 80 105 130 155 180 50 100 150 200 250 300 PTH (pg ml–1) PTH (pg ml–1) Figure 3 | Estimated log relative hazards of all-cause mortality for continuous PTH in a multivariable regression spline model in subgroups of patients with CKD stage 3 and stages 4–5, adjusted for age, race, BMI, smoking status, Charlson comorbidity index, diabetes mellitus, use of activated vitamin D and calcium-containing medications, estimated GFR, and serum levels of calcium, phosphorus, albumin and cholesterol. Dashed lines, 95% pointwise CIs.

1 discernible upper or lower threshold level. The higher risk of mortality was evident above the upper limit of the normal 1 0.5 range for PTH (465 pg ml ) in all the examined subgroups, even though the associations were not uniformly statistically significant because of lower patient numbers and event rates 0 in some of these subgroups. Patients with an estimated GFR o30 ml per min per 1.73 m2 (CKD stages 4 and 5) also

Log relative hazard Log relative –0.5 showed higher mortality associated with PTH levels 465 pg ml1. Currently, the Kidney/Dialysis Outcome –1 Quality Initiative (K/DOQI) bone and mineral metabolism 1 30 80 130 180 230 280 330 380 guidelines recommend an intact PTH level of 70–110pg ml PTH (pg ml–1) for patients with CKD stage 4.19 Our observation is in Figure 4 | Estimated log relative hazards of the composite disagreement with this opinion-based guideline; further outcome of predialysis all-cause mortality and end-stage renal research may be necessary to clarify what the ideal treatment disease for continuous PTH in a multivariable regression spline targets should be for SHPT. The lack of a lower threshold model, adjusted for age, race, BMI, smoking status, Charlson level for mortality risk in our study is in contrast to studies in comorbidity index, diabetes mellitus, estimated GFR, serum levels of calcium, phosphorus, albumin and cholesterol, dialysis where the association of PTH level with mortality was proteinuria, and the use of activated vitamin D, angiotensin- U-shaped and showing higher mortality in patients with low converting enzyme inhibitors, statins and calcium-containing PTH levels.5,20 A significant proportion of this inverse medications. Dashed lines, 95% pointwise CIs. association in dialysis patients was, however, related to confounding by markers of malnutrition and inflammation,5 and patients with earlier stages of CKD (such as ours) have effect of potential confounders, higher PTH was associated significantly lower PTH levels compared to those on dialysis1 with higher all-cause predialysis mortality. These results were and hence low PTH levels would more likely be normal present even after adjustment for potential confounders such rather than confounded by pathologic states such as as serum phosphorus and calcium levels and the use of malnutrition and inflammation. activated vitamin D therapy, suggesting that SHPT is The mechanism of the higher mortality seen in patients associated with mortality independent of the effect of with higher PTH levels is speculative. Elevated PTH levels concomitant hyperphosphatemia or vitamin D therapy. We have been shown to induce a wide range of cardiovascular, found significant negative confounding by the treatment metabolic, hematologic, and immunologic abnormalities. status with activated vitamin D products in the association These include lower cardiac contractility, myocardial calcium between PTH levels and mortality. This is not surprising, as deposition, hypertrophy and fibrosis and vascular calcifica- these agents were used more often in patients with higher tion,21 mitral annular calcification,22 impaired insulin PTH levels and their main effect is the lowering of PTH sensitivity23 and glucose intolerance,24 abnormal lipid levels, and also their application is independently associated metabolism,25 bone marrow fibrosis26 with ineffective with favorable outcomes.18 A similar negative confounding erythropoiesis,27 and abnormal immune function.28 Animal phenomenon was previously described in a study examining models showed that PTH increases the myocardial calcium the association of PTH and mortality in patients with CKD content and adversely affects energy utilization in myocardial on dialysis.5 tissue29 and that it could play a role in myocardial fibrosis,30 The association of higher PTH levels with higher mortality impaired vasodilatation,31 and blood pressure-independent in our study was linear and strictly up going, without a wall thickening of the intramyocardial arterioles.32 In a

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population-based cross-sectional study, higher PTH level was one serum intact PTH level measured before the initiation of predictive of coronary heart disease.33 These data suggest that maintenance dialysis. We excluded another 22 (4%) patients whose the higher mortality associated with SHPT seen in our study first serum PTH measurement was performed after 10 August 2005 could have been resulting from higher cardiovascular (when the assay for intact PTH measurement was changed at Salem mortality related to coronary ischemia, arrhythmias, left VAMC), given the significant inter-method variability between different PTH assays.34 Only six patients had an estimated GFR of ventricular hypertrophy, or congestive heart failure, or from 2 460 ml per min per 1.73 m , and they were also excluded. The final higher infectious disease mortality. cohort consisted of 515 patients. Our study has several limitations. The design of the study Participants’ baseline characteristics were recorded at the time (historical cohort) does not allow us to infer causality but when the first PTH measurement occurred, and they included merely associations. We examined exclusively male patients demographic and anthropometric measures, blood pressure, from a single institution; hence, our results may not apply to comorbid conditions (including the Charlson comorbidity index), female subjects or patients from other geographical areas. We treatments at any time during the follow-up period with activated used a single baseline PTH level to categorize patients as vitamin D and calcium- and non-calcium-based phosphate binders, 35,36 having SHPT, which could have led to misclassification. and laboratory results, as detailed elsewhere. The use of Estimation of kidney function (rather than GFR measure- angiotensin-converting enzyme inhibitors or angiotensin receptor ment) could also have led to residual confounding by the blockers and HMG-CoA inhibitors (statins) was examined as a surrogate marker of health-care quality to address the possibility level of kidney function. Our results could have been affected that more frequent use of activated vitamin D or phosphate binders by confounding related to better care, as higher PTH could might indicate better medical care independent of the primary have been a surrogate marker of suboptimal care. Patients indications for these agents. GFR was estimated using the with higher PTH were, however, more likely to receive abbreviated equation developed for the Modification of Diet in interventions such as activated vitamin D and phosphate Renal Disease Study37 and categorized according to the staging binders, and they were equally likely to receive other system introduced by the K/DOQI Clinical Practice Guidelines for interventions frequently used in CKD (angiotensin-conver- CKD: Evaluation, Classification, and Stratification.38 Serum calcium ting enzyme inhibitors and statins), making it less likely that concentration was corrected for serum albumin concentration 39 they were neglected in other areas of their care. Therapy with using the following formula: corrected calcium ¼ measured activated vitamin D had a significant impact on the calcium þ 0.8(4serum albumin level in g per 100 ml). association between PTH and mortality through negative Intact PTH was measured in the clinical laboratory at Salem VAMC by the Allegro-intact PTH assay (Nichols Institute, San confounding, making it difficult to examine the effect of 1 Clemente, CA, USA), with a normal range of 10–65pg ml and a untreated SHPT on outcomes. In the subgroup of patients coefficient of variation of o3.4%. who were not treated with activated vitamin D therapy, the association between PTH level and mortality showed a trend similar to the overall group, but PTH levels in this subgroup Statistical analyses were significantly lower, making it difficult to derive Variables with skewed distribution (proteinuria and PTH level) were conclusions about the natural history of patients with higher transformed to their natural logarithm. Missing data points for PTH levels. We speculated that the higher all-cause mortality comorbidity index (1% missing), BMI (4.8% missing), serum seen in association with SHPT in our cohort might have been phosphorus (0.2% missing), 24-h urine protein (1% missing), blood related to cardiovascular causes or infectious causes, but we cholesterol (1.7% missing), white blood cell count (3.7% missing), did not have recordings of causes of death to test this percent lymphocytes (3.7% missing), and serum albumin (0.8% missing) were imputed using linear regression, with all other patient hypothesis. The relatively smaller number of patients in our characteristics serving as independent variables. Smoking status (3% cohort limited our ability to detect statistically significant missing) was analyzed as a categorical variable with the introduction associations in subgroup analyses. of a dummy variable for missing smoking status. In summary, we describe an independent and graded Survival modeling. The starting time for survival analysis was association between higher PTH levels and higher all-cause the date of the first PTH measurement, and patients were followed mortality in patients with CKD stages 3–5 who are not yet on until death or loss of follow-up, with the recording of initiation dialysis. These findings complement earlier results gained of maintenance hemodialysis. The main outcome measure was from hemodialysis patients and should form the basis of predialysis all-cause mortality, and the secondary outcome was clinical trials to prove that treatment of SHPT could lower the composite of predialysis mortality and end-stage renal disease mortality in CKD. (defined as the initiation of maintenance dialysis). Deaths were recorded from the VA Computerized Patient Record System and cross-checked against death certificate-based records from the MATERIALS AND METHODS National Death Index. Initiation of end-stage renal disease was Study population and data collection recorded from local medical records at Salem VAMC and included Data were collected retrospectively from 1012 patients who were reviews of Medicare Form 2728. Patients were considered lost to managed for CKD at Salem VA Medical Center (VAMC) between 1 follow-up if no contact was documented with them for more than January 1990 and 31 March 2007. Eleven (1.1%) female patients and 6 months and they were censored in survival analyses at the date five (0.5%) patients whose race was other than White or Black were of the last documented contact with the medical center. PTH levels excluded. Of the remaining 996 patients, 543 (54.5%) had at least were analyzed both as a natural log-transformed continuous

1300 Kidney International (2008) 73, 1296–1302 CP Kovesdy et al.: PTH and outcomes in CKD original article

measure and after categorization by levels based on the K/DOQI 9. Schwarz S, Trivedi BK, Kalantar-Zadeh K et al. Association of disorders in guidelines, which incidentally also approximated quartile values (to mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol 2006; 1: 825–831. examine trends of linearity), and dichotomization using a cutoff 10. Voormolen N, Noordzij M, Grootendorst DC et al. High plasma phosphate level of 65 pg ml1 (the upper limit of normal for the laboratory as a risk factor for decline in renal function and mortality in pre-dialysis assay). Nonlinear associations for PTH as a continuous predictor patients. Nephrol Dial Transplant 2007; 22: 2909–2916. were examined by using restricted cubic splines; to limit the 11. Teng M, Wolf M, Ofsthun MN et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. 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