Hyperphosphatemia is an inevitable consequence of end-stage chronic kidney disease and is present in the majority of dialysis patients. Hyperphosphatemia is observationally and statistically ...associated with increased cardiovascular mortality among dialysis patients. Dietary restriction of phosphate and current dialysis modalities are not sufficiently effective to maintain serum phosphate levels within the recommended range, so the majority of dialysis patients require oral phosphate binders. However, the benefits of achieving the recommended range have yet to be shown prospectively. Unfortunately, conventional phosphate binders are not reliably effective and are associated with a range of limitations and side effects. Aluminum-containing agents are highly efficient but no longer widely used because of proven toxicity. Calcium-based salts are inexpensive, effective, and most widely used, but there is now concern about their association with hypercalcemia and vascular calcification. Sevelamer hydrochloride is associated with fewer adverse effects, but a large pill burden and high cost are limiting factors to its wider use. Lanthanum carbonate is another non-aluminum, calcium-free phosphate binder. Preclinical and clinical studies have shown a good safety profile, and it appears to be well tolerated and effective in reducing phosphate levels in dialysis patients; however, it is similarly expensive. Data on its safety profile over 6 years of treatment are now published. Achievement of opinion-based guidelines appears to have become an end in itself. Dialysis patient outcomes are worse than outcomes for many types of cancer, yet prospective, outcome-based randomized controlled trials are not being undertaken for reasons that are difficult to explain.
Despite 10 years of post‐marketing safety monitoring of the phosphate binder lanthanum carbonate, concerns about aluminium‐like accumulation and toxicity persist. Here, we present a concise overview ...of the safety profile of lanthanum carbonate and interim results from a 5‐year observational database study (SPD405‐404; ClinicalTrials.gov identifier: NCT00567723). The pharmacokinetic paradigms of lanthanum and aluminium are different in that lanthanum is minimally absorbed and eliminated via the hepatobiliary pathway, whereas aluminium shows appreciable absorption and is eliminated by the kidneys. Randomised prospective studies of paired bone biopsies revealed no evidence of accumulation or toxicity in patients treated with lanthanum carbonate. Patients treated with lanthanum carbonate for up to 6 years showed no clinically relevant changes in liver enzyme or bilirubin levels. Lanthanum does not cross the intact blood–brain barrier. The most common adverse effects are mild/moderate nausea, diarrhoea and flatulence. An interim Kaplan–Meier analysis of SPD405‐404 data from the United States Renal Data System revealed that the median 5‐year survival was 51.6 months (95% CI: 49.1, 54.2) in patients who received lanthanum carbonate (test group), 48.9 months (95% CI: 47.3, 50.5) in patients treated with other phosphate binders (concomitant therapy control group) and 40.3 months (95% CI: 38.9, 41.5) in patients before the availability of lanthanum carbonate (historical control group). Bone fracture rates were 5.9%, 6.7% and 6.4%, respectively. After more than 850 000 person‐years of worldwide patient exposure, there is no evidence that lanthanum carbonate is associated with adverse safety outcomes in patients with end‐stage renal disease.
Summary at a Glance
Lanthanum carbonate is a non‐calcium‐based phosphate binder, and although it is a metal cation, its effects are not comparable with those of aluminium. This article discusses safety data of lanthanum with clinical studies showing no significant toxic effects after 10 years of follow‐up.
Sucroferric oxyhydroxide is a new calcium-free polynuclear iron(III)-oxyhydroxide compound that binds phosphate by ligand exchange. Floege et al. report equivalent phosphate control with a mean dose ...of three pills daily compared with eight of sevelamer, and suggest that a reduced pill burden may represent an aid to improved adherence. However, there is still no prospective interventional study to demonstrate that reduction in serum phosphate improves patient outcomes for any oral phosphate binder.
Despite 10years of post-marketing safety monitoring of the phosphate binder lanthanum carbonate, concerns about aluminium-like accumulation and toxicity persist. Here, we present a concise overview ...of the safety profile of lanthanum carbonate and interim results from a 5-year observational database study (SPD405-404; ClinicalTrials.gov identifier: NCT00567723). The pharmacokinetic paradigms of lanthanum and aluminium are different in that lanthanum is minimally absorbed and eliminated via the hepatobiliary pathway, whereas aluminium shows appreciable absorption and is eliminated by the kidneys. Randomised prospective studies of paired bone biopsies revealed no evidence of accumulation or toxicity in patients treated with lanthanum carbonate. Patients treated with lanthanum carbonate for up to 6years showed no clinically relevant changes in liver enzyme or bilirubin levels. Lanthanum does not cross the intact blood-brain barrier. The most common adverse effects are mild/moderate nausea, diarrhoea and flatulence. An interim Kaplan-Meier analysis of SPD405-404 data from the United States Renal Data System revealed that the median 5-year survival was 51.6months (95% CI: 49.1, 54.2) in patients who received lanthanum carbonate (test group), 48.9months (95% CI: 47.3, 50.5) in patients treated with other phosphate binders (concomitant therapy control group) and 40.3months (95% CI: 38.9, 41.5) in patients before the availability of lanthanum carbonate (historical control group). Bone fracture rates were 5.9%, 6.7% and 6.4%, respectively. After more than 850000 person-years of worldwide patient exposure, there is no evidence that lanthanum carbonate is associated with adverse safety outcomes in patients with end-stage renal disease. Lanthanum carbonate is a non-calcium-based phosphate binder, and although it is a metal cation, its effects are not comparable with those of aluminium. This article discusses safety data of lanthanum with clinical studies showing no significant toxic effects after 10years of follow-up.
Hyperphosphataemia in 2019: have we made progress? Hutchison, Alastair J; Wald, Ron; Hiemstra, Thomas F
Current opinion in nephrology and hypertension,
2019-September, 2019-09-00, 20190901, Volume:
28, Issue:
5
Journal Article
Peer reviewed
PURPOSE OF REVIEWThis review describes recent developments in the management of serum phosphate in dialysis patients, with a focus on the development of recent trials which randomize patients to ...different levels of control.
RECENT FINDINGSWe review the uncertainties around clinical benefits of serum phosphate control and alternative approaches to current management, as well as a multinational attempt to conduct randomized controlled trials in this area. We discuss novel methods of limiting oral phosphate absorption.
SUMMARYAlthough numerous guidelines and target ranges for serum phosphate management exist, they are largely based on observational data and there is no definitive evidence that good control improves the length or quality of life of dialysis patients. New phosphate binders continue to appear on the market with increasing financial cost but without additional meaningful outcome data. Two recently published trials have demonstrated the feasibility of a large-scale study of differing phosphate levels to test the hypothesis that reduction of serum phosphate is beneficial to dialysis patients. Restriction of oral phosphate intake should not be overlooked.
Patients with chronic kidney disease have a high burden of cardiovascular morbidity and mortality. The vast majority of patients with chronic kidney disease do not progress to end stage renal ...failure, but do have a significantly higher incidence of all cardiovascular co-morbidities. Traditional cardiovascular risk factors only partially account for this increased incidence of cardiovascular disease. In patients with kidney disease the basic biology underlying cardiovascular disease may be similar to that in patients without kidney disease, but it would seem many more risk factors are involved as a consequence of renal dysfunction. Although emphasis is placed on delaying the progression of chronic kidney disease, it must be appreciated that for many patients it is vital to address their cardiovascular risk factors at an early stage to prevent premature cardiovascular death. This review examines available epidemiological evidence, discusses common cardiovascular risk factors in patients with chronic kidney disease, and suggests possible treatment strategies. Potential areas for important research are also described.
AKI is common among hospital in-patients and places a huge financial burden on the UK National Health Service, causing increased length of hospital stay and use of critical care services, with ...increased requirement for complex interventions including dialysis. This may account for up to 0.6% of the total Health Service budget. To investigate the incidence and consequences of AKI, all unselected emergency admissions to a large acute UK single centre University Teaching Hospital over two separate 7 day periods were reviewed.
A retrospective audit of 745 case records was undertaken (54.6% male) including laboratory data post-discharge or death, with classification of AKI by RIFLE, AKIN and AKIB criteria. Participants were included whether admitted via their general practitioners, the emergency department, or as tertiary specialty transfers. Outcome measures were presence or absence of AKI recorded using each of the three AKI criteria, length of hospital stay (LOS), admission to, and LOS in critical care, and mortality. The most severe grade of AKI only, at any time during the admission, was recorded to prevent double counting. Renal outcome was determined by requirement for renal replacement therapy (RRT), and whether those receiving RRT remained dialysis dependent or not.
AKI incidence was 25.4% overall. With approximately one third present on admission and two thirds developing post admission. The AKI group had LOS almost three times higher than the non AKI group (10 vs 4 days). Requirement for critical care beds was 8.1% in the AKI group compared to 1.7% in non AKI group. Overall mortality was 5.5%, with the AKI group at 11.4% versus 3.3% in the non AKI group.
AKI in acute unselected hospital admissions is more common than existing literature suggests, affecting 25% of unselected admissions. In many this is relatively mild and may resolve spontaneously, but is associated with increased LOS, likelihood of admission to critical care, and risk of death. If targeted effective interventions can be developed it seems likely that substantial clinical benefits for the patient, as well as financial and structural benefits for the healthcare organisation may accrue.
The ideal serum level of phosphate in patients on dialysis, and the benefits of controlling levels of phosphate in serum remain unclear despite observational studies that associate phosphate levels ...with mortality. In the absence of robust data from trials, current guidelines are necessarily based on opinion. Oral phosphate binders are required by the majority of patients on dialysis, and all of these binders can control serum levels of phosphate to similar degrees. Patient preference and adherence to prescribed therapy is at least as important as the efficacy of the prescribed binder. Avoidance of calcium-containing binders has become accepted practice where the alternatives are affordable, but incontrovertible evidence in favor of this approach is lacking. Use of sevelamer and lanthanum avoids calcium loading, but at considerable financial cost and with no reliable patient outcome data to prove their value. Additional approaches to aid control of serum levels of phosphate include blockade of gastrointestinal phosphate absorption and possibly binding of salivary phosphate. Importantly, the role of phosphate control in determining patient outcomes must be quantified, which is likely to require a large randomized, controlled study of two levels of phosphate control. Without such a study we will continue to rely on observational data with all its uncertainties and potential to mislead.
Hyperphosphataemia in dialysis subjects is associated with increased mortality. However cause and effect has not been proven, and the ideal phosphate target range is unknown despite KDOQI's call for ...studies over 12 years ago. The design and conduct of a randomized controlled trial is challenging because maintaining two groups within differing target ranges of serum phosphate has not been achieved over a long follow-up of 1 year, in a trial setting, before. The SPIRiT study examines the subject acceptance, recruitment and retention rates for such a study in which subjects were randomised to two distinct serum phosphate concentrations, then titrated and maintained over 12 months.
A two center trial of 104 hemodialysis subjects randomized to lower range LRG 0.8-1.4 mmol/L or 2.5-4.3 mg/dL) and higher range (HRG 1.8-2.4 mmol/L or 5.6-7.4 mg/dL) serum phosphate groups. Two months' titration and ten months' maintenance phase. Interventions were non-calcium phosphate binders, self-help questionnaires, with blood tests at specified time intervals.
Thirteen percent of the eligible dialysis population were successfully recruited. A mean separation by serum phosphate of 1.1 mg/dL was achieved and maintained between the groups over 10 months. Drop-out rate was 27% with mortality 10%. Nine subjects in the HRG (17.6%) and two subjects in the LRG (3.8%) died during the study, however the study was not powered to detect significant differences in outcomes.
Randomizing dialysis subjects to separate treatment targets for serum phosphate can achieve a clinically significant sustained separation over 12 months. A large scale longer term study is required to examine outcomes including mortality.
The trial registration number is ISRCTN24741445 - Date of registration 16th January, retrospectively registered.
Background. Despite recognized risks associated with hyperphosphataemia in patients with chronic kidney disease (CKD) Stage 5 on dialysis, the achievement of target levels of serum phosphate is poor. ...It is likely that this is partly due to poor adherence by patients to their phosphate-binder treatment regimens, which often comprise large daily tablet burdens. Methods. In this multicentre, open-label trial, patients on a stable dialysis regimen were screened while receiving phosphate-binder therapy, then entered into a washout phase. Patients with serum phosphate > 1.78 mmol/L after washout entered into the main 12-week treatment phase (N = 367), during which they were treated to target Kidney Disease Outcomes Quality Initiative (K/DOQI): 1.13–1.78 mmol/L; 3.5–5.5 mg/dL) with lanthanum carbonate monotherapy. Efficacy variables included serum phosphate levels and the percentage of patients with serum phosphate control. Safety and tolerability assessments were also conducted. Results. Mean serum phosphate levels were significantly reduced following 12 weeks of lanthanum carbonate monotherapy versus previous phosphate-binder therapy. The mean number of phosphate-binder tablets being taken per day at screening was 7.6, but during treatment with lanthanum carbonate, most patients were taking doses of up to 3000 mg/day, achievable with 3 × 1000 mg tablets per day (maximum of 6). Conclusion. These findings suggest that lanthanum carbonate monotherapy offers effective control of serum phosphate and, due to a low tablet burden, may help to simplify the management of hyperphosphataemia in patients with CKD Stage 5.
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