Is there an association between elevated or low serum levels of phosphorus, parathyroid hormone, and calcium and mortality in patients with end stage renal disease? A meta-analysis

BMC Nephrology

Vasily Belozeroff³  William G Goodman³  Silvia Chiroli⁴  Ross M Miller¹  Brian H Nathanson²  Rob Boer¹  Jaime L Natoli¹ 

[1] Cerner Research, Culver City, CA, USA;OptiStatim, LLC, Longmeadow, MA, USA;Amgen, Thousand Oaks, CA, USA;Amgen Europe, Zug, Switzerland

关键词: Parathyroid hormone;    Mortality;    Mineral metabolism;    Meta-analysis;    Dialysis;    Calcium;   

Others  :  1083484
DOI  :  10.1186/1471-2369-14-88

 received in 2012-12-05, accepted in 2013-03-25,  发布年份 2013

【 摘 要 】

Background

Biochemical markers of altered mineral metabolism have been associated with increased mortality in end stage renal disease patients. Several studies have demonstrated non-linear (U-shaped or J-shaped) associations between these minerals and mortality, though many researchers have assumed linear relationships in their statistical modeling. This analysis synthesizes the non-linear relationships across studies.

Methods

We updated a prior systematic review through 2010. Studies included adults receiving dialysis and reported categorical data for calcium, phosphorus, and/or parathyroid hormone (PTH) together with all-cause mortality. We performed 2 separate meta-analyses to compare higher-than-referent levels vs referent and lower-than-referent levels vs referent levels.

Results

A literature review showed that when a linear relationship between the minerals and mortality was assumed, the estimated associations were more likely to be smaller or non-significant compared to non-linear models. In the meta-analyses, higher-than-referent levels of phosphorus (4 studies, RR = 1.20, 95% CI = 1.15-1.25), calcium (3 studies, RR = 1.10, 95% CI = 1.05-1.14), and PTH (5 studies, RR = 1.11, 95% CI = 1.07-1.16) were significantly associated with increased mortality. Although no significant associations between relatively low phosphorus or PTH and mortality were observed, a protective effect was observed for lower-than-referent calcium (RR = 0.86, 95% CI = 0.83-0.89).

Conclusions

Higher-than-referent levels of PTH, calcium, and phosphorus in dialysis patients were associated with increased mortality risk in a selection of observational studies suitable for meta-analysis of non-linear relationships. Findings were less consistent for lower-than-referent values. Future analyses should incorporate the non-linear relationships between the minerals and mortality to obtain accurate effect estimates.

【 授权许可】

   
2013 Natoli et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Owda A, Elhwairis H, Narra S, Towery H, Osama S: Secondary hyperparathyroidism in chronic hemodialysis patients: prevalence and race. Ren Fail 2003, 25:595-602.
• [2]Slatopolsky E, Brown A, Dusso A: Pathogenesis of secondary hyperparathyroidism. Kidney Int Suppl 1999, 73:S14-S19.
• [3]Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998, 32:S112-S119.
• [4]Foley RN, Parfrey PS: Cardiovascular disease and mortality in ESRD. J Nephrol 1998, 11:239-245.
• [5]Slinin Y, Foley RN, Collins AJ: Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol 2005, 16:1788-1793.
• [6]Suliman ME, Qureshi AR, Barany P, Stenvinkel P, Filho JC, Anderstam B, Heimburger O, Lindholm B, Bergstrom J: Hyperhomocysteinemia, nutritional status, and cardiovascular disease in hemodialysis patients. Kidney Int 2000, 57:1727-1735.
• [7]Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK: Association of elevated serum PO(4), Ca x PO(4) product, and parathyroid hormone with cardiac mortality risk in chronic hemodialysis patients. J Am Soc Nephrol 2001, 12:2131-2138.
• [8]Marco MP, Craver L, Betriu A, Belart M, Fibla J, Fernandez E: Higher impact of mineral metabolism on cardiovascular mortality in a European hemodialysis population. Kidney Int Suppl 2003, 85:S111-S114.
• [9]Young EW, Albert JM, Satayathum S, Goodkin DA, Pisoni RL, Akiba T, Akizawa T, Kurokawa K, Bommer J, Piera L, Port FK: Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study. Kidney Int 2005, 67:1179-1187.
• [10]Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM: Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 2004, 15:2208-2218.
• [11]de Francisco AL: Secondary hyperparathyroidism: review of the disease and its treatment. Clin Ther 2004, 26:1976-1993.
• [12]Blayney MJ, Pisoni RL, Bragg-Gresham JL, Bommer J, Piera L, Saito A, Akiba T, Keen ML, Young EW, Port FK: High alkaline phosphatase levels in hemodialysis patients are associated with higher risk of hospitalization and death. Kidney Int 2008, 74:655-663.
• [13]Avram MM, Mittman N, Myint MM, Fein P: 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, 38:1351-1357.
• [14]Kalantar-Zadeh K, Kuwae N, Regidor DL, Kovesdy CP, Kilpatrick RD, Shinaberger CS, McAllister CJ, Budoff MJ, Salusky IB, Kopple JD: Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int 2006, 70:771-780.
• [15]Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J, Young EW, Akizawa T, Akiba T, Pisoni RL, Robinson BM, Port FK: Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2008, 52:519-530.
• [16]Floege J, Kim J, Ireland E, Chazot C, Drueke T, de Francisco A, Kronenberg F, Marcelli D, Passlick-Deetjen J, Schernthaner G, Fouqueray B, Wheeler DC: Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population. Nephrol Dial Transplant 2011, 26:1948-1955.
• [17]Covic A, Kothawala P, Bernal M, Robbins S, Chalian A, Goldsmith D: Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease. Nephrol Dial Transplant 2009, 24:1506-1523.
• [18]Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, Strippoli GF: Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA 2011, 305:1119-1127.
• [19]Cunningham J, Silver J: CKD-MBD: comfort in the trough of the U. Nephrol Dial Transplant 2011, 26:1764-1766.
• [20]Shinaberger CS, Greenland S, Kopple JD, Van WD, Mehrotra R, Kovesdy CP, Kalantar-Zadeh K: Is controlling phosphorus by decreasing dietary protein intake beneficial or harmful in persons with chronic kidney disease? Am J Clin Nutr 2008, 88:1511-1518.
• [21]Shinaberger CS, Kopple JD, Kovesdy CP, McAllister CJ, Van WD, Greenland S, Kalantar-Zadeh K: Ratio of paricalcitol dosage to serum parathyroid hormone level and survival in maintenance hemodialysis patients. Clin J Am Soc Nephrol 2008, 3:1769-1776.
• [22]Miller JE, Kovesdy CP, Norris KC, Mehrotra R, Nissenson AR, Kopple JD, Kalantar-Zadeh K: Association of cumulatively low or high serum calcium levels with mortality in long-term hemodialysis patients. Am J Nephrol 2010, 32:403-413.
• [23]Noordzij M, Korevaar JC, Boeschoten EW, Dekker FW, Bos WJ, Krediet RT: The Kidney Disease Outcomes Quality Initiative (K/DOQI) Guideline for Bone Metabolism and Disease in CKD: association with mortality in dialysis patients. Am J Kidney Dis 2005, 46:925-932.
• [24]Rodriguez-Benot A, Martin-Malo A, Alvarez-Lara MA, Rodriguez M, Aljama P: Mild hyperphosphatemia and mortality in hemodialysis patients. Am J Kidney Dis 2005, 46:68-77.
• [25]Stevens LA, Djurdjev O, Cardew S, Cameron EC, Levin A: Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes. J Am Soc Nephrol 2004, 15:770-779.
• [26]Noordzij M, Korevaar JC, Dekker FW, Boeschoten EW, Bos WJ, Krediet RT, Bossuyt PM, Geskus RB: Mineral metabolism and mortality in dialysis patients: a reassessment of the K/DOQI guideline. Blood Purif 2008, 26:231-237.
• [27]Greenland S, Longnecker MP: Methods for trend estimation from summarized dose–response data, with applications to meta-analysis. Am J Epidemiol 1992, 135:1301-1309.
• [28]Hamling J, Lee P, Weitkunat R, Ambuhl M: Facilitating meta-analyses by deriving relative effect and precision estimates for alternative comparisons from a set of estimates presented by exposure level or disease category. Stat Med 2008, 27:954-970.
• [29]Dukkipati R, Kovesdy CP, Colman S, Budoff MJ, Nissenson AR, Sprague SM, Kopple JD, Kalantar-Zadeh K: Association of relatively low serum parathyroid hormone with malnutrition-inflammation complex and survival in maintenance hemodialysis patients. J Ren Nutr 2010, 20:243-254.
• [30]Tangri N, Wagner M, Griffith JL, Miskulin DC, Hodsman A, Ansell D, Naimark DM: Effect of Bone Mineral Guideline Target Achievement on Mortality in Incident Dialysis Patients: An Analysis of the United Kingdom Renal Registry. Am J Kidney Dis 2011, 57:415-421.
• [31]Block GA, Hulbert-Shearon TE, Levin NW, Port FK: Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998, 31:607-617.
• [32]Block GA, Zaun D, Smits G, Persky M, Brillhart S, Nieman K, Liu J, St Peter WL: Cinacalcet hydrochloride treatment significantly improves all-cause and cardiovascular survival in a large cohort of hemodialysis patients. Kidney Int 2010, 78:578-589.
• [33]Chang JJ, Concato J, Wells CK, Crowley ST: Prognostic implications of clinical practice guidelines among hemodialysis patients. Hemodial Int 2006, 10:399-407.
• [34]Drechsler C, Grootendorst DC, Boeschoten EW, Krediet RT, Wanner C, Dekker FW: Changes in parathyroid hormone, body mass index and the association with mortality in dialysis patients. Nephrol Dial Transplant 2011, 26:1340-1346.
• [35]Drechsler C, Verduijn M, Pilz S, Dekker FW, Krediet RT, Ritz E, Wanner C, Boeschoten EW, Brandenburg V: Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD study. Nephrol Dial Transplant 2011, 26:1024-1032.
• [36]Etter C, Straub Y, Hersberger M, Raz HR, Kistler T, Kiss D, Wuthrich RP, Gloor HJ, Aerne D, Wahl P, Klaghofer R, Ambuhl PM: Pregnancy-associated plasma protein-A is an independent short-time predictor of mortality in patients on maintenance haemodialysis. Eur Heart J 2010, 31:354-359.
• [37]Foley RN, Parfrey PS, Harnett JD, Kent GM, Hu L, O'Dea R, Murray DC, Barre PE: Hypocalcemia, morbidity, and mortality in end-stage renal disease. Am J Nephrol 1996, 16:386-393.
• [38]Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, Smith K, Lee H, Thadhani R, Juppner H, Wolf M: Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008, 359:584-592.
• [39]Hakemi MS, Golbabaei M, Nassiri A, Kayedi M, Hosseini M, Atabak S, Ganji MR, Amini M, Saddadi F, Najafi I: Predictors of patient survival in continuous ambulatory peritoneal dialysis: 10-year experience in 2 major centers in Tehran. Iran J Kidney Dis 2010, 4:44-49.
• [40]Hsiao CH, Chao A, Chu SY, Lin KK, Yeung L, Lin-Tan DT, Lin JL: Association of severity of conjunctival and corneal calcification with all-cause 1-year mortality in maintenance haemodialysis patients. Nephrol Dial Transplant 2011, 26:1016-1023.
• [41]Isakova T, Gutierrez OM, Chang Y, Shah A, Tamez H, Smith K, Thadhani R, Wolf M: Phosphorus binders and survival on hemodialysis. J Am Soc Nephrol 2009, 20:388-396.
• [42]Jassal SV, Douglas JF, Stout RW: Prognostic markers in older patients starting renal replacement therapy. Nephrol Dial Transplant 1996, 11:1052-1057.
• [43]Jean G, Terrat JC, Vanel T, Hurot JM, Lorriaux C, Mayor B, Chazot C: High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant 2009, 24:2792-2796.
• [44]Kalantar-Zadeh K, Miller JE, Kovesdy CP, Mehrotra R, Lukowsky LR, Streja E, Ricks J, Jing J, Nissenson AR, Greenland S, Norris KC: Impact of race on hyperparathyroidism, mineral disarrays, administered vitamin D mimetic, and survival in hemodialysis patients. J Bone Miner Res 2010, 25:2448-2458.
• [45]Kimata N, Albert JM, Akiba T, Yamazaki S, Kawaguchi Y, Fukuhara S, Akizawa T, Saito A, Asano Y, Kurokawa K, Pisoni RL, Port FK: Association of mineral metabolism factors with all-cause and cardiovascular mortality in hemodialysis patients: the Japan dialysis outcomes and practice patterns study. Hemodial Int 2007, 11:340-348.
• [46]Komaba H, Igaki N, Takashima M, Goto S, Yokota K, Komada H, Takemoto T, Kohno M, Kadoguchi H, Hirosue Y, Goto T: Calcium, phosphorus, cardiovascular events and all-cause mortality in hemodialysis patients: a single-center retrospective cohort study to reassess the validity of the Japanese Society for Dialysis Therapy guidelines. Ther Apher Dial 2008, 12:42-48.
• [47]Lacson E Jr, Wang W, Hakim RM, Teng M, Lazarus JM: Associates of mortality and hospitalization in hemodialysis: potentially actionable laboratory variables and vascular access. Am J Kidney Dis 2009, 53:79-90.
• [48]Leggat JE Jr, Orzol SM, Hulbert-Shearon TE, Golper TA, Jones CA, Held PJ, Port FK: Noncompliance in hemodialysis: predictors and survival analysis. Am J Kidney Dis 1998, 32:139-145.
• [49]Lin JL, Lin-Tan DT, Chen KH, Hsu CW, Yen TH, Huang WH, Huang YL: Blood lead levels association with 18-month all-cause mortality in patients with chronic peritoneal dialysis. Nephrol Dial Transplant 2010, 25:1627-1633.
• [50]Lowrie EG, Lew NL: Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990, 15:458-482.
• [51]Lukowsky L, Kovesdy CP, McNeill G, Streja E, Jing J, Krishnan M, Nissenson AR, Kalantar-Zadeh K: Comparing mortality-predictability of hyperphosphatemia in maintenance hemodialysis patients with and without Polycystic Kidney Disease (PKD). Am J Kidney Dis 2010, 55:A76.
• [52]Maeda S, Sawayama Y, Furusyo N, Shigematsu M, Hayashi J: The association between fatal vascular events and risk factors for carotid atherosclerosis in patients on maintenance hemodialysis: plaque number of dialytic atherosclerosis study. Atherosclerosis 2009, 204:549-555.
• [53]McNeill G, Streja E, Lukowsky L, Kovesdy CP, Jing J, Krishnan M, Nissenson AR, Kalantar-Zadeh K: Secondary hyperparathyroidism & survival in hemodialysis patients with & without polycystic kidney. Am J Kidney Dis 2010, 55:A79.
• [54]Melamed ML, Eustace JA, Plantinga L, Jaar BG, Fink NE, Coresh J, Klag MJ, Powe NR: Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study. Kidney Int 2006, 70:351-357.
• [55]Miller JE, Streja E, Kovesdy CP, Wyck DV, Nissenson AR, Kalantar-Zadeh K: Mortality of 5-Year time-averaged low serum calcium <8.5 mg/dL in subgroups of hemodialysis (HD) patients. Am J Kidney Dis 2009, 53:A55.
• [56]Morrone LF, Mazzaferro S, Russo D, Aucella F, Cozzolino M, Facchini MG, Galfre A, Malberti F, Mereu MC, Nordio M, Pertosa G, Santoro D: Interaction between parathyroid hormone and the Charlson comorbidity index on survival of incident haemodialysis patients. Nephrol Dial Transplant 2009, 24:2859-2865.
• [57]Naves-Diaz M, Passlick-Deetjen J, Guinsburg A, Marelli C, Fernandez-Martin JL, Rodriguez-Puyol D, Cannata-Andia JB: Calcium, phosphorus, PTH and death rates in a large sample of dialysis patients from Latin America. The CORES Study. Nephrol Dial Transplant 2011, 26:1938-1947.
• [58]Naves-Diaz M, Varez-Hernandez D, Passlick-Deetjen J, Guinsburg A, Marelli C, Rodriguez-Puyol D, Cannata-Andia JB: Oral active vitamin D is associated with improved survival in hemodialysis patients. Kidney Int 2008, 74:1070-1078.
• [59]Phelan PJ, O'Kelly P, Walshe JJ, Conlon PJ: The importance of serum albumin and phosphorous as predictors of mortality in ESRD patients. Ren Fail 2008, 30:423-429.
• [60]Port FK, Pisoni RL, Bragg-Gresham JL, Satayathum SS, Young EW, Wolfe RA, Held PJ: DOPPS estimates of patient life years attributable to modifiable hemodialysis practices in the United States. Blood Purif 2004, 22:175-180.
• [61]Saran R, Bragg-Gresham JL, Rayner HC, Goodkin DA, Keen ML, Van Dijk PC, Kurokawa K, Piera L, Saito A, Fukuhara S, Young EW, Held PJ, Port FK: Nonadherence in hemodialysis: associations with mortality, hospitalization, and practice patterns in the DOPPS. Kidney Int 2003, 64:254-262.
• [62]Simic-Ogrizovic S, Dopsaj V, Bogavac-Stanojevic N, Obradovic I, Stosovic M, Radovic M: Serum amyloid-A rather than C-reactive protein is a better predictor of mortality in hemodialysis patients. Tohoku J Exp Med 2009, 219:121-127.
• [63]Sit D, Kadiroglu AK, Kayabasi H, Kara IH, Yilmaz Z, Yilmaz ME: The evaluation incidence and risk factors of mortality among patients with end stage renal disease in Southeast Turkey. Ren Fail 2008, 30:37-44.
• [64]Takemoto F, Katori H, Sawa N, Hoshino J, Suwabe T, Nakanishi S, Arai S, Fukuda S, Kodaka K, Shimada M, Yamazaki C, Yokoyama K, Nakano Y, Funahashi T, Ubara Y, Yamada A, Takaichi K, Uchida S: Plasma adiponectin: a predictor of coronary heart disease in hemodialysis patients–a Japanese prospective eight-year study. Nephron Clin Pract 2009, 111:c12-c20.
• [65]Wald R, Sarnak MJ, Tighiouart H, Cheung AK, Levey AS, Eknoyan G, Miskulin DC: Disordered mineral metabolism in hemodialysis patients: an analysis of cumulative effects in the Hemodialysis (HEMO) Study. Am J Kidney Dis 2008, 52:531-540.
• [66]Young EW, Akiba T, Albert JM, McCarthy JT, Kerr PG, Mendelssohn DC, Jadoul M: Magnitude and impact of abnormal mineral metabolism in hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004, 44:34-38.
• [67]Harrell FE: Regression modeling strategies with applications to linear models, logistic regression, and survival analysis. New York, NY: Springer-Verlag; 2001.
• [68]Ammirati AL, Dalboni MA, Cendoroglo M, Draibe SA, Santos RD, Miname M, Canziani ME: The progression and impact of vascular calcification in peritoneal dialysis patients. Perit Dial Int 2007, 27:340-346.
• [69]Fensterseifer DM, Karohl C, Schvartzman P, Costa CA, Veronese FJ: Coronary calcification and its association with mortality in haemodialysis patients. Nephrology (Carlton) 2009, 14:164-170.
• [70]Matsuoka M, Iseki K, Tamashiro M, Fujimoto N, Higa N, Touma T, Takishita S: Impact of high coronary artery calcification score (CACS) on survival in patients on chronic hemodialysis. Clin Exp Nephrol 2004, 8:54-58.
• [71]Shantouf RS, Budoff MJ, Ahmadi N, Ghaffari A, Flores F, Gopal A, Noori N, Jing J, Kovesdy CP, Kalantar-Zadeh K: Total and individual coronary artery calcium scores as independent predictors of mortality in hemodialysis patients. Am J Nephrol 2010, 31:419-425.
• [72]Sigrist MK, Taal MW, Bungay P, McIntyre CW: Progressive vascular calcification over 2 years is associated with arterial stiffening and increased mortality in patients with stages 4 and 5 chronic kidney disease. Clin J Am Soc Nephrol 2007, 2:1241-1248.