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New Mechanistic Understanding of Phosphate Absorption and Potential Implications for the Management of Hyperphosphatemia

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New Mechanistic Understanding of Phosphate Absorption and Potential Implications for the Management of Hyperphosphatemia New Mechanistic Understanding of Phosphate Absorption and Potential Implications for the Management of Hyperphosphatemia 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 PARACELLULAR TRANSCELLULAR PATHWAY PATHWAY phosphorus absorption occurs: paracellular and transcellular. INTESTINAL LUMEN • The paracellular pathway is a NAPI2B passive transport mechanism in which phosphate movement occurs along an electrochemical gradient through tight TIGHT JUNCTIONTIGHT junction complexes between adjacent ENTEROCYTE intestinal epithelial cells. Paracellular phosphate absorption does not saturate. TIGHT JUNCTIONTIGHT Rather, paracellular phosphate absorption INTESTINE increases in a linear fashion with an increasing phosphate concentration gradient. BASOLATERAL • Transcellular transport is active BLOOD TRANSPORT movement via carrier or transporter STREAM 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. Targeting the paracellular pathway may be the key to mediating phosphate absorption. Current management of hyperphosphatemia The current approach to managing hyperphosphatemia includes dialysis, a low phosphorus diet and phosphate binders. SMALL INTESTINE 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 PHOSPHATE phosphorus the body absorbs from food. • Phosphate binders do not target or directly act on PHOSPHATE phosphate absorption pathways. BINDER Use of phosphate binders, along with dialysis and a low-phosphorous diet, can improve phosphorus levels. BOUND Yet, there are some patients that are still unable to PHOSPHATE 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 FECAL month. EXCRETION • 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 Large pills that may Average of 10.8 pills Dosing with duration of action be hard to swallow per day meals and snacks and limited binding capacity per pill. Patients with hyperphosphatemia on dialysis experience some of the highest They require reported daily pill burdens of any chronic disease state, resulting in lower health- frequent dosing and related quality of life (HR-QOL). According to one study, the greater number often, many large of pills does not appear to improve serum phosphorus levels and may further decrease HR-QOL. This suggests that increasing the number of prescribed pills in order to bind phosphate binders may not be an appropriate response to hyperphosphatemia in enough phosphorus. many patients. Elevated serum phosphorus levels are associated with increased risk of cardiovascular morbidity and mortality Maintaining normal phosphate As phosphorus levels increase, relative risk of cardiovascular balance may reduce risk of severe hospitalization and death increase dramatically. consequences associated with hyperphosphatemia, including: RELATIVE RISK OF CARDIOVASCULAR HOSPITALIZATION BASED ON SERUM PHOSPHORUS LEVEL INCREASED RELATIVE RISK 1.4 38% OF HOSPITALIZATION 1.2 1.29 1.38 Cardiovascular 1.28 1.0 1.10 1.15 calcification 0.8 0.6 0.4 0.2 RELATIVE RISK OF HOSPITALIZATION OF RISK RELATIVE 0.0 Cardiovascular 4.0–5.0 5.0–6.0 6.0–7.0 7.0–8.0 8.0–9.0 ≥9.0 disease SERUM PHOSPHORUS LEVEL, mg/dL RELATIVE RISK OF DEATH BASED ON SERUM PHOSPHORUS LEVEL 2.0 INCREASED RELATIVE 102% RISK OF MORTALITY 2.02 Metabolic bone 1.5 1.67 disease 1.43 1.25 1.0 1.07 RELATIVE RISK OF DEATH OF RISK RELATIVE .5 0 4.0–5.0 5.0–6.0 6.0–7.0 7.0–8.0 8.0–9.0 ≥9.0 Secondary SERUM PHOSPHORUS LEVEL, mg/dL hyperparathyroidism n REFERENCE RANGE n ELEVATED SERUM PHOSPHORUS LEVEL 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. KidneyFund.org US-DA-0023 03/21.
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