With 1,25-(OH)2 vitamin D de \201 ciency and/or hyperpar- athyroidism, osteoclastic activi ty may be enhanced result- ing in increased bone resorption. There is a steep inverse relat ionship between the serum ionized calcium concentration and PTH release that is mediated by the calcium-sensing receptor (CaSR) on the chief cells of the parathyroid gland. Kidney Sixty- \201 ve percent of \201 ltered calcium is reabsorbed in the proximal tubul e. This is not under hormonal regulation but is closely associated with sodium and water ba lance. Approximately 25% of the \201 ltered calcium is reabsorbed in the loop of Henle an d 10% in the distal convoluted tubule under the in \202 uence of PTH. PTH also stimulates 1A-hydroxylase activity in the kidney, leading to increased formation of 1,25-(OH)2 vitami n D and thus indirectly regulates intestinal calcium and phos- phate absorption. There is a lso evidence that vitamin D may independently increase renal calcium reabsorption. Functions of calcium The functions of calcium in the body include: \200 maintenance of sk eletal and dental structure; \200 muscle contraction and relaxation; \200 stimulation o f blood clotting; \200 maintenance of cell membrane integrity; \200 nerve transmission; \200 regulation of intracellular signaling; \200 stimulation of hormone secretion; \200 augmentation of enzyme activity (enzyme cofactor). Hypocalcemia Hypocalcemia is regarded as mild when the serum calcium concentration (adjuste d for albumin) is 1.75 \200\2232.10 mmol/L, and severe when it is <1.75 mmol/L. Calcium homeostasis The serum calcium concentration is maintained in a very narrow range wi th <2% variability. The three key organs involved in calcium homeostasis are the gut, bone, and kidney. The main calcium regulators are parathyroid hormone (PTH) and 1,25-(OH)2 vitam in D. A critical level of serum magnesium concentration is required for PTH secretion, thus severe hypomagnesemia may impair PTH release even in the presence of signi \201 cant hypo calcemia. Causes of hypocalcemia \200 25-(OH) vitamin D de \201 ciency Nutritional de \201 ciency in Asians, the elderly in nursing homes or those who are home-b ound and vegetarian. Malabsorption of fat soluble vitamins, e.g. Crohn \200\231s dis- ease, chronic pancreatitis, hepatobiliary disorders. In renal diseases such as nephrotic syndrom e, vitamin D binding proteins may be lost leading to vitamin D de \201 ciency. Antiepilept ic drugs such as phenytoin and phenobarbital. Gut Gastrointestinal absorption of calcium can be passive or active. About 40% of the daily dietary calcium intake ( 25 mmol) is absorbed in the gut (10 mmol). The absorption can be greatly increased if the body is in negative calcium balance. Passive absorption is by the paracellular junctions driven by the concentration gradients between the gut lumen and the serosal surfaces. Active transportation is mediated by entry of luminal calcium through api cal calcium channels, binding to the calcium binding protein, calbindin, and extrusion by a n active Na/ Ca-ATPase and Na/Ca exchanger. This is a saturable proc- ess which is tightly regulated by 1,25-(OH)2 vitamin D. Calcium absorption can be inhibited by citrates, phytate s, and drugs such as colchicine and theophylline. 1,25-(OH)2 vitamin D de \201 ciency Chronic renal failure with GFR <30 mL/min. Inherited disorders, e.g. vitamin D-dependent ri ckets type I due to 1-A-hydroxylase de \201 ciency; and vitamin D dependent rickets type I I due to end-organ unrespon- siveness to 1,25-(OH)2 vitamin D. Hypoparathyroidism Postoperative. Autoimmune. Congenital (e.g. activating mutations of the CaSR, par- athyroid aplasia). In \201 ltrative disorders. Pseudohyperparathyroidism. Hyperphosphatemia (resulting in increased calcium \227 phosphate (Ca \227 P) product caus ing ectopic calci \201 cation) Renal failure. Tumor lysis syndrome. Rhabdomyolysis. Intrav enous phosphate administration. \200 Severe magnesium de \201 ciency/depletion. \200 A cute pancreatitis. \200 Hungry bone syndrome. \200 Sepsis, burns or severe illness. Bone Both PTH and 1,25-(OH)2 vitamin D play a key in bone metabolism through regulation of both bone formation and resorption. Under normal circumstances in adults, bone formation an d resorption are in balance and there is no net movement of calcium from bone. CHAPTER 2.3 Hypo-/hypercalcemia 53 If hyperphosphatemia is present (e.g. in renal failure), saline infusions should be adminis tered cautiously since this may worsen the hypocalcemia. Dialysis may be nec- essary in sev ere hyperphosphatemia. Drugs, e.g. bisphosphonates, cinacalcet. \200 Artefactual, e.g. chelation with EDTA. Clin ical manifestations of hypocalcemia Both the rate of fall and the severity of hypocalcemia determine the severity of the signs and symptoms. Patients may be asymptomatic or have subt le symptoms and signs but they may also present acutely with life-threat- ening manifestati ons. Hypomagnesemia, hypokalemia and alkalosis may coexist and worsen the clinical picture. Oral calcium and vitamin D supplements may be given concurrently with IV infusions. Once th e patient can tol- erate adequate oral supplements, the infusions may be stopped. Chronic hypocalcemia \200 In patients with CKD the goal is to prevent metabolic bone dise ase and vascular mineralization. Serum calcium should be maintained within the target range and Ca \227 P kept at <4.8 mmol2/L2 and ideally <4.2 mmol2/L2. Neuromuscular \200 Tetany and seizures. \200 Trousseau \200\231s and Chvostek \200\231s sign. \200 Muscle cramps/tenderness/myopathy. \200 Laryngeal stridor, bronchospasm and respiratory arrest. \200 Perioral numbness and paresthesias. \200 Calcifications of th e basal ganglia, cerebrum and In dialysis patients, serum calcium should ideally be kept at <2.5 mmol/L. PTH measurement is not routinely required in the absence of suspected disorder of bone and mineral metabolism in CKD stages 1 and 2 or in nonprogressive stage 3, although PTH levels should be maintained within normal reference ranges. cerebellum. Depression and irritability. \200 Dementia and movement disorders. \200 Papilloedema. C ardiovascular \200 Syncope, rarely congestive heart failure and angina. \200 Prolongati on of QT interval, ventricular \201 brillation and PTH needs to be routinely measured 3-monthly in patients with CKD 5. Measurement of PTH sho uld also be considered in earlier stages of CKD (CKD 4 and possibly CKD 3) although opinion varies about the required frequency and utility of this. In stage 4, the PTH should be bet ween the upper limit and two times the upper limit of the normal range, and in stage 5 pati ents not on dialysis it should be between two and four times the upper limit of the normal range. If neces- sary, surgical treatment for hyperparathyroidism may be considered. heart block. Other manifestations \200 Biliary and intestinal cramps. \200 Resistance to digoxin the rapy. \200 Cataracts. \200 Poor dentition (age of \211 5 years). \200 Dry, coarse sk in, brittle nails, alopecia. \200 Bone changes (rickets) and osteodystrophy. Investigatio n of hypocalcemia Measure: \200 Serum urea, creatinine and electrolytes, calcium, phospha te, albumin, alkaline phosphatase and magnesium. In patients with hypocalcemia and CKD stages 3 \200\2235, ther- apy with active oral vitami n D sterols (calcitriol, alfacal- cidol) is indicated with close monitoring of serum calciu m and phosphate, and to maintain plasma PTH within the de \201 ned limits. Patients with hypoparathyroidism are treated with 1,25-(OH)2 vitamin D and the 24 h urine c alcium excre- tion is monitored in order to avoid hypercalciuria. Hypercalcemia A serum total calcium concentration (adjusted for albu- min) of >2.60 and <3. 0 mmol/L is considered mild, >3.0 and <3.5 mmol/L is moderate and >3.5 mmol/L severe hyperc alcemia. PTH and 25-(OH) vitamin D. \200 Serum bicarbonate and arterial blood gasses if acidosis i s suspected. 24 h urine calcium excretion (reference range: 2.5 \200\223 7.5 mmol/24 h). This is useful for monitoring patients on treatment for hypoparathyroidsm. Causes of hypercalcemia \200 Primary hyperparathyroidism (adenoma 80 \200\22385%, multig- landular or associated with MEN1 and MEN2 A 15 \200\22320%, and rarely due to carcinoma 1% ) accounts for >50% of all cases of hypercalcemia. Treatment of hypocalcemia The decision to treat hypocalcemia will depend on the presenting symptoms, their severity and rapidity of onset. Acute symptomatic hypocalcemia (particularl y if calcium <1.75 mmol/L) Treat the underlying cause \200 10 ml of 10% calcium gluconate is given IV over 10 min. This may be followed by slow IV infusion of up to 20 mL of 10% ca lcium gluconate over >6 h with ECG monitoring. This may be repeated once within a 24 h peri od. Malignancy (30% of all cancers: 35% of lung cancers, 25% of breast and 14% of hematological malignancies particu- larly myeloma). This is mediated mainly by parathyroid- hormone-rela ted peptides (PTHrP) whose N-terminal is similar to that of PTH or by cytokines (IL-1, IL-6 , TGF, TNF etc.). Lymphoma cells may activate conversion of 25-(OH) vitamin D to 1,25-(OH)2 vitamin D. Drugs, e.g. thiazides, lithium. \200 Vitamin D toxicity. \200 Vitamin A toxicity. \200 Tertiary hyperparathyroidism. \200 During recovery from acute renal failure. \200 Gra nulomatous diseases, e.g. sarcoidosis, tuberculosis. Hypomagnesemia and hypokalemia may coexist and should be treated as appropriate. If correct ion of hypomagnesemia is undertaken it should be done cau- tiously in patients with CKD as they have impaired renal excretion of magnesium. P. GUPTA AND W. MADIRA 54 Immobilization. \200 Familial hypocalciuric hypercalcemia. \200 Endocrine e.g. thyrotox icosis, Addison \200\231s disease, pheo- The main treatment for hypercalcemia is IV bisphospho- nates, e.g. pamidronate 30 \200\2239 0 mg over 2 \200\2234 h depending on the degree of the hypercalcemia. It may take up to 4 d ays to achieve normocalcemia. Persistent or recur- rent hypercalcemia may require repeated infusions at 3 \200\2234 week intervals but paradoxical hypocalcemia may occur with repeate d infusions. Bisphosphonates should be used with caution in patients with renal impairment. chromocytoma, acromegaly. Milk alkali syndrome. \200 Aluminum toxicity. \200 Parenteral nutrition. Clinical manif estations of hypercalcemia About 80% of cases of hypercalcemia are asymptomatic. The occurr ence of symptoms depends on the severity of hypercalcemia and rapidity of onset. Calcitonin (200 \200\223400 U per day in divided doses) may be given and acts within minute s, but due to tachyphylaxis it is effective for only up to 48 h. Glucocortocoids are particularly effective in hypercal- cemia due to granulomatous disorder s, multiple mye- loma and other hematological malignancies, and may be tried in these cases for a period of 10 days. Neurological \200 Lethargy, drowsiness and coma. \200 Apathy and cognitive impairment. \200 Confusion. \200 Depression. \200 Hypotonia and decreased deep tendon re \202 ex es. Gastrointestinal \200 Dyspepsia with or without peptic ulcer disease. \200 Acute pa ncreatitis. \200 Constipation. \200 Abdominal pain. \200 Anorexia, nausea and vomitin g. Renal \200 Polyuria and polydipsia. \200 Hypercalciuria, nephrolithiasis and nephroc alcinosis. Cardiovascular \200 Arrhythmias. \200 Hypertension. \200 Increased sensiti vity to digoxin. Other manifestations \200 Osteopenia and osteoporosis. \200 Soft tissu e calci \201 cation with chondrocalcinosis and band Chronic hypercalcemia \200 The general measures in the treatment of chronic hyper- calcem ia are adequate oral hydration and avoidance of thiazide diuretics. In CKD patients with hypercalcemia who are taking cal- cium-based phosphate binders, dose r eduction or use of noncalcium containing binders is appropriate. Again, for the CKD patient s on vitamin D sterols, the therapy can be stopped or dose reduced when the target serum ca l- cium levels have been reached. In patients on dialysis, low calcium dialyzate can be use d for a short period of 3 \200\2234 weeks. During the course of renal failure, parathyroid hyperpla- sia and associated hyperparathyro idism often develops and may persist following renal transplantation when hypercalcemia may result. Hypercalcemia due to tertiary hyperparathyroidism may require parathyroidectemy. C inacalcet, a calcium mimetic drug, may offer an alterna- tive to surgery. Cinacalcet direct ly decreases PTH levels and thus calcium concentrations by directly activating the CaSR in the parathyroid gland. Further reading Baker SB, Worthley LIG. The essentials of calcium, magnesium and phosphate metabolism: Part 1 and 2. Crit Care Resusc 2002; 4: 301 \200\223315. keratopathy. Investigation of hypercalcemia Measure: \200 Serum urea, creatinine, electrolytes, total calcium, inorganic phosphate, a lbumin, alkaline phosphatase. Body J, Bouillon R. Emergencies in calcium homeostasis. Rev Endocr Metab Dis 2003; 4: 167 \200\223175. Bushinsky DA, Monk RD. Calcium. Lancet 1998; 352: 306 \200\223311. Clines GA, Guise TA. Hyp ocalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and os teoblastic metastasis to bone. Endocr-Rltd Cancer 2005; 12: 549 \200\223583. PTH (and 25-(OH) vitamin D where indicated). \200 ECG. Treatment of hypercalcemia The tre atment of hypercalcemia depends on its severity, chronicity and the underlying cause. Sympt oms of hypercalcemia are more common at calcium concentrations >3.0 mmol/L. Calcium concent rations >3.5 mmol/L are considered severe and require emergency treatment. Davison AM, Cameron JS, Grun \201 eld J-P, Ponticelli C, Ritz E, Winearls CG, Ypersele CV. Hypo- hypercalcaemia. Oxford textbook of clinical nephrology, vol. 1. Oxford: OUP; 2005. p p. 269 \200\223286. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol \200\223 Renal Physiol 2005; 289: F8 \200\223F28. Gunn IR, Gaffney D. Clinical and laboratory features of calcium- sensing receptor disorders : a systemic review. Ann Clin Biochem 2004; 41: 441 \200\223458. Acute symptomatic hypercalcemia \200 Initial treatment in patients with preserved renal f unc- tion is volume expansion with normal saline (2 \200\2236 L for a period of 24 h). Leca N, et al. Early and severe hyperparathyroidism associated with hypercalcaemia after re nal transplant treated with Cinacalcet. Am J Transpl 2006; 6: 2391 \200\2232395. Moe SM, Dr eke TB. Management of secondary hyperparathy- roidism: the importance and the c hallenge of controlling parathy- roid hormone levels without elevating the calcium, phospho rus and calcium-phosphorus product. Am J Nephrol 2003; 23: 368 \200\223379. Loop diuretics may be given cautiously with close moni- toring of the volume status. These measures may reduce serum calcium by 0.5 mmol/L. CHAPTER 2.3 Hypo-/hypercalcemia 55 Skugor M, Milas M (2004). Hypocalcaemia. The Cleveland Clinic: http://www.clevelandclinicme ded.com/ medicalpubs/diseasemanagement/endocrinology/ hcalcemia/hcalcemia.htm The Renal Ass ociation. Clinical Practice Guidelines (2007): http://www.renal.org/guidelines/index.html Silverberg SJ, Bilezikian JP. The diagnosis and management of asymp- tomatic primary hyperp arathyroidism. Nat Clin Pract Endocrinol Metab 2006; 2: 94 \200\223503. Singh J, Moghal N, Pearce SHS, Cheetham T. The investigations of hypocalcaemia and rickets. Archs Dis Childh 2003; 88: 403 \200\223407. Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 2005; 42 : 35 \200\22370. See also Skeletal disorders in CKD, p. 432 Hypo-/hyperphosphatemia, p. 56 Hypo-/hypermagnes emia, p. 60 Nephrocalcinosis, p. 278 Medical management of stone disease, p. 270 Sarcoidosi s , p. 164 Internet resources National Kidney Foundation: K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. http://www.kidney.org/professionals/ kdo qi/guidelines_bone/index.htm Porter RS, Kaplan JL, Beer MH (eds), The Merck manual, 18th ed n; 2006 \200\2232007: http://www.merck.com/mmpe/index.html P. GUPTA AND W. MADIRA 56 Hypo-/hyperphosphatemia Phosphate is the most abundant intracellular anion. It is stored predominantly in the bones and teeth, 80% of which is in the form of hydroxyapatite. Approximately 9% of phosphate is in skeletal muscles and 10.9% in the viscera. Only 0.1% of the total body phosphate is in the extracel- lular compartment. The normal serum phosphate concentration ranges from 0.80 to 1.40 mmol/L and is slightly higher in children. PTH and PTH-related peptides (PTHrP) decrease phos- phate reabsorption by activating intrac ellular signaling pathways which increase internalization of NaPi IIa. Glucocorticoids, hyp okalemia, chronic hypocalcemia, and volume expansion will also cause hypophosphatemia. Phos phatonins such as fibroblast growth factor 23 (FGF-23) and frizzled-related protein-4 are a lso important phosphaturic agents. Important factors that increase phosphate reabsorption a re: \200 1,25-(OH)2 vitamin D. \200 other hormones including thyroid hormones, growth Functions of phosphate \200 Phosphate is a component of lipid membranes, phos- hormone, and insulin; high calcium intake increases phosphate reabsorption probably as a result of suppression of PTH secretion; \200 low dietary phosphate intake stimulates 1A-hydroxylase activity whic h increases 1,25-(OH)2 vitamin D levels and thereby enhances phosphate resorption. pholipids, nucleic acids and nucleoproteins. It is essential for adenosine triphosphate (ATP) synthe- sis and is required for the functi on of most metabolic pathways. It is important for signaling pathways that involve pro- tein phosphorlyation. \200 It is an important buffer. \200 It also upregulates osteopon tin gene activity, thereby Bone remodeling The release and uptake of phosphate from and into bone depends on bone reso rption and formation respectively. The serum phosphate concentration is critical for bone m ineralization and resorption. The vast majority of phosphate in the bone is in the form of hydroxyapatite. The factors affecting bone remodeling are listed in Table 2.4.1. playing a role in bone mineralization. Phosphate homeostasis Phosphate regulation is closely linked to calcium homeostasis. The pl asma phosphate concentration is dependent on dietary inorganic phosphate intake, intestinal absorption, renal \201 ltration and reabsorption, and exchange between the intracellular and bone reservoirs. Hypophosphatemia The plasma phosphate concentration refers to the concen- tration of the in organic moiety. This varies with age, gender and dietary intake. In adults hypophosphatemia is considered mild when the serum phosphate concentration is 0.5 \200\2230.75 mmol/L, mod- erate 0.3 \200\2230.5 mmol/L and severe when <0.3 mmol/L. Patients susceptible to severe h ypophosphatemia include those with: \200 sepsis; \200 severe trauma; \200 malnutritio n (especially with a BMI <18 kg/m2, and/or Gastrointestinal absorption of phosphate Phosphorus is ubiquitous in food and there is usua lly an excess of phosphate in the diet. Up to 80% of the ingested phosphate ( 40 mmol/day) is absorbed, mainly in the duodenum and upper jejunum. Phosphate absorption occurs by an ac tive, saturatable process in the duodenum and jejunum (mediated by the sodium phosphate cot ransporter: NaPi IIb), and by passive paracellular diffusion along a concentration gradient in the rest of the small intestine. 1,25-(OH)2 vitamin D increases intestinal absorption b y increasing the transcription of the NaPi cotransporter. Raised parathyroid hormone (PTH) levels and low serum phosphate indirectly increase absorption via 1,25-(OH)2 vitamin D. 3 \200\2234 mmol/day of phosphate is secreted into the intestinal lumen. lack of nutrition for >5 \200\22310 days); diabetic ketoacidosis; \200 alcoholism; \200 chronic obstructive pulmonary disease. Cau ses of hypophosphatemia Gastrointestinal causes \200 Malabsorption. \200 Vitamin D de \201 ciency/resistance. \200 Prolonged vomiting. \200 Prolonged intake of high doses of phosphate-binding Renal excretion of phosphate The kidney is the key organ in maintaining phosphate homeostas is. Approximately 180 mmol of phosphate is \201 ltered daily, of which 80% is reabsorbed in the proximal tubules along with sodium through the NaPi IIa cotransporter. This can be i ncreased to >95% in de \201 ciency states. There is a renal threshold for reabsorption of phosphate (Tm) that varies with GFR. The Tm/GFR ratio can be used as a surrogate marker of proximal tubular function. A decrease in GFR to <30 mL/min (CKD 4) will impair phosphate ex cretion. antacids (containing magnesium or aluminum). Low intake alone rarely causes hypophosphatemia, since phosphate is ubiquitously present in food. Renal causes \200 Hyperparathyroidism or secretion of PTHrP. \200 Vitamin D de \201 ci ency or resistance. \200 Renal tubular dysfunction (e.g. Fanconi syndrome). CHAPTER 2.4 Hypo-/hyperphosphatemia 57 Increased cell turnover or formation (hungry bone Table 2.4.1 Hormonal factors regulating bone formation and resorption: direct/indirect effe cts syndrome or acute leukemia). Increased steroid production resulting in metabolic Formation Resorption alkalosis. Calcium-regulating hormones Parathyroid hormone 1,25-(OH)2 vitamin D Calcitonin Clinical manifestations of hypophosphatemia There is a four-fold increase in mortality in p atients with severe hypophosphatemia. Low serum phosphate levels do not necessarily imply d epletion since hypophosphatemia may be due to shifts from the extracellular to the intracel lular compartments. The symptoms of hypophosphatemia and phosphate depletion are generally associated with decreased availabil- ity of intracellular ATP and impaired oxygenation. Increase Increase Decrease Increase Increase/decrease \200\223 Systemic hormones Glucocorticoids Insulin Growth hormone Insulin-like growth factor-1 Thyro xine Sex hormone de \201 ciency Leptin/neuropeptide Y Decrease Increase Increase Increase Increase \200\223 \200\223 \200\223 Musculoskeletal effects \200 Muscle weakness. \200 Proximal myopathy. \200 Rhabdomyol ysis, especially in alcoholic and severely mal- Increase Decrease Decrease Increase (in excess) Increase \200\223 Other circulating and local factors Postaglandin E2 Interleukin-1 Interleukin-6 Transformin g growth factor RANK ligand/RANK receptor Osteoprotegerin Lipoprotein receptor- related pro tein 5 PTHrP Interferon-G nourished patients with acute hypophosphatemia. \200\223 Increase \200\223 Increase Increase Increase Increase Increase/decrease Bone pain and fractures. \200 Osteomalacia. \200 Respiratory failure (from poor diaphra gmatic function). Cardiac effects \200 Reduced myocardial contractility. Central nervous system effects \200 Altered mental state. \200 Polyneuropathy similar to Guillain \200 \223Barr syndrome. \200 Paresthesias. \200 Metabolic encephalopathy. \200 Convulsio ns and coma. Hematological effects \200 Impaired leukocyte chemotaxis and phagocytosis. \200 Impaired platelet function. \200 Increased af \201 nity of red blood cells for oxy gen. Renal effects \200 Decreased buffering capacity. \200 Hyperchloremic metabolic aci dosis. \200 Glycosuria and bicarbonaturia. \200 Increased 1,25-(OH)2 vitamin D synthesi s. \200 Hypercalciuria due to increased bone turnover and \200\223 Increase \200\223 Increase Decrease \200\223 Increase Decrease Increase Decrease RANK, receptor activator of NF- B; PTHrP, PTH-related peptides. Postrenal transplantation. \200 Post dialysis. \200 Osmotic diuresis (e.g. with glycosu ria). \200 Volume expansion. \200 Diuretics. \200 Glucocorticoid excess. \200 Tumor -induced osteomalacia (oversecretion of FGF-23 by mesenchymal tumors). Genetic defects: X-linked dominant hypophosphatemic rickets: mutations have been identi \201 ed in the phos phate- regulating (PHEX) gene. Autosomal dominant hypophosphatemic rickets and oncogenic os teomalacia: FGF-23 gain-of-function gene mutations have been identi \201 ed as causing aut osomal dominant hypophosphatemic rickets, and overproduc- tion of FGF-23 arises from some o ncogenic tumors. hypercalcemia. Increased magnesium excretion. Investigation of hypophosphatemia Measure the serum urea, cr eatinine, electrolytes, bicarbo- nate, chloride calcium, phosphate, albumin, alkaline phos- phatase, and magnesium. Liver function tests. Arterial blood gasses (especially if respira tory alkalosis is suspected). PTH and 25-(OH) vitamin D levels 24 hour urine phosphate excr etion: \200 Reference range is 15 \200\22320 mmol/24 h. \200 <10 mmol/24 h suggests the presence of a gastrointesti- nal cause such as malabsorption, antacid use, or chronic alco hol abuse. Internal redistribution \200 Refeeding syndrome. This usually occurs within 3 \200\2234 d ays after starting feeds in malnourished patients. \200 Malnourished patients may have depletion of phos- phate even though the serum levels appear normal due to redistribution from the intracellular compartment. In these circumstances ad ministration of glucose with increased insulin secretion may lead to a rapid uptake of gluc ose, magnesium and phosphate into cells result- ing in potentially life-threatening hypopho sphatemia. If excretion is >20 mmol/24 h, estimate the maximal rate of tubular reabsorption of phospha te (TRP) from Recovery from diabetic ketoacidosis. \200 Respiratory alkalosis. P. GUPTA AND W. MADIRA 58 Increased release from the intracellular compartment \200 Rhabdomyolysis. \200 Tumor ly sis syndrome (common). \200 In vivo hemolysis. Redistribution \200 Metabolic or respira tory acidosis. Increased intake \200 Can occur due to vitamin D intoxication, although th is is nomograms or calculate the phosphate/creatinine clear- ance ratio (Cp/Ccr): urine PO4 \227 serum creatinine serum PO4 \227 urine creatinine Cp/Ccr = TRP = (1 \200\223 Cp/Ccr) \227 100 (reference range: 78 \200\22398%). A low TRP indicates an inappropriate renal loss of phos- phate. Skeletal X-rays and bone densitometry if osteopenia and/ or osteomalacia suspected. rare. Absorption of very large amounts of phosphate (can be caused by phosphate enemas). Treatment of hypophosphatemia The treatment of hypophosphatemia depends on the underlying c ause and its severity. Mild hypophosphatemia Mild hypophosphatemia, particularly when it is due to redistribution with increased uptake into the cells, may not necessarily require sp eci \201 c treatment. Severe or symptomatic hypophosphatemia Phosphate concentrations <0.3 mmol/L are likely to require IV treatment. Phosphate infusion should be given at a rate of 9 mmol every 12 h and in critically ill patients the dose can be increased up to a maximum of 50 \200\22360 mmol over 24 h. It is recommended that plasma phosphate should be mon- it ored 6-hourly and where possible oral supplementation should be commenced when the serum co ncentration is >0.6 mmol/L. Administration of IV phosphate can be associated with potential ly serious adverse effects due to precipitation with calcium. This can lead to hypocalcemia , renal failure and potentially fatal arrhythmias. It is therefore essential to closely mon itor serum calcium, potassium and magnesium concentrations during the infusion. Treatment w ith oral phosphate ( 30 mmol per day) should be considered in patients with mild to moderat e hypo- phosphatemia. In the refeeding syndrome, patients may become sympto- matic with pho sphate levels of <0.5 mmol/L and therefore may require IV phosphate replacement. Patients a t high risk of refeeding syndrome include those with a BMI <16 kg/m2, an unintentional weig ht loss of >15% in the preceding 3 \200\2236 months, or no food intake for \211 10 days. I n such patients oral or IV nutrition should be given at a maximum of 5 \200\22310 kcal/kg p er day and increased slowly over the following 4 \200\2237 days. Endocrine causes \200 Acromegaly. \200 Thyrotoxicosis. \200 Glucocorticoid de \201 c iency. Miscellaneous causes \200 Tumor calcinosis. Artifactual causes \200 In vitro hem olysis. \200 Raised immunoglobulins. Clinical manifestations of hyperphosphatemia There a re no specific symptoms and signs related to hyperphosphatemia, but patients may present wi th features of hypocalcemia. The calcium \227 phosphate (Ca \227 P) product needs to be m aintained at <4.2 mmol2/L2. A raised Ca \227 P product may lead to ectopic calci \201 cat ion and/or deposits in acral tissue, skin or subcutaneous tissue causing painful necrosis. Asymptomatic corneal calci \201 ca- tion, conjunctivitis and large deposits around joints may also develop. Ectopic calci \201 cation in the medial wall of blood vessels may result in hypertension and left ventricular hypertrophy. Calci \201 cation may also involve the myocardium and heart valves. Persistent hyperphosphatemia plays an important role in the pa thogenesis of secondary hyperparathyroidism and contributes to the development of osteitis \201 brosa cystica. Investigation of hyperphosphatemia Investigations for hyperphosphatemia are similar to thos e for hypophosphatemia. In addition, serum creatine kinase and urine myoglobin (for rhabdom yolysis), and potassium, urate, and lactate dehy- drogenase (for tumor lysis syndrome) shou ld be measured as appropriate. Hyperphosphatemia The normal serum phosphate concentration is 0.8 \200\223 1.4 mmol. The Re nal Association clinical practice guidelines recommend that in patients with CKD stages 3 a nd 4: \200 serum phosphate should be maintained at 0.9 \200\223 1.5 mmol/L, and in patien ts on dialysis 1.1 \200\2231.8 mmol/L. \200 serum calcium \227 phosphate (Ca \227 P) pr oduct should be Treatment of hyperphosphatemia Acute and severe hyperphosphatemia This may be life-threaten ing, particularly when associated with symptomatic hypocalcemia. When kidney function is in tact, resolution of hyperphos- phatemia can be achieved by enhancing renal phosphate excret ion with saline infusion. Care must be taken to avoid the development of hypocalcemia. Hemo dialysis is often required in patients with concurrent renal impairment and symptomatic hyp ocalcemia. kept to <4.8 mmol2/L2 and ideally <4.2 mmol2/L2. Causes of hyperphosphatemia Renal causes \200 Acute kidney injury or chronic kidney disea se (almost universal in those with GFR <30 mL/min) Hypoparathyroidism. \200 Pseudohypoparathyroidism. CHAPTER 2.4 Hypo-/hyperphosphatemia 59 Chronic hyperphosphatemia Depending on the stage of CKD, renal patients may require ongoing therapy to control chronic hyperphosphatemia. \200 The dietary phosphate intake should b e restricted to 800 \200\2231000 mg/day. Renal dietetic input is required for this to be ac hieved. Murer H, Hernando N, Forster I, Biber J. Proximal tubular phosphate: a molecular perspectiv e. Kidney Int 2006; 70: 1548 \200\223 1559. Nordin BEC, Fraser R. Assessment of urinary phosphate excretion. Lancet 1960; 60: 947 \200\223951. Quinbi WY. Consequences of hyperphosphataemia in patients with end-stage renal disease (ESRD). Kidney Int 2004; 66: S8 \200\223S12. Phosphate binders may be required for CKD stages 4 and 5 as dietary phosphate restriction a lone may be insuf \201 cient in controlling hyperphosphatemia. The choice of binder depend s on calcium requirements for individ- ual patients and local practice guidelines. Sinclair D, Smith H, Woodhead P. Spurious hyperphosphataemia caused by IgA paraprotein: a t opic revisited. Ann Clin Biochem 2004; 14: 119 \200\223124. Internet resources National Collaborating Center for Acute Care (2006) Nutrition Support in Adults: Oral nutrition support, enteral tube feeding and parenteral nutrition. London (UK) : National Institute for Health and Clinical Excellence: http://www.guideline.gov/summary/s ummary. aspx?doc_id=8739 National Kidney Foundation. K/DOQI clinical practice guidelines fo r bone metabolism and disease in chronic kid- ney disease: http://www.kidney.org/profession als/ kdoqi/guidelines_bone/index.htm The Renal Association (2007) Clinical Practice Guideli nes: http://www.renal.org/guidelines/index.html The calcium intake should be restricted to <2 g daily. \200 PTH is usually measured every 3 months in patients with stage 5 CKD. Measurement of PTH should also be considered in ear- lier stages of CKD (CKD 4 and possibly CKD 3) although opinion varies about the required frequency and utility of this. There is no indication to measure PTH in CKD 1 and 2 in the absence of a suspected disorder of bone and mineral metabolism. In stage 4, the PTH should be between the upper limit and two times the upper limit of the normal range, and between two and four times the upper limit of the normal range in CKD sta ge 5 patients not on dialysis. These PTH targets may be achieved by the use of 1,25-(OH)2 v itamin D and/or calcimimetics, and if neces- sary parathyroidectomy. See also Hypo-/hypercalcemia, p. 52 Isolated defects of tubular function, p. 200 Fanconi sy ndrome, p. 204 Medical management of dialysis patients, p. 528 Skeletal disorders in (K1), p. 432 Further reading Amanzadeh J, Reilly Jr, RF. Hypophosphataemia: an evidence-based approach t o its clinical consequences and management. Nat Clin Pract Nephrol 2006; 2: 136 \200\223148 . Baeksgaard L, Sorensen JB. Acute tumor lysis syndrome in solid tumors: a case report and re view of the literature. Cancer Chemother Pharmacol 2003; 51: 187 \200\223192. Baker SB, Worthley LIG. The essentials of calcium, magnesium and phosphate metabolism: Part 1 and 2. Crit Care Resusc 2002; 4: 301 \200\223315. Berndt TJ, Schiavi S, Kumar R. Phosphatonins and the regulation of phosphorus homeostasis. Am J Physiol, Renal Physiol 2005; 289: F1170 \200\223F1182. Bessmertny O, Robitaille LM, Cairo SM. Rasburicase: a new approach for preventing and/or tr eating tumor lysis. Curr Pharm Design 2005; 11: 4177 \200\2234185. Block GA. Control of serum phosphorus: implications for coronary artery calci \201 cation and calci \201 c uraemic ateriolopathy (calciphylaxis). Curr Opin Nephrol Hypertens 2001; 10: 741 \200\223747. Brunelli SM, Goldfarb S. Hypophosphataemia: clinical consequences and management. J Am Soc Nephrol 2007; 18: 1999 \200\2232003. Davison AM, Cameron JS, Grun \201 eld J-P, Ponticelli C, Ritz E, Winearls CG, Ypersele C V . Hypo- hyperphosphataemia. Oxford Textbook of Clinical Nephrology, vol. 1; 2005. pp. 287 \200\223308. Gaasbeek A, Meinders E. Hypophosphataemia: an update on its etiology and treatment. Am J Med 2005; 118: 1094 \200\2231101. Giachelli CM, Speer MY, Li X, Rajachar RM, Yang H. Regulation of vascular calci \201 catio n: roles of phosphate and osteopontin. Circuln Res 2005; 96: 717 \200\223722. Jan de Beur SM. Tumoral calcinosis: a look into the metabolic mirror of phosphate homeostas is. J Clin Endocrinol Metab 2005; 90: 2469 \200\2232471. Ketteler, M. Phosphorus control in chronic kidney disease. Eur Renal Dis Issue 1 2007; 24 \200\22326. Moe S, Dr ke TB. Management of secondary hyperparathyroidism: the importance and the chall enge of controlling parathyroid hormone levels without elevating the calcium, phosphorus an d calcium-phosphorus product. Am J Nephrol 2003; 23: 368 \200\223379. P. GUPTA AND W. MADIRA 60 Hypo-/hypermagnesemia and calcium in the TAL is facilitated by the tight junction protein, claudin 16. Mutations in this protein result in hypomagnesemia with associated hypercalciuria and nephrocalcinosi s. Magnesium is the second most abundant intracellular cation. It is stored predominantly in b one, muscle and soft tissue. Less than 1% of the total body magnesium stores are in the ext racellular \202 uid of which 55 \200\22370% is ionized (physiologically active), 20 \200 \22330% is protein-bound (mainly to albumin) and 10 \200\22315% is complexed to serum anion s (e.g. phosphate, citrate, bicarbonate). The normal serum magnesium concentration is 0.7 \200\223 1.0 mmol/L. 5 \200\22315% in the distal convoluted tubule (DCT). This involves an active transcellular transportation process (stimulated by aldosterone, antidiuretic hormone and glucagon) and i s the site where \201 ne adjustments of mag- nesium excretion are made. The understanding of the hormonal regulation of magnesium homeostasis remains incomplete. Functions of magnesium Magnesium is an essential part of many metalloenzymes and acts as a cofactor of many enzyme systems, especially those associated with the metabolism of ATP, pr oteins, car- bohydrates, and DNA. Magnesium acts as a calcium channel antagonist and modu- lates activities that are dependent on intracellular calcium \202 uxes, e.g. muscle contr action and insulin release. Along with potassium and calcium ions, magnesium also regulates neuromuscular function and the clotting mechanism. Magnesium, calcium and potassium are cl osely linked func- tionally and metabolically, including in their handling by the kidney. Approximately 3 \200\2235% of the \201 ltered magnesium is excreted in the urine ( 4 mmol /day) but this may vary considerably in order to maintain magnesium homeostasis. The fracti onal reabsorption of magnesium can decline from 95% to nearly zero in hypermagnesemic state s or when the GFR is severely reduced (<5 \200\22310 mL/min), or increase to 99.5% in sever e hypomagnesemic states (i.e. magnesium excretion <0.5 mmol/day). There are several inherit ed disorders of magnesium handling, many of which are directly or indirectly associ- ated w ith disturbed calcium metabolism and homeostasis. These are listed in Table 2.5.1. Hypomagnesemia Hypomagnesemia is defined as a serum magnesium concentration <0.7 mmol/L, an d is considered severe when <0.5 mmol/L. A magnesium deficit may exist even when the serum magnesium concentration is normal (serum magnesium levels may remain normal even when total body stores are depleted by 20%). Since 30% of serum magnesium is bound to protein, 75% o f which is albumin, the routinely measured total mag- nesium concentration is affected by t he serum albumin concentration. Magnesium homeostasis Magnesium balance is normally regulated by intestinal absorption and renal excretion. Gastrointestinal absorption of magnesium About 30 \200\22340% of dietary magnesium intake ( 10 \200\22315 mmol/ day) is absorbed in the small intestine with smaller amounts being abso rbed in the colon. The TRPM6 protein, which is a transient receptor potential cation channe l, is crucial for the epithelial absorption of magnesium in both the intes- tine and the di stal convoluted tubule. Mutations in TRPM6 lead to severe hypomagnesemia and hypocalcemia. Absorption can vary from 25 to 80% depending on the intracellular magnesium stores. Absorpt ion is by both saturable active transcellular transportation and by nonsaturable paracellul ar passive transportation. Approximately 1 mmol/day of magnesium is secreted into the intes tinal lumen. This may increase during diarrheal episodes and lead to signi \201 cant losse s. Epidemiology The prevalence of severe hypomagnesemia (serum magnesium <0.5 mmol/L) in hospi tal populations is high (10 \200\22320%) but may be as high as 65% among critically ill pat ients. Patients at particular risk of hypomagnesemia include: \200 the elderly (up to one -third of elderly subjects living in residential homes are hypomagnesemic);