Less Is More: Parathyroidectomy and Association with Postoperative Hypocalcemia in Dialysis Patients.

BACKGROUND: Parathyroidectomy (PTx) is the most effective treatment for secondary hyperparathyroidism. Literature regarding the effect of surgical approaches on postoperative hypocalcemia is limited and mainly focuses on postoperative calcium levels. This study aims to evaluate the association of subtotal PTx and total PTx with autotransplantation for secondary hyperparathyroidism with postoperative hypocalcemia. STUDY DESIGN: We reviewed all dialysis patients who underwent PTx (n = 143) at our institution from 2010 to 2021. Postoperative hypocalcemia adverse events were defined as postoperative intravenous calcium requirement or 30-day readmission due to hypocalcemia. Postoperative hypocalcemia adverse events, length of stay, and oral calcium requirement at 1-month follow-up were compared between the 2 groups. RESULTS: Of the 143 patients, 119 (83.2%) underwent total PTx with autotransplantation, and 24 (16.8%) underwent subtotal PTx. Patients who underwent subtotal PTx had shorter mean ± SD length of stay (1.8 ± 1.7 vs 3.5 ± 3.2, p = 0.002), were less likely to develop hypocalcemia adverse events (8.3% vs 47.1%, p < 0.001), and required less median elemental calcium supplementation at 1-month follow-up (1,558 vs 3,193 mg, p < 0.001). There was no significant difference in surgical success between the 2 groups (91.7% vs 89.1%, p = 0.706). Stepwise multivariable regression demonstrated that patients who underwent total PTx with autotransplantation were 11.9 times more likely to develop hypocalcemia adverse events (adjusted odds ratio 11.9, 95% CI 2.2 to 66.2, p = 0.004), had 1.24 days longer length of stay (95% CI 0.04 to 2.44, p = 0.044), and required 1,776.1 mg more elemental calcium (95% CI 661.5 to 2,890.6 mg, p = 0.002). CONCLUSIONS: Subtotal parathyroidectomy is associated with less postoperative hypocalcemia and provides similar surgical cure for dialysis patients with secondary hyperparathyroidism.

Effects of phosphorus and calcium to phosphorus consumption ratio on mineral metabolism and cardiometabolic health.

Phosphorus is a common additive used in food processing that is typically consumed in excess of the recommended daily allowance; however, our knowledge of its effects on health, in the context of normal renal function, is limited. Unlike phosphorus, calcium intake is generally less than recommended, and it has been hypothesized that the calcium to phosphorus ratio may be partly responsible for the proposed negative health consequences. Therefore, this study sought to determine the effects of increased phosphorus additive intake, in the context of high calcium consumption, on endocrine markers of mineral metabolism and cardiometabolic health. An outpatient feeding study was performed in which healthy adults were fed a run-in control diet for 2 weeks followed by a phosphorus additive enhanced diet with supplemental calcium to an approximate ratio of 1 (experimental diet) for 2 weeks. Blood and urine samples were collected, and participants had brachial flow-mediated dilatation measured, with analyses comparing follow-up measures to baseline. Two weeks of experimental diet increased serum fibroblast growth factor 23 concentrations but lowered body weight and serum leptin; however, other phosphorus responsive factors such as osteopontin and osteocalcin did not increase. A complementary study in male mice also demonstrated that the regulation of known dietary phosphorus responsive factors was mostly abrogated when dietary calcium was raised in parallel with phosphorus. In conclusion, the study identifies weight, leptin and insulin as responsive to dietary phosphorus and that certain aspects of the systemic phosphorus response are attenuated by a corresponding high calcium intake.

The Role of Vitamin D in CKD Stages 3 to 4: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Deficiency of 25-hydroxyvitamin D (25[OH]D) is common in patients with chronic kidney disease stages 3 and 4 and is associated with poor outcomes. However, the evaluation and management of vitamin D deficiency in nephrology remains controversial. This article reports on the proceedings from a "controversies conference" on vitamin D in chronic kidney disease that was sponsored by the National Kidney Foundation. The report outlines the deliberations of the 3 work groups that participated in the conference. Until newer measurement methods are widely used, the panel agreed that clinicians should classify 25(OH)D "adequacy" as concentrations > 20ng/mL without evidence of counter-regulatory hormone activity (ie, elevated parathyroid hormone). The panel also agreed that 25(OH)D concentrations < 15ng/mL should be treated irrespective of parathyroid hormone level. Patients with 25(OH)D concentrations between 15 and 20ng/mL may not require treatment if there is no evidence of counter-regulatory hormone activity. The panel agreed that nutritional vitamin D (cholecalciferol, ergocalciferol, or calcifediol) should be supplemented before giving activated vitamin D compounds. The compounds need further study evaluating important outcomes that observational studies have linked to low 25(OH)D levels, such as progression to end-stage kidney disease, infections, fracture rates, hospitalizations, and all-cause mortality. We urge further research funding in this field.

Genetic African Ancestry and Markers of Mineral Metabolism in CKD.

BACKGROUND AND OBJECTIVES: Disorders of mineral metabolism are more common in African Americans with CKD than in European Americans with CKD. Previous studies have focused on the differences in mineral metabolism by self-reported race, making it difficult to delineate the importance of environmental compared with biologic factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a cross-sectional analysis of 3013 participants of the Chronic Renal Insufficiency Cohort study with complete data, we compared markers of mineral metabolism (phosphorus, calcium, alkaline phosphatase, parathyroid hormone, fibroblast growth factor 23, and urine calcium and phosphorus excretion) in European Americans versus African Americans and separately, across quartiles of genetic African ancestry in African Americans (n=1490). RESULTS: Compared with European Americans, African Americans had higher blood concentrations of phosphorus, alkaline phosphatase, fibroblast growth factor 23, and parathyroid hormone, lower 24-hour urinary excretion of calcium and phosphorus, and lower urinary fractional excretion of calcium and phosphorus at baseline (P<0.001 for all). Among African Americans, a higher percentage of African ancestry was associated with lower 24-hour urinary excretion of phosphorus (Ptrend<0.01) in unadjusted analyses. In linear regression models adjusted for socio-demographic characteristics, kidney function, serum phosphorus, and dietary phosphorus intake, higher percentage of African ancestry was significantly associated with lower 24-hour urinary phosphorus excretion (each 10% higher African ancestry was associated with 39.6 mg lower 24-hour urinary phosphorus, P<0.001) and fractional excretion of phosphorus (each 10% higher African ancestry was associated with an absolute 1.1% lower fractional excretion of phosphorus, P=0.01). CONCLUSIONS: A higher percentage of African ancestry was independently associated with lower 24-hour urinary phosphorus excretion and lower fractional excretion of phosphorus among African Americans with CKD. These findings suggest that genetic variability might contribute to racial differences in urinary phosphorus excretion in CKD.

High-dose cholecalciferol reduces parathyroid hormone in patients with early chronic kidney disease: a pilot, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Vitamin D deficiency contributes to secondary hyperparathyroidism, which occurs early in chronic kidney disease (CKD). OBJECTIVES: We aimed to determine whether high-dose cholecalciferol supplementation for 1 y in early CKD is sufficient to maintain optimal vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] concentration ≥30 ng/mL) and decrease serum parathyroid hormone (PTH). A secondary aim was to determine the effect of cholecalciferol on blood pressure and serum fibroblast growth factor-23 (FGF23). DESIGN: This was a double-blind, randomized, placebo-controlled trial. Forty-six subjects with early CKD (stages 2-3) were supplemented with oral cholecalciferol (vitamin D group; 50,000 IU/wk for 12 wk followed by 50,000 IU every other week for 40 wk) or a matching placebo for 1 y. RESULTS: By 12 wk, serum 25(OH)D increased in the vitamin D group only [baseline (mean ± SD): 26.7 ± 6.8 to 42.8 ± 16.9 ng/mL; P < 0.05] and remained elevated at 1 y (group-by-time interaction: P < 0.001). PTH decreased from baseline only in the vitamin D group (baseline: 89.1 ± 49.3 to 70.1 ± 24.8 pg/mL; P = 0.01) at 12 wk, but values were not significantly different from baseline at 1 y (75.4 ± 29.5 pg/mL; P = 0.16; group-by-time interaction: P = 0.09). Group differences were more pronounced in participants with secondary hyperparathyroidism (group-by-time interaction: P = 0.004). Blood pressure and FGF23 did not change in either group. CONCLUSIONS: After 1 y, this oral cholecalciferol regimen was safe and sufficient to maintain serum 25(OH)D concentrations and prevent vitamin D insufficiency in early CKD. Furthermore, serum PTH improved after cholecalciferol treatment, particularly in patients who had secondary hyperparathyroidism.

Associations of socioeconomic status and processed food intake with serum phosphorus concentration in community-living adults: the Multi-Ethnic Study of Atherosclerosis (MESA).

OBJECTIVE: Higher serum phosphorus concentrations are associated with cardiovascular disease events and mortality. Low socioeconomic status is linked with higher serum phosphorus concentration, but the reasons are unclear. Poor individuals disproportionately consume inexpensive processed foods commonly enriched with phosphorus-based food preservatives. Accordingly, we hypothesized that excess intake of these foods accounts for a relationship between lower socioeconomic status and higher serum phosphorus concentration. DESIGN: Cross-sectional analysis. SETTING AND PARTICIPANTS: We examined a random cohort of 2,664 participants with available phosphorus measurements in the Multi-Ethnic Study of Atherosclerosis, a community-based sample of individuals free of clinically apparent cardiovascular disease from across the United States. PREDICTOR VARIABLES: Socioeconomic status, the intake of foods commonly enriched with phosphorus-based food additives (processed meats, sodas), and frequency of fast-food consumption. OUTCOMES: Fasting morning serum phosphorus concentrations. RESULTS: In unadjusted analyses, lower income and lower educational achievement categories were associated with modestly higher serum phosphorus concentration (by 0.02 to 0.10 mg/dL, P < .05 for all). These associations were attenuated in models adjusted for demographic and clinical factors, almost entirely due to adjustment for female gender. In multivariable-adjusted analyses, there were no statistically significant associations of processed meat intake or frequency of fast-food consumption with serum phosphorus. In contrast, each serving per day higher soda intake was associated with 0.02 mg/dL lower serum phosphorus concentration (95% confidence interval, -0.04, -0.01). CONCLUSIONS: Greater intake of foods commonly enriched with phosphorus additives was not associated with higher serum phosphorus concentration in a community-living sample with largely preserved kidney function. These results suggest that excess intake of processed and fast foods may not impact fasting serum phosphorus concentrations among individuals without kidney disease.

Fibroblast growth factor 23, cardiovascular disease risk factors, and phosphorus intake in the health professionals follow-up study.

BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 (FGF23) regulates phosphorus and vitamin D metabolism. Elevated FGF23 concentrations are associated with cardiovascular disease events and mortality across a broad range of kidney function, but the predictors of FGF23 concentrations in the general population are unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We examined cross-sectional associations of dietary and nondietary parameters with plasma FGF23 in 1261 participants of the Health Professionals Follow-up Study (mean age 64 ± 9, mean creatinine 0.9 ± 0.2 mg/dl, mean FGF23 64 ± 28 RU/ml). RESULTS: In multivariable-adjusted analyses, each 5-year increase in age was associated with 2.1 RU/ml higher FGF23, each 500-mg increase in phosphorus intake was associated with 3.4 RU/ml higher FGF23, and each 0.1-mg/dl increase in creatinine was associated with 3.4 RU/ml higher FGF23. Participants in the highest category of body mass index had 9.5 RU/ml higher FGF23 than those in the lowest, smokers had 17.1 RU/ml higher FGF23 than nonsmokers, and participants with hypertension had 6.0 RU/ml higher FGF23 than those without hypertension. With respect to biochemical parameters, higher parathyroid hormone, phosphate, uric acid, and triglyceride levels all were associated independently with higher FGF23 in models adjusted for age, creatinine, and other factors. In a subset of 748 participants with available data, some inflammatory biomarkers were associated independently with higher FGF23. CONCLUSIONS: In community-dwelling adults with largely preserved kidney function, established cardiovascular risk factors and higher phosphorus intake were associated with higher FGF23. These results might explain the link between FGF23 and cardiovascular disease.

Impact of poverty on serum phosphate concentrations in the Third National Health and Nutrition Examination Survey.

OBJECTIVE: Increased serum phosphate is associated with adverse health outcomes. High intake of inexpensive processed and fast foods is common in impoverished communities, and is linked with excessive dietary phosphorus intake and elevated serum phosphate concentrations in chronic kidney disease patients. We examined the impact of socioeconomic status on dietary phosphorus intake and serum phosphate concentrations in the general population. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 14,261 adult participants in the Third National Health and Nutrition Examination Survey. PREDICTORS AND OUTCOMES: Poverty to income ratio (PIR; family income indexed to the federal poverty level) was the primary index of socioeconomic status. Serum phosphate was the primary outcome variable. RESULTS: Although estimated phosphorus intake decreased with decreasing quartiles of PIR (P < .001), serum phosphate was inversely associated with PIR (P = .003). The relationship between lower PIR and higher serum phosphate remained significant after adjustment for demographic, laboratory, and dietary intake characteristics (P = .02). Compared with participants in the highest PIR quartile (income >300% of the federal poverty level), participants in the lowest quartile (income < the federal poverty level) had more than twice the odds of hyperphosphatemia (≥ 4.4 mg/dL) in unadjusted and multivariable-adjusted logistic regression analyses (OR, 2.2; 95% CI, 1.5 to 3.2). CONCLUSIONS: Although lower income was associated with decreased estimated phosphorus intake, increasing poverty was independently linked with increased serum phosphate and higher likelihood of hyperphosphatemia. These findings may indicate that conventional dietary instruments underestimate phosphorus intake, especially among impoverished individuals. Further studies are needed to explore these possibilities.

A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease.

The diagnosis of chronic kidney disease (CKD) confers dismal clinical outcomes regardless of whether patients are initiating dialysis and face a median survival of only 2-3 years or they have earlier-stage CKD and face a risk of death that is greater than the risk of progression to dialysis. These poor outcomes are driven by extraordinarily high rates of cardiovascular disease that historically have not responded to risk-factor modification strategies proven to attenuate risk in the general population. Nor have measures aimed at increasing the dose or quality of dialysis made an appreciable dent in mortality. Still worse, interventions that were expected to be beneficial resulted in increased mortality in recent trials. Although this apparent lack of progress in advancing the care of CKD is discouraging, resignation is not an option. On the contrary, with the rising rates of CKD worldwide, there is an urgent need to rigorously test novel therapeutic strategies in randomized trials. The breadth of accumulating evidence linking disordered phosphorus metabolism to adverse outcomes spans in vitro, animal, and human studies, and positions phosphorus management as an attractive target for intervention. Although opinion-based practice guidelines promote phosphorus management strategies that are widely accepted in dialysis patients, there is a clear need to perform randomized controlled trials to prove or disprove the benefits of therapy. Perhaps even more important, the discovery of fibroblast growth factor 23 (FGF23) and its potential as a novel diagnostic to identify disordered phosphorus metabolism at an early, subclinical state has presented the opportunity to develop placebo-controlled randomized trials in pre-dialysis CKD patients with normal serum phosphate levels. This commentary considers the justification and challenges for such trials and presents a 'first-draft' blueprint of distinct trial approaches to initiate a dialog that will ultimately culminate in studies aimed at improving survival across the spectrum of CKD.

Phosphorus binders and survival on hemodialysis.

Although hyperphosphatemia is a risk factor for mortality, there are limited data on whether therapy with phosphorus binders affects survival. We analyzed a prospective cohort study of 10,044 incident hemodialysis patients using Cox proportional hazards analyses to compare 1-yr all-cause mortality among patients who were or were not treated with phosphorus binders. We performed intention-to-treat analyses to compare patients who began treatment with phosphorus binders during the first 90 d after initiating hemodialysis (n = 3555) with those who remained untreated during that period (n = 5055). We also performed as-treated analyses that modeled phosphorus binder treatment as a time-dependent exposure. We compared survival in a subcohort of treated (n = 3186) and untreated (n = 3186) patients matched by their baseline serum phosphate levels and propensity score of receiving phosphorus binders during the first 90 d. One-year mortality was 191 deaths/1000 patient-years at risk. Treatment with phosphorus binders was independently associated with decreased mortality compared with no treatment in the intention-to-treat, as-treated, and matched analyses. The results were independent of baseline and follow-up serum phosphate levels and persisted in analyses that excluded deaths during the first 90 d of hemodialysis. In summary, treatment with phosphorus binders is independently associated with improved survival among incident hemodialysis patients. Although confirmatory studies are needed in the dialysis setting, future placebo-controlled, randomized trials of phosphorus binders might focus on predialysis patients with chronic kidney disease and normal serum phosphate levels.