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The vast majority of patients with chronic kidney disease (CKD) on dialysis have hyperphosphatemia—an abnormally high level of phosphorus (phosphate) in the blood. Hyperphosphatemia is a condition that occurs when the kidneys cannot effectively remove phosphorus from the blood. It is one of the most common conditions managed by renal professionals. Despite dialysis, low phosphorus diet and use of phosphate binders (the only class of medication currently approved to treat this condition), many patients are unable to achieve target phosphorus levels.
Dietary phosphorus absorption occurs primarily through the paracellular pathway
There are 2 mechanisms by which dietary phosphorus absorption occurs: paracellular and transcellular.
• The paracellular pathway is a passive transport mechanism in which phosphate movement occurs along an electrochemical gradient through tight junction complexes between adjacent intestinal epithelial cells. Paracellular phosphate absorption does not saturate. Rather, paracellular phosphate absorption increases in a linear fashion with an increasing phosphate concentration gradient.
• Transcellular transport is active movement via carrier or transporter proteins through intestinal epithelial cells. Transcellular transport mediates phosphate uptake through the intestinal
cell membrane via active transport through the sodium-phosphate co-transporter NaPi2b. Although NaPi2b has been established as a major phosphate transporter in rodents, the transcellular pathway is less physiologically relevant in phosphate absorption in humans because it saturates in the presence of high amounts of phosphorus that are typical in the Western diet.
• We now know that the paracellular pathway is predominant in humans because phosphate is highly permeable through the tight junctions in the small intestine. High amounts of phosphate in the Western diet drive the concentration gradients in the intestine toward paracellular absorption.
New Mechanistic Understanding of Phosphate Absorption and Potential Implications for the Management of Hyperphosphatemia
Targeting the paracellular pathway may be the key to mediating phosphate absorption.
INTESTINE
INTESTINAL LUMEN
BASOLATERAL TRANSPORT
NAPI2B
ENTE
ROCY
TE
TIGH
T JU
NCTI
ON
TIGHT JUNCTION
PARACELLULAR PATHWAY
TRANSCELLULAR PATHWAY
PHOSPHORUS
BLOOD STREAM
Current management of hyperphosphatemia
The current approach to managing hyperphosphatemia includes dialysis, a low phosphorus diet and phosphate binders.
Dietary restriction is typically inadequate for patients with advanced CKD and those on dialysis. These patients often require phosphate binders.
• Approximately 80% of patients with CKD on dialysis are prescribed phosphate binders.
• As a class, phosphate binders act by binding dietary phosphate in the GI tract to limit the amount of phosphorus the body absorbs from food.
• Phosphate binders do not target or directly act on phosphate absorption pathways.
Use of phosphate binders, along with dialysis and a low-phosphorous diet, can improve phosphorus levels. Yet, there are some patients that are still unable to achieve and maintain recommended phosphate levels of 3.5–5.5 mg/dL or 1.13–1.78 mmol/L (KDOQI 2003), let alone the more recent KDIGO recommendation to lower phosphorus to normal (e.g. 2.5–4.5 mg/dL or 0.81–1.45 mmol/L).
• Approximately 40% of CKD patients on dialysis have phosphorus levels >5.5 mg/dL (1.78 mmol/L) in a given month.
• Approximately 80% of CKD patients on dialysis are unable to consistently maintain phosphorus levels ≤5.5 mg/dL (1.78 mmol/L) over a 6-month period.
Understanding the challenges with the binding mechanism
Phosphate binders have a short duration of action and limited binding capacity per pill. They require frequent dosing and often, many large pills in order to bind enough phosphorus.
Large pills that may be hard to swallow
Average of 10.8 pills per day
Dosing with meals and snacks
Patients with hyperphosphatemia on dialysis experience some of the highest reported daily pill burdens of any chronic disease state, resulting in lower health-related quality of life (HR-QOL). According to one study, the greater number of pills does not appear to improve serum phosphorus levels and may further decrease HR-QOL. This suggests that increasing the number of prescribed phosphate binders may not be an appropriate response to hyperphosphatemia in many patients.
SMALL INTESTINE
FECAL EXCRETION
BOUND PHOSPHATE
PHOSPHATE BINDER
PHOSPHATE
Cardiovascular disease
Elevated serum phosphorus levels are associated with increased risk of cardiovascular morbidity and mortality
KidneyFund.org
Novel targeted therapies aim to inhibit phosphorus absorption through the paracellular pathway. Blocking phosphorus absorption through the paracellular pathway may help improve our ability to consistently and effectively achieve established clinical practice guideline phosphorus goals, while reducing pill size, number of required pills and dosing frequency.
As phosphorus levels increase, relative risk of cardiovascular hospitalization and death increase dramatically.
Cardiovascular calcification
Metabolic bone disease
Secondary hyperparathyroidism
Maintaining normal phosphate balance may reduce risk of severe consequences associated with hyperphosphatemia, including:
n REFERENCE RANGE n ELEVATED SERUM PHOSPHORUS LEVEL
RELATIVE RISK OF CARDIOVASCULAR HOSPITALIZATION BASED ON SERUM PHOSPHORUS LEVEL
RELATIVE RISK OF DEATH BASED ON SERUM PHOSPHORUS LEVEL
0.2
0
4.0–5.0
SERUM PHOSPHORUS LEVEL, mg/dL
RELA
TIVE
RIS
K OF
HOS
PITA
LIZA
TION
RELA
TIVE
RIS
K OF
DEA
TH
SERUM PHOSPHORUS LEVEL, mg/dL
≥9.0
0.4
0.6
0.8
1.0
1.2
.5
1.5
1.4
1.0
2.0
0.0
4.0–5.0 5.0–6.0
1.10
6.0–7.0
1.15
7.0–8.0
1.29
8.0–9.0
1.28
≥9.0
1.38
5.0–6.0
1.07
6.0–7.0
1.25
7.0–8.0
1.43
8.0–9.0
1.67
2.02
38% INCREASED RELATIVE RISK OF HOSPITALIZATION
102% INCREASED RELATIVE RISK OF MORTALITY
US-DA-0023 03/21