Association of single and serial measures of serum phosphorus with adverse outcomes in patients on peritoneal dialysis: results from the international PDOPPS.

BACKGROUND: While high serum phosphorus levels have been related to adverse outcomes in hemodialysis patients, further investigation is warranted in persons receiving peritoneal dialysis (PD). METHODS: Longitudinal data (2014-17) from the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS), a prospective cohort study, were used to examine associations of serum phosphorus with all-cause mortality and major adverse cardiovascular events via Cox regression adjusted for confounders. Serum phosphorus levels were parameterized by four methods: (i) baseline serum phosphorus; (ii) mean 6-month serum phosphorus; (iii) number of months with serum phosphorus >4.5 mg/dL; and (iv) mean area-under-the-curve of 6-month serum phosphorus control. RESULTS: The study included 5847 PD patients from seven countries; 9% of patients had baseline serum phosphorus <3.5 mg/dL, 24% had serum phosphorus ≥3.5 to ≤4.5 mg/dL, 30% had serum phosphorus >4.5 to <5.5 mg/dL, 20% had serum phosphorus ≥5.5 to <6.5 mg/dL, and 17% had serum phosphorus ≥6.5 mg/dL. Compared with patients with baseline serum phosphorus ≥3.5 to ≤4.5 mg/dL, the adjusted all-cause mortality hazard ratio (HR) was 1.19 (0.92,1.53) for patients with baseline serum phosphorus ≥5.5 to <6.5 mg/dL and HR was 1.53 (1.14,2.05) for serum phosphorus ≥6.5 mg/dL. Associations between serum phosphorus measurements over 6 months and clinical outcomes were even stronger than for a single measurement. CONCLUSIONS: Serum phosphorus >5.5 mg/dL was highly prevalent (37%) in PD patients, and higher serum phosphorus levels were a strong predictor of morbidity and death, particularly when considering serial phosphorus measurements. This highlights the need for improved treatment strategies in this population. Serial serum phosphorus measurements should be considered when assessing patients' risks of adverse outcomes.

The risk of medically uncontrolled secondary hyperparathyroidism depends on parathyroid hormone levels at haemodialysis initiation.

BACKGROUND: Optimal parathyroid hormone (PTH) control during non-dialysis chronic kidney disease (ND-CKD) might decrease the subsequent risk of parathyroid hyperplasia and uncontrolled secondary hyperparathyroidism (SHPT) on dialysis. However, the evidence for recommending PTH targets and therapeutic strategies is weak for ND-CKD. We evaluated the patient characteristics, treatment patterns and PTH control over the first year of haemodialysis (HD) by PTH prior to HD initiation. METHODS: We studied 5683 incident HD patients from 21 countries in Dialysis Outcomes and Practice Patterns Study Phases 4-6 (2009-18). We stratified by PTH measured immediately prior to HD initiation and reported the monthly prescription prevalence of active vitamin D and calcimimetics over the first year of HD and risk of PTH >600 pg/mL after 9-12 months on HD. RESULTS: The 16% of patients with PTH >600 pg/mL prior to HD initiation were more likely to be prescribed active vitamin D and calcimimetics during the first year of HD. The prevalence of PTH >600 pg/mL 9-12 months after start of HD was greater for patients who initiated HD with PTH >600 (29%) versus 150-300 (7%) pg/mL (adjusted risk difference: 19%; 95% confidence interval : 15%, 23%). The patients with sustained PTH >600 pg/mL after 9-12 months on HD were younger, more likely to be black, and had higher serum phosphorus and estimated glomerular filtration rates at HD initiation. CONCLUSIONS: Increased PTH before HD start predicted a higher PTH level 9-12 months later, despite greater use of active vitamin D and calcimimetics. More targeted PTH control during ND-CKD may influence outcomes during HD, raising the need for PTH target guidelines in these patients.

Replicating Randomized Trial Results with Observational Data Using the Parametric g-Formula: An Application to Intravenous Iron Treatment in Hemodialysis Patients.

BACKGROUND: Reproducibility of clinical and epidemiologic research is important to generalize findings and has increasingly been scrutinized. A recently published randomized trial, PIVOTAL, evaluated high vs low intravenous iron dosing strategies to manage anemia in hemodialysis patients in the UK. Our objective was to assess the reproducibility of the PIVOTAL trial findings using data from a well-established cohort study, the Dialysis Outcomes and Practice Patterns Study (DOPPS). METHODS: To overcome the absence of randomization in the DOPPS, we applied the parametric g-formula, an extension of standardization to longitudinal data. We estimated the effect of a proactive high-dose vs reactive low-dose iron supplementation strategy on all-cause mortality (primary outcome), hemoglobin, two measures of iron concentration (ferritin and TSAT), and erythropoiesis-stimulating agent dose over 12 months of follow-up in 6325 DOPPS patients. RESULTS: Comparing high- vs low-iron dose strategies, the 1-year mortality risk difference was 0.020 (95% CI: 0.008, 0.031) and risk ratio was 1.20 (95% CI: 1.07, 1.33), compared with null 1-year findings in the PIVOTAL trial. Differences in secondary outcomes were directionally consistent but of lesser magnitude than in the PIVOTAL trial. CONCLUSION: Our findings are somewhat consistent with the recent PIVOTAL trial, with discrepancies potentially attributable to model misspecification and differences between the two study populations. In addition to the importance of our results to nephrologists and hence hemodialysis patients, our analysis illustrates the utility of the parametric g-formula for generalizing results and comparing complex and dynamic treatment strategies using observational data.

Impact of longer term phosphorus control on cardiovascular mortality in hemodialysis patients using an area under the curve approach: results from the DOPPS.

BACKGROUND: Serial assessment of phosphorus is currently recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, but its additional value versus a single measurement is uncertain. METHODS: We studied data from 17 414 HD patients in the Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, and calculated the area under the curve (AUC) by multiplying the time spent with serum phosphorus >4.5 mg/dL over a 6-month run-in period by the extent to which this threshold was exceeded. We estimated the association between the monthly average AUC and cardiovascular (CV) mortality using Cox regression. We formally assessed whether AUC was a better predictor of CV mortality than other measures of phosphorus control according to the Akaike information criterion. RESULTS: Compared with the reference group of AUC = 0, the adjusted hazard ratio (HR) of CV mortality was 1.12 [95% confidence interval (CI) 0.90-1.40] for AUC > 0-0.5, 1.26 (95% CI 0.99-1.62) for AUC > 0.5-1, 1.44 (95% CI 1.11-1.86) for AUC > 1-2 and 2.03 (95% CI 1.53-2.69) for AUC > 2. The AUC was predictive of CV mortality within strata of the most recent phosphorus level and had a better model fit than other serial measures of phosphorus control (mean phosphorus, months out of target). CONCLUSIONS: We conclude that worse phosphorus control over a 6-month period was strongly associated with CV mortality. The more phosphorus values do not exceed 4.5 mg/dL the better is survival. Phosphorus AUC is a better predictor of CV death than the single most recent phosphorus level, supporting with real-world data KDIGO's recommendation of serial assessment of phosphorus to guide clinical decisions.

Phosphate binder pill burden, patient-reported non-adherence, and mineral bone disorder markers: Findings from the DOPPS.

Because of multiple comorbidities, hemodialysis (HD) patients are prescribed many oral medications, including phosphate binders (PBs), often resulting in a high "pill burden." Using data from the international Dialysis Outcomes and Practice Patterns Study (DOPPS), we assessed associations between PB pill burden, patient-reported PB non-adherence, and levels of serum phosphorus (SPhos) and parathyroid hormone (PTH) using standard regression analyses. The study included data collected from 5262 HD patients from dialysis units participating in the DOPPS in 12 countries. PB prescription ranged from a mean of 7.4 pills per day in the United States to 3.9 pills per day in France. About half of the patients were prescribed at least 6 PB pills per day, and 13% were prescribed at least 12 PB pills per day. Overall, the proportion of patients who reported skipping PBs at least once in the past month was 45% overall, ranging from 33% in Belgium to 57% in the United States. There was a trend toward greater PB non-adherence and a higher number of prescribed PB pills per day. Non-adherence to PB prescription was associated with high SPhos (>5.5 mg/dL) and PTH (>600 pg/mL). Adherence to PB is a challenge for many HD patients and may be related to the number of PB pills prescribed. Prescription of a simplified PB regimen could improve patient adherence and perhaps improve SPhos and PTH levels.

Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study.

BACKGROUND AND OBJECTIVES: Elevated parathyroid hormone levels may be associated with adverse clinical outcomes in patients on dialysis. After the introduction of practice guidelines suggesting higher parathyroid hormone targets than those previously recommended, changes in parathyroid hormone levels and treatment regimens over time have not been well documented. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from the international Dialysis Outcomes and Practice Patterns Study, trends in parathyroid hormone levels and secondary hyperparathyroidism therapies over the past 15 years and the associations between parathyroid hormone and clinical outcomes are reported; 35,655 participants from the Dialysis Outcomes and Practice Patterns Study phases 1-4 (1996-2011) were included. RESULTS: Median parathyroid hormone increased from phase 1 to phase 4 in all regions except for Japan, where it remained stable. Prescriptions of intravenous vitamin D analogs and cinacalcet increased and parathyroidectomy rates decreased in all regions over time. Compared with 150-300 pg/ml, in adjusted models, all-cause mortality risk was higher for parathyroid hormone=301-450 (hazard ratio, 1.09; 95% confidence interval, 1.01 to 1.18) and >600 pg/ml (hazard ratio, 1.23; 95% confidence interval, 1.12 to 1.34). Parathyroid hormone >600 pg/ml was also associated with higher risk of cardiovascular mortality as well as all-cause and cardiovascular hospitalizations. In a subgroup analysis of 5387 patients not receiving vitamin D analogs or cinacalcet and with no prior parathyroidectomy, very low parathyroid hormone (<50 pg/ml) was associated with mortality (hazard ratio, 1.25; 95% confidence interval, 1.04 to 1.51). CONCLUSIONS: In a large international sample of patients on hemodialysis, parathyroid hormone levels increased in most countries, and secondary hyperparathyroidism treatments changed over time. Very low and very high parathyroid hormone levels were associated with adverse outcomes. In the absence of definitive evidence in support of a specific parathyroid hormone target, there is an urgent need for additional research to inform clinical practice.

Potassium-binding resins: Associations with serum chemistries and interdialytic weight gain in hemodialysis patients.

BACKGROUND: Although potassium-binding sodium-based resins (K resins) have been prescribed to treat hyperkalemia for 50 years, there have been no large studies of their effects among hemodialysis (HD) patients. METHODS: Data from 11,409 patients in the Dialysis Outcomes and Practice Patterns Study in Belgium, Canada, France, Italy, and Sweden (nations where ≥5% of patients were prescribed a sodium- based K resin; seven other countries had <5% use) between 2002 and 2011 were analyzed. Linear mixed models examined associations between K resin use and interdialytic weight gain (IDWG) and serum electrolyte concentrations. Mortality was analyzed using Cox regression. An instrumental variable approach was used to partially account for unmeasured confounders. RESULTS: The K resin prescription rate was 20% overall. As hypothesized, patients prescribed a K resin had greater IDWG and higher serum bicarbonate, phosphorus, and sodium (but not calcium) concentrations. Patients prescribed a K resin had higher serum K levels, but serum K levels were lower in an instrumental variable analysis limiting treatment by indication bias. K resin use was not associated with mortality risk. CONCLUSION: We report the first large study of K resin use and associated laboratory and clinical outcomes in HD patients. The prescription rate of K resins varied dramatically by country and dialysis center. The results suggest that K resin use may effectively lower serum K, although at the expense of somewhat higher phosphatemia and greater IDWG, and had no clear association with mortality. Further study is warranted to elucidate the optimal role for K resins in modern dialysis care.