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• W2059099969 abstract "Secondary hyperparathyroidism is associated with mortality in patients undergoing maintenance dialysis treatment. We studied 515 male US veterans with chronic kidney disease, who were not yet on dialysis, to see what outcomes were associated with secondary hyperparathyroidism in this population. Relationships between intact parathyroid hormone levels and all-cause mortality along with the composite of mortality or incidence of dialysis were measured in unadjusted and adjusted Cox models for case-mix and laboratory variables. Elevated parathyroid hormone levels above the upper limit compared to the lower limit of the normal range were significantly associated with mortality after adjustments. Higher intact parathyroid hormone levels in the upper limit of normal were significantly associated with higher mortality overall and showed similar trends in subgroups of patients with stage 3 and stage 4–5 chronic kidney disease and with higher and lower serum calcium and phosphorus levels. Similar associations were found with the composite outcome of mortality or dialysis. Our study shows that secondary hyperparathyroidism is independently associated with higher mortality in patients with chronic kidney disease but not yet on dialysis. Secondary hyperparathyroidism is associated with mortality in patients undergoing maintenance dialysis treatment. We studied 515 male US veterans with chronic kidney disease, who were not yet on dialysis, to see what outcomes were associated with secondary hyperparathyroidism in this population. Relationships between intact parathyroid hormone levels and all-cause mortality along with the composite of mortality or incidence of dialysis were measured in unadjusted and adjusted Cox models for case-mix and laboratory variables. Elevated parathyroid hormone levels above the upper limit compared to the lower limit of the normal range were significantly associated with mortality after adjustments. Higher intact parathyroid hormone levels in the upper limit of normal were significantly associated with higher mortality overall and showed similar trends in subgroups of patients with stage 3 and stage 4–5 chronic kidney disease and with higher and lower serum calcium and phosphorus levels. Similar associations were found with the composite outcome of mortality or dialysis. Our study shows that secondary hyperparathyroidism is independently associated with higher mortality in patients with chronic kidney disease but not yet on dialysis. Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD)1.Levin A. Bakris G.L. Molitch M. et al.Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.Kidney Int. 2007; 71: 31-38Abstract Full Text Full Text PDF PubMed Scopus (1046) Google Scholar and has been linked to higher cardiovascular morbidity2.De Boer I.H. Gorodetskaya I. Young B. et al.The severity of secondary hyperparathyroidism in chronic renal insufficiency is GFR-dependent, race-dependent, and associated with cardiovascular disease.J Am Soc Nephrol. 2002; 13: 2762-2769Crossref PubMed Scopus (132) Google Scholar,3.Fellner S.K. Lang R.M. Neumann A. et al.Parathyroid hormone and myocardial performance in dialysis patients.Am J Kidney Dis. 1991; 18: 320-325Abstract Full Text PDF PubMed Scopus (25) Google Scholar and mortality4.Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2080) Google Scholar, 5.Kalantar-Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar, 6.Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1433) Google Scholar in patients on maintenance hemodialysis. SHPT develops gradually as kidney function deteriorates.1.Levin A. Bakris G.L. Molitch M. et al.Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.Kidney Int. 2007; 71: 31-38Abstract Full Text Full Text PDF PubMed Scopus (1046) Google Scholar Patients with earlier stages of CKD by far outnumber those undergoing maintenance dialysis treatment,7.Coresh J. Astor B.C. Greene T. et al.Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey.Am J Kidney Dis. 2003; 41: 1-12Abstract Full Text Full Text PDF PubMed Scopus (2211) Google Scholar but the impact on mortality associated with SHPT in this group is unknown. It is also unclear to what extent the outcomes linked to SHPT could be confounded by other factors associated with higher parathyroid hormone (PTH) levels, such as hyperphosphatemia (associated with higher mortality8.Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (868) Google Scholar and more severe progression of kidney disease9.Schwarz S. Trivedi B.K. Kalantar-Zadeh K. et al.Association of disorders in mineral metabolism with progression of chronic kidney disease.Clin J Am Soc Nephrol. 2006; 1: 825-831Crossref PubMed Scopus (192) Google Scholar,10.Voormolen N. Noordzij M. Grootendorst D.C. et al.High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients.Nephrol Dial Transplant. 2007; 22: 2909-2916Crossref PubMed Scopus (256) Google Scholar in CKD) and the use of activated vitamin D (associated with better survival in dialysis patients5.Kalantar-Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar,11.Teng M. Wolf M. Ofsthun M.N. et al.Activated injectable vitamin D and hemodialysis survival: a historical cohort study.J Am Soc Nephrol. 2005; 16: 1115-1125Crossref PubMed Scopus (713) Google Scholar). We examined outcomes (all-cause mortality and the composite of predialysis mortality or initiation of maintenance dialysis) as a function of PTH level in 515 male US veterans with predialysis CKD stages 3–5, with special attention to the confounding effect of hyperphosphatemia, hypocalcemia, and treatment with activated vitamin D. The patient cohort had a mean age of 69.4±10.2 years and included 24% black patients. The mean estimated glomerular filtration rate (GFR) was 31.1±10.9 ml per min per 1.73 m2 and the median PTH level was 103 pg ml−1 (interquartile range: 65–179 pg ml−1). 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 (dialysis initiation rate: 107/1000 patient-years, 95% CI: 90–127) during a median follow-up of 2.3 years. Six patients were lost to follow-up and their characteristics were not significantly different (data not shown).Table 1Baseline characteristics of individuals stratified by categories of intact PTH levelPTH (pg ml−1)<65 (N=128)65–110 (N=146)111–179 (N=113)>179 (N=128)P-valueAge (years)68.4±10.370.1±9.971.1±9.168.1±11.20.06Race (% Black)26 (20)29 (20)29 (26)38 (30)0.18DM76 (59)84 (58)60 (53)70 (55)0.7ASCVD77 (60)80 (55)75 (66)68 (53)0.14Smoking29 (24)30 (21)22 (21)39 (31)0.2Comorbidity index2.3±1.62.6±1.92.4±1.42.7±1.70.2Vitamin D analog use16 (12)64 (44)87 (77)89 (70)<0.001Calcium-containing medication use25 (20)29 (20)34 (30)80 (62)<0.001Sevelamer HCl use9 (7)19 (13)21 (19)43 (34)<0.001ACEI/ARB use100 (78)113 (77)78 (69)99 (77)0.3Statin use94 (73)105 (72)81 (72)85 (66)0.6BMI (kg m−2)28.7±5.229.4±6.029.2±5.729.0±6.10.8SBP (mm Hg)143±26145±24148±27152±250.02DBP (mm Hg)72±1570±1569±1675±140.01eGFR (ml per min per 1.73 m2)35.7±10.034.7±10.430.9±8.722.5±9.1<0.0001CKD stage 3/4/591 (71)/33 (26)/4 (3)96 (66)/46 (32)/4 (3)60 (53)/49 (43)/4 (4)23 (18)/76 (59)/29 (23)<0.0001Serum albumin (g per 100 ml)3.6±0.43.6±0.53.6±0.43.4±0.50.005Serum cholesterol (mg per 100 ml)181±46186±49179±49190±530.23Serum bicarbonate (mg per 100 ml)26.0±3.126.3±3.026.0±3.624.0±3.9<0.0001Serum calcium (mg per 100 ml)9.4±0.69.2±0.59.2±0.58.8±0.7<0.0001Serum phosphorus (mg per 100 ml)3.9±0.73.8±0.64.0±0.74.4±0.9<0.0001Blood Hgb (g per 100 ml)12.7±1.812.8±1.612.4±1.711.8±1.7<0.0001Blood WBC (1000 mm−3)7.4±2.47.5±2.57.4±2.07.2±2.20.7Blood lymphocytes (% WBC)24.3±8.421.8±7.922.5±7.822.4±8.40.08Proteinuria (g per 24 h)613 (476–790)526 (418–660)488 (381–627)1404 (1094–1801)<0.0001ACEI/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 χ2 test. Open table in a new tab 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 χ2 test. PTH level was not associated with mortality in unadjusted analyses (unadjusted hazard ratios (95% CI) for PTH 65–110, 110–179, and >179 versus <65 pg ml−1: 0.90 (0.58–1.42), 0.89 (0.54–1.46), and 0.89 (0.53–1.48); P=0.6 for trend), but higher PTH levels were associated with higher mortality after adjustment for age, race, body mass index (BMI), smoking, comorbidities, estimated GFR, serum calcium, phosphorus, albumin and cholesterol levels, and the use of activated vitamin D and calcium-containing medications (adjusted hazard ratios (95% CI) for PTH 65–110, 110–179, and >179 versus <65 pg ml−1: 1.49 (0.91–2.43), 1.67 (0.95–2.94), and 2.00 (1.06–3.80); P=0.028 for trend). Adjustment for treatment with activated vitamin D had the largest impact on the association between PTH and mortality (P=0.4 for linear trend before and P=0.028 for linear trend after inclusion of variable for activated vitamin D use in the multivariable model). 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 (95% CI) associated with PTH when examined as a continuous variable, along with mortality hazard ratios (95% CI) associated with the other components included in the multivariable Cox model. A 1 s.d. higher natural log-transformed PTH level was associated with a fully adjusted death hazard ratio of 1.28 (95% CI: 1.04–1.58; P=0.021).Table 2Hazard ratios of all-cause mortality for variables included in the multivariable Cox modelHazard ratio95% CIPTH1.281.04–1.58Age1.801.39–2.31Black race (referent: white race)0.970.62–1.51BMI0.780.62–0.98Active smoking (referent: non-smoking)1.921.21–3.05Comorbidity index1.311.08–1.59DM (referent: no DM)1.370.90–2.06Activated vitamin D use (referent: no activated vitamin D use)0.280.18–0.42Calcium use (referent: no calcium use)0.310.18–0.52eGFR0.880.69–1.13Serum calcium1.100.89–1.35Serum phosphorus1.651.30–2.09Serum albumin0.610.49–0.75Serum cholesterol0.810.66–0.99BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; PTH, parathyroid hormone.Shown for all continuous variables are hazard ratios (95% CIs) associated with a 1 s.d. higher level of the variable. Open table in a new tab BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; PTH, parathyroid hormone. Shown for all continuous variables are hazard ratios (95% CIs) associated with a 1 s.d. higher level of the variable. Figure 2 shows hazard ratios of mortality associated with a PTH level of >65 pg ml−1 compared to a level of ≤65 pg ml−1, overall and in selected subgroups. A PTH level of >65 pg ml−1 was associated with higher mortality overall, and similar trends were present in the studied subgroups, albeit without reaching statistical significance in most; this association was less pronounced in diabetic patients, but the interaction with diabetes mellitus was not statistically significant. A PTH level of >65 pg ml−1 tended to be associated with higher mortality in both patients who never received an activated vitamin D product (adjusted hazard ratio: 1.47 (95% CI: 0.89–2.41)) and in patients who received such treatment (adjusted hazard ratio: 2.40 (95% CI: 0.55–10.47)), although none of these associations reached statistical significance; there was also no statistically significant interaction with activated vitamin D treatment status. Patients with CKD stages 4 and 5 showed a stronger association between PTH >65 pg ml−1 and mortality (adjusted hazard ratio: 2.10 (95% CI: 0.99–4.45)) compared to patients with CKD stage 3 (adjusted hazard ratio: 1.32 (95% CI: 0.72–2.44)), but no statistically significant interaction with CKD stage was present. Figure 3 shows the multivariable-adjusted estimated log relative hazard of mortality associated with continuous PTH in subgroups of patients with CKD stage 3 and stages 4 and 5, indicating an increase in mortality with higher levels of serum PTH level in both subgroups.Figure 3Estimated 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.View Large Image Figure ViewerDownload (PPT) The composite end point of predialysis mortality or end-stage renal disease also showed an association with higher PTH, with adjusted hazard ratios of the composite end point (95% CI) for PTH 65–110, 110–179, and >179 versus <65 pg ml−1 being 1.30 (0.88–1.90), 1.69 (1.11–2.58), and 1.83 (1.17–2.85), P=0.004 for trend. Figure 4 shows the multivariable-adjusted estimated log relative hazard of the combined end point associated with continuous PTH, indicating a monotonic increase in mortality with higher levels of serum PTH level. SHPT develops early and shows a progressive worsening during the course of CKD.1.Levin A. Bakris G.L. Molitch M. et al.Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.Kidney Int. 2007; 71: 31-38Abstract Full Text Full Text PDF PubMed Scopus (1046) Google Scholar Higher PTH levels have been associated with multiple complications, including bone disease,12.Rix M. Andreassen H. Eskildsen P. et al.Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure.Kidney Int. 1999; 56: 1084-1093Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar,13.Sherrard D.J. Hercz G. Pei Y. et al.The spectrum of bone disease in end-stage renal failure—an evolving disorder.Kidney Int. 1993; 43: 436-442Abstract Full Text PDF PubMed Scopus (637) Google Scholar uremic pruritus,14.Massry S.G. Popovtzer M.M. Coburn J.W. et al.Intractable pruritus as a manifestation of secondary hyperparathyroidism in uremia. Disappearance of itching after subtotal parathyroidectomy.N Engl J Med. 1968; 279: 697-700Crossref PubMed Scopus (168) Google Scholar cognitive and sexual dysfunction,15.Bogicevic M. Stefanovic V. Relationship between parathyroid hormone and pituitary-testicular axis in patients on maintenance hemodialysis.Exp Clin Endocrinol. 1988; 92: 357-362Crossref PubMed Scopus (13) Google Scholar,16.Tonner D.R. Schlechte J.A. Neurologic complications of thyroid and parathyroid disease.Med Clin North Am. 1993; 77: 251-263PubMed Google Scholar and higher cardiovascular morbidity2.De Boer I.H. Gorodetskaya I. Young B. et al.The severity of secondary hyperparathyroidism in chronic renal insufficiency is GFR-dependent, race-dependent, and associated with cardiovascular disease.J Am Soc Nephrol. 2002; 13: 2762-2769Crossref PubMed Scopus (132) Google Scholar, 3.Fellner S.K. Lang R.M. Neumann A. et al.Parathyroid hormone and myocardial performance in dialysis patients.Am J Kidney Dis. 1991; 18: 320-325Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 17.Slinin Y. Foley R.N. Collins A.J. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study.J Am Soc Nephrol. 2005; 16: 1788-1793Crossref PubMed Scopus (336) Google Scholar and mortality.4.Block G.A. Klassen P.S. Lazarus J.M. et al.Mineral metabolism, mortality, and morbidity in maintenance hemodialysis.J Am Soc Nephrol. 2004; 15: 2208-2218Crossref PubMed Scopus (2080) Google Scholar, 5.Kalantar-Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar, 6.Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), Ca × PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1433) Google Scholar The higher morbidity and mortality associated with SHPT has been described in patients receiving maintenance hemodialysis, but it is unclear if the same associations hold true in patients with earlier stages of CKD. We described outcomes associated with higher PTH levels in a cohort of male patients with CKD stages 3–5 who were not yet on dialysis, and found that once we accounted for the effect of potential confounders, higher PTH was associated with higher all-cause predialysis mortality. These results were present even after adjustment for potential confounders such as serum phosphorus and calcium levels and the use of activated vitamin D therapy, suggesting that SHPT is associated with mortality independent of the effect of concomitant hyperphosphatemia or vitamin D therapy. We found significant negative confounding by the treatment status with activated vitamin D products in the association between PTH levels and mortality. This is not surprising, as these agents were used more often in patients with higher PTH levels and their main effect is the lowering of PTH levels, and also their application is independently associated with favorable outcomes.18.Kovesdy C.P. Ahmadzadeh S. Anderson J.E. et al.Association of treatment with activated vitamin D and mortality in chronic kidney disease.Arch Intern Med. 2008; 168: 397-403Crossref PubMed Scopus (251) Google Scholar A similar negative confounding phenomenon was previously described in a study examining the association of PTH and mortality in patients with CKD on dialysis.5.Kalantar-Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar The association of higher PTH levels with higher mortality in our study was linear and strictly up going, without a discernible upper or lower threshold level. The higher risk of mortality was evident above the upper limit of the normal range for PTH (>65 pg ml−1) in all the examined subgroups, even though the associations were not uniformly statistically significant because of lower patient numbers and event rates in some of these subgroups. Patients with an estimated GFR <30 ml per min per 1.73 m2 (CKD stages 4 and 5) also showed higher mortality associated with PTH levels >65 pg ml−1. Currently, the Kidney/Dialysis Outcome Quality Initiative (K/DOQI) bone and mineral metabolism guidelines recommend an intact PTH level of 70–110 pg ml−1 for patients with CKD stage 4.19.Eknoyan G. Levin A. Levin N. Bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: 1-201Abstract Full Text Full Text PDF PubMed Google Scholar Our observation is in disagreement with this opinion-based guideline; further research may be necessary to clarify what the ideal treatment targets should be for SHPT. The lack of a lower threshold level for mortality risk in our study is in contrast to studies in dialysis where the association of PTH level with mortality was U-shaped and showing higher mortality in patients with low PTH levels.5.Kalantar-Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar,20.Avram M.M. Mittman N. Myint M.M. et al.Importance of low serum intact parathyroid hormone as a predictor of mortality in hemodialysis and peritoneal dialysis patients: 14 years of prospective observation.Am J Kidney Dis. 2001; 38: 1351-1357Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar A significant proportion of this inverse association in dialysis patients was, however, related to confounding by markers of malnutrition and inflammation,5.Kalantar-Zadeh K. Kuwae N. Regidor D.L. et al.Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients.Kidney Int. 2006; 70: 771-780Abstract Full Text Full Text PDF PubMed Scopus (750) Google Scholar and patients with earlier stages of CKD (such as ours) have significantly lower PTH levels compared to those on dialysis1.Levin A. Bakris G.L. Molitch M. et al.Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease.Kidney Int. 2007; 71: 31-38Abstract Full Text Full Text PDF PubMed Scopus (1046) Google Scholar and hence low PTH levels would more likely be normal rather than confounded by pathologic states such as malnutrition and inflammation. The mechanism of the higher mortality seen in patients with higher PTH levels is speculative. Elevated PTH levels have been shown to induce a wide range of cardiovascular, metabolic, hematologic, and immunologic abnormalities. These include lower cardiac contractility, myocardial calcium deposition, hypertrophy and fibrosis and vascular calcification,21.Massry S.G. Smogorzewski M. Mechanisms through which parathyroid hormone mediates its deleterious effects on organ function in uremia.Semin Nephrol. 1994; 14: 219-231PubMed Google Scholar mitral annular calcification,22.Mazzaferro S. Coen G. Bandini S. et al.Role of ageing, chronic renal failure and dialysis in the calcification of mitral annulus.Nephrol Dial Transplant. 1993; 8: 335-340PubMed Google Scholar impaired insulin sensitivity23.Chiu K.C. Chuang L.M. Lee N.P. et al.Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level.Metabolism. 2000; 49: 1501-1505Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar and glucose intolerance,24.Wareham N.J. Byrne C.D. 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Vormbrock K. et al.Impaired flow-mediated vasodilation of the brachial artery in patients with primary hyperparathyroidism improves after parathyroidectomy.Cardiovasc Res. 2000; 47: 813-818Crossref PubMed Scopus (103) Google Scholar and blood pressure-independent wall thickening of the intramyocardial arterioles.32.Amann K. Tornig J. Flechtenmacher C. et al.Blood-pressure-independent wall thickening of intramyocardial arterioles in experimental uraemia: evidence for a permissive action of PTH.Nephrol Dial Transplant. 1995; 10: 2043-2048PubMed Google Scholar In a population-based cross-sectional study, higher PTH level was predictive of coronary heart disease.33.Kamycheva E. Sundsfjord J. Jorde R. Serum parathyroid hormone levels predict coronary heart disease: the Tromso Study.Eur J Cardiovasc Prev Rehabil. 2004; 11: 69-74Crossref PubMed Scopus (122) Google Scholar These data suggest that the higher mortality associated with SHPT seen in our study could have been resulting from higher cardiovascular mortality related to coronary ischemia, arrhythmias, left ventricular hypertrophy, or congestive heart failure, or from higher infectious disease mortality. Our study has several limitations. The design of the study (historical cohort) does not allow us to infer causality but merely associations. We examined exclusively male patients from a single institution; hence, our results may not apply to female subjects or patients from other geographical areas. We used a single baseline PTH level to categorize patients as having SHPT, which could have led to misclassification. Estimation of kidney function (rather than GFR measurement) could also have led to residual confounding by the level of kidney function. Our results could have been affected by confounding related to better care, as higher PTH could have been a surrogate marker of suboptimal care. Patients with higher PTH were, however, more likely to receive interventions such as activated vitamin D and phosphate binders, and they were equally likely to receive other interventions frequently used in CKD (angiotensin-converting enzyme inhibitors and statins), making it less likely that they were neglected in other areas of their care. Therapy with activated vitamin D had a significant impact on the association between PTH and mortality through negative confounding, making it difficult to examine the effect of untreated SHPT on outcomes. In the subgroup of patients 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 were significantly lower, making it difficult to derive conclusions about the natural history of patients with higher PTH levels. We speculated that the higher all-cause mortality seen in association with SHPT in our cohort might have been related to cardiovascular causes or infectious causes, but we did not have recordings of causes of death to test this hypothesis. The relatively smaller number of patients in our cohort limited our ability to detect statistically significant associations in subgroup analyses. In summary, we describe an independent and graded association between higher PTH levels and higher all-cause mortality in patients with CKD stages 3–5 who are not yet on dialysis. These findings complement earlier results gained from hemodialysis patients and should form the basis of clinical trials to prove that treatment of SHPT could lower mortality in CKD. Data were collected retrospectively from 1012 patients who were managed for CKD at Salem VA Medical Center (VAMC) between 1 January 1990 and 31 March 2007. Eleven (1.1%) female patients and five (0.5%) patients whose race was other than White or Black were excluded. Of the remaining 996 patients, 543 (54.5%) had at least one serum intact PTH level measured before the initiation of maintenance dialysis. We excluded another 22 (4%) patients whose first serum PTH measurement was performed after 10 August 2005 (when the assay for intact PTH measurement was changed at Salem VAMC), given the significant inter-method variability between different PTH assays.34.Souberbielle J.C. Boutten A. Carlier M.C. et al.Inter-method variability in PTH measurement: implication for the care of CKD patients.Kidney Int. 2006; 70: 345-350Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar Only six patients had an estimated GFR of >60 ml per min per 1.73 m2, and they were also excluded. The final cohort consisted of 515 patients. Participants’ baseline characteristics were recorded at the time when the first PTH measurement occurred, and they included demographic and anthropometric measures, blood pressure, comorbid conditions (including the Charlson comorbidity index), treatments at any time during the follow-up period with activated vitamin D and calcium- and non-calcium-based phosphate binders, and laboratory results, as detailed elsewhere.35.Kovesdy C.P. Trivedi B.K. Anderson J.E. Association of kidney function with mortality in patients with chronic kidney disease not yet on dialysis: a historical prospective cohort study.Adv Chronic Kidney Dis. 2006; 13: 183-188Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar,36.Kovesdy C.P. Trivedi B.K. Kalantar-Zadeh K. et al.Association of low blood pressure with increased mortality in patients with moderate to severe chronic kidney disease.Nephrol Dial Transplant. 2006; 21: 1257-1262Crossref PubMed Scopus (102) Google Scholar The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and HMG-CoA inhibitors (statins) was examined as a surrogate marker of health-care quality to address the possibility that more frequent use of activated vitamin D or phosphate binders might indicate better medical care independent of the primary indications for these agents. GFR was estimated using the abbreviated equation developed for the Modification of Diet in Renal Disease Study37.Levey A.S. Bosch J.P. Lewis J.B. et al.A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.Ann Intern Med. 1999; 130: 461-470Crossref PubMed Scopus (12277) Google Scholar and categorized according to the staging system introduced by the K/DOQI Clinical Practice Guidelines for CKD: Evaluation, Classification, and Stratification.38.National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar Serum calcium concentration was corrected for serum albumin concentration using the following formula:39.Payne R.B. Little A.J. Williams R.B. et al.Interpretation of serum calcium in patients with abnormal serum proteins.BMJ. 1973; 4: 643-646Crossref PubMed Scopus (585) Google Scholar corrected calcium=measured calcium+0.8(4-serum albumin level in g per 100 ml). Intact PTH was measured in the clinical laboratory at Salem VAMC by the Allegro-intact PTH assay (Nichols Institute, San Clemente, CA, USA), with a normal range of 10–65 pg ml−1 and a coefficient of variation of <3.4%. Variables with skewed distribution (proteinuria and PTH level) were transformed to their natural logarithm. Missing data points for comorbidity index (1% missing), BMI (4.8% missing), serum phosphorus (0.2% missing), 24-h urine protein (1% missing), blood cholesterol (1.7% missing), white blood cell count (3.7% missing), percent lymphocytes (3.7% missing), and serum albumin (0.8% missing) were imputed using linear regression, with all other patient characteristics serving as independent variables. Smoking status (3% missing) was analyzed as a categorical variable with the introduction of a dummy variable for missing smoking status. The starting time for survival analysis was the date of the first PTH measurement, and patients were followed until death or loss of follow-up, with the recording of initiation of maintenance hemodialysis. The main outcome measure was predialysis all-cause mortality, and the secondary outcome was the composite of predialysis mortality and end-stage renal disease (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 National Death Index. Initiation of end-stage renal disease was recorded from local medical records at Salem VAMC and included reviews of Medicare Form 2728. Patients were considered lost to follow-up if no contact was documented with them for more than 6 months and they were censored in survival analyses at the date of the last documented contact with the medical center. PTH levels were analyzed both as a natural log-transformed continuous measure and after categorization by levels based on the K/DOQI guidelines, which incidentally also approximated quartile values (to examine trends of linearity), and dichotomization using a cutoff level of 65 pg ml−1 (the upper limit of normal for the laboratory assay). Nonlinear associations for PTH as a continuous predictor were examined by using restricted cubic splines; to limit the instability of such models at extreme PTH levels, model building was restricted to PTH values between the 5th and 95th percentiles of the studied groups. The association of baseline PTH levels with the outcome measures was examined in unadjusted Cox models, and the impact of potential confounders was analyzed in multivariable Cox models. Selection of variables to be included in the multivariable model was performed by a multivariable regression spline function using backward elimination of weak predictors using a closed test approach.40.Royston P. Sauerbrei W. Multivariable modeling using cubic regression splines: a principled approach.Stata J. 2007; 7: 45-70Google Scholar Age, race, diabetes mellitus, and serum calcium and phosphorus levels were forced into the final model. The proportionality assumption was tested by comparing predicted and actual survival curves and by Schoenfeld residuals. Analyses were repeated in subgroups divided by age, race, diabetes mellitus, any type of activated vitamin D use, and levels of PTH, estimated GFR, serum calcium and phosphorus. Interactions were formally tested for by the inclusion of interaction terms. P-values less than 0.05 were considered statistically significant. Statistical analyses were performed using STATA statistical software version 10 (STATA Corporation, College Station, TX, USA). The study protocol was approved by the Research and Development Committee at the Salem Veterans Affairs Medical Center. Parts of this material were presented at the American Society of Nephrology Renal Week 2007, 31 October to 5 November, San Francisco, CA, USA. KKZ and CPK were supported by the Grant R01DK078106 from the National Institute of Diabetes, Digestive and Kidney Disease of the National Institutes of Health. CPK was supported by an investigator-initiated research grant from Abbott Laboratories." @default.
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• W2059099969 title "Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease" @default.
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