Prevalence and severity of disordered mineral metabolism in Blacks with chronic kidney disease
2008; Elsevier BV; Volume: 73; Issue: 8 Linguagem: Inglês
10.1038/ki.2008.4
ISSN1523-1755
AutoresOrlando M. Gutiérrez, Tamara Isakova, D.L. Andress, Adeera Levin, Myles Wolf,
Tópico(s)Vitamin D Research Studies
ResumoDisorders of mineral metabolism develop early in chronic kidney disease, but it appears that Blacks with stage-5 disease have more severe secondary hyperparathyroidism than other races. We measured levels of parathyroid hormone, calcium, phosphorus, 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) in 227 Black and 1633 non-Black participants in the SEEK study, a multi-center cohort of patients with early chronic kidney disease. Overall, Blacks had similar 1,25D levels compared with non-Blacks, but significantly lower levels of 25D with higher levels of calcium, phosphorus, and parathyroid hormone, and were significantly more likely to have hyperphosphatemia than non-Blacks. In multivariable analyses adjusted for age, gender, estimated glomerular filtration rate, body mass index, and diabetes, Blacks had significantly lower 25D and higher parathyroid hormone levels than non-Blacks, with the latter parameter remaining significant after further adjustment for calcium, phosphorus, 25D, and 1,25D. The association between Black race and secondary hyperparathyroidism, independent of known risk factors, suggests that novel mechanisms contribute to secondary hyperparathyroidism in Blacks with chronic kidney disease. Disorders of mineral metabolism develop early in chronic kidney disease, but it appears that Blacks with stage-5 disease have more severe secondary hyperparathyroidism than other races. We measured levels of parathyroid hormone, calcium, phosphorus, 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) in 227 Black and 1633 non-Black participants in the SEEK study, a multi-center cohort of patients with early chronic kidney disease. Overall, Blacks had similar 1,25D levels compared with non-Blacks, but significantly lower levels of 25D with higher levels of calcium, phosphorus, and parathyroid hormone, and were significantly more likely to have hyperphosphatemia than non-Blacks. In multivariable analyses adjusted for age, gender, estimated glomerular filtration rate, body mass index, and diabetes, Blacks had significantly lower 25D and higher parathyroid hormone levels than non-Blacks, with the latter parameter remaining significant after further adjustment for calcium, phosphorus, 25D, and 1,25D. The association between Black race and secondary hyperparathyroidism, independent of known risk factors, suggests that novel mechanisms contribute to secondary hyperparathyroidism in Blacks with chronic kidney disease. Disordered mineral metabolism, secondary hyperparathyroidism (sHPT), and deficiencies of vitamin D are common complications 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,2.Gutierrez O. Isakova T. Rhee E. et al.Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease.J Am Soc Nephrol. 2005; 16: 2205-2215Crossref PubMed Scopus (689) Google Scholar While their contributions to the development of renal osteodystrophy are well known,3.Llach F. Yudd M. Pathogenic, clinical, and therapeutic aspects of secondary hyperparathyroidism in chronic renal failure.Am J Kidney Dis. 1998; 32: S3-S12Abstract Full Text PDF PubMed Scopus (86) Google Scholar recent evidence has linked these factors to cardiovascular disease, including non-atherosclerotic vascular calcification, excessive activation of the renin–angiotensin system, hypertension, left ventricular hypertrophy, and death.4.Li Y.C. Kong J. Wei M. et al.1, 25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin–angiotensin system.J Clin Invest. 2002; 110: 229-238Crossref PubMed Scopus (1614) Google Scholar, 5.Xiang W. Kong J. Chen S. et al.Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin–angiotensin systems.Am J Physiol Endocrinol Metab. 2005; 288: E125-E132Crossref PubMed Scopus (480) Google Scholar, 6.Moe S.M. Vascular calcification and renal osteodystrophy relationship in chronic kidney disease.Eur J Clin Invest. 2006; 36: 51-62Crossref PubMed Scopus (106) Google Scholar, 7.Block G.A. Port F.K. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: recommendations for a change in management.Am J Kidney Dis. 2000; 35: 1226-1237Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar, 8.London G.M. Guerin A.P. Verbeke F.H. et al.Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency.J Am Soc Nephrol. 2007; 18: 613-620Crossref PubMed Scopus (367) Google Scholar, 9.Giachelli C.M. Jono S. Shioi A. et al.Vascular calcification and inorganic phosphate.Am J Kidney Dis. 2001; 38: S34-S37Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 10.Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), CaxPO(4), and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1432) Google Scholar Indeed, large observational studies suggest that abnormalities of parathyroid hormone (PTH), calcium, phosphorus, 25-hydroxyvitamin D (25D), and 1,25-dihydroxyvitamin D (1,25D) are associated with mortality on dialysis, and that management strategies to treat these disorders may improve survival.11.Block G.A. Raggi P. Bellasi A. et al.Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar, 12.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, 13.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, 14.Wolf M. Shah A. Gutierrez O. et al.Vitamin D levels and early mortality among incident hemodialysis patients.Kidney Int. 2007; 72: 1004-1013Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar On the basis of these encouraging results, renewed emphasis has shifted to the screening and treatment of these abnormalities early in the course of CKD when they first develop and may be most amenable to therapy. In the general population, Blacks demonstrate increased rates of 25D deficiency and increased PTH levels compared with non-Blacks.15.Dawson-Hughes B. Racial/ethnic considerations in making recommendations for vitamin D for adult and elderly men and women.Am J Clin Nutr. 2004; 80: 1763S-1766SPubMed Google Scholar, 16.Nesby-O′Dell S. Scanlon K.S. Cogswell M.E. et al.Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988–1994.Am J Clin Nutr. 2002; 76: 187-192PubMed Google Scholar, 17.Bell N.H. Greene A. Epstein S. et al.Evidence for alteration of the vitamin D-endocrine system in blacks.J Clin Invest. 1985; 76: 470-473Crossref PubMed Scopus (361) Google Scholar These differences are magnified on dialysis when Blacks manifest more severe sHPT and 25D deficiency than Caucasians.14.Wolf M. Shah A. Gutierrez O. et al.Vitamin D levels and early mortality among incident hemodialysis patients.Kidney Int. 2007; 72: 1004-1013Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar, 18.Gupta A. Kallenbach L.R. Zasuwa G. et al.Race is a major determinant of secondary hyperparathyroidism in uremic patients.J Am Soc Nephrol. 2000; 11: 330-334PubMed Google Scholar, 19.Sawaya B.P. Butros R. Naqvi S. et al.Differences in bone turnover and intact PTH levels between African American and Caucasian patients with end-stage renal disease.Kidney Int. 2003; 64: 737-742Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar However, few population-based studies have examined racial differences in the prevalence and severity of mineral metabolism disorders in pre-dialysis CKD.20.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 This is especially noteworthy since Blacks bear a disproportionately higher burden of CKD,21.Cooper L. USRDS. 2001 Annual Data Report.Nephrol News Issues. 2001; 15 (34-35 31,38 passim)Google Scholar, 22.McClellan W. Warnock D.G. McClure L. et al.Racial differences in the prevalence of chronic kidney disease among participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study.J Am Soc Nephrol. 2006; 17: 1710-1715Crossref PubMed Scopus (119) Google Scholar, 23.Xue J.L. Eggers P.W. Agodoa L.Y. et al.Longitudinal study of racial and ethnic differences in developing end-stage renal disease among aged medicare beneficiaries.J Am Soc Nephrol. 2007; 18: 1299-1306Crossref PubMed Scopus (87) Google Scholar yet current Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for the management of mineral metabolism in CKD primarily considered studies that did not specifically account for potential racial differences in abnormalities of mineral metabolism.24.National Kidney Foundation K/DOQI guidelines: bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S52-S57Google Scholar, 25.Martinez I. Saracho R. Montenegro J. et al.The importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure.Am J Kidney Dis. 1997; 29: 496-502Abstract Full Text PDF PubMed Scopus (207) Google Scholar, 26.Pitts T.O. Piraino B.H. Mitro R. et al.Hyperparathyroidism and 1, 25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure.J Clin Endocrinol Metab. 1988; 67: 876-881Crossref PubMed Scopus (197) Google Scholar, 27.Wilson L. Felsenfeld A. Drezner M.K. et al.Altered divalent ion metabolism in early renal failure: role of 1, 25(OH)2D.Kidney Int. 1985; 27: 565-573Abstract Full Text PDF PubMed Scopus (100) Google Scholar, 28.Fajtova V.T. Sayegh M.H. Hickey N. et al.Intact parathyroid hormone levels in renal insufficiency.Calcif Tissue Int. 1995; 57: 329-335Crossref PubMed Scopus (58) Google Scholar We examined the Study for Early Evaluation of Kidney Disease (SEEK) cohort to test the hypotheses that sHPT, hypocalcemia, hyperphosphatemia, and deficiencies of 25D and 1,25D are more common and more severe among Blacks compared with non-Blacks, and that Blacks manifest these abnormalities earlier along the spectrum of pre-dialysis CKD. A total of 1860 subjects were analyzed, of whom 12% (227) were Black, which is similar to their representation in the US population.29.Sondik E.J. Lucas J.W. Madans J.H. et al.Race/ethnicity and the 2000 census: implications for public health.Am J Public Health. 2000; 90: 1709-1713Crossref PubMed Scopus (58) Google Scholar Demographic and clinical data by race are presented in Table 1. Compared with non-Blacks, Blacks were younger, more likely to be female, had lower estimated glomerular filtration rate (eGFR), and higher body mass index and systolic blood pressure. Blacks were more likely to have a history of diabetes mellitus and hypertension than non-Blacks, but less likely to have a history of coronary artery disease. Blacks were more likely to be treated with angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics than non-Blacks, but were less likely to be treated with calcium supplements. Among patients with a history of coronary artery disease, Blacks were as likely as non-Blacks to be treated with angiotensin-converting enzyme inhibitors (44 vs 38%, P=0.4), aspirin (76 vs 70%, P=0.3), β-blockers (71 vs 60%, P=0.08), and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (65 vs 73%, P=0.2), suggesting that there were minimal differences in access to quality medical care according to race.Table 1Description of subjects by raceBlackNon-BlackVariablen=227n=1633PAge67±1171±11<0.01Female (%)6151<0.01Body mass index (kg m−2)33±831±7<0.01SBP (mm Hg)136±20130±170.02EGFR (ml min 1.73m−2)45±2048±180.04Comorbidities (%) Diabetes5946<0.01 CAD31390.01 CHF2418NS CVA610NS HTN9786<0.01 PVD1717NS Smoking2319NSMedications (%) ACE inhibitor4837<0.01 ARB4333<0.01 CCB5134<0.01 Diuretics7562 65 pg ml−1), hyperphosphatemia (>4.6 mg per 100 ml), 25D deficiency (<30 ng ml−1), and severe 25D deficiency (<10 ng ml−1) compared with non-Blacks (Table 2).Table 2Laboratory variables in the overall population by raceBlackNon-BlackVariablen=227n=1633P1,25D (pg ml−1)28 (18–39)29 (19–40)NS %<30 pg ml−14950NS25D (ng ml−1)22±1130±12<0.01 %<30 ng ml−18360<0.01 %<10 ng ml−1113<0.01PTH (pg ml−1)92 (55–171)53 (34–84) 65 pg ml−16538<0.01Albumin (g per 100 ml)4.2±0.34.3±0.4<0.01Bone alkaline phosphatase (U l−1)25 (19–34)21 (17–27)<0.01Calcium (mg per 100 ml)9.2±0.69.1±0.4<0.01 %<8.5 mg per 100 ml54NSPhosphorus (mg per 100 ml)3.9±0.73.7±0.7 4.6 mg per 100 ml158<0.0125D, 25-hydroxyvitamin D; 1,25D, 1,25-dihydroxyvitamin D; NS, not significant; PTH, parathyroid hormone.Results are reported as mean±s.d., median (interquartile range), or proportions. Open table in a new tab 25D, 25-hydroxyvitamin D; 1,25D, 1,25-dihydroxyvitamin D; NS, not significant; PTH, parathyroid hormone. Results are reported as mean±s.d., median (interquartile range), or proportions. Racial differences in the levels of PTH, calcium, phosphorus, 25D, and 1,25D by CKD stage and the stage-specific prevalence of values outside the normal range are presented in Table 3 and Figure 1. There were no significant racial differences in median 1,25D levels across the spectrum of CKD. Blacks had a similar prevalence of 1,25D deficiency as non-Blacks in each stage of CKD except in the most advanced stage (eGFR<30 ml min−1 1.73 m−2), where Blacks had a significantly lower prevalence of 1,25D deficiency compared with non-Blacks (Figure 1a). In contrast, Blacks had significantly lower 25D and higher PTH levels, and a significantly higher prevalence of both 25D deficiency and sHPT than non-Blacks in all stages of CKD (Figure 1b and c). Importantly, median levels of PTH first exceeded 65 pg ml−1 at an eGFR 60% of patients with an eGFR of 45–60 ml min−1 1.73 m−2. Blacks had higher calcium and phosphorus levels than non-Blacks in each stage of CKD, although differences did not reach statistical significance in every stage. Similarly, Blacks had a higher prevalence of hyperphosphatemia in each stage of CKD (Figure 1d), although differences were only statistically significant in the earliest stage of CKD (eGFR>60 ml min−1 1.73 m−2). There were no statistically significant differences in the prevalence of hypocalcemia in Blacks compared with non-Blacks (Figure 1e).Table 3Laboratory values by race and eGFRGFR>60GFR 45–59GFR 30–44GFR<30BlackNon-BlackBlackNon-BlackBlackNon-BlackBlackNon-Blackn=47n=385n=51n=513n=82n=466n=47n=2691,25D (pg ml−1)34 (26–53)37 (27–52)32 (25–43)32 (23–44)25 (15–36)25 (16–34)25 (14–33)19 (10–28)25D (ng ml−1)22±9**P<0.01 for comparison between Black and non-Black.32 ±1223±11**P<0.01 for comparison between Black and non-Black.31±1221±11**P<0.01 for comparison between Black and non-Black.29±1121±14*P<0.0527±13PTH (pg ml−1)54 (34–81)**P<0.01 for comparison between Black and non-Black.40 (29–56)71 (52–116)**P<0.01 for comparison between Black and non-Black.49 (31–69)107 (63–172)**P<0.01 for comparison between Black and non-Black.61 (40–93)218 (119–459)**P<0.01 for comparison between Black and non-Black.101 (62–173)Ca (mg per 100 ml)9.3±0.4**P<0.01 for comparison between Black and non-Black.9.1±0.49.3±0.4**P<0.01 for comparison between Black and non-Black.9.2±0.49.2±0.59.2±0.59.1±0.99.0±0.6P (mg per 100 ml)3.6±0.73.5±0.53.7±0.63.6±0.53.9±0.5**P<0.01 for comparison between Black and non-Black.3.7±0.64.4±0.94.2±0.91,25D, 1,25-dihydroxyvitamin D; 25D, 25-hydroxyvitamin D; Ca, calcium; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; NS, not significant; P, phosphorus; PTH, parathyroid hormone. 25D, Ca, and P are reported as mean±s.d.; 1,25D and PTH are reported as median (interquartile range).* P<0.05** P<0.01 for comparison between Black and non-Black. Open table in a new tab 1,25D, 1,25-dihydroxyvitamin D; 25D, 25-hydroxyvitamin D; Ca, calcium; eGFR, estimated glomerular filtration rate; GFR, glomerular filtration rate; NS, not significant; P, phosphorus; PTH, parathyroid hormone. 25D, Ca, and P are reported as mean±s.d.; 1,25D and PTH are reported as median (interquartile range). In multivariable linear regression models adjusted for age, gender, diabetes, body mass index, and eGFR, Black, race was independently associated with increased log PTH (β=0.49, P<0.01), calcium (β=0.1, P<0.01), phosphorus (β=0.11, P=0.04), and log alkaline phosphatase (β=0.12, P<0.01), and decreased levels of 25D (β=-6.2, P<0.01). Thus, whereas there were no significant racial differences in multivariable-adjusted 1,25D levels, the Black race was independently associated with 40% higher PTH, 2% higher calcium, 3% higher phosphorus, 14% higher alkaline phosphatase, and 21% lower 25D levels. When further adjusted for 25D, 1,25D, calcium, and phosphorus levels, the Black race remained independently associated with increased log PTH (β=0.44, P<0.01), but the association between race and log alkaline phosphatase was completely attenuated when adjusted for log PTH (β=0.02, P=0.7). In addition, when further adjusted for 25D levels, an association between Black race and increased log 1,25D levels became evident (β=0.16, P<0.01). In logistic regression models adjusted for age, gender, diabetes, body mass index, and eGFR, there were no significant racial differences in risk of 1,25D deficiency or hypocalcemia on the basis of clinical cut-off points defined above. In contrast, Blacks had a 1.8-fold greater risk of hyperphosphatemia (95% confidence interval: 1.01, 3.3, P=0.04), a 2.9-fold greater risk of sHPT (95% confidence interval: 1.9, 4.4; P<0.01), a 2.7-fold greater risk of 25D deficiency (<30 ng ml−1, 95% confidence interval: 1.7, 4.5, P<0.01), and a 4.6-fold greater risk of severe 25D deficiency (<10 ng ml−1, 95% confidence interval: 2.2, 9.6, P<0.01) than non-Blacks. In this cross-sectional study of 1860 pre-dialysis CKD patients, Blacks had significantly increased PTH, calcium, phosphorus, and bone-specific alkaline phosphatase levels; significantly decreased 25D levels; and a higher prevalence of sHPT and 25D deficiency overall and in all stages of CKD compared with non-Blacks. Blacks also developed sHPT and 25D deficiency earlier in the course of CKD (at eGFR of 45–60) compared with non-Blacks (at GFR<30). To our knowledge, this is the largest study of racial disparities in the prevalence and severity of disordered mineral metabolism in pre-dialysis CKD. The results suggest that screening for disorders of mineral metabolism should be performed earlier in Blacks with CKD. Furthermore, the observation that Blacks manifest more severe sHPT independent of age, gender, diabetes, eGFR, calcium, phosphorus, 25D, and 1,25D suggests that other pathophysiological mechanisms may play a role in the early development of sHPT in Blacks with CKD. Disorders of mineral metabolism are common complications of CKD that are associated with increased risk of cardiovascular disease and mortality.4.Li Y.C. Kong J. Wei M. et al.1, 25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin–angiotensin system.J Clin Invest. 2002; 110: 229-238Crossref PubMed Scopus (1614) Google Scholar, 5.Xiang W. Kong J. Chen S. et al.Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin–angiotensin systems.Am J Physiol Endocrinol Metab. 2005; 288: E125-E132Crossref PubMed Scopus (480) Google Scholar, 6.Moe S.M. Vascular calcification and renal osteodystrophy relationship in chronic kidney disease.Eur J Clin Invest. 2006; 36: 51-62Crossref PubMed Scopus (106) Google Scholar, 7.Block G.A. Port F.K. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: recommendations for a change in management.Am J Kidney Dis. 2000; 35: 1226-1237Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar, 8.London G.M. Guerin A.P. Verbeke F.H. et al.Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency.J Am Soc Nephrol. 2007; 18: 613-620Crossref PubMed Scopus (367) Google Scholar, 9.Giachelli C.M. Jono S. Shioi A. et al.Vascular calcification and inorganic phosphate.Am J Kidney Dis. 2001; 38: S34-S37Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 10.Ganesh S.K. Stack A.G. Levin N.W. et al.Association of elevated serum PO(4), CaxPO(4), and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients.J Am Soc Nephrol. 2001; 12: 2131-2138Crossref PubMed Scopus (1432) Google Scholar, 12.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 Hyperphosphatemia, sHPT, 25D, and 1,25D deficiency have all been linked with increased risk of mortality on dialysis.11.Block G.A. Raggi P. Bellasi A. et al.Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients.Kidney Int. 2007; 71: 438-441Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar, 12.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, 13.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, 14.Wolf M. Shah A. Gutierrez O. et al.Vitamin D levels and early mortality among incident hemodialysis patients.Kidney Int. 2007; 72: 1004-1013Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar Whereas these associations have been studied in less detail in non-dialysis populations, increases in serum phosphorus even in the high normal range have been associated with accelerated kidney disease progression and increased mortality in patients with pre-dialysis CKD,30.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 (869) Google Scholar,31.Schwarz S. Trivedi B. Kalanter-Zadeh K. et al.Association of disorders of mineral metabolism with progression of chronic kidney disease.Clin J Am Soc Nephrol. 2006; 1: 825-831Crossref PubMed Scopus (192) Google Scholar suggesting that even mildly elevated levels of phosphorus may have deleterious consequences. Among subjects with normal kidney function, higher serum phosphorus and PTH levels and lower 25D levels have been associated with an increased risk of CVD events, including congestive heart failure, hypertension, and stroke.32.Tonelli M. Sacks F. Pfeffer M. et al.Relation between serum phosphate level and cardiovascular event rate in people with coronary disease.Circulation. 2005; 112: 2627-2633Crossref PubMed Scopus (645) Google Scholar, 33.Dhingra R. Sullivan L.M. Fox C.S. et al.Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community.Arch Intern Med. 2007; 167: 879-885Crossref PubMed Scopus (611) Google Scholar, 34.Lind L. Hanni A. Lithell H. et al.Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men.Am J Hypertens. 1995; 8: 894-901Crossref PubMed Scopus (258) Google Scholar, 35.Poole K.E. Loveridge N. Barker P.J. et al.Reduced vitamin D in acute stroke.Stroke. 2006; 37: 243-245Crossref PubMed Scopus (233) Google Scholar, 36.Wang T. Pencina M. Booth S. et al.Vitamin D deficiency and the risk of cardiovascular disease.Circulation. 2008; 117: 503-511Crossref PubMed Scopus (1817) Google Scholar Low 25D levels have also been associated with a variety of malignancies, autoimmune diseases, and impaired immune response to tuberculosis infection, especially among Blacks.37.Liu P.T. Stenger S. Li H. et al.Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.Science. 2006; 311: 1770-1773Crossref PubMed Scopus (2739) Google Scholar,38.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (9711) Google Scholar While the pathophysiological mechanisms that account for these associations must be elucidated, a growing number of in vitro animal and human studies have linked elevated serum phosphorus and PTH levels and low 25D and 1,25D levels with left ventricular hypertrophy, impaired myocardial contractile function, accelerated vascular calcification, and atherosclerosis.9.Giachelli C.M. Jono S. Shioi A. et al.Vascular calcification and inorganic phosphate.Am J Kidney Dis. 2001; 38: S34-S37Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 39.Zittermann A. Schleithoff S.S. Tenderich G. et al.Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure?.J Am Coll Cardiol. 2003; 41: 105-112Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar, 40.Weishaar R.E. Kim S.N. Saunders D.E. et al.Involvement of vitamin D3 with cardiovascular function. III. Effects on physical and morphological properties.Am J Physiol. 1990; 258: E134-E142PubMed Google Scholar Altogether, these observations suggest that disorders of mineral metabolism may be important and potentially modifiable risk factors for the abysmal cardiovascular outcomes in patients with CKD. Recognizing the possibility that abnormal mineral, PTH, and vitamin D metabolism may represent novel risk factors for cardiovascular disease in CKD, current K/DOQI clinical practice guidelines advocate screening for and treating these abnormalities as early as eGFR<60 ml min−1 1.73 m−2.24.National Kidney Foundation K/DOQI guidelines: bone metabolism and disease in chronic kidney disease.Am J Kidney Dis. 2003; 42: S52-S57Google Scholar The validity of this approach was supported by several studies that demonstrated a high prevalence of abnormal mineral metabolism starting in CKD stage 3.1.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, 2.Gutierrez O. Isakova T. Rhee E. et al.Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease.J Am Soc Nephrol. 2005; 16: 2205-2215Crossref PubMed Scopus (689) Google Scholar, 25.Martinez I. Saracho R. Montenegro J. et al.The importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure.Am J Kidney Dis. 1997; 29: 496-502Abstract Full Text PDF PubMed Scopus (207) Google Scholar, 26.Pitts T.O. Piraino B.H. Mitro R. et al.Hyperparathyroidism and 1, 25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure.J Clin Endocrinol Metab. 1988; 67: 876-881Crossref PubMed Scopus (197) Google Scholar, 27.Wilson L. Felsenfeld A. Drezner M.K. et al.Altered divalent ion metabolism in early renal failure: role of 1, 25(OH)2D.Kidney Int. 1985; 27: 565-573Abstract Full Text PDF PubMed Scopus (100) Google Scholar, 28.Fajtova V.T. Sayegh M.H. Hickey N. et al.Intact parathyroid hormone levels in renal insufficiency.Calcif Tissue Int. 1995; 57: 3
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