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

Background. Chronic kidney disease (CKD) is a powerful risk factor for all-cause mortality and its most common aetiology, cardiovascular (CV) mortality. Mineral metabolism disturbances occur very early during the course of CKD but their control has been poor. A number of studies have assessed the relationship between all-cause mortality, CV mortality and events with mineral disturbances in CKD patients, but with considerable discrepancy and heterogeneity in results. Thus, a systematic review was conducted to assess methodological and clinical heterogeneity by comparing designs, analytical approaches and results of studies. Methods. Medline, EMBASE and Cochrane databases were systematically searched for articles published between January 1980 and December 2007. Results. Thirty-five studies were included in the review. All-cause mortality was the most commonly assessed outcome (n = 29). Data on CV mortality risk (n = 11) and CV events (congestive heart failure, stroke, myocardial infarction) (n = 4) are limited. The studies varied in populations scrutinized, exposure assessments, covariates adjusted and reference mineral levels used in risk estimation. A significant risk of mortality (all-cause, CV) and of CV events was observed with mineral disturbances. The data supported a greater mortality risk with phosphorus, followed by calcium and parathyroid hormone (PTH). The threshold associated with a significant all-cause mortality risk varied from 3.5-3.9 mg/dL (reference: 2.5-2.9) to 6.6-7.8 mg/dL (reference: 4.4-5.5) for high phosphorus, < 3 mg/dL (reference: 5-7) to < 5 mg/dL (reference: 5-6) for low phosphorus, 9.7-10.2 mg/dL (reference: <= 8.7) to > 10.5 mg/dL (reference: 9-9.5) for high calcium, <= 8.8 mg/dL (reference: > 8.8) to < 9 mg/dL (reference: 9-9.5) for low calcium and > 300 pg/mL (reference: 200-300) to > 480 pg/mL (reference: <= 37) for PTH. Thresholds at which the CV mortality risk significantly increased were > 5.5 (reference: 3.5-5.5) and > 6.5 mg/dL (reference: < 6.5) for phosphorus and > 476.1 pg/mL (reference: < 476.1) for PTH. Conclusions. Serious limitations were observed in the quality and methodology across studies. In spite of enormous heterogeneity across studies, a significant mortality risk was observed with mineral disturbances in dialysis patients. Data on risk in pre-dialysis patients were less conclusive due to even more limited (numerically) evidence.