Both in hospitalized and clinic patients, hypophosphatemia is a common electrolyte disorder. Which one of the following drugs does NOT cause hypophosphatemia ?

Corticosteroids cause a decrease in intestinal absorption of PO ₄ and they also promote renal excretion of phosphate (PO ₄ ). Both these processes account for hypophosphatemia. Intravenous glucose or carbohydrate intake transports PO ₄ into the cell, causing hypophosphatemia.

Bisphosphonates , as a class, cause an increase in renal tubular reabsorption without significant excretion of PO ₄ , resulting in hyperphosphatemia. Therefore, option E is incorrect.

Which one of the following metabolic abnormalities is NOT related to severe hypophosphatemia (<1.0 mg/dL)?

Moderate hypophosphatemia is defined as serum PO ₄ level between 1.2 and 1.8 mg/dL, whereas severe hypophosphatemia constitutes serum PO ₄ level <1.0 mg/dL. Metabolic complications are clearly evident with severe hypophosphatemia. Muscle requires adequate amounts of ATP and creatine PO ₄ for its actions. PO ₄ depletion leads to low intracellular PO ₄ and an increase in Na ⁺, Cl ⁻ , and water, resulting in myopathy, weakness, and muscle injury. Rhabdomyolysis is a complication of low serum PO ₄ , which may present with acute kidney injury (AKI).

Metabolic acidosis due to severe hypophosphatemia is related to a decrease in net acid excretion (titratable acid and ammonium), resulting in retention of H ⁺. Also, hypophosphatemia decreases renal tubular reabsorption of HCO ₃ ⁻ . Thus, metabolic acidosis in severe hypophosphatemia is due to the above mechanisms.

Increased susceptibility to infection is related to leukocyte dysfunction caused by decreased ATP production.

Severe hypophosphatemia is associated with cardiomyopathy and low cardiac output, which are due to low myocyte concentration of PO ₄ , ATP, and creatine PO ₄ . Metabolic alkalosis is not a complication of severe hypophosphatemia, and thus option E is incorrect.

A 67-year-old thin woman with colon cancer and colostomy is admitted for poor oral intake, weakness, dizziness, and weight loss. She is receiving chemotherapy. The oncologist starts her on total parenteral nutrition with 2000 calories a day. Serum chemistry is normal, including Ca²⁺, Mg²⁺, and PO₄. Two days later, the patient complains of worsening weakness. Repeat lab shows: K⁺ 3.1 mEq/L, Ca²⁺ 7.8 mg/dL, Mg²⁺ 1.8 mEq/L, PO₄ 1.1 mg/dL. Which one of the following describes the BEST for the above lab abnormalities?

Refeeding syndrome ( RFS ) occurs in malnourished individuals following administration of oral, enteral, or parenteral nutrition. It is commonly seen in hospitalized patients, who are malnourished due to poor oral intake, starvation, anorexia nervosa, or systemic illness such as malignancy. Hypophosphatemia is the most commonly observed electrolyte abnormality induced by RFS. Many mechanisms contribute to hypophosphatemia: (1) a high carbohydrate meal causes intracellular shift of PO ₄ ; (2) increased consumption of PO ₄ during glycolysis; (3) depleted body stores of PO ₄ during poor oral intake of food; and (4) consumption of PO ₄ for formation of ATP and increased production of products such as creatine kinase and 2,3-diphosphoglycerate.

Sudden deaths also have been reported following RFS with high caloric diet due to hypophosphatemia. Almost all organ systems fail. To prevent hypophosphatemia, the feeding should consist of low calories with gradual increase to maintain the target caloric intake. Along with hypophosphatemia other electrolyte abnormalities such as hypokalemia and hypomagnesemia also occur due to high glucose. Supplementation of K ⁺, Mg ²⁺ , and PO ₄ along with nutrition will prevent RFS.

Regarding treatment of hypophosphatemia , which one of the following statements is FALSE?

The treatment of hypophosphatemia depends on its signs and symptoms and the degree (severity) of PO ₄ deficiency. Asymptomatic patients should be treated with oral preparations (Table 5.1 ). Serum PO ₄ levels can rise by as much as 1.5 mg/dL 60–120 min after oral intake of 1 g of elemental PO ₄ . In children and malnourished individuals, skim milk is an adequate repletion of PO ₄ because each liter contains 1 g of elemental PO ₄ and better tolerated than regular milk.

IV administration of PO ₄ is reserved for patients with severe hypophosphatemia (<1 mg/dL) with symptoms and those receiving hyperalimentation and critically ill patients. In hyperalimentation-induced hypophosphatemic (<1.5 mg/dL) patients in an intensive care setting, an infusion of 1 mmol/kg (1 mmol = 3.1 mg/dL) phosphorus diluted in 100 or 250 mL of either normal saline or D5W at a rate not to exceed 7.5 mmol/h was sufficient to normalize serum PO ₄ in 48 h.

In surgical intensive care patients, Taylor et al. used a weight- and serum PO ₄ -based protocol for IV PO ₄ repletion (Table 5.2 ). Either sodium PO ₄ or potassium PO ₄ , depending on serum K ⁺ levels, was dissolved in 250 mL of D5W and infused over 6 h as a single dose to severely hypophosphatemic (<1 mg/dL) or moderately hypophosphatemic (1.5–1.8 mg/dL) patients. Successful repletion occurred in 63 % of severe and 78 % of moderate hypophosphatemic patients. Thus, severe hypophosphatemic patients may benefit from more aggressive and tailored IV phosphorous regimens.

Transcellular distribution of PO ₄ from ECF to ICF occurs after a carbohydrate load or glucose infusion, which does not require immediate treatment. Serum PO ₄ level >1 mg/dL may not cause severe metabolic complications, and vigorous IV treatment is not necessary. Thus, option E is false. Be aware of complications such as hypocalcemia, hyperphosphatemia, AKI, and hyperkalemia with potassium PO ₄ that are common with vigorous IV administration.

High serum phosphate (PO₄) level is an independent risk factor for cardiovascular morbidity and mortality in CKD 4 and dialysis patients. Which one of the following factors regarding hyperphosphatemia is FALSE?

Studies have shown that hyperphosphatemia can stimulate PTH secretion directly and indirectly. Regulation of PTH secretion by PO ₄ alone was demonstrated in CKD animals with PO ₄ -restricted diet. In these studies, low PO ₄ diet reduced PTH secretion independent of serum Ca ²⁺ and 1,25(OH) ₂ D ₃ levels. These results were reproduced in CKD patients. It appears that the parathyroid gland responds to changes in serum PO ₄ at the level of secretion, gene expression, and cell proliferation through phospholipase A ₂ -activated signal transduction mechanism. It was also shown that hyperphosphatemia may promote cell proliferation and growth of parathyroid via TGF-α and epidermal growth factor.

Hyperphosphatemia has also been shown to reduce the expression of CaSR, thereby decreasing the ability of the parathyroid gland to respond to changes in ionized Ca ²⁺ . Restriction of PO ₄ in diet restores the expression and sensitivity of the receptor.

Hyperphosphatemia stimulates PTH secretion indirectly by lowering Ca via inhibition of 1-α hydroxylase in the kidney, thereby reducing the conversion of 25(OH) ₂ to 1,25(OH) ₂ D ₃ . Also, several studies have shown that hyperphosphatemia alone can cause vascular calcification in CKD patients without the combination of hypercalcemia and vitamin D. Thus, option E is false.

A 68-year-old woman with diabetes mellitus is admitted for mucormycosis of the left ear. She is started on high doses of liposomal amphotericin B (L-AMP). One week later, her serum PO₄ increased from 4.2 to 10.8 mg/dL, and repeat PO₄ is 11.2 mg/dL. Her creatinine, Ca ²⁺ , uric acid, and creatine kinase (CK) are normal. Which one of the following is the MOST likely cause of her hyperphosphatemia ?

The sudden increase in serum PO ₄ in a patient who is not on PO ₄ replacement is suspicious of laboratory error. Repeat analysis confirmed hyperphosphatemia. The patient was asymptomatic. Rhabdomyolysis was ruled out based on normal creatinine, Ca ²⁺ , uric acid, and CK levels. ABG showed chronic respiratory alkalosis, which causes hypophosphatemia by transcellular distribution of PO ₄ . Tumor calcinosis is a rare genetic disorder that is characterized by hyperphosphatemia, elevated levels of 1,25(OH) ₂ D ₃ and decreased renal excretion of PO ₄ . Thus, options A, B, and D are incorrect.

L-AMP is an antifungal preparation that contains amphotericin B embedded in a phospholipid bilayer of unilamellar liposomes. Measurement of PO ₄ from L-AMP-treated patients with a specific autoanalyzer called Synchron LX20 (Beckman Coulter) gives a high level with normal Ca ²⁺ levels. This autoanalyzer measures the PO ₄ at low pH (<1.0). At this acid pH, organic PO ₄ contained in the lipid bilayer of the liposomes is hydrolyzed and gives falsely high levels of serum PO ₄ . Thus, high doses of L-AMP will give pseudohyperphosphatemia when measured with LX20 system. Other autoanalyzers measure the reaction at high pH, and do not give pseudohyperphosphatemia. Thus, option C is correct.

Other conditions such as hyperbilirubinemia, paraproteinemia, and hyperlipidemia also cause pseudohyperphosphatemia, which is due to assay interference.

With regard to phosphate (PO ₄ ) binders , which one of the following statements is FALSE?

The best practice of hyperphosphatemia management in dialysis patients is restriction of dietary protein, avoidance of PO ₄ -containing foods, and optimal dialysis. However, the patients do not adhere to diet because of low palatability. Therefore, control of hyperphosphatemia with intestinal PO ₄ binding agents is necessary to meet the target range of KDOQI guidelines.

Historically aluminum hydroxide was used as a PO ₄ 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, Ca-containing binders, such as Ca carbonate (Caltrate, Oscal) and Ca acetate (PhosLo), became available. Although they reduce serum PO ₄ 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 (Renagel).

Sevelamer has been shown to control PO ₄ 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 LDL-cholesterol levels in dialysis patients, and survival benefit has also been reported. However, it is expensive and causes hyperchloremic metabolic acidosis. To avoid metabolic acidosis, the next generation sevelamer compound has been introduced. It is called sevelamer carbonate (Renvela). The effectiveness of this agent on various outcomes is being evaluated.

Another non-Ca-containing PO ₄ binder is lanthanum carbonate (Fosrenol), which binds PO ₄ ionically. Unlike other binders, the potency of lanthanum carbonate as a binder is so great that the pill burden is reduced which may aid patient 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. However, attenuation of vascular calcification and lipid-lowering effect has not been proven with lanthanum carbonate. Thus, option E is false.

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 (Table 5.3 ) summarizes the effects of PO ₄ binders on various biochemical parameters relevant to mineral bone disease.

With regard to PO ₄ binders and vascular calcification (VC), which one of the following statements is FALSE?

There are at least seven studies that evaluated the effects of Ca-based and non-Ca-based binders on VC: 6 in HD and 1 in predialysis patients. The following table (Table 5.4 ) summarizes the results of these studies.

With regard to PO ₄ binders and mortality , which one of the following statements is FALSE?

Only a few studies addressed the issue of PO ₄ binders and mortality in HD patients. The RIND study (Block et al.) showed that the all-cause mortality was higher in Ca-treated patients than sevelamer-treated patients over a 4-year period. A retrospective VA study also showed a survival advantage with sevelamer over CaCO ₃ for up to 2 years. In contrast, the DCOR study showed no overall mortality advantage with sevelamer compared to Ca acetate up to 2 years. However, there was a 20 % reduction in mortality in patients over the age of 65 years who were treated with sevelamer. Also, multiple all-cause hospitalization rate and hospital days were much lower in the sevelamer group. In general, these studies demonstrate a survival advantage with sevelamer.

It is the experience of many investigators that sevelamer lowers PO ₄ similar to Ca-based binders without increasing serum Ca ²⁺ . Thus, option C is false.

Regarding chronic kidney disease-fibroblast growth factor-23 (CKD-FGF-23), which one of the following statements is FALSE?

Recent studies have shown that FGF-23 levels increase gradually with declining GFR. Also, a correlation between FGF-23 levels and microalbuminuria (albumin 30–300 mg/day) and LVH has been reported in CKD patients. In newly started HD patients, higher levels of FGF-23 have been found to be associated with higher mortality. In early stages of CKD, higher levels of FGF-23 are found even before any changes in serum PO ₄ , Ca ²⁺ , and PTH are apparent. This suggests that an increase in FGF-23 may be an adaptive response to maintain normal PO ₄ level in a patient with declining renal function.

Serum PO ₄ levels in stage 4 CKD patients have been reported to be 4.1 ± 1.1 mg/dL, compared to 3.5 ± 0.5 mg/dL in stage 3 patients. This slight elevation in PO ₄ in stage 4 patients despite elevated FGF-23 may represent a relative hyperphosphatemia, which may be sensed by the parathyroid gland. In addition to the relative hyperphosphatemia, low levels of active vitamin D stimulate PTH secretion. Thus, FGF-23 seems to play an indirect role in secondary hyperparathyroidism. Thus, option E is false.

Match the following serum values with the patient history ?

The patient described in option 1 seems to have sarcoidosis . The patient with sarcoidosis usually has hypercalcemia due to elevated calcitriol secreted by the granuloma. PTH is generally low because of its inhibition by high levels of calcitriol and hypercalcemia. Phosphorus levels are normal. FGF-23 may be elevated or remains normal. Labs shown in option C are consistent with sarcoidosis.

The patient with lung mass (option 3) seems to have lung cancer which secretes PTH _rp (PTH-related protein), which causes hypercalcemia. Patients with humoral hypercalcemia also demonstrate hypophosphatemia, inappropriately low calcitriol, and low calcitriol-induced high FGF-23 levels, the latter causing hypophosphatemia. PTH may be either normal or slight low. Labs shown in B are consistent with lung malignancy.

The newly introduced IV iron preparation for iron deficiency anemia causes severe hypophosphatemia possibly by increasing FGF-23 levels. Values shown in F are consistent in a patient with iron deficiency anemia (option 6).

Which one of the following functions is NOT related to FGF-23?

FGF-23 was originally identified as one of the phosphatonins that was responsible for hypophosphatemia, renal PO ₄ wasting, and reduced active vitamin D 1,25-dihydroxyvitamin D3 [1,25(OH) ₂ D ₃ or calcitriol] in patients with tumor-induced osteomalacia. This hormone is secreted by osteoblasts and osteocytes. In the proximal tubule, FGF-23 inhibits Na-dependent PO ₄ cotransporter, thus promoting PO ₄ excretion. Also FGF-23 inhibits 1α-hydroxylase activity, leading to reduced levels of 1,25(OH) ₂ D _3. Since 1,25(OH) ₂ D ₃ promotes intestinal PO ₄ absorption, reduced level of this vitamin can cause hypophosphatemia.

Animal studies have shown that FGF-23 directly regulates osteoblast differentiation while absence of FGF-23 impairs skeletal mineralization despite normal levels of PO ₄ and vitamin D.

So far, FGF-23 has not been shown to have direct effect on renal Ca ²⁺ excretion. Thus, option D is incorrect.

Which one of the following factors is reported to LOWER the levels of FGF-23?

FGF-23 is regulated by PO ₄ , vitamin D, and possibly PTH. Studies have shown that high diet containing high PO ₄ induces FGF-23 secretion, whereas low PO ₄ diet suppresses FGF-23 secretion. Low PO ₄ diet lowers FGF-23 secretion. Thus, option D is correct.

Exogenous administration of 1,25(OH) ₂ D ₃ is shown to increase FGF-23 expression and secretion due to a direct effect of this vitamin on FGF-23 via a vitamin D response element located upstream of the FGF-23 promoter.

PTH also seems to increase FGF-23 levels by stimulating the skeletal release of FGF-23, but the mechanism is unclear.

Which one of the following human phosphate wasting diseases is ASSOCIATED with high levels of active vitamin D (1,25(OH) ₂ D ₃ )?

The etiology for hypophosphatemia in the above disorders other than primary hyperparathyroidism is elevated levels of FGF-23. In these disorders, the active vitamin D levels are generally low to normal, but in hyperparathyroidism they are elevated. Thus, option E is incorrect. Table 5.5 shows the levels of phosphorous (PO ₄ ), calcium (Ca), vitamin D, PTH, and FGF-23 in all of the above disorders.

ADHR is a rare disorder caused by activating mutations in the FGF-23 gene , and these mutations prevent proteolytic cleavage of FGF-23 with the resultant increase in circulating levels of this hormone. The disorder is characterized by hypophosphatemia due to renal excretion of PO ₄ , low 1,25(OH) ₂ D ₃ and rickets as well as osteomalacia.

X-linked dominant disease is the most common form of inherited disorder. It is caused by inactivating mutations in the PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) gene encoding a zinc-dependent endopeptidase. The clinical and laboratory findings are similar to ADHR/ARHR.

Primary hyperparathyroidism is characterized by elevated serum Ca, 1,25(OH) ₂ D ₃ , PTH, and near normal FGF-23 levels. Serum PO ₄ levels may be low or low normal.

FGF-23 exerts its effects on the kidney by which ONE of the following mechanisms?

Most of the FGF family members exert their effects through interaction with FGF receptors (FGFRs). At least 4 FGFRs with various subtypes have been identified. Studies have shown that FGF-23 can interact with FGFR1c, 3c, and 4c. However, FGF-23-mediated receptor activation requires a cofactor called KLOTHO. The klotho gene is an aging-suppressor gene, and its deficiency causes premature aging. Overexpression of this gene extends life span in animals. FGF-23 fails to exert its effects in the absence of klotho. Thus, klotho is required for phosphaturic and other effects of FGF-23. Thus, option D is correct. The interaction of FGF-23 with other receptors has not been described as yet.

Excess PTH in patients with CKD has deleterious effects on various organ systems, including the cardiovascular system (CVS). Of the following, which is NOT the effect of PTH on CVS?

For years, PTH has been considered a potent toxin with several adverse effects such as anemia, bone disease, neuromuscular myopathy, insulin resistance, and dyslipidemia. In addition, PTH has several deleterious effects on CVS. These include impaired myocardial contractility, leading to both systolic and diastolic dysfunction, myocardial and interstitial fibrosis, LVH, valvular calcifications, and arrhythmias. All of these change lead to impaired myocardial contractility. There are certain blood pressure-independent effects of PTH, including thickening of intramyocardial arterioles and impaired endothelial vasodilatory functions, and the latter may lead to arterial vasoconstriction and hypertension. Thus, option D is incorrect.

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