Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): evaluation of possible confounding by nutritional status

Abstract

Background: Poor nutritional status and both hyper- and hypophosphatemia are associated with increased mortality in maintenance hemodialysis (HD) patients. We assessed associations of phosphate binder prescription with survival and indicators of nutritional status in maintenance HD patients.

Study design: Prospective cohort study (DOPPS [Dialysis Outcomes and Practice Patterns Study]), 1996-2008.

Setting & participants: 23,898 maintenance HD patients at 923 facilities in 12 countries.

Predictors: Patient-level phosphate binder prescription and case-mix-adjusted facility percentage of phosphate binder prescription using an instrumental-variable analysis.

Outcome: All-cause mortality.

Results: Overall, 88% of patients were prescribed phosphate binders. Distributions of age, comorbid conditions, and other characteristics showed small differences between facilities with higher and lower percentages of phosphate binder prescription. Patient-level phosphate binder prescription was associated strongly at baseline with indicators of better nutrition, ie, higher values for serum creatinine, albumin, normalized protein catabolic rate, and body mass index and absence of cachectic appearance. Overall, patients prescribed phosphate binders had 25% lower mortality (HR, 0.75; 95% CI, 0.68-0.83) when adjusted for serum phosphorus level and other covariates; further adjustment for nutritional indicators attenuated this association (HR, 0.88; 95% CI, 0.80-0.97). However, this inverse association was observed for only patients with serum phosphorus levels ≥3.5 mg/dL. In the instrumental-variable analysis, case-mix-adjusted facility percentage of phosphate binder prescription (range, 23%-100%) was associated positively with better nutritional status and inversely with mortality (HR for 10% more phosphate binders, 0.93; 95% CI, 0.89-0.96). Further adjustment for nutritional indicators reduced this association to an HR of 0.95 (95% CI, 0.92-0.99).

Limitations: Results were based on phosphate binder prescription; phosphate binder and nutritional data were cross-sectional; dietary restriction was not assessed; observational design limits causal inference due to possible residual confounding.

Conclusions: Longer survival and better nutritional status were observed for maintenance HD patients prescribed phosphate binders and in facilities with a greater percentage of phosphate binder prescription. Understanding the mechanisms for explaining this effect and ruling out possible residual confounding require additional research.

Figure 1

Distribution of facility percentage of patients with phosphate binder (PB) prescription, by DOPPS country and study phase n=23,898 patients (923 facilities) in DOPPS I (1996–2001), DOPPS II (2002–2004), and DOPPS III (2005–2008). Abbreviations: ANZ=Australia and New Zealand, BE=Belgium, CA=Canada, FR=France, GE=Germany, IT=Italy, JPN=Japan, SP=Spain, SW=Sweden.

Figure 2

Percentage of patients with phosphate binder (PB) prescription, by baseline serum phosphorus level. US to International Conversions: serum phosphorus in mg/dL to mmol/L, x0.3229.

Figure 3

Nutritional indicator levels by phosphate binder prescription and serum phosphorus category. The results in Figures 3A to 3E are based on separate mixed linear regression models estimating the mean level of the indicated nutritional indicator within each serum phosphorus concentration depending on whether patients were prescribed a phosphate binder. The associations accounted for facility clustering effects and were adjusted for age, male, race, 13 summary comorbid conditions, region and study phase. BMI=body mass index; PB=phosphate binder, No PB=phosphate binder was not prescribed. US to International Conversions: serum albumin in g/dL to g/L, x10; serum creatinine in mg/dL to µmol/L, x88.4; serum phosphorus in mg/dL to mmol/L, x0.3229.

Figure 4

Odds ratios of the associations of quintile of case-mix adjusted facility percentage of patients who received a prescription of phosphate binders with the odds of nutritional measures below the 25th percentile (n=23,952). US to International Conversions: serum albumin in g/dL to g/L, x10; serum creatinine in mg/dL to µmol/L, x88.4. Ref. = reference group. The results are based on data of 23,898 prevalent hemodialysis patients with ESRD duration at least 90 days from 923 facilities in DOPPS I–III (1996–2008). Case mix adjusted facility percentage of phosphate binder prescription was calculated from mixed linear regression adjusted for age, male gender, ESRD duration, 10 comorbid conditions, serum phosphorus, catheter use, serum calcium (albumin adjusted). Second stage logistic regression models used the same adjustments as in the first stage, phase, and region and accounted for facility clustering.

Figure 5

^*Nutritional factors were normalized PCR, cachexia, serum albumin, creatinine, and body mass index. Adjusted hazard ratios and 95% confidence intervals of the association of all-cause mortality with patient-level phosphate binder prescription by serum phosphorus levels, without adjustment for nutritional indicators (Figure 5A) and with adjustment for nutritional indicators (Figure 5B). The analysis was based on data of 23,898 prevalent MHD patients with ESRD duration at least 90 days from 923 facilities in DOPPS I–III (1996–2008). US to International Conversions: serum phosphorus in mg/dL to mmol/L, x0.3229. Reference group was comprised of patients with serum phosphorus 3.5–5.5 mg/dL and with phosphate binder prescription. All models were adjusted for age, male gender, ESRD duration, residual kidney function, 13 comorbid conditions, serum phosphorus, catheter use, serum calcium (albumin adjusted), stratified by phase and region and accounted for facility clustering.