Disorders of Phosphate: Hyperphosphatemia

Cause

Mechanism

Addition of phosphate to ECF compartment Endogenous

Hemolysis

Release from hemolyzed red blood cells

Rhabdomyolysis

Release from muscle cells

Tumor lysis syndrome

Release from tumor cells due to chemotherapy or cell turnover

High catabolic state

Release from cells

Exogenous

Oral intake or through i.v. route

Ingestion of sodium phosphate solution for bowl preparation, or i.v. Na/K-phosphate in hospitalized patients

Phosphate-containing enemas

Phosphate absorption from enemas (Fleet enema)

Respiratory acidosis

Release from cells

Lactic acidosis

Phosphate utilization during glycolysis, leading to its depletion and subsequent release from cells

Diabetic ketoacidosis

Shift of phosphate from ICF to ECF due to insulin deficiency and metabolic acidosis

Decreased renal excretion

Chronic kidney disease stages 4 and 5

Inability of the kidneys to excrete phosphate load

Acute kidney injury

Inability to excrete phosphate and release from muscle during rhabdomyolysis

Hypoparathyroidism

Increased renal phosphate reabsorption

Pseudohypoparathyroidism

Renal and skeletal resistance to PTH

Familial tumor calcinosis

Mutations in GALNT3, FGF-23, and KLOTHO genes

Drugs

Excess Vitamin D

Increased gastrointestinal (GI) absorption of phosphate

Bisphosphonates

Decreased phosphate excretion, cellular shift

Growth hormone

Increased proximal tubule reabsorption

Liposomal amphotericin B

Contains phosphatidyl choline and phosphatidyl serine

Sodium phosphate (oral)

GI absorption of phosphate

Some Specific Causes of Hyperphosphatemia

Acute Kidney Injury (AKI)

Serum phosphate levels between 5 and 10 mg/dL are common in patients with AKI. However, when AKI is caused by rhabdomyolysis, tumor lysis syndrome, hemolysis, or severe burns, serum levels may be as high as 20 mg/dL. The mechanisms for hyperphosphatemia in AKI include: (1) decreased 1,25(OH)₂D₃ production, (2) skeletal resistance to parathyroid hormone (PTH) action, and (3) metastatic deposition as calcium phosphate in soft tissues.

Chronic Kidney Disease (CKD)

In early stages of CKD (glomerular filteration rate (GFR) 30–60 ml/min), phosphate homeostasis is maintained by progressive increase in phosphate excretion by the surviving nephrons. As a result, FE_PO4 increases to > 35 % (normal 5–7 %).

This increased phosphate excretion is due to high levels of FGF-23, which subsequently inhibits 1,25(OH)₂D₃ production. The low production of 1,25(OH)₂D₃ stimulates the secretion of PTH causing secondary hyperparathyroidism. Both FGF-23 and PTH inhibit reabsorption of phosphate in the proximal tubule and enhance its urinary excretion. Thus, FE_PO4 increases to > 35 % to maintain normal serum phosphate level at the cost of high FGF-23 and PTH.

In CKD stages 4 and 5, the GFR is < 30 %. In these stages of CKD, hyperphosphatemia develops due to decreased excretion and release of phosphate from bone. Also, KLOTHO expression is decreased. This decrease in KLOTHO causes an increase in FGF-23 secretion, which lowers 1,25(OH)₂D₃. This active vitamin D stimulates PTH secretion. Increased PTH induces more FGF-23 levels, which reduces the levels of 1,25(OH)₂D₃ even further. Resistance to FGF-23 occurs. This cycle—of decreased KLOTHO, which results in increased FGF-23, which in turn decreases 1,25(OH)₂D₃ that increases PTH and decreases phosphate excretion—leads to hyperphosphatemia in CKD stages 4 and 5.

Phosphate Binders

The best practice of hyperphosphatemia management in CKD stages 4 and 5 or dialysis patients is restriction of dietary protein and avoidance of phosphate-containing foods
However, the patients do not adhere to the diet because of low palatability. Therefore, control of hyperphosphatemia with intestinal phosphate-binding agents is necessary
Historically aluminum hydroxide was used as a phosphate binder. However, it caused adynamic bone disease with bone pain and fractures, microcytic anemia, and dementia in a substantial number of patients. Therefore, its use has been abandoned
Subsequently, calcium (Ca-containing binders, such as Ca carbonate (Caltrate, Oscal) and Ca acetate (PhosLo)) became available. Although they reduce serum phosphate level, it became apparent that they cause hypercalcemia and vascular calcification. These complications prompted the nephrologists to use non-Ca-containing binders such as sevelamer HCl
Sevelamer HCl (Renagel) has been shown to control phosphate as much as Ca-containing binders without causing hypercalcemia. Studies also have shown that sevelamer slowed the progression of coronary artery calcification, as compared with a Ca-containing binder. In addition, sevelamer lowered low-density lipoprotein (LDL) cholesterol levels in dialysis patients, and survival benefit has also been reported. However, it is expensive and causes hyperchloremic metabolic acidosis. To improve metabolic acidosis, the next generation sevelamer compound has been introduced. It is called sevelamer carbonate (Renvela). It was shown that sevelamer carbonate has the physiologic and biochemical profile as sevelamer HCl except for an increase of serum HCO₃ ⁻ level of approximately 2 mEq/L
Another non-Ca-containing phosphate binder is lanthanum carbonate (Fosrenol), which binds phosphate ionically. Unlike other binders, the potency of lanthanum carbonate as a binder is so great that the pill burden is reduced which may aid the patient’s adherence to therapy. Several concerns have been raised about its long-term safety as it belongs to the family of aluminum in the periodic table. However, studies have shown no adverse effects in dialysis patients who were followed for a period of 6 years. In one study, the incidence of hypercalcemia was 0.4 % in the lanthanum group compared to 20.2 % in the Ca-treated group
Magnesium (Mg) carbonate is less effective than Ca-containing binder, but it less often used in dialysis patients because of the fear of diarrhea and aggravation of hypermagnesemia. However, Mg carbonate may improve vascular calcification. Despite this beneficial effect, the use of Mg carbonate is not preferred at this time. The following table summarizes the effects of phosphate binders on various biochemical parameters relevant to mineral bone disease in CKD stage 5 (on dialysis) patients

Sodium Phosphate Use and Hyperphosphatemia

Oral sodium phosphate (OSP) solution is the most commonly used agent for bowl preparation for colonoscopy. It is given as two 45-mL doses, 9–12 h apart. The 90-mL solution contains 43.2 g of monobasic and 16.2 g of dibasic sodium phosphate. Because of its high phosphate content, hyperphosphatemia is an early-observed electrolyte abnormality. Death due to severe hyperphosphatemia had been reported.

Hypocalcemia develops because of hyperphosphatemia. Hyponatremia is also a common electrolyte abnormality because of excessive water intake, particularly in elderly women who are on thiazide diuretics, antidepressants, or angiotensin-converting enzyme inhibitors. Hypokalemia has also been observed because of K⁺ loss in the GI tract and kidneys. In some patients, hypernatremia has been observed, which is due to high Na⁺ content in OSP solutions.

About 1–4 % of subjects develop acute phosphate nephropathy with normal or near normal renal function. Besides electrolyte abnormalities, AKI also develops after OSP administration

Familial Tumor Calcinosis (FTC)

Familial tumor calcinosis (FTC) is a rare autosomal recessive disorder
This disease has been described in families from Africa and Mediterranean areas
Hyperphosphatemia is related to increased proximal tubular reabsorption of phosphate
The disease is caused by loss-of-function mutations in three genes:

1.

GALNT3 (the uridine-diphosphate-N-acetyl-α-D-galactosamine), which causes aberrant FGF-23 glycosylation,

2.

FGF-23, a missense mutation in the gene inhibiting FGF-23 secretion, and

3.

KLOTHO, causing resistance to FGF-23 action
Clinically, the patients present deposition of calcium phosphate crystals in the hip, elbow, or shoulder
Serum Ca²⁺, PTH, and alkaline phosphatase levels are normal, but 1,25(OH)₂D₃ levels are slightly elevated
Treatment includes low phosphate diet, phosphate binders, and acetazolamide. Surgery may occasionally be needed

Clinical Manifestations

Clinical manifestations are related to hyperphosphatemia-induced hypocalcemia (paresthesia, tetany). In patients with CKD stage 5 and patients on dialysis, hyperphosphatemia is common, and precipitation of calcium phosphate occurs in vascular and muscular systems. Skin deposition is also common. Hyperphosphatemia is an independent risk factor for all-cause or cardiovascular mortality in CKD stages 4 and 5 (see Question 1).

Diagnosis

Step1

Following the history and physical examination, obtain complete metabolic panel, hemoglobin, and iron indices. Obtain PTH and 1,25(OH)₂D₃ levels.

Step 2

Confirm true hyperphosphatemia after ruling out pseudohyperphosphatemia.

Step3

Establish the severity and onset of hyperphosphatemia.

Step 4

Check blood urea nitrogen (BUN) and creatinine. If normal, look for causes (exogenous or endogenous) of acute phosphate load and those that promote renal reabsorption of phosphate.
If BUN and creatinine are elevated, differentiate between AKI and CKD.

Treatment

Acute Hyperphosphatemia

Eliminate the cause. Use phosphate binders as needed. Aluminum hydroxide, although not recommended for chronic use, has been found to be useful in controlling moderate hyperphosphatemia in hospitalized patients with normal renal function. At times, hemodialysis is necessary when hyperphosphatemia is due to rhabdomyolysis or tumor lysis syndrome.