Dietary Phosphate and the Forgotten Kidney Patient: A Critical Need for FDA Regulatory Action.

Careful dietary management that reduces high phosphate intake is recommended to slow the progression of chronic kidney disease (CKD) and prevent complications of CKD and may help reduce chronic disease risks such as incident CKD associated with high phosphate intake in the healthy general population. For patients treated with maintenance dialysis, control of serum phosphorus levels is considered a marker of good care and requires a coordinated plan that limits dietary phosphate intake, uses oral phosphate binders, and provides an adequate dialysis prescription. Even with traditional thrice-weekly hemodialysis or peritoneal dialysis, use of phosphate binders, and a concerted effort to limit dietary phosphate intake, adequately controlled serum phosphorus levels are not possible in all dialysis patients. Efforts to limit phosphate intake are thwarted by the underestimated and unquantified phosphate content of processed foods and some medications due to the hidden presence of phosphate additives or excipients added during processing or drug formulation. Effectively limiting phosphate intake could potentially be achieved through simple US Food and Drug Administration regulatory actions. Mandatory labeling of phosphate content on all packaged foods and drugs would enable identification of healthy low-phosphate foods and medications and permit critically important control of total phosphate intake. Simple changes in regulatory policy and labeling are warranted and would enable better management of dietary intake of phosphate at all stages of kidney disease, as well as potentially reduced health risks in the general population.

Assessment and misassessment of potassium, phosphorus, and protein in the hemodialysis diet.

Diet is a key determinant of several common and serious disease complications in hemodialysis (HD) patients. The recommended balance and variety of foods in the HD diet is designed to limit high potassium and phosphorus foods while maintaining protein adequacy. In this report, we examine the potassium, phosphorus, and protein content of foods, and identify critical challenges, and potential pitfalls when translating nutrient prescriptions into dietary guidelines. Our findings highlight the importance of individualized counseling based on a comprehensive dietary assessment by trained diet professionals, namely renal dietitians, for managing diet-related complications in HD patients.

We Lower Blood Flow for Intradialytic Hypotension.

Whether hemodialysis is performed through a fistula, graft, or a dialysis catheter, it is a common practice to lower the dialyzer blood flow in patients who develop intradialytic hypotension. Lowering dialyzer blood flow is assumed to reduce AV access blood flow and thus increase peripheral vascular resistance tending to raise blood pressure. As a general rule, however, such a reduction in dialyzer blood flow does not lower access flow; only in the case of an intra-access stenosis could this be the case. Reducing access blood flow (in both catheter and AV accesses) did ameliorate a number of potential contributors to intradialytic hypotension when older dialysis technologies were routinely used. A lower dialyzer blood flow reduced acetate influx, decreased extracorporeal blood volume, and decreased the release of vasodilatory products of blood-membrane interactions. However, none of these considerations are applicable to current dialysis practice.

Correcting Acidosis during Hemodialysis: Current Limitations and a Potential Solution.

The deleterious catabolic and pro-inflammatory effects of acidosis in hemodialysis (HD) patients and the importance of its correction for limiting mineral bone disease (MBD) are well known. Although oral base therapy could be a solution for correcting acidosis in HD patients, it increases their already enormous medication load and sodium intake; this approach is not used commonly. Therefore, we need to rely more on correcting acidosis during the HD procedure, which is difficult to achieve, in part, because HD is an intermittent therapy. The currently used fixed dialysate bicarbonate concentrations are associated with pre-HD acidosis and intra-dialytic alkalosis. We suggest that a decreasing dialysate bicarbonate concentration from an initially high concentration be considered as a means of correcting acidosis with limited intra-dialytic alkalosis. Some evidence, as well as theoretical considerations, supports such an approach.

Hyperphosphatemia in Dialysis Patients: Beyond Nonadherence to Diet and Binders.

Hyperphosphatemia in dialysis patients is routinely attributed to nonadherence to diet, prescribed phosphate binders, or both. The role of individual patient variability in other determinants of phosphate control is not widely recognized. In a manner that cannot be explained by dialysis parameters or serum phosphate levels, dialytic removal of phosphate may vary by >400mg per treatment. Similarly, enteral phosphate absorption, unexplained by diet or vitamin D intake, may differ by ≥250mg/d among patients. Binder efficacy also varies among patients, with 2-fold differences reported. One or more elements of this triple threat-varying dialytic removal, phosphate absorption, and phosphate binding-may account for hyperphosphatemia in dialysis patients rather than nonadherence to therapy. Just as the cause(s) of hyperphosphatemia may vary, so too may an individual patient's response to different therapeutic interventions.

A dearth of data: the problem of phosphorus in prescription medications.

A high dietary intake of phosphorus is considered by most to be a significant health threat for dialysis patients. Efforts to include the phosphorus content of foods on the nutrition label in the US have, to date, been fruitless. Another source of phosphorus, largely unrecognized, is prescription medications. These may contain phosphorus as indicated on their package label; the amount is not quantified. We examined the labels of the branded forms of 200 of the most widely prescribed medications in Dialysis Clinic centers in the United States and found that 23 (11.5%) contained phosphorus. A sampling of different doses and manufacturers (generic and branded) of these drugs was analyzed for phosphorus content and found levels as high as 111.5 mg/dose (40 mg paroxetine). Notable were the phosphorus content of a generic 10 mg lisinopril (32.6 mg) and a generic 10 mg amlodipine (40.1 mg). The significant potential for iatrogenic injury accruing from the use of these drugs warrants efforts at remediation. Specific information on the phosphorus content of medications used by dialysis population needs to be made available to the dialysis community.

The Phosphate Content of Prescription Medication: A New Consideration.

BACKGROUND: Phosphate restriction is needed in most dialysis patients. The package inserts from some medications indicate that phosphate may be part of the excipient fraction of drugs. It is unclear whether its amount may be clinically significant since the phosphate content is unquantified. METHODS: We reviewed the package inserts for the branded formulations of the most widely used drugs at a dialysis chain. We measured the phosphate levels in a sample of the branded form of these drugs and some of their generic formulations. We also reviewed the available package inserts of 16 selected generic drug manufacturers for the presence of phosphate in drugs that were phosphate free in their branded formulation. RESULTS: We identified 12 prescription products that contained phosphate, 9 of which contained clinically significant quantities (>10 mg per daily dose) notably in both branded and generic forms of amlodipine, lisinopril, paroxetine and bisoprolol. Phosphate was rarely present in a generic drug when its corresponding branded formulation was phosphate free. CONCLUSION: Commonly prescribed drugs may contain clinically important levels of phosphate.

Twice-weekly and incremental hemodialysis treatment for initiation of kidney replacement therapy.

Mortality is highest in the first months of maintenance hemodialysis (HD) therapy. In many Western countries, patients who transition to kidney replacement therapy usually begin thrice-weekly HD regardless of their level of residual kidney function (RKF). RKF is a major predictor of survival. RKF may decline more rapidly with thrice-weekly HD treatments, is associated with a reduced need for dialytic solute clearance, and is an important factor in the prescription of peritoneal dialysis. In this article, we review the concept of incremental HD, in which weekly dialysis dose, in particular HD treatment frequency, is based on a variety of clinical factors, such as RKF (including urine output > 0.5 L/d), volume status, cardiovascular symptoms, body size, potassium and phosphorus levels, nutritional status, hemoglobin level, comorbid conditions, hospitalizations, and health-related quality of life. These 10 clinical criteria may identify which patients might benefit from beginning maintenance HD therapy twice weekly. Periodic monitoring of these criteria will determine the timing for increasing dialysis dose and frequency. We recognize that twice-weekly HD represents a major paradigm shift for many clinicians and jurisdictions. Therefore, we propose conducting randomized controlled trials of twice-weekly versus thrice-weekly HD to assess the potential of twice-weekly HD to improve survival and health-related quality of life while simultaneously reducing costs, protecting fragile vascular accesses, and optimizing resource use during the first year of hemodialysis therapy. Such incremental and individualized HD therapy may prove to be the most appropriate approach for transitioning to dialytic therapy.

Should dialysate calcium be individualized?

The growing interest in a personalized choice of dialysate calcium concentration faces some important unsolved questions. First, the desired aims to be achieved should be clarified, as different d-Ca concentrations might differentially impact dialysis calcium balance and serum calcium concentration. A second point to be addressed is how to achieve the desired goals; the kinetics of calcium during dialysis treatment are complex. This is not an easy task and probably only an automatic device able to read serum calcium concentration in real-time and adjust d-Ca to it might supply an effective method for individualizing d-Ca. Finally, it is not even clear whether individualizing d-Ca is worth doing; cost-effectiveness studies might give some further insights into this intricate issue.

Iron indices and intravenous ferumoxytol: time to steady-state.

BACKGROUND: The ongoing nature of iron loss in patients receiving hemodialysis makes it difficult to maintain adequate iron stores without supplementation. The effects of ferumoxytol on iron indices have been measured 35 days after baseline, but no study has assessed indices at earlier points in time. OBJECTIVE: To evaluate the time to transferrin saturation (TSAT) and ferritin stabilization, the point at which TSAT and serum ferritin levels can be accurately measured during a 13-treatment period following a loading dose of ferumoxytol. METHODS: Ferumoxytol was administered according to the package insert to 15 adults undergoing hemodialysis. Vital signs were recorded before treatment, 30 and 60 minutes after receiving ferumoxytol, and at the end of treatment to monitor for adverse reactions and hemodynamic instability. Monitoring continued for a 13-treatment period (30 days) after drug administration. Blood was collected throughout the study to measure TSAT, ferritin, hemoglobin (Hb), and C-reactive protein (CRP). RESULTS: TSAT values at 14, 21, and 28 days after drug administration were not significantly different from those at 7 days, signifying that TSAT values stabilized by day 7. Serum ferritin values at day 14 were significantly lower than those 7 days after drug administration (p = 0.028). Although serum ferritin values at days 21 and 28 tended to decrease relative to values at day 14, the differences were not statistically significant. Therefore, it appears that serum ferritin stabilized by day 14 after drug administration. Mean (SD) Hb values at screening and at end of the study were 11.7 (1.0) g/dL and 12.0 (0.9) g/dL, respectively (p = NS). CRP also did not change significantly throughout the study period. CONCLUSIONS: Dialysis patients achieve stable iron indices quickly. TSAT stabilized by day 7 and ferritin stabilized 14 days after a loading dose of ferumoxytol 1 g. Adverse effects were minimal and did not necessitate discontinuation of ferumoxytol.

N-acetylcysteine use for amelioration of aminoglycoside-induced ototoxicity in dialysis patients.

Use of aminoglycoside antibiotics is associated with significant ototoxicity, especially on patients with decreased renal function. The risk of aminoglycoside ototoxicity may approach 60%. Oxidative stress has been suggested as a general mechanism of aminoglycoside ototoxicity and is prevalent in dialysis population. N-acetylcysteine (NAC) is an effective antioxidant and has been safely used in dialysis patients. New experimental and clinical data, explored in this review, provide a good case to recommend NAC administration to all dialysis patients, receiving aminoglycosides.

Phosphorus and potassium content of enhanced meat and poultry products: implications for patients who receive dialysis.

BACKGROUND AND OBJECTIVES: Uncooked meat and poultry products are commonly enhanced by food processors using phosphate salts. The addition of potassium and phosphorus to these foods has been recognized but not quantified. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We measured the phosphorus, potassium, and protein content of 36 uncooked meat and poultry products: Phosphorus using the Association of Analytical Communities (AOAC) official method 984.27, potassium using AOAC official method 985.01, and protein using AOAC official method 990.03. RESULTS: Products that reported the use of additives had an average phosphate-protein ratio 28% higher than additive free products; the content ranged up to almost 100% higher. Potassium content in foods with additives varied widely; additive free products all contained <387 mg/100 g, whereas five of the 25 products with additives contained at least 692 mg/100 g (maximum 930 mg/100 g). Most but not all foods with phosphate and potassium additives reported the additives (unquantified) on the labeling; eight of 25 enhanced products did not list the additives. The results cannot be applied to other products. The composition of the food additives used by food processors may change over time. CONCLUSIONS: Uncooked meat and poultry products that are enhanced may contain additives that increase phosphorus and potassium content by as much as almost two- and three-fold, respectively; this modification may not be discernible from inspection of the food label.

Dietary phosphorus restriction in dialysis patients: potential impact of processed meat, poultry, and fish products as protein sources.

BACKGROUND: Dietary intake of phosphorus is derived largely from protein sources and is a critical determinant of phosphorus balance in patients with chronic kidney disease. Information about the phosphorus content of prepared foods generally is unavailable, but it is believed to contribute significantly to the phosphorus burden of patients with chronic kidney disease. DESIGN: Analysis of dietary components. SETTING: We measured the phosphorus content of 44 food products, including 30 refrigerated or frozen precooked meat, poultry, and fish items, generally national brands. OUTCOMES: Measured and reported phosphorus content of foods. MEASUREMENTS: Phosphorus by using Association of Analytical Communities official method 984.27; protein by using Association of Analytical Communities official method 990.03. RESULTS: We found that the ratio of phosphorus to protein content in these items ranged from 6.1 to 21.5 mg of phosphorus per 1 g of protein. The mean ratio in the 19 food products with a label listing phosphorus as an additive was 14.6 mg/g compared with 9.0 mg/g in the 11 items without listed phosphorus. The phosphorus content of only 1 precooked food product was available in a widely used dietary database. LIMITATIONS: Results cannot be extrapolated to other products. Manufacturers also may alter the phosphorus content of foods at any time. Protein content was not directly measured for all foods. CONCLUSION: Better reporting of phosphorus content of foods by manufacturers could result in improved dietary phosphorus control without risk of protein malnutrition.

Adherence to K/DOQI guidelines for calcium-based phosphate binders in clinical practice.

OBJECTIVE: The Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines for bone metabolism in chronic kidney disease recommend that calcium-based phosphate binders (CBPBs) be used in limited doses and be reduced or withheld when albumin-adjusted serum calcium exceeds target values, or when parathyroid hormone is below the target range. We sought to assess the pattern of CBPB use in a clinical practice setting. DESIGN: This was a retrospective review. PATIENTS: We reviewed 283 patients at three hemodialysis units in New York and New Jersey in which 39 physicians practice. METHODS: Data collected included intact parathyroid hormone levels (from February and May, 2006), blood chemistries (from April and May, 2006), and the use of CBPBs, vitamin D, and cinacalcet. The use of CBPBs was classified as "consistent" or "inconsistent" with the guidelines 1 month after the blood tests of May 2006 (to allow time for dosing adjustments). Because cinacalcet was not available when the K/DOQI guidelines were published, a failure to reduce or stop CBPBs in the presence of elevated calcium levels was still considered to be "consistent" use if cinacalcet was initiated in the appropriate time frame (5 patients). RESULTS: CBPBs were used in 172 of 283 patients (61%). In 10% (17 patients), doses exceeded the 1500-mg limit for calcium. Adjusted serum calcium levels exceeded 2.5 mmol/L (10.2 mg/dL) in 8 cases; CBPBs were not reduced or stopped in any of these. Similarly, CBPBs were reduced in only 2 of 27 patients on vitamin D, with an adjusted serum calcium level of 2.38 to 255 mmol/L (9.5 to 10.2 mg/dL). In all 10 patients with consecutive intact parathyroid hormone values of less than 150 ng/L (150 pg/mL), CBPBs were not discontinued or reduced. CONCLUSIONS: Overall, 50 of 172 patients (29%) receiving CBPBs did so in a manner inconsistent with K/DOQI guidelines. The reasons for this inconsistency are speculative, and may include disagreement with the opinion-based recommendations, insufficient knowledge of the guidelines, or individual patient considerations (including cost, tolerance, and effectiveness).