Facility-level CKD-MBD composite score and risk of adverse clinical outcomes among patients on hemodialysis

In this study of nearly 1300 US dialysis centers and 39,000 patients receiving in-center hemodialysis between 2009 and 2011, we characterized all facilities using a facility-level CKD-MBD composite score defined by at least two of three biochemical parameters out of target, or separately, above target. A fifth of all facilities had ≥ 24 % of their patients out of target and ≥ 11 % of their patients above target. Using this composite score, we conducted a facility-level analysis and found that patients receiving care at facilities with higher composite scores were at elevated risk of adverse clinical outcomes compared with patients receiving care at facilities with the lowest composite scores. The increased risk was nearly 15 % for cardiovascular hospitalization or death over a 1-year period and ~300 % for parathyroidectomy. The results were more pronounced when the analysis was conducted using a composite score defined by above-target values. These data provide additional evidence that characterizing CKD-MBD using a construct that classifies patients simultaneously on all three biochemical parameters is achievable, has significant prognostic value, and may be a useful framework for identifying clinically meaningful differences in severity of CKD-MBD.

The results of this study extend previous patient-level analyses showing that two or more of the three biochemical hallmarks of CKD-MBD, PTH, calcium, and phosphate, out of or above the target ranges established by KDOQI or Kidney Disease: Improving Global Outcomes (KDIGO) strongly predicts the risk of major clinical outcomes, independent of case-mix and baseline comorbidity [2, 3, 7]. In addition, these results support the consistently observed independent relationships between individual biochemical variables and clinical outcomes [8–10] and of robust pre-clinical literature describing the adverse effects of exposure of vascular cells to media containing high phosphate and/or high calcium [11, 12]. These findings also provide important context for the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial findings; EVOLVE, a randomized, double blind placebo-controlled clinical study [13], was designed to test whether treatment with cinacalcet in addition to standard of care in patients with SHPT receiving hemodialysis would reduce the risk of death and cardiovascular events relative to placebo plus standard of care. The primary unadjusted intention-to-treat analysis demonstrated reductions in PTH, calcium, and phosphate, and a greater than 50 % reduction in risk of parathyroidectomy for patients randomized to cinacalcet, but a non-definitive reduction in the primary composite end point of death or cardiovascular events (hazard ratio, 0.93; 95 % CI, 0.85–1.02). Post-hoc analyses adjusting for the age imbalance in the treatment groups despite randomization showed nominally significant reduction in the primary composite end point (death or cardiovascular events), providing further evidence of the potential benefit of lowering PTH, calcium, and phosphate levels. The current facility-level analysis findings reinforce the strong link between SHPT management (as reflected in facility-level target achievement) and subsequent clinical outcome risk, parathyroidectomy in particular.

Complex inter-relationships between PTH, calcium, and phosphate are such that a change in any one of them is accompanied by changes in the others, often in opposite directions. Considering any in isolation of the others (as analyses evaluating the independent effects of one adjusting for the others would inform) is inconsistent with the clinical situations physicians encounter. It is exceedingly common for clinicians to encounter scenarios in which clinical guidelines seemingly give contradictory guidance relative to these three biochemical measures of quality of care, and providers must decide the relative risks of achieving one particular goal while potentially abandoning another. In addition, therapy directed at a single measure often has unintended consequences (direct and indirect) on the others that must be addressed [14, 15]. In such a complex clinical situation, a composite measure that incorporates PTH, calcium, and phosphate can help physicians identify patients at greatest risk of adverse outcomes who might benefit most from therapeutic intervention. In the current investigation, we aggregated the previously identified patient-level composite score into a facility-level measure and showed similar significant prognostic value, reinforcing the construct validity of this measure as a reliable marker of clinically meaningful CKD-MBD.

While our facility-level study provides a simple, integrated approach to identify facilities at highest risk of adverse clinical outcomes, we did not address directly the means by which different dialysis centers achieve lower proportions of out-of-target patients. Management of SHPT is complicated and the strategies employed by dialysis providers in clinical practice are not easily defined, aside from calculating average utilization, which by itself does not accurately capture the complex interplay of the various therapeutic interventions. Understanding which therapeutic approaches enable improved composite biochemical control without increasing safety risks will be an important benefit/risk calculation. For example, using aluminum as a phosphate binder is a therapeutic approach that could simultanesouly reduce both PTH and phosphate and might enable greater composite biochemical control; however, this would be at the expense of patient safety. An instructive contemporary example is the recent use of lower dialysate calcium concentrations in dialysis centers. A large non-interventional study using dialysis provider data found that patients receiving care in centers that predominantly use a < 2.5 mEq/L dialysate calcium concentration (compared with patients at centers using a ≥ 2.5 mEq/L concentration) achieved less biochemical control and were at elevated risk of heart failure hospitalization, intradialytic hypotension, and hypocalcemia [16]. Some of these decisions could be motived by the economic pressures introduced by the prospective payment system encouraging use of lower cost treatments, but they should be guided by efficacy and safety data obtained from rigorously conducted clinical trials or high-quality non-experimental research conducted in large populations of patients on dialysis.

This study should be evaluated in light of the following limitations: Our primary analyses used a PTH target range of 150–600 pg/mL to reflect current clinical practice guidelines despite prior patient-level work demonstrating that a PTH target range of 150–300 pg/mL also provides significant discrimination [3]. Although the analyses were conducted at the facility level and accounted for various patient risk factors, we cannot exclude the possibility of residual confounding. However, it should be acknowledged that the adjustments made only attenuated the observed effect estimates modestly, suggesting the findings are fairly robust. Our modeling effort did not account for other facility practices or quality of care indicators (e.g., standardized mortality ratio), so it is not possible to conclude definitively from our analysis that the CKD-MBD score reflects a facility’s quality of care related only to CKD-MBD. However, our models do account for a wide range of clinical prognostic indicators that have been used extensively in studies of dialysis (e.g., vascular access, comorbid conditions such as congestsive heart failure, peripheral vascular disease, cancer). Although there may be some residual error, it is unlikely that it would materially affect the study’s conclusions. For example, the clear relation between higher CKD-MBD quintile and risk of parathyroidectomy is unlikely to be affected by a facility’s mortality performance over a calendar year. The assessment of CKD-MBD biochemical variables was conducted during a 4-month baseline period; thus, up to four values were available for calcium and phosphate, but likely only one or two values were available for PTH. If those values represent spurious measurements, our findings likely underestimate the true risk of out-of-target values. As noted, our study did not address the mechanisms facilities used to achieve improved biochemical outcomes, and we are unable to comment on whether any single treatment strategy that modifies multiple biochemical targets may be associated with benefit or harm. Clinical trials randomizing patients to different treatment protocols would provide the most reliable evidence to address those questions.