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); alcoholics (30% are hypomagnesemic and nearly all are Renal excretion of magnesium About 100 mmol of magnesium is \201 ltered daily, of which > 95% is reabsorbed by the renal tubule: \200 15 \200\22320% in the proximal convoluted tub ule (PCT). \200 60 \200\22370% in the thick ascending limb (TAL) of the loop of Henle. Th is occurs by passive and paracellular transportation that is to some extent stimulated by p arathyroid hormone, glucagon and antidiuretic hormone. Passive diffusion depends on the ele ctrochemical gradient cre- ated by the Na-K-2Cl transporter and the potassium-rec- tifying channel, ROMK. The gradient is abolished by factors that reduce the positive luminal charge (e.g. loop diuretics, hypercalcemia). Magnesium reabsorption is also decreased by increase d tubular \202 ow (e.g. osmotic diuresis, saline infusion). Paracellular transit of magne sium magnesium deplete); the chronically ill; \200 those receiving parenteral nutrition (high incidence of hypomag nesemia with or without refeeding syndrome); \200 those with refractory hypokalemia and/o r hypocalcemia; \200 those with ventricular arrhythmias (particularly follow- ing an isch emic event), and rarely atrial arrhythmias; \200 postoperative patients in the first 24 h after major surgery. Serum magnesium is not routinely requested and measured, therefore hypomagnesemia may be un diagnosed. Magnesium de \201 ciency is also often associated with an imbalance of other el ectrolytes such as hypokalemia and hypocalcemia. CHAPTER 2.5 Hypo-/hypermagnesemia 61 Renal tubular acidosis. \200 Osmotic diuresis. \200 Chronic alcoholism. \200 Diabetes type I and II. \200 Diabetic ketoacidosis. \200 Hyperaldosteronism. \200 Hyperthyroi dism. \200 Hypoparathyroidism. \200 Congenital magnesium renal wasting. \200 Bartter \200\231s syndrome (one-third of cases). \200 Gitelman \200\231s syndrome (universal). Mi scellaneous causes \200 Major burns. \200 Hungry bone syndrome postparathyroidectomy. \200 Syndrome of inappropriate ADH secretion. \200 Insulin infusion. \200 Excessive la ctation and sweating. Clinical manifestations of hypomagnesemia Although hypomagnesemia is usually asymptomatic, the clinical spectrum of its manifestations include dysfunction of th e cardiac, neuromuscular and CNS systems. Seizures, tetany and cardiac arrhythmias are comm oner at serum magnesium levels <0.5 mmol/L whereas neuromus- cular irritability, hypokalemi a and hypocalcemia may be seen even with levels of 0.5 \200\2230.70 mmol/L. However, the se verity of the symptoms may not be directly related to the serum magnesium concentration. Table 2.5.1 Inherited diseases of magnesium handling Thick ascending limb (TAL) Mutations in TAL transporters Bartter \200\231s syndrome Calcium sensor receptor disorders Mutation activating Mg2+/Ca2+ sensing (autosomal dominant hypoparathyroidism) Mutation inactivating Mg2+/Ca2+ sensing (familial hypocalciuric hypercalcemia) Claudin 16 (paracellin-1) (protein involved in controlling the magnesium and calcium permea bility of the cortical TAL) Familial hypomagnesemia associated with hypercalciuria and nephrocalcinosis Distal convoluted tubule (DCT) Gitelman \200\231s syndrome Hypomagnesemia associated with abnormal renal NaCl transportation (mutations in thiazide-se nsitive co-transporter) Isolated dominant hypomagnesemia with hypocalciuria (mutation in D- subunit of ATPase) Hypomagnesemia with secondary hypocalcemia (mutation in TRPM6-Mg2+ chann el) Causes of hypomagnesemia Gastrointestinal causes: \200 In \202 ammatory bowel disease. \200 Short bowel syndrome. \200 Biliary or intestinal \201 stulae. \200 Small intest inal bypass surgery. \200 Celiac disease. \200 Congenital malabsorption. \200 General malabsorption syndromes. \200 Acute or chronic pancreatitis. \200 Acute or chronic dia rrhea. \200 Prolonged vomiting or nasogastric suction. \200 Alcoholism. \200 Laxative abuse. \200 Malnutrition. \200 Prolonged IV administration of magnesium-free \202 ui ds. Renal causes: \200 Drugs \200 \200 Clinical consequences of hypomagnesemia Hypokalemia occurs in 30 \200\22360% of patients wi th hypomag- nesemia and conversely 60% of patients with hypokalemia are hypomagnesemic. Thi s may be due to common etiologies. Hypocalcemia is found in 12 \200\22350% of patients wit h hypomagnesemia. Cardiovascular: \200 Cardiac arrhythmias (some ventricular arrhythmias may only respond to magnesium infusion): \200 \200 \200 \200 \200 Premature ventricular contractions. Ventricular \201 brillation. Torsade de Pointes. Incr eased susceptibility to digoxin induced arrhythmias. Atrial \201 brillation and tachycard ia. Loop or thiazide diuretics. Cisplatin (hypomagnesemia very common and rou- tine monitoring in all patients on cisplatin therapy is recommended). Amphotericin B. Ciclosporin. Aminogly cosides (hypokalemia, hypocalcemia and magnesium wasting may persist for months after ces- sation of treatment). Pentamidine toxicity. Foscarnet. Hypertension. \200 Coronary artery spasm. \200 Symptomatic mitral valve prolapse. \200 Sudden death. \200 ECG changes (similar to those seen in hypokalemia): \200 \200 \200 \200 \200 ST segment depression. T wave changes which may be progressive. Prolongation of the PR inte rval. Widening of the QRS complex. \200 Tubulointerstial nephropathies. \200 Postrenal transplantation. \200 Postobstructive di uresis. \200 Diuretic phase of acute tubular necrosis. \200 Hypercalcemia and hyperpara thyroidism. Magnesium has membrane stabilizing properties and some of the cardiac complications may re \202 ect abnor- mal cardiac repolarization resulting mainly from the effects of low magnes ium concentration on the Na/K- ATPase pump. P. GUPTA AND W. MADIRA 62 Neuromuscular: \200 Tetany. \200 Tremors, muscle twitching with positive Trousseau \200 \231s and Asymptomatic hypomagnesemia Patients should be given oral magnesium in divided doses, 15 \200\22330 mmol daily for severe depletion or 5 \200\22315 mmol daily for mild de \201 cie ncy. Chovstek \200\231s signs. Seizures (tonic, clonic or multifocal). \200 Respiratory muscle weakness or paralysis. Ce ntral nervous system: \200 Confusion. \200 Apathy, depression, psychosis. \200 Anxiet y, delirium. \200 Weakness, fatigue. \200 Vertigo, vertical nystagmus. \200 Wernicke \200\231s encephalopathy. \200 Coma. Investigation of hypomagnesemia Measure serum magnes ium, electrolytes, urea, creatinine, albumin, calcium, and inorganic phosphate. The serum m agnesium concentration may be an unreliable indicator of total body stores as serum levels may be nor- mal in the presence of signi \201 cant magnesium depletion. When serum levels are signi \201 cantly low, however, this does indicate depletion of magnesium stores. Tota l body stores may be assessed by a magnesium loading test but this is not a routine investi gation. Since about 30% of serum magnesium is protein-bound, the magnesium concentration sh ould be corrected for the albumin concentration. There is no general agreement about how th is may be achieved but the following formula has been proposed: Mgc = MgT + 0.005 (40 \200 \223 Alb) where Mgc is the corrected magnesium concentration (mmol/L), MgT is the measured total serum magnesium concentration (mmol/L), and Alb is the concentration of albumin in g/ L. The adjustment may not be reliable for serum albumin concentrations of 39 \200\22345 g/L . The cause of hypomagnesemia may be determined (in patients without signi \201 cant renal impairment) by measur- ing the fractional excretion of magnesium (FeMg). This requires a b lood and spot urine sample: \227 100 Symptomatic hypomagnesemia In patients with hypomagnesemic tetany, seizures or ven- tricula r arrhythmias, rapid intravenous administration of 4 \200\2238 mmol magnesium over 10 \200 \22360 min with close cardiac monitoring is indicated. This is followed by magnesium infusi on: 12 \200\22390 mmol over a period of 24 h depending on the severity of the symptoms, sig ns, and magnesium deple- tion. Up to 160 mmol of magnesium may be required over 5 \200\2236 days to replenish the de \201 cit and maintain serum mag- nesium at >0.5 mmol/L. Hypocalc emia and hypokalemia may coexist with hyper- magnesemia and should be treated as appropriat e. In patients with signi \201 cant renal impairment, the magne- sium infusion rate should be reduced by 25 \200\22350% and serum levels monitored more frequently. Amiloride or tria mterene may be helpful in reversing diu- retic-induced renal magnesium wasting, and in trea ting the renal loss due to Gitelman \200\231s or Bartter \200\231s syndromes, or cisplatin nephrotoxicity. Hypermagnesemia Hypermagnesemia (serum magnesium >1.0 mmol/L) is relatively rare and has a prevalence of 4 \200\2235% in the hospital population. Normally the kidney excretes 3 \200 \2235% daily of the \201 ltered magnesium but is capable of increasing FeMg to nearly 100 % in the presence of hypermagnesemia in patients with normal GFR. When the GFR falls to <30 mL/min and magnesium intake is maintained or increased, hypermagnesemia may occur. Causes of hypermagnesemia Acute or chronic renal failure (GFR <30 mL/min), often in associa tion with excess magnesium intake (e.g. magnesium infusions, antacids, laxative abuse, Epso m salts, cathartics and enemas). Causes of mild to moderate hypermagnesemia include: \200 Hypothyroidism. \200 Lithium therapy. \200 Addison \200\231s disease. \200 Familial hypocalciuric hypercalcemia. \200 Cell necrosis, rhabdomyolysis, especially with renal fa ilure. Clinical manifestations of hypermagnesemia Serum magnesium concentrations <2.0 mmol/ L are not usually associated with any symptoms. (sCr \227 uMg) (0.7 \227 sMg \227 uCr) FeMg = where sCr is serum creatinine (mmol/L), sMg is serum magnesium (mmol/L), uMg is urine magne sium (mmol/L) and uCr is urine creatinine (mmol/L). The serum magne- sium is multiplied by 0.7 to correct for the 30% of magne- sium that is protein bound and therefore not \201 lt ered. In the presence of hypomagnesemia, a FeMg >2% indicates inappropriate renal wasting w hereas a FeMg <2% is com- patible with appropriate renal magnesium conservation (indicating extrarenal loss). The normal 24 h urine magnesium excretion is 1.0 \200\2237.0 mmol. In th e presence of hypomagnesemia a 24 h magnesium excretion of <0.5 mmol indicates appropriate renal mag- nesium conservation. Neuromuscular toxicity With serum magnesium levels of 2.1 \200\2232.9 mmol/L, lethargy, \202 ushing, drowsiness, nausea and vomiting, and suppression of deep tendon re \202 exes may occur. With concentr ations of 2.9 \200\2235.0 mmol/L, loss of deep ten- don reflexes becomes more evident and w ith levels >5.0 mmol/L paralysis, coma and apnea may ensue. Other neuromuscular toxic effec ts include ileus, urinary retention, and parasympathetic nervous system inhibition with \201 xed dilated pupils. Treatment of hypomagnesemia The type of treatment and the speed of correction of hypomagnes emia are determined by the underlying cause and the severity of the clinical signs and symp toms. CHAPTER 2.5 Hypo-/hypermagnesemia 63 Cardiovascular toxicity These usually become evident with serum magnesium concentrations >2 .9 mmol/L and include bradycardia, hypotension, ECG changes (prolongation of PR and QT inte rvals, and widening of the QRS complex). With higher levels, complete heart block, ventricu lar \201 bril- lation and cardiac arrest may develop. Cole DEC, Quamme GA. Inherited disorders of renal magnesium handling. J Am Soc Nephrol 2000; 11: 1937 \200\2231947. Davison AM, Cameron JS, Grun \201 eld J-P, et al. Hypo- hypermagne- saemia. Oxford Textboo k of Clinical Nephrology, vol. 1; 2005. pp. 309 \200\223319. Dub L, Granry J-C. The therapeutic use of magnesium in anaesthi- ology, intensive care an d emergency medicine: a review. Can J Anaesth 2003; 50: 732 \200\223736. Innerarity S. Hypomagnesaemia in acute and chronic illness. Metabolic disturbance Crit Care Nurs Quart 2000; 23: 1 \200\22319. Mild hypocalcemia and variable degrees of hyperkalemia have been observed. Konrad M, Schlingmann KP, Gudermann T. Insights into the molecu- lar nature of magnesium ho meostasis. Am J Physiol, Renal Physiol 2004; 286: F599 \200\223F605. Investigation of hypermagnesemia The investigation of hypermagnesemia is very similar to th at for hypomagnesemia. In the presence of hypermagnesemia, FeMg <2% indicates inappropriate renal conservation of magnesium, whereas FeMg of >2% is compatible with an appropriate ren al response. Kroll MH, Elin RJ. Relationships between magnesium and protein concentrations in serum. Clin Chem 1985; 31 244 \200\223246. Long-Jun D, et al. Magnesium transportation in the renal distal convo- luted tubule. Physiol Rev 2001; 81: 51 \200\22384. Topf JM, Murray PT. Hypomagnesaemia and hypermagnesaemia. Rev Endocr Metabol Dis 2003; 4: 195 \200\223206. Internet resources Review of hypomagnesemia: Treatment of hypermagnesemia Mild magnesium toxicity requires no treatment except to stop f urther administration of magnesium. For symptomatic patients with cardiovascular toxicity a nd respiratory depression, 10 mL of 10% calcium gluconate is given IV and slowly over 10 mi n, and can be repeated as necessary. Calcium gluconate will antagonize the effects of the h igh magnesium concentration. Volume expansion with normal saline followed by IV furo- semid e will greatly increase FeMg. Serum potassium should be monitored. Hemodialysis or peritone al dialysis with a low or zero mag- nesium dialyzate may be necessary and will reduce serum magnesium by 30 \200\22350% within 3 \200\2234 h. Repeated dialysis treatment may be neces sary. http://www.emedicine.com/emerg/topic274.htm Review of hypermagnesemia: http://www.intox.org/databank/documents/treat/ treate/trt23_e.htm See also Hypo-/hypercalcemia, p. 52 Hypo-/hyperkalemia, p. 46 Hypokalemic tubular disorders , p. 200 Further reading Agus ZS. Hypomagnesaemia. J Am Soc Nephrol 1999;10:1616 \200\2231622. Ameri can Heart Association Guidelines for: Cardiopulmonary resus- citation and emergency cardiov ascular care. Life-threatening elec- trolyte abnormalities: Circulation 2005; 112(Suppl): I V-121 \200\223IV-125. P. GUPTA AND W. MADIRA 64 Clinical acid \200\223base disorders The respiratory system contributes to acid \200\223base home- ostasis by regulating the eli mination of CO2 by the lungs. CO2 generated in the tissues passes into red blood cells down a concentration gradient and combines with water to form carbonic acid (catalyzed by carbo nic anhydrase). \200\223 and hydrogen Carbonic acid then dissociates into HCO3 ions, and t he hydrogen ions bind to reduced hemoglobin to form HHb. Through an exchange process with c hloride, the generated HCO3 This process is reversed in the lungs and the H+ ions bound \200\223 to form CO2 which to hemoglobin recombine with HCO3 diffuses into the alveoli. An increase in nonvolatile acid production lowers pH and \200\223 concentrations and leads to increased alveolar HCO3 ventilation which lowers PCO2. Thus even small changes in ventilat ion can profoundly change the hydrogen ion concentration and pH. Mixed respiratory \200\223 metabolic acid \200\223base disorders should be considered when the PCO2 is too high or too low for a given abnormal serum HCO3 In general, respiratory compensation does not entirely normalize blood pH. In any case, the buffer system would become depleted if there were no other mechanism(s) for elimination of non- volatile acids from the body. The kidneys provid e the ultimate route of excretion of nonvolatile acids. A normal daily diet generates nonvolatile acids such as sul- furic acid and phosphoric acid from protein metabolism, and lactate from anerobic breakdown of glucose. In addition, vola tile acid (CO2) is produced primarily from carbohydrate metabolism. Acid \200\223base homeo stasis maintains systemic pH within a narrow range (7.35 \200\2237.45) by the integration o f a number of physiological processes including intracellular and extracel- lular buffering , and compensatory processes in the kidneys and lungs. The kidney both excretes the acid lo ad generated from dietary protein and reclaims \201 ltered bicarbonate. The lungs mediate the excretion of CO2. Bicarbonate is the most important buffer at physiologi- cal pH. The primary changes in bicarbonate concentration are meta- bolic whereas those in CO2 concentra tion are respiratory. Respiratory causes of acid \200\223base disturbance are compen- sated for by the kidneys and metabolic causes are compen- sated for by the lungs. \200\223 passes back into plasma. Acid \200\223base homeostasis Intracellular and extracellular physiological buffers serve t o attenuate the changes in pH that would occur with retention of either acids or bases. The regulation of CO2 tension by the respiratory system and the control of the bicarbonate con centration by the kidney constitute the regulatory processes that act together with physiol ogical buffers to stabilize the arte- rial pH. The major buffer systems are comprised of: \200 a base (H+ acceptor) which is predominantly bicarbonate; \200 an acid (H+ donor) wh ich is predominately carbonic acid. The addition of acid leads to the conversion of bicarbo nate to CO2. For the pH to be maintained, CO2 is eliminated by the lungs. \200\223 concentration. The role of the kidneys in acid \200\223base metabolism The kidney \200\231s role in acid \200\223base homeostasis includes: \200\223. \200 Reclamation of \201 ltered HCO3 \200 Regeneration of HCO3 \200\223 consumed in the buffering of nonvolatile acids. Excretion of hydrogen ions buffered by phosphate or ammonia (to form of ammonium). \200\223 n H2CO3 n H2O + CO2 In order for acid \200\223base homeostasis to be maintained t he correct ratio of HCO3 H+ + HCO3 Reclamation of \201 ltered bicarbonate \200\223 that is The kidneys reclaim all of the 4 000 mmol of HCO3 \201 ltered daily. Of this amount, 70 \200\22380% occurs in the proxi- m al convoluted tubule (PCT) and the rest is reabsorbed by the thick ascending loop (TAL) of Henle (10 \200\22325%) with a minor contribution by the distal nephron (5 \200\22310%). Thi s reclamation process prevents bicarbonaturia but does not result in the elimination of aci d from the body. \200\223 to CO2 ( 5:1) is required. \200\223 ] 0.03 \227 PCO2 pH = 6.1 + log [HCO3 [H+] \210\235 PCO2 \200\223 HCO3 Therefore, any condition which alters the concentration of \200\223 or PCO2 will change th e pH. either HCO3 In addition to the HCO3 systems are physiologically important and these i nclude: \200 hemoglobin and other proteins; \200 organophosphate complexes; \200 bone apatite. The role of the respiratory system in acid \200\223base metabolism Following the addition or generation of an acid or an alkali, buffers attenuate the change in pH, but do not remove acid/alkali from the body. Excretion of hydrogen ions \200\223, the kidney must In addition to reclamation of HCO3 ex crete the hydrogen ions produced from the dissociation of H2CO3. The excreted hydrogen ions are trapped in the lumen by urinary buffers (principally phosphate and ammonia) and then e xcreted. Phosphate buffers contribute to the excretion of 20 \200\223 30 mmol of H+ per da y. The capacity of this system is limited by the \201 xed quantity of phosphate that is \201 ltered into the tubular \202 uid. \200\223/PCO2 buffer system, other buffer CHAPTER 2.6 Clinical acid \200\223base disorders 65 The remaining 20 \200\22340 mmol per day of H+ are buffered by ammonia that is generated in the renal tubule from glutamine and other amino acids. The capacity of the system can be i ncreased ten-fold in conditions where enhanced H+ excretion is required. Urine pH can vary from 4.5 \200\2238 depending on the acid \200\223base load that needs to be excreted. The P CT and the distal convoluted tubule (DCT) are able to maintain pH gradients of 1 and 3 unit s respectively. Therefore, the minimum pH of the \201 nal urine is 4.5. This acidi \201 cation process is impaired in distal renal tubular acidosis. There are many factors which regulate renal acidi \201 cation. \200\223 in the PCT is mediated by Na+/H+ Reabsorption of HCO3 exchange. The peritubular HCO3 ing PCO2 in \202 uence HCO3 A decrease in extracell ular volume enhances HCO3 sorption and vise versa. \200\223 is also stimulated by increase d Reabsorption of HCO3 arterial PCO2 and potassium depletion, and it is inhibited by hypoca pnia, PTH and phosphate depletion. Net hydrogen excretion in the DCT is in \202 uenced by the electrical gradient in the tubule cells and lumen with sodium reabsorption favoring H+ secretion. This process can be enhanced by aldosterone and the availability of buffers (NH3 and HPO4 Excessive loss of renal bicarbonate \200 Type 2 (proximal) RTA. \200 Carbonic anhydrase inhibitors, e.g. acetazolamide. Excessive loss of gastrointestinal bicarbonate \200 Diar rhea. \200 External loss of pancreatic or biliary secretions. \200 Urinary \200\223gast rointestinal connections. Increased acid production \200 Ketoacidosis (diabetes mellitus or alcohol excess). \200 Lactic acidosis. \200 Inborn errors of metabolism (methylmalon ic aciduria, propionic aciduria, isovaleric aciduria). Poisoning (ethylene glycol, methanol, salicylate, iron, paraldehyde). \200\223 concentration, pH and the prevail- Systemic effects of metabolic acidosis Metabolic acidosis may lead to a variety of changes in tissues and organs. The associated symptoms and signs will depend on the rate and magnit ude of fall of the pH and the underlying pathology. reabsorption. \200\223 reab- Cardiovascular \200 Tachycardia or bradycardia. \200 Reduced cardiac contractility. \200 Chest pain. \200 Fatal cardiac arrhythmia. \200 Vascular changes resulting in hyp otension and conges- \200\223). Disorders of acid \200\223base homeostasis Disturbances in acid \200\223base homeostasis ar e due to proc- esses that lead to either: \200 production or retention of an excess of hy drogen ions tive cardiac failure. Life-threatening hyperkalemia. Pulmonary \200 Hyperpnea. \200 Kussmaul respiratory patt ern. Gastrointestinal \200 Nausea and vomiting. \200 Abdominal pain. \200 Gastric dis tension. \200 Diarrhea. Neurological \200 Confusion. \200 CNS depression progressing to coma. Nutritional \200 Systemic in \202 ammation. \200 Increased protein catabolism and hypoalbuminemia. \200 Insulin resistance. \200 Decreased leptin. Bone \200 Decre ased function of osteoblasts. \200 Increased function of osteoclasts. \200 Increased pa rathyroid hormone secretion and action. \200 Hypercalciuria. \200 Reduced activity of 1 A-hydroxylase. Others \200 Natriuresis. \200 Hypertriglyceridemia. \200 Leukocytosis. (acidosis); or retention of bicarbonate ions (alkalosis). If these processes are severe enough then there may be: \200 increase in arterial hydrogen ion concentration (acidemia: blood pH <7.35); reduction in arterial hydrogen ion concentration (alkalemia: blood pH >7.45). Respiratory (i.e. changes in ventilation leading to altered PCO2) or nonrespiratory (metabo lic) causes are responsi- ble for these disturbances. Metabolic acidosis Metabolic acidosis is characterized by: \200 low arterial blood pH (ac idemia); \200 reduced serum HCO3 \200 decreased PCO2 ( from respiratory compensation). Etiology of metabolic acidosis Metabolic acidosis may result from: \200 inability of the kidneys to excrete the obligate dietary \200\223 concentration; hydrogen load; inappropriate loss of bicarbonate in the kidneys or the gastrointestinal tract; increase in the generation of the hydrogen ions (such as in lactic acidosis or ketoacidosis). Impaired excretion of the dietary acid load \200 Uremic acidosis (usually GFR <15 \200 \22320 mL/min). \200 Type 1 (distal) renal tubular acidosis (RTA). \200 Type 4 RTA. P. GUPTA AND W. MADIRA 66 Low serum bicarbonate ? Metabolic acidosis ? Compensated respiratory alkalosis Arterial blood gasses Low pH Low pCO2 Low HCO3 Metabolic acidosis Calculate serum anion gap \210\222 AG = Na+ \200\223 Cl 3 \200\223 reference range 12 5 mmol/l \210\222 \200\223 HCO Increased AG metabolic acidosis Lactic acidosis Ketoacidosis diabetic alcohol-associated st arvation Ingestions methanol ethylene glycol aspirin Renal failure Normal AG metabolic acidosis Renal tubular acidosis (types 1, 2 and 4) Diarrhea and other i ntestinal losses (e.g. biliary or pancreatic drainage) Carbonic anhydrase inhibitors Ureter al diversion (e.g. ileal conduit) Toluene ingestion Further investigations Serum potassium (elevated in type 4 RTA) Urine pH (>5.5 in type 1 an d possibly type 4 RTA) Urine anion gap (urine AG = Urine (Na+ + K+ \200\223 Cl \210\222)) Positive value = type 1 RTA, type 4 RTA Negative value = All other causes Urine pH after bi carbonate loading Type 2 RTA: urine pH rises Type 1 RTA: urine pH unchanged Renal imaging: type 1 RTA: nephrocalcinosis and stones Further investigations Serum lactate Urine for ketones Blood glucose Renal function tests O smolal gap Ethanol, ethylene glycol and methanol levels Salicylate level Fig. 2.6.1 Algorithm for the investigaation of metabolic acidosis. Table 2.6.1 Etiology of renal tubular acidosis (RTA) Type 1 (distal RTA) Type 2 (proximal RTA) Type 4 (distal RTA) Primary or idiopathic \200 familial \200 sporadic Primary or idiopathic \200 familial \200 sporadic Hyper-reninemic hypoaldosteronism \200 Addison \200\231s disease \200 congenital adrena l hyperplasia (21-hydroxylase de \201 ciency) \200 drugs (ACEIs, ARBs, heparin, ketocona zole) Hypo-reninemic hypoaldosteronism \200 diabetes mellitus \200 drugs (NSAIDs, cyclo sporin, tacrolimus) \200 interstitial nephritis \200 urinary tract obstruction \200 s ickle cell disease \200 gout Genetic \200 Ehlers \200\223Danlos syndrome \200 Marfan \200\231s syndrome Inherited systemic diseases (Fanconi-like syndromes): \200 cystinosis \200 galactosemia \200 Wilson \200\231s disease \200 glycogen storage disease (type 1) \200 inherited fructose tolerance \200 tyrosinemia Disorders associated with hyperparathyroidism \200 primary hyperparathyroidism \200 vitamin D de \201 ciency \200 vitamin D resistance Immunological diseases \200 Sj gren \200\231s syndrome \200 systemic lupus erythematos us \200 primary biliary cirrhosis \200 chronic renal transplant rejection \200 hyperg ammaglobulinemia Diseases associated with nephrocalcinosis \200 vitamin D toxication \200 idiopathic hypercalcuria \200 primary hyperparathyroidism Distal tubule dysfunction \200 chronic tubulointerstitial disease Drugs/toxins \200 spironolactone \200 amiloride \200 triamterene \200 trimethoprim Drugs/toxins \200 lead poisoning \200 cadmium poisoning \200 mercury poisoning \200 acetazolamide \200 gentamicin and \200 topiramate and zonisamide Miscellaneous renal d iseases \200 multiple myeloma \200 amyloidosis \200 nephrotic syndrome \200 medulla ry cystic disease \200 renal transplantation (early) Drugs/toxins \200 amphotericin \200 toluene \200 lithium Signi \201 cant volume depletion CHAPTER 2.6 Clinical acid \200\223base disorders 67 An increased OG (particularly if >25 mOsm/kg) in the presence of a high AG metabolic acidos is, without evi- dence of lactic or ketoacidosis, should prompt treatment for methanol/ethy lene glycol intoxication (i.e. ethanol infusion) pending results of methanol and ethylene g lycol assays. Evaluation of metabolic acidosis The following investigations are required to evaluate pati ents with suspected metabolic acidosis (reduced serum bicarbonate). An algorithm for the ev aluation of such patients is described in Fig. 2.6.1. Renal tubular acidosis (RTA) Hyperchloremic, normal AG metabolic acidosis is the hall- mark of renal tubular acidosis. RTA results from a defect in tubular function which causes a de crease in either net tubular hydrogen secretion or \200\223 HCO3 There are three main type s of RTA: \200 type 1 (distal); \200 type 2 (proximal); \200 type 4. The causes of th ese forms of RTA and the clinical differ- ences between them are indicated in Tables 2.6.1 and 2.6.2 respectively. Renal tubular acidosis is discussed in more detail in Chapter 5.3. Initial investigations Step 1 Measure the blood pH on an arterial blood sample (arterial bl ood gasses (ABGs)) to: \200 con \201 rm the presence of acidemia \200\223 \200 exclud e respiratory alkalosis as cause of low HCO3 Step 2 Calculate the serum anion gap: \200 \223 + Cl \200\223) \200 Serum AG = Na+ \200\223 (HCO3 \200 (reference range 12 5 m mol/L) or \200 Serum AG = (Na+ +K+) \200\223 (HCO3 \200 (reference range 16 5 mmol/ L). In the critically ill patient, a correction for the albumin concentration (AGc) may be necessary: AGc = AG + 0.25[40 \200\223 albumin] reabsorption. \200\223 + Cl \200\223) Uremic acidosis Metabolic acidosis occurs in renal failure due to a decreased ability to ex crete H+ or due to an inability to produce ammonia. In the early stages of chronic kidney d isease (CKD) (GFR <40 mL/min), metabolic acidosis with a normal anion gap (AG) (see below) may become evident. As CKD progresses (GFR <20 mL/min) a high AG metabolic acidosis may res ult. In 80% of patients with CKD and GFR <20 \200\22330 mL/min, there is mild to moderate metabolic acidemia with the pH usually remaining >7.2 and bicarbonate levels of 12 \200\223 22 mmol/L. In advanced CKD an increased AG is typical due to the presence of retained acids such as sulfates, phosphates, urate and hippurate. The presence of normal AG acidosis in t his setting would imply a second pathology such as \200\223 wasting. HCO3 \200\223 concen tration <10 mmol/L and an AG A serum HCO3 >20 mmol/L are infrequent in renal failure and ma y be indicative of coexistent disorders, e.g. lactic acidosis or ketoacidosis. \200\223 an d pH in dialysis patients are Serum levels of HCO3 determined by the dialysis process, exog enous alkali inges- tion and endogenous acid production. \200\223] of 17.5 \200\223 In hem odialysis patients, a predialysis [HCO3 20 mmol/L has been shown to be associated with the lowest risk of death. Postdialysis metabolic alkalosis which may result from complete corre ction of predialysis metabolic acidosis may lead to hypoventilation, phosphate transfer int o cells and vascular calci \201 cation. Although there is no general agreed guidance on th e optimal pre-dialysis bicarbonate concentration, a value of 20 \200\22326 mmol/L has been recommended as good practice. The anion gap will be either: \200 normal: due to the presence of an acid in which the an ion is Cl \200\223 (hyperchloremic metabolic acidosis); or \200 high: due the presence of an acid in which the anion (unmeasured) is not Cl \200\223 The causes of \200\230normal \200\231 and \200\230high \200\231 AG metabolic acidosis are listed in Fig. 2.6.1.