Hyperphosphatemia

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A hyperphosphatemia is an increase in phosphate levels in the blood . Hyperphosphatemia occurs with massive phosphate intake, massive release of phosphate through tissue destruction, reduced phosphate excretion in advanced kidney failure and conditions with increased phosphate reabsorption by the kidneys. The increase in serum phosphate leads to the deposition of calcium phosphate in blood vessels and tissues. In acute hyperphosphataemia, the symptoms of a drop in calcium are in the foreground: muscle cramps and cardiac arrhythmias that can even lead to death. Chronic hyperphosphataemia leads to calcification of tissues and blood vessels, which can lead to circulatory disorders , heart attacks and strokes . The treatment of acute hyperphosphatemia by saline - infusion and dialysis . Chronic hyperphosphataemia is treated with a low-phosphate diet and drugs that bind the phosphate in the intestine that is present in food. The upper limit value for inorganic phosphate in blood serum is 1.45 mmol / l (5 mg / dl) for adults and in some cases significantly higher for children.

Pathogenesis

We ingest about 1000–1200 mg of phosphate daily with our food , of which about 800 mg are absorbed into the body and end up in the exchangeable phosphate pool. This consists of the intracellular space , which contains around 70% of the exchangeable phosphate, and the mineralization front in the bone with 29% of the exchangeable phosphate. The blood contains less than 1% of the exchangeable phosphate. Phosphate can be excreted from the exchangeable phosphate pool via the kidneys and intestines , or it can be built into the bones as calcium phosphate. The skeleton acts as a large phosphate reservoir (Fig. Below)

In healthy people, the phosphate level is kept constant through the excretion of phosphate through the kidneys. The phosphate excretion of the kidneys is regulated by parathyroid hormone , fibroblast growth factor 23 (FGF23) and by the phosphate concentration in the blood:

  • Parathyroid hormone , a hormone of the parathyroid gland , increases the excretion of phosphate via the kidneys, but also promotes the release of phosphate from the skeleton.
  • Fibroblast Growth Factor 23 increases the excretion of phosphate via the kidneys.
  • Increased phosphate levels reduce the concentration of sodium phosphate cotransport proteins in the proximal tubule of the kidney, thereby inhibiting phosphate reabsorption via the proximal tubular cells and thus increasing phosphate excretion.

An increase in the phosphate intake of up to 4000 mg / d leads to an increased phosphate excretion, the phosphate level in the blood only increases slightly. A massive intake of phosphate within a few hours, on the other hand, can lead to an acute rise in the phosphate level. A chronic increase in the phosphate level occurs due to reduced phosphate excretion in chronic kidney diseases or increased phosphate reabsorption, e.g. B. in disorders of the parathyroid hormone or FGF23 metabolism.

etiology

Hyperphosphatemia develops

  • due to massive acute exogenous or endogenous phosphate intake, which exceeds the ability of the kidneys to excrete phosphate,
  • with impaired kidney function due to decreased filtration of phosphate in the kidney corpuscle (decreased glomerular filtration),
  • with normal kidney function through increased reabsorption of phosphate from the primary urine in the renal tubule (increased tubular reabsorption).

Massive acute phosphate intake

In order to cause an increase in serum phosphate, so much phosphate must accumulate in a short time that the capacity of the kidneys to excrete phosphate is exceeded.

Massive endogenous phosphate release

Phosphate is the most important intracellular anion . Any extensive destruction of tissues therefore leads to the release of large amounts of phosphate. Examples are tumor lysis syndrome , muscle destruction (rhabdomyolysis) or the destruction of red blood cells ( hemolysis ), for example due to a transfusion incident .

Acute hyperphosphataemia leads to the exceeding of the solubility product of calcium and phosphate, thus to the precipitation of calcium phosphate in the tissues and thus to a decrease in calcium in the serum. The resulting hypocalcemia can cause severe symptoms and even death.

Other causes of acute hyperphosphataemia are lactic acidosis or diabetic ketoacidosis .

Massive exogenous phosphate intake

Solutions containing phosphates are used to clean the colon before a colonoscopy . Especially in elderly patients and pre-existing renal impairment , after colon cleansing with these solutions, a massive increase in the phosphate level can occur; deaths from massive hypocalcaemia and irreversible kidney failure due to calcium-phosphate deposits in the kidneys ( acute phosphate nephropathy ) have been reported.

Decreased phosphate excretion in chronic kidney failure

A common cause of chronic hyperphosphatemia is reduced excretion of phosphate in renal insufficiency .

About 4–8 g of phosphate are filtered per day in the kidney corpuscles , the greater part is reabsorbed in the tubular system of the kidney, only 5–20% of the filtered phosphate appears in the urine. When the glomerular filtration rate decreases, the phosphate reabsorption initially decreases; the phosphate excretion can be kept constant in this way without the phosphate level rising. Only when the glomerular filtration rate falls below 20-25 ml / min is an increase in the serum phosphate level necessary in order to ensure adequate phosphate excretion and to avoid a positive phosphate balance.

The regulation of phosphate reabsorption in renal insufficiency is complex: less active vitamin D ( calcitriol ) is formed in the damaged kidney, calcium absorption in the intestine decreases, the calcium level in the serum drops, as a result of which the parathyroid gland produces more Parathyroid hormone , which in turn inhibits phosphate reabsorption in the renal tubule system . With impaired kidney function, the formation of the bone hormone Fibroblast Growth Factor 23 (FGF23) in the bone decreases due to the low calcitriol level, but at the same time less FGF23 is excreted via the kidneys. In the end, the FGF23 level in the serum rises, which also inhibits phosphate reabsorption in the kidneys. In addition, increased phosphate levels are able to directly inhibit phosphate reabsorption in the renal tubule.

In addition, with chronic renal insufficiency there is a disorder of the bone metabolism , which is characterized by the predominance of bone loss over new bone formation. The breakdown of bones releases phosphate, which aggravates the existing hyperphosphatemia.

With impaired kidney function, the skeleton can no longer adequately fulfill its task as a phosphate reservoir. When the phosphate level rises, soft tissue calcification occurs due to calcium phosphate deposits, particularly in the intima and media of the blood vessels . The intima calcification leads to circulatory disorders, the media calcification to increased vascular stiffness. The serious consequences are coronary heart disease , arterial occlusive disease and cerebrovascular insufficiency , which ultimately lead to a significantly reduced life expectancy for people with chronic kidney disease. (Fig. Below)

Increased reabsorption of phosphate in the renal tubule

With normal kidney function and thus normal filtration of phosphate in the [kidney corpuscles], the phosphate excretion can also be reduced if more phosphate is reabsorbed from the primary urine in the renal tubule adjoining the kidney corpuscle . Increased tubular reabsorption is observed in the following conditions:

Hypoparathyroidism

With reduced secretion of the parathyroid hormone Parathyroid hormone ( hypoparathyroidism ) or at a resistance of the renal tubule cells to the action of parathyroid hormone ( Pseudohypoparathyroidism ), there is an increased phosphate reabsorption increases from the primary, the phosphorus levels in the serum. Since bone loss is reduced at the same time when the parathyroid hormone is low, and so less calcium is released from the skeleton, the calcium level in the serum drops ( hypocalcaemia ).

Acromegaly

Hyperphosphatemia has been observed in some patients with acromegaly ; phosphate reabsorption may be stimulated by the increased levels of growth hormone and insulin like growth factor I.

Bisphosphonates

Treatment with bisphosphonates can result in increased phosphate reabsorption as a side effect, which can lead to hyperphosphataemia.

Vitamin D poisoning

In the case of vitamin D poisoning, there is an increased absorption of calcium and phosphate in the intestine . The increased calcium level ( hypercalcaemia ) inhibits the secretion of parathyroid hormone, the tubular phosphate reabsorption in the kidneys increases and with it the phosphate level. In addition, the hypercalcaemia leads to a narrowing (vasoconstriction) of the kidney vessels, the filtration of phosphate in the kidney corpuscle decreases, the phosphate level continues to rise.

Familial tumorous calcinosis

The familial tumoral calcinosis is a rare autosomal recessive inherited disorder associated with elevated serum phosphate due to an increased phosphate tubular reabsorption. Mutations in various genes can lead to familial tumorous calcinosis:

Mutations in the GALNT3 gene , which codes for a glycosyltransferase , and the Fibroblast Growth Factor 23 gene lead to a reduced secretion of Fibroblast Growth Factor 23, which increases the excretion of phosphate via the kidneys. Fibroblast Growth Factor 23 can only bind to its receptor in the presence of the co-receptor Klotho , so mutations in the Klotho gene also lead to hyperphosphatemia.

Phosphate levels are increased in patients with familial tumorous calcinosis. The hyperphosphataemia leads to soft tissue calcifications due to an increased deposition of calcium phosphate. A decrease in the calcium level is compensated for by an increased production of calcitriol . Calcitriol increases the absorption of calcium through the intestine. Serum calcium and parathyroid hormone are therefore in the normal range in familial tumorous calcinosis.

Other causes

Intravenous feeding

If an immobile ( immobilized ) patient is artificially fed intravenously (total parenteral nutrition) , the phosphate level can also rise if the amount of phosphate administered corresponds to the normal daily requirement. When immobilisation syndrome there is an inhibition of bone formation, with increased bone resorption, whereby additional phosphate is released, the phosphate requirement decreases.

Pseudohyperphosphatemia

Various substances present in the test material can falsify the laboratory phosphate determination and simulate an increased phosphate level (pseudohyperphosphataemia). Pseudohyperphosphatemia is described:

If pseudohyperphosphatemia is suspected, the phosphate determination should be carried out using an alternative test method.

Symptoms

Symptoms of acute hyperphosphatemia

An acute massive increase in phosphate leads to an increase in the calcium phosphate product, calcium phosphate precipitates in the tissues, the serum calcium decreases, hypocalcemia occurs . In tumor lysis syndrome, additional potassium is released from the disintegrating cells . Hyperphosphataemia, hypocalcaemia and hyperkalemia can lead to nausea , vomiting , diarrhea , loss of appetite , lethargy , hematuria , seizures , muscle cramps , tetany , circulatory collapse , as well as cardiac arrhythmias up to sudden cardiac death .

Symptoms of chronic hyperphosphatemia

Chronic hyperphosphataemia does not cause any symptoms at first. However, an increased calcium phosphate product leads to deposits of calcium phosphate in arteries, joints, connective tissue and organs, it leads to circulatory disorders which can lead to heart attacks , strokes and blockages of the extremities arteries. A rare and particularly severe form is calciphylaxis , in which extensive and extremely painful necrosis of the skin occurs due to severe medial calcification of the skin vessels .

Hyperphosphatemia and an increased calcium phosphate product reduce the life expectancy of dialysis patients.

therapy

Treatment depends on whether you have acute or chronic hyperphosphatemia.

Therapy of acute hyperphosphataemia

Acute hyperphosphataemia with hypocalcaemia is a potentially life-threatening clinical picture. With normal kidney function, the phosphate level normalizes within 6-12 hours after the acute attack of phosphate, but permanent kidney damage can occur. Phosphate excretion can be accelerated by infusing physiological saline solution or by dialysis treatment .

Therapy of chronic hyperphosphataemia

Chronic hyperphosphatemia is treated by inhibiting the absorption of phosphate in the intestine and the release of phosphate from the bones. Low-phosphate food and phosphate binders such as calcium carbonate , calcium acetate , aluminum hydroxide and lanthanum carbonate or the two calcium- and metal-free, non-absorbable polymers colestilan and sevelamer reduce the amount of phosphate ingested from food. By taking vitamin D or vitamin D metabolites ( calcitriol , alfacalcidol , paricalcitol ) and calcimimetica ( cinacalcet ), excessive bone remodeling ( osteitis fibrosa ) can be inhibited and the release of phosphate from the bone can be reduced. An overdose of vitamin D and calcimimetic leads to reduced bone remodeling (low-turnover bone disease, adult bone disease). In adynamic bone disease, phosphate ingested with food cannot be incorporated into the bones to a sufficient extent, the consequences are also hyperphosphataemia and vascular calcification. The bone turnover must therefore be set in a relatively narrow target range based on the parathyroid hormone level. It should be noted that with impaired kidney function, higher parathyroid hormone levels than in healthy people are necessary to maintain adequate bone remodeling. Treatment with phosphate binders and vitamin D metabolites can improve the life expectancy of dialysis patients.

literature

Individual evidence

  1. ↑ Laborlexikon.de .
  2. ↑ Fig .: Hruska: Physiological Phosphate Balance .
  3. ↑ a b c Keith A Hruska, Suresh Mathew, Richard Lund, Ping Qiu, Raymond Pratt: Hyperphosphatemia of chronic kidney disease . In: Kidney International . 74, No. 2, July 2008, ISSN  1523-1755 , pp. 148-57. doi : 10.1038 / ki.2008.130 . PMID 18449174 .
  4. ^ R Fass, S Do, LJ Hixson: Fatal hyperphosphatemia following Fleet Phospo-Soda in a patient with colonic ileus . In: American Journal of Gastroenterology . 88, No. 6, June 1993, ISSN  0002-9270 , pp. 929-32. PMID 8503390 .
  5. ↑ Yaacov Ori, Michal Herman, Ana Tobar, Gil Chernin, Uzi Gafter, Avry Chagnac, Ofer Ben Izhak, Asher Korzets: Acute phosphate nephropathy-an emerging threat . In: The American Journal of the Medical Sciences . 336, No. 4, October 2008, ISSN  0002-9629 , pp. 309-14. doi : 10.1097 / MAJ.0b013e318167410c . PMID 18854672 .
  6. ↑ Fig .: Hruska: Bone metabolism in renal insufficiency .
  7. ↑ GA Block, TE Hulbert-Shearon, NW Levin, FK Port: Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study . In: American Journal of Kidney Diseases . 31, No. 4, April 1998, ISSN  1523-6838 , pp. 607-17. PMID 9531176 .
  8. ↑ KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease ( Memento of February 14, 2015 in the Internet Archive ). National Kidney Foundation, 2003.
  9. ↑ Tamara Isakova, Orlando M Gutiérrez, Yuchiao Chang, Anand Shah, Hector Tamez, Kelsey Smith, Ravi Thadhani, Myles Wolf: Phosphorus binders and survival on hemodialysis . In: Journal of the American Society of Nephrology . 20, No. 2, February 2009, ISSN  1533-3450 , pp. 388-96. doi : 10.1681 / ASN.2008060609 . PMID 19092121 .
  10. ↑ Ming Teng, Myles Wolf, Edmund Lowrie, Norma Ofsthun, J Michael Lazarus, Ravi Thadhani: Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy . In: The New England Journal of Medicine . 349, No. 5, July 31, 2003, ISSN  1533-4406 , pp. 446-56. doi : 10.1056 / NEJMoa022536 . PMID 12890843 .