NSAIDs (indometacin) if i u-PGE2. ACE-I may help normalize K + . Often dif \201 cult to treat and demanding of patient (child!) compliance. Gitelman \200\231s syndrome Autosomal recessive inheritance, characterized by hypomagnesaem ia, hypokalaemia with hypocalciuria, and metabolic alkalosis. Heterogeneous loss-of-function mutations largely affecting the SLC12A3 gene encoding the th iazide-sensitive Na-Cl co-transporter in the DCT, with impaired Na + reabsorption. i Na + l oss leads to s hyperaldoster- onism and a hypokalaemic metabolic alkalosis. It is, in effec t, what is seen with thiazide diuretic use . Increased urinary Mg 2+ loss, with signi \201 - cant hypomagnesaemia, is thought to occur as a result of a reduction in TRPM6 (an epithe lial magnesium channel) density in the DCT. BARTTER \200\231S, GITELMAN \200\231S AND LIDDLE \200\231S SYNDROMES 801 Diagnosis In young adults, with often asymptomatic d K + (2.0 \200\223 3.0mmol/L). May be weakness and myalgia, and symptoms of d urinary concentrating ability (nocturia, in particular, polyuria, and polydipsia). Investigations Include d Mg 2+ . Mild metabolic alkalosis. i renin, i aldosterone. Urinary u-PGE2 is not raised (unlike Bartter \200\231s). Genetic testing is available though not wi dely so. Treatment Generally good prognosis. Amiloride 5 \200\223 40mg od 9 K + supplementation ( b p. 799). No role for NSAIDs. Liddle \200\231s syndrome Autosomal dominant inheritance. Caused by gain-of-function mutations in ENaC (epithelial so dium channel expressed on the apical surface of collecting duct cells), resulting in a fail ure to endocytose ENaC from the surface membrane of collecting duct cells. Constitutive ove rexpression leads to i Na + reabsorption which leads to d BP 9 oedema. Enhanced Na + uptake renders the lumen more electronegative, opening the tran- sepithelial ROMK K + channel, le ading to K + wasting and a hypokalaemic metabolic alkalosis. Aldosterone is appropriately s uppressed. Diagnosis In young hypertensives (often with severe i BP and a +ve family history), with d K + (may be mild) and mild metabolic alkalosis. d renin, d aldoster- one (see Table 10.3). Treatment Low-salt diet (<100mmol/day) 9 amiloride 5 \200\223 10mg od (or triamterene \200\224 directly inhibits ENaC). Table 10.3 Differentiating inherited channelopathies Bartter \200\231s Gitelman \200\231s Liddle \200\231s N/ d i BP N K + d d d Mg 2+ N or d d N i u-PGE2 N N i i d Aldosterone Age Infancy Early adulthood Childhood CHAPTER 10 Fluids and electrolytes 802 Calcium, magnesium, and phosphorus Calcium 99% of total body Ca 2+ ( 7 1kg) is stored in bo ne. Extracellular Ca 2+ accounts for a small fraction: of this; 7 40% is bound to albumin, with 50% available as physiologically active, free (or ionized) Ca 2+ . The remainder is co m- plexed with anions, such as bicarbonate or phosphate. Free intracellular Ca 2+ is found at 10 4 higher a concentration than in the extracellular space, a gradient maintained by an energy-dependent membrane Ca 2+ ATPase. Intracellular Ca 2+ is key to many signaling pathw ays within cells \200\224 Ca 2+ is also important in skeletal health, membrane function, n euromuscular integrity, and coagulation. The serum normal range is 2.1 \200\223 2.5mmol/L ( 7 1.2mmol/L ionized), with Ca 2+ availa ble from both the gut and bone stores. Gut Ca 2+ absorption occurs via transcellular (uptak e via TRPV6, the apical Ca 2+ channel with subsequent energy-dependent basolateral ef \202 ux) and paracellular path- ways. Uptake is under the control of (active) 1,25(OH) 2 vitami n D 3 . The ionized fraction is freely \201 ltered across the glomerulus and mainly reabsorbed in the PCT and loop of Henle. Most Ca 2+ is resorbed paracel- lularly along a concentration g radient, but TRPV5 regulates (the \201 nal 10% of total) distal calcium uptake in a PTH- and vitamin D-dependent manner. Urinary Na + is able to strongly in \202 uence urinary Ca 2+ excretion: in the thick ascending loop of Henle, i Na + delivery forces i Na + uptake, a t the expense of Ca 2+ resorption l hypercalciuria. This is a key factor in stone formation ( b p. 716). Falling Ca 2+ activates parathyroid calcium-sensing receptors (CaRs), leading to parathyroi d hormone (PTH) release. PTH increases renal tubu- lar Ca 2+ reabsorption and hydroxylation of vitamin D 3 to the active metab- olite, increasing intestinal uptake. PTH also enhances bone osteoclastic activity. There is also evidence that PTH receptors are present on cells not directly involved in calcium homeostasis (such as endothelial cells and cardiomyocytes ), suggesting that PTH may have effects beyond its role in calcium/phosphate regulation. Magnesium Magnesium (Mg 2+ ) is the fourth most common cation in the body and is found larg ely in the intracellular compartment or stored in bone. Only 1% of the 25g total body Mg 2+ is in the ECF, with the majority found in bone or muscle. It is a key component of ATP-req uiring reactions and is necessary for the synthesis of protein and maintaining membrane fun ction, nerve conduction, and muscle contraction. Mg 2+ , like Ca 2+ , also regulates PTH secretion \200\224 d Mg 2+ leads to PTH release and vise versa. Profound d Mg 2+ l symptomatic d Ca 2+ . The normal range is 0.75 \200\223 0.95mmol/L in plasma. The kidney dominates the control o f Mg 2+ homeostasis. Mg 2+ is absorbed from the gut and freely \201 ltered across the glo merulus. In health, 70% is then reabsorbed in the thick ascending loop of Henle (TALH) \200\224 the strongly negative paracellular CALCIUM, MAGNESIUM, AND PHOSPHORUS 803 protein paracellin-1 allows ef \201 cient absorption of the cations Mg 2+ and Ca 2+ under control of both PTH and the calcium-sensing receptor. Fine control is achieved in the DCT w here the transmembrane (transcel- lular) protein TRPM6 allows further uptake. Loss of funct ion of either paracellin-1 or TRPM6 leads to urinary Mg 2+ wasting and d Mg 2+ . Phosphorus Phosphorus occurs largely as the inorganic fraction phosphate in the cir- culati on. Organic phosphorus exists as protein-bound phospholipids and is not measured in clinica l practice. Phosphate is essential to almost all biochemical systems. Absorbed by the type II sodium/phosphate co-transporter (NaPi) from the intestine, again in a vitamin D 3 -dependent manner, 80% is found in bone. The normal range for plasma phospha te is 0.8 \200\223 1.4mmol/L (higher in children). Freely \201 ltered in the kidney, it is largely reabsorbed in the PCT (depending on oral intake) by the type II NaPi. Tubular reabsorption of phosphate is controlled by PTH (which inhibits reabsorption) and al so by \201 broblast growth factor 23 (produced by osteo- cytes which leads to lower level s of serum phosphate by reducing tubular reabsorption and by inhibition of 1 A -hydroxylati on of vitamin D). CHAPTER 10 Fluids and electrolytes 804 Hypocalcaemia Total serum Ca 2+ is low with d albumin, though the free fraction may be norm al. Always correct for albumin: Corrected Ca 2+ = measured Ca 2+ + [40 \200\223 serum Alb] \227 0.02 Causes of hypocalcaemia \200 Vitamin D de \201 ciency: Malnutrition (osteomalacia). \200 Malabsorption (gastrectomy, short bowel, coeliac diseas e, chronic pancreatitis). CKD (loss of 1 A -hydroxylase). \200 Vitamin D-dependent rickets (anticonvulsants, nephro tic or Fanconi syndrome). \200 Hypoparathyroidism: Post-parathyroidectomy \200\224 \200\231 hungry bone syndrome \200\231 ( b p. 254). (cid:2) Inadvertent after thyroidectomy! \200 Inherited, pseudohypoparathyroidism. Hyperphosphataemia ( i phosphate increases bone Ca 2+ deposition): Tumor lysis ( b p. 160). \200 Rhabdomyolysis ( b p. 152). \200 Administered or ingested . Acute pancreatitis. \200 d Mg 2+ . \200 Acute alkalosis (reduction in ionized calcium). Symptoms and signs Depression and anxiety, (perioral) paraesthesiae, carpopedal spasm, tet- any, respiratory depression, convulsions, hypotension, and arrhythmias. Examine for Chvost ek \200\231s sign (tap over the parotid for facial muscle twitch- ing, as CN VII excited) a nd Trousseau \200\231s sign (occlude brachial artery with BP cuff in \202 ated > SBP; obse rve wrist and \201 nger \202 exion). If chronic, cata- racts, dry skin, dental changes, bone pain, and muscle weakness 9 skeletal deformities. Investigations 2 ECG: prolonged QT interval. U&E, Ca 2+ , phosphate, Mg 2+ , alkaline phosp hatase, and intact PTH. If appropriate, amylase, CK, urate. Consider 25-(OH) vitamin D 3 an d 1,25-(OH) 2 vitamin D 3 . Consider X-ray long bones and hands. Treatment 2 Only treat if symptomatic 9 acute. If mild (>1.9): increase dietary Ca 2+ . Add in oral Ca 2+ (e.g. calcium car- bonate) 0.5 \200\223 1.5g tds 2 hours after meals. If vitamin D-de \201 cient, oral ergo- calciferol ( inactive vitamin D) or colecalciferol 10 micrograms \200\223 1mg od, usually in a preparat ion with Ca 2+ . If d , Mg 2+ supplement, as described on b p. 808. HYPOCALCAEMIA 805 (cid:2) If acute or symptomatic, infuse Ca 2+ at 2mg/kg/h: start IVI 10% calcium gluconate 60mL in 500mL 5% glucose or 0.9% saline at 125mL/h. Recheck Ca 2+ at +4 hours, and adjust i nfusion rate accordingly. (cid:2) If tetany, give 10mL 10% calcium gluconate 10mL (2.2mmol) IVI over 3 minutes ( (cid:2) extravasation). Repeat, if necessary, or infusion as describe d. CHAPTER 10 Fluids and electrolytes 806 Hypercalcaemia Usually the result of increased absorption from gut, bone resorption, or bot h. Due to increased PTH or analogs, or osteolytic metastases. Mild i Ca 2+ (2.6 \200\223 2 .9mmol/L) is usually asymptomatic, but rapidly evolving i Ca 2+ >3.5 may be fatal. Symptoms and signs \200\230 Bones, stones, groans, and psychic moans \200\231 . Nausea, a bdominal pain, anorexia, constipation, depression, confusion, polydipsia, and polyuria. Deh ydration (? postural drop), renal calculi, nephrocalcinosis. Signs from associated malignan cy. Take a full medication history (milk-alkali syn- drome) (see Table 10.4). Causes \200 p hyperparathyroidism (10 \200\223 20%) \200\224 less commonly tertiary wit h CKD. \200 Malignancy: Local osteolytic bone lesions. \200 Humoral hypercalcaemia (tumor-derived PTH-related pro tein PTHrP has similar actions to PTH). Common cancers include breast, lung, myeloma, ovary, lymphoma, esophagus, renal, prostate, and head and neck primaries. \200 Granulomatous diseases (sar coidosis, TB) activated macrophages 1 A -hydroxylase vitamin D. Drugs (vitamin D, vitamin A, lithium, thiazide diuretics). \200 Immobilization (repetitiv e mechanical skeletal stress prevents bone and mineral loss). Thyrotoxicosis, (phaeochromocytoma), milk-alkali syndrome (antacids, calcium carbonate therapy). Familial hypocalciuric hypercalcaemia: due to dysfunction of the calcium-sensing receptor. Investigations \200 U&E, Ca 2+ , phosphate, alkaline phosphatase, albumin. \200 PTH 9 P THrP, 25-(OH) and 1,25-(OH) 2 vitamin D 3 . If indicated, serum ACE, protein electrophoresi s, urinary Bence \200\223 Jones proteinuria, serum free light chains, PSA. CXR. Plain KUB. Consider CT. 2 ECG: short QT interval. Treatment \200 Treat the underlying cause: Stop drugs which cause i Ca 2+ . \200 p hyperparathyroidism: either cinacalcet or surgery if end-organ damage or uncontrolled hypercalcaemia. Malignancy: surgical resection, radiotherapy, bisphosphonates. Corticosteroids (prednisolone 30mg od) is effective when i Ca 2+ is driven by increased ext rarenal (macrophage or tumor) 1,25-(OH) 2 vitamin D 3 synthesis. HYPERCALCAEMIA 807 Treat the calcium if symptomatic \200 Mild hypercalaemia (<3.0): increase \202 uid inta ke 9 salt intake (promotes u-Ca 2+ loss). Aim to treat underlying cause. (cid:2) Severe i Ca 2+ (>3.0): Vigorous rehydration with 0.9% saline, initially at 250 \200\223 500mL/h, aiming for +2L p ositive balance (and giving 3 \200\223 5L/day). 2 Assess \202 uid balance regularly. Furosemide (increases renal i Ca 2+ wasting) 10 \200\223 20mg 4-hourly, or as IVI infusion (5 \200\223 40mg hourly). Do not dehydrate. If urgent control required (and volume-resuscitated), calcitonin 4 \200\223 8IU/ kg SC/IM (inhibits osteoclast activity, promotes urinary calcium excre- tion). Repeat 12-hourly. Mus t add on bisphosphonate therapy, as tachy- phylaxis develops. Bisphosphonates are powerful and prolonged inhibitors of osteoclasts. Options include zoledronic acid (4 \200\223 8mg in 100mL in 0.9% saline over 30min, duration of effect 30 days) or pamidronate (60 \200\223 90mg in 500mL 0.9% saline o ver 4h. Effect 7 7 days). Monitor SCr. Treat d K + or d Mg 2+ with IVI supplements. If signi \201 cant hyperparathyroidism associated with hypercalcaemia, cina- calcet 30mg o d, dose rapidly titrated upwards, if tolerated. 2 Hypercalcaemia in ESRD may need treatment by haemodialysis. Will rapidly lower Ca 2+ and should be considered if Ca 2+ >3.5 or depre ssed level of consciousness. Table 10.4 Distinguishing p hyperparathyroidism from malignancy Humoral Ca 2+ of malignancy n or i d HPT Metastases to bone n or i d d Phosphate i PTH d n i i d PTHrP d d n n Albumin i Chloride d d pH CHAPTER 10 Fluids and electrolytes 808 Hypomagnesaemia Occurs in up to 12% of hospitalized patients. Often exacerbated by under- n utrition, chronic diarrhea, diuretics, nephrotoxins. Those with diabetes are particularly p rone to d Mg 2+ . Causes include: \200 Renal: Diuretic use (loop or thiazide) or prolonged natriuresis. \200 Recovery phase of obstruct ion or ATN. \200 Nephrotoxins (aminoglycosides, cisplatin, ciclosporin, amphotericin, foscarnet, pentamidine). Hypercalciuria or phosphate depletion. \200 Gitelman \200\231s or Bartter \200\231s syndr omes ( b p. 800) or familial hypomagnesaemia-hypercalciuria. Gut: Gut losses due to diarrhoeal disease, prolonged NG suction, intestinal surgery, or malabsorption. Pancreatitis (saponi \201 cation in necrotic fat). \200 Alcohol abuse. Symptoms and signs d Mg 2+ occurs in conjunction with d K + (50% of cases), d Ca 2+ , and a metabolic alkalosis. Weakness, cramps, carpopedal spasm, positive Chvostek \200\231s and T rousseau \200\231s signs ( b p. 804), tetany, and convulsions may occur. Delirium, movement disorders, vertigo, and nystagmus also occur. Signi \201 cant d Mg 2+ may induce supra- o r ventricular arrhythmias. Investigations d Mg 2+ , d K + (<3.0mmol/L). Hypokalaemia is often resistant to K + sup- pl ementation until Mg 2+ is normalized. d Ca 2+ (if Mg 2+ <0.5mmol/L), with inappropriately l ow/normal PTH. (cid:2) ECG changes: i QRS width, i PR interval, \202 attened T waves. Fat al ventricular arrhythmias in the context of underlying heart disease (esp. acute coronary syndromes and CCF). 24h urinary Mg2+ (NR <10 \200\223 30mg/day) or fractional excretion of Mg2+ will distingui sh renal losses from other causes of d Mg2+ but is not usually required for diagnosis. Treatment \200 Asymptomatic with modest d Mg 2+ (>0.4mmol/L): oral slow-release Mg 2+ 6 \200\223 18mmol/day in four divided doses. Preparations include Mg glycerophosphate or Mg o xide. Symptomatic , or with hypocalcaemia or hypokalaemia: 10mmol MgSO 4 IVI bolus over 5min, the n 20mmol MgSO 4 in 100mL 0.9% saline IVI over 4 hours. Repeat, as required. 2 Can be given as a painful IMI. Oral supplementation once Mg 2+ >0.5mmol/L with 18 \200\223 24mmol Mg 2+ / day in four divided doses. Diarrhea may limit use of oral Mg 2+ . 3 With arrhythmias (e.g. torsade de pointes): IVI MgSO 4 4 \200\223 8mmol stat, then 20mmo l/12-hourly against plasma Mg 2+ . Aim for >0.4mmol/L. HYPOMAGNESAEMIA 809 50% of administered Mg 2+ will be lost in the urine, so prolonged therapy may be needed. Th e total body de \201 cit in symptomatic d Mg 2+ may be 0.5 \200\223 1mmol/kg body weight, so up to 150mmol may be required over 5 days (with urine losses). In diuretic-induced chro nic Mg 2+ wasting states, add-on amiloride 5mg od may limit Mg 2+ losses. CHAPTER 10 Fluids and electrolytes 810 Hypermagnesaemia Urine losses of Mg 2+ can compensate for rising plasma Mg 2+ , so i Mg 2+ is unusual. Occurs usually if excess Mg 2+ administered IVI (as in treating pre-eclampsia) or in patients with impaired renal function given exoge- nous Mg 2+ . Mg 2+ -containing pre parations include: antacids (Mg 2+ hydroxide or carbonate), MgSO 4 enemas. Clinically i Mg 2+ depresses the CNS and reduces neuromuscular function through increasing resistance to ac etylcholine-induced depolarization at the neu- romuscular junction. Paraesthesiae and hypor e \202 exia (Mg 2+ >2.0mmol/L) progress to weakness, swallowing dif \201 culty, and respi ratory depression (Mg 2+ >3.5mmol/L). Bradycardia and d BP with severe toxicity (>3.5mmol/L). ECG: i PR and QT interval. May also see mild hypocalcaemia due to Mg 2+ -induced inhibition of PTH secretion. Treatment If clinically stable, with a good UO and normal renal function, stop Mg 2+ -conta ining preparation, and monitor. Excess Mg 2+ will be rapidly renally excreted. 2 If respira tory depression, cardiac arrhythmias or Mg 2+ >5 mmol/L, give IVI calcium gluconate 10% 10m L as slow IVI bolus. May require repeated doses. Consider forced Mg 2+ diuresis with IV furosemide 40 \200\223 80mg, replacing UO on a mL/mL basis with 0.45% NaCl. In patients with impaired renal function, haemodialysis provides rapid and effective normal ization of Mg 2+ . Expect normalization of Mg 2+ within 4 hours. HYPERPHOSPHATAEMIA 811 Hyperphosphataemia Almost always occurs in patients with renal impairment. Calcium and phos - phate are at the limits of solubility in plasma, so i calcium x phosphate product leads t o precipitation and ectopic calci \201 cation. Over time, this leads to vascular calci \201 cation (and is associated with i mortality in CKD). s hyperparathyroidism will attempt to i renal losses as compensation. Usually asymptomatic, causes include: CKD. \200 Tumor lysis ( b p. 160) and rhabdomyolysis ( b p. 152). \200 Hypoparathyroidi sm. \200 Phosphate-containing enemas (usually with renal impairment). \200 Vitamin D to xicity. No treatment is usually required in the acute setting though, if with d Ca 2+ (tumor lysis, rhabdomyolysis), can be life-threatening. 2 If so, give 10IU soluble insulin in 100mL 50% glucose over 30 minutes. This works by redistributing PO 4 \200\223 into cells. Promote di uresis through volume resuscitation (0.9% NaCl). If chronic, aim to restrict dietary phosphate; use oral phosphate binders to limit uptake and in those with ESRD and dialysis. For a fuller discussion, see b p. 246. CHAPTER 10 Fluids and electrolytes 812 Hypophosphataemia Important hypophosphataemia occurs in 9 1% of hospitalized patients, part icularly chronic abusers of alcohol , diabetics , and those on TPN . 2 Becomes clinically m eaningful <0.4mmol/L. Causes include: \200 Redistribution: Refeeding in malnourished (alcoholic) patients. * \200 Respiratory alkalosis ( i pH intra cellularly stimulates glycolysis). * \200 Exogenous insulin administration (DKA, critical care). * \200 Hungry bone syndrome (massive Ca 2+ and PO 4 \200\223 deposition). i renal losses: Hyperparathyroidism. \200 Impaired vitamin D metabolism. \200 Renal tubular disorders ( Fanconi syndrome), ATN, or resolving obstructive uropathy. Gut uptake: Malnutrition or vitamin D de \201 ciency. \200 Chronic diarrhea or malabsorption. \200 Antacid abuse. \200 Inappropriate use of phosphate binders (calcium carbonate, sevalamer, or lanthanum). Note: reduced phosphate intake alone rarely causes hypophosphataemia due to compensatory in creased renal phosphate reabsorption. Symptoms and signs Largely due to falling intracellular ATP levels and red cell 2,3-DPG (wi th impaired O 2 release from hemoglobin). Proximal muscle weakness l spontaneous rhabdomyol ysis ( 9 diaphragmatic weakness and underventila- tion), ileus, myocardial depression (even heart failure), haemolysis, throm- bocytopenia. altered mental state and \201 ts, if pro longed, osteomalacia. Investigations Urine pH, U&E, bicarbonate, Ca 2+ , phosphate. If indicated, PTH, FGF-23, 25 -(OH) vitamin D 3 , calcitriol. Urine phosphate determines if low phos- phate is due to ren al losses or due to redistribution/reduced gut uptake. 24h urine phosphate <16mmol/day = no n-renal cause. Treatment If phosphate >0.4mmol/L, i dietary phosphate (milk and dairy products). Oral phos phate (e.g. Phosphate-Sandoz ) 1g tds (3g = 7 100mmol). 2 If <0.4mmol/L or, if criticall y unwell, IVI phosphate (eg Addiphos ) 0.15mmol/kg in 500mL 5% dextrose or feed over 12 hours. Calcitriol PO or IVI may reduce urinary phosphate losses. Check Ca 2+ repeatedly (as phosphate may precipitate sudden hypocalcaemia and tetany). Glycolysis = intracellular shift of phosphorylated glucose metabolites. HYPOPHOSPHATAEMIA 813 CHAPTER 10 Fluids and electrolytes 814 Acid \200\223base Understanding normal physiology The concentration of hydrogen ions ([H+]) is tightly controlled within and without cells, in various tissues and \202 uid compartm ents of the body. A key function of the kidneys is to regulate the blood [H*] and consequen tly total body [H*]. pH is the negative logarithmic expression of the concen- tration of hy drogen ions in any \202 uid. In the ECF, pH is maintained within a normal range of 7.38 \200\223 7.42 where [H + ] at pH 7.40 is 40nmol/L \200\224 at pH 7.0 (the intracellular pH ), [H + ] = 100nmol/L. Remember the pH of water is 6.8 \200\224 note the role of buffers i n biological \202 uids. Intake and generation Acid loads can be categorized as volatile (CO 2 ) and non-volatile. N on-volatile acid loads can be subdivided into metabolizable (via inter- mediary metabolism, e.g. lactic acid) and non-metabolizable (e.g. HCl). Non-metabolizable acid amounts to 1mmo l/kg acid/day in adults, largely derived from the breakdown of ingested protein (sulfur-con taining amino acids l H 2 SO 4 ) and by-products of cellular metabolism. Metabolizable acids are eventually metabolized to CO 2 and H 2 O, so eliminating the acid. The addition of salts of metabolizable acids (e.g. sodium lactate) to the body are equivale nt to the addition of bicarbonate, as a proton will be used to metabolize lactate to CO 2 a nd H 2 O (resulting in a net generation of bicarbonate). It is this principle that allows f or the use of acetate and lactate as buffers in various forms of renal replacement therapy. Buffering To prevent rapid changes in pH with i dietary intake or excess production of [H + ], e.g. during exercise, a system of local (tissue) and systemic buffers has evolved. Thes e buffers include: \200 Bicarbonate (HCO 3 \200\223 ). \200 Bone salts (calcium carbon ate and calcium phosphate). \200 Blood proteins (albumin, hemoglobin, and other globulins ). In the short term, bicarbonate is, by far, the most important, though bone buffers play a m ore signi \201 cant role in chronic acidosis. ACID \200\223BASE 815 Acid math 3 \206\224 H 2 CO 3 \206\224 CO 2 + H 2 O H+ + HCO \200\223 Adding H + (acidosis) consumes bicarbonate and generates CO 2 , as the reaction is driven r ightwards. Removing CO 2 (hyperventilation) returns the pH toward normal, according to the Henderson \200\223 Hasselbach equation: pH = pK log [HCO \200\223 3 ] where pK = 6.1, the dissociation coef \201 cient of carbonic acid (H 2 CO 3 ). This does not generate more bicarbonate, so the kidney has to i H + excretion to balance the system. Models of acid \200\223base balance There are two principal models to explain the physiolog ical acid \200\223 base balance. \200 The traditional \200\230 base excess \200\231 mo del (see Fig. 10.1). \200 Stewart \200\231s theory \200\224 see M http://www.acidbase.or g . Base excess (traditional method) Building on the work of Singer and Hastings, Siggaard \200\223 Andersen intro- duced the concept of \200\230 base excess \200\231 (BE) in 1960. De \201 ned as the number of mmol of acid or base that are needed to titrate 1L of blood to pH 7.40 at 37 * C in the presence of a p CO 2 of 5.33kPa (40mmHg). The base excess allow s differentiation between metabolic and respiratory acidosis/ alkalosis. The term \200\230 base de \201 cit \200\231 is synonymous with negative values of base excess (i.e. metabo lic acidosis). Values for HCO 3 and BE are derived from the directly measured vari- ables of pH, p CO 2 , and Hb. CHAPTER 10 Fluids and electrolytes 816 pCO2 in arterial blood (mm Hg) 150 (kPa) 20.0 19.0 18.0 17.0 16.0 15.0 BASE EXCESS A L excess concentration of BASE in extracellular fluid M R O 140 N +10 +15 +20 +25 +30 (mmol/l) +5 0 130 BASE DEFICIT 120 \200\2235 110 14.0 \200\22310 100 13.0 C H A R C \200\22315 O U 12.0 90 T N I E C H 11.0 Y H P Y 80 E P R E \200\22320 C R 10.0 H Y P E R C A P N A A C P A P N I 70 N A I 9.0 A 8.0 60 I N IC B A S E E X C E SS O 7.0 R H C 50 concentration of BICARBONATE in plasma (mmol/l) 1 6.0 \200\22325 N O R M A L NORMAL 40 10 E D E 15 50 20 30 40 AREA 5.0 F I C I T 35 S A E B T U C H R O N C A 30 4.0 H Y P O C A P N A I C H Y P O C A P N A 3.5 25 A C I 3.0 U T FICIT E D S A NIC B E I H Y 20 P E E R C 2.5 A P N I A O R H C 15 2.0 \200\22330 pH in arterial plasma 1.5 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 6.9 90 80 70 60 ACIDEMIA 50 40 NORMAL 35 25 30 ALKALEMIA 20 140 \200\234concentration \200\235 of HYDROGEN ION in plasma (nano mol/l) 120 100 Fig. 10.1 Siggaard \200\223 Andersen acid \200\223 base chart. Reproduced with permission from Astrup P, Severinghaus JW: The History of Blood Gasses, Acids and Bases. Copenhagen, Munksgaard, 1986. ACID \200\223BASE 817 CHAPTER 10 Fluids and electrolytes 818 Excretion: the kidney in acid \200\223base Preventing bicarbonate loss 80 \200\223 90% of \201 ltered HCO 3 \200\223 is actively reabsorbed in the proximal tubule: \200 Proxima l tubular cell Na + is pumped basolaterally into the interstitium, creating an inward gradient l Na + movement from the lumen. \200 NHE-3, the Na + /H + ant iporter, allows Na + entry from the lumen, exchanged for H + . In the lumen, H + + HCO 3 \200\223 = H 2 CO 3 (carbonic acid). \200 Luminal carbonic anh ydrase then l CO 2 and H 2 O, taken up into cells. \200 Intracellular carbonic anhydrase then l H + + HCO 3 \200\223 . \200 Intracellular HCO 3 \200\223 is then transported int o the peritubular capillaries. \200 The remaining H + is available for recycling. Excreting proton \200 Almost all H + in the proximal tubule is reabsorbed with HCO 3 \200\223 . \200 Acid excretion occurs in the collecting duct. \200 Na + absorbed under the in \202 uence of aldosterone (in the principal cells, b p. 931) means the tubular lume n becomes increasingly electronegative. K + is secreted from principal cells, and H + is secreted from A -intercalated cells into the lumen (aldosterone acts directly on this cell \200\231s H + -ATPase to effect this) to maintain electrical neutrality. Buffering urinary proton The luminal pH rapidly falls to <4.0, inhibiting A -intercalated c ell H + -ATPase. For ongoing net acid excretion, urinary H + is buffered (to keep u-pH >4.0 ) by: \200 Titratable acids (H + incorporated into phosphoric acid H 3 PO 4 or sulphuric acid H 2 SO 4 ). Ammonium (NH 4 + ). In health, titratable acids and ammonium carry 9 50% of the dietary H + load, but, with metabolic acidosis, more ammonium is needed for acid excretion. EXCRETION: THE KIDNEY IN ACID \200\223BASE 819 Ammonium Proximal tubular cells deaminate glutamine to form bicarbonate and ammonia (NH 3 ) , then released and acidi \201 ed in the lumen as NH 4 + . \200 NH 4 + is absorbed into the medullary interstitium from the ascending limb of the loop of Henle where it dissociate s to form NH 3 and H + once more. NH 3 can now move down a concentration gradient into the lumen of the collecting duct, avai lable to buffer H + , and is then excreted as NH 4 Cl in the urine. Ammonia synthesis is enhanced by acidosis and d K + . The urine anion gap (UAG) = u-[Na + + K + ] \200\223 u-[Cl \200\223 ]. This difference is urinary NH 4 + . If the kidney responds normally to aci- dosis (non-renal acidosis), it wi ll i NH 4 + excretion to waste H + into the urine. The UAG will then be negative (as i Cl \200\223 will accompany i NH 4 + ). If the renal response is inappropriate (e.g. RTA, b p. 824), the UAG will be 0 or positive. CHAPTER 10 Fluids and electrolytes 820 Metabolic acidosis Acidosis occurs if the systemic pH falls <7.35 and is considered metabol ic in origin if d [HCO 3 \200\223 ]. This occurs through: \200 i bicarbonate losses (gut or kidney). \200 i acid retention. \200 Excessive acid production or administration (H Cl). \200 Administration of Cl \200\223 -rich solutions during resuscitation. With pure metabolic acidosis, compensation occurs through increasing ventilation and blowin g off CO 2 ( d p CO 2 ). Why do chloride-rich solutions lead to acidosis? Solutions, such as 0.9% NaCl, normal salin e, are bicarbonate-free. Falling bicarbonate is replaced by chloride (Cl \200\223 ) withou t a proportional d in p CO 2 . This is a so-called \200\230 dilution acidosis \200\231 . In determining the cause of a metabolic acidosis, it is helpful to estimate the anion gap \200\224 this may be calculated for both the plasma and urine (UAG, b see below). In health , the difference between cations and ani- ons is made up of organic (negatively charged) ac ids. An i AG occurs if acids, other than carbonic acid ( l phosphate, lactate, or sulfate), accu- mulate or i exogenous acids are added to plasma. Calculating the anion gap \200 AG = [Na + + K + ] \200\223 [Cl \200\223 + HCO 3 \200 \223 ] = 8 \200\223 16 in health. \200 Albumin is negatively charged: d Alb l underestim ates the AG. \200 To correct for hypoalbuminaemia, add 0.25 x (44 \200\223 s-Alb) to the AG. \200 In the USA, the contribution of [K + ] to the anion gap is frequently ignored. UAG = u[Na + + K + ] \200\223 u[Cl \200\223 ]. \200 As uCl \200\223 usually exceeds uN a + and uK + , this should return a negative value. UAG is an estimate of renal ammonia production ( b p. 819). Clinical features of an acidosis Systemic effects of severe metabolic acidosis (pH <7.1): \200 Air hunger (Kussmaul \200\231s breathing, an increase in tidal volume, with deep, sig hing respiration) and hyperventilation (to blow off CO 2 ). d myocardial contractility ( d Ca 2+ release from sarcoplasmic reticulum), arteriodilatation, and venoconstriction (central blood pooling). \200 Shifts oxygen dissociation curve rightwards (more O 2 release). \200 Reduced binding of noradren aline (norepinephrine) to receptors. Resistant arrhythmias (esp. VF). The associated underlying cause may be apparent. METABOLIC ACIDOSIS 821 Investigations \200 U&E, venous pH (in a blood gas syringe), or ABG. \200 Urine pH. In health, the urine pH <5.3 in the face of acid loading. \200 Lactate, ketones, blood gluco se. \200 Urinary dipstix, electrolytes (UAG), and ketones. \200 Microscopy for crystals . Toxicology screen, including salicylates. Normal AG acidosis Due to retained H + or HCO 3 \200\223 loss. Both Cl \200\223 and H + a re increased, so a normal AG acidosis is also referred to as \200\230 hyperchloraemic \200\231 . Cl \200\223 displays a reciprocal relationship with HCO 3 \200\223 , increasing when bica r- bonate is lost to maintain electrical neutrality. The UAG is useful in evaluating a normal AG acidosis: Non-renal losses of bicarbonate ( 2 negative UAG): Diarrhea or high-output ileostomy. \200 Ureterosigmoidostomy (gut absorption of urinary N H 4 + and Cl \200\223 ). Renal bicarbonate losses (UAG >0): Impaired reabsorption (acetazolamide). \200 Proximal RTA ( b p. 824) or Fanconi-like synd romes ( b p. 825). \200 Hypoaldosteronism or mineralocorticoid receptor blockade. Failure of renal acid excretion (UAG >0): \200 RTA (distal or type 4, b p. 825). Increased acid production/load: Toluene poisoning, lysine or arginine administered in TPN (metabolized to HCl), or NH 4 Cl administration. Increased AG acidosis ( \200\230 Hypo- \200\231 or \200\230 normochloraemic \200\231 ac idosis). Causes remembered, using the mnemonic KUSMAL: \200 K \200\224 ketoacidosis (acetoacetate or B -hydroxybutyrate). \200 U \200\224 uraemia/CKD; acidosis uncommon until eGFR <20 \200\223 25mL/min. \200 S \200\224 salicylates (aspirin). \200 M \200\224 methanol (a nd other alcohols, e.g. ethylene glycol). \200 A \200\224 aldehydes. \200 L \200\224 lactic acidosis. Causes of a ketoacidosis include diabetes, starvation, and alcohol \200\224 all induced by insulin de \201 ciency and relative glucagon excess l i fatty acid mobilization and subse quent oxidation to keto-acids. Treating severe acidosis with IVI NaHCO 3 is controversial \200 Corrects extracellular pH . \200 May worsen intracellular acidosis (normal intracellular pH is 7.1), as generated C O 2 crosses the cell membrane faster than HCO 3 \200\223 so i intracellular acidosis. Generates CO 2 that must be blown off ( (cid:2) \201 xed or d respiratory rate). CHAPTER 10 Fluids and electrolytes 822 Ionized calcium can fall abruptly. \200 Na + load is substantial (150mmol in 500mL 1.26% NaHCO 3 and 1mmol Na + /mL of 8.4% NaHCO 3 ) and poorly tolerated in volume-overloaded pati ents. Studies of bicarbonate supplementation in severe acidosis have consistently failed to demonstrate a bene \201 t \200\224 and some have suggested an asso ciation with mortality (as BP and cardiac output fall with correction). Reduced CO 2 -generating buffers (such as Carbicarb ) are promising but have not been ad equately assessed clinically. Managing severe and life-threatening acidosis Consider NaHCO 3 if pH <7.0 in patients with impaired cardiac perfor- mance. If correcting, aim to correct to pH >7.2 or a minimum [HCO 3 \200\223 ] >10, at which pH life-threatening complications of acidosis would be unusual. HCO 3 \200\223 de \201 cit = (target \200\223 measured [HCO 3 \200\223 ]) x bicarbonate space. \200 Bicarbonate space = (0.4 + 2.6/[HCO 3 \200\223 ]) x weight (kg). For example, in a 70 kg \231\202 with pH 6.9 and [HCO 3 \200\223 ] = 4mmol/L with car- di ac instability: de \201 cit = (10 \200\223 4) x ([0.4 + 2.6/4] x 70) = 420mmol HCO 3 \200\223 . (cid:2) Note that the target bicarbonate is 10mmol/L and NOT normal (24mmol/L). Aim to give as 1.26% NaHCO 3 (1,000mL = 150mmol HCO 3 \200\223 ) IVI over 4 \200\223 6 hours. 50mL 8.4% NaHCO 3 contains 50mmol HCO 3 \200\223 . 2 IVI bicarbonate is almost never needed in diabetic ketoacidosis \200\224 it delays the removal of blood ke tone bodies. Respiratory acidosis Occurs if pH <7.35 and i pCO 2 \200\224 may be metabolic compensation if chronic ( i [HCO 3 \200\223 ]). Causes include advanced pulmonary disease, respira- to ry muscle fatigue, impaired central ventilatory control (drugs or stroke), or as a result o f mechanical ventilation. Treatment (if warranted) usually involves mechanical ventilation. METABOLIC ACIDOSIS 823 Oral bicarbonate supplementation in progressive CKD Emerging evidence supports the use of o ral bicarbonate salts in slowing the progression of renal failure and improving the nutriti onal status of patients with CKD stages 4 \200\2235. The optimal bicarbonate level in CKD has yet to be de \201 ned. However, a level between 2 3 and 29mmol/L is associated with a reduced rate of deterioration in renal function, and ob servational studies suggest it may be associated with reduced mortality. Aim to treat with oral NaHCO 3 1.5 \200\2234.5g/day in 2 \200\2233 divided doses. Alternati ves include Na citrate or a diet in fruit and vegetables (rich in alkali). Advantages in no t using NaHCO 3 include lowering the salt load. Other bene \201 ts in treating chronic acidosis include: Reducing bone demineralization. \200 Improving appetite. \200 Reducing muscle wasting a nd malnutrition. CHAPTER 10 Fluids and electrolytes 824 Renal tubular acidosis A group of disorders characterized by impaired renal handling of aci d, usually with normal renal function. The basis for the, often confusing, ter- minology us ed for RTA revolves around physiology: almost all \201 ltered bicarbonate (HCO 3 \200 \223 ) is reabsorbed in the proximal tubule, with no net acid excretion. All net acid excre tion occurs in the distal nephron ( b p. 930). See Table 10.5 for distinguishing types of R TA. Distal RTA (type 1) Disordered excretion of acid (H + ) from the A -intercalated cell in th e col- lecting duct leads to acidosis. Presents as a hyperchloraemic, hypokalae- mic metabo lic acidosis, with hypophosphataemic metabolic bone disease, renal stones, or diffuse nephr ocalcinosis (requirement to chronically buffer acidosis l bone buffering). Is (rarely) inhe rited or, more commonly, acquired secondary to: \200 Sj gren \200\231s syndrome, RA, S LE, and other autoimmune diseases. \200 Nephrocalcinosis (distal RTA is confusingly both a cause and result of nephrocalcinosis) of any cause. Drugs (analgesic nephropathy, ifosfamide, amphotericin, lithium). \200 Chronic tubulointe rstitial disease (of any cause, b p. 582). \200 Dysproteinaemias (hypergammaglobulinaemia , amyloidosis). Investigations \200 i u-pH (>5.3 in the face of acidosis). \200 d K + , d HCO 3 \200 \223 <12mmol/L, normal AG ( i Cl \200\223 ). \200 Positive urinary AG ( b p. 820), i u-C a 2+ , d u-citrate (absorbed to buffer acidosis). Plain KUB or USS may show nephrocalcinosis. \200 ANF, anti-Ro/La, rheumatoid factor. If partial RTA suspected, either: \200 Acid loading test: 0.1g/kg NH 4 Cl PO, with u-pH h ourly, HCO 3 \200\223 at +3 hours. If HCO 3 \200\223 <21 and u-pH >5.3, diagnose RTA. Furosemide (40mg PO) and \202 udrocortisone (1mg PO) test: stat simultanous dose, then hourly urine pH to 6 hours. At +6 hours, if HCO 3 \200\223 <21 and u-pH >5.3, diagnose RTA. Treatment Potassium citrate 3 \200\223 10g/day in three divided doses (citrate generates t wo bicarbonate molecules) or sodium bicarbonate 4 \200\223 12g/day in four divided doses, aiming for s-HCO 3 \200\223 >22mmol/L. Proximal RTA (type 2) Impaired retention of HCO 3 \200\223 in the proximal tubule leads to bicarbo- nate wasting and a systemic acidosis. Pre sents as a hyperchloraemic meta- bolic acidosis, usually with other features of proximal tu bular dysfunction (so-called Fanconi syndrome, see b p. 825). Commoner causes include: \200 Myeloma and amyloidosis. \200 Cystinosis, Wilson \200\231s disease, or heavy metal toxicity (lead, cadmium). \200 Drugs (acetazolamide, antiretroviral drugs, aminoglycoside s). RENAL TUBULAR ACIDOSIS 825 Investigations Although the u-pH may be >5.5, usually d u-pH <5.3, once steady state achiev ed with chronic acidosis (as falling \201 ltered bicarbonate means less bicarbonate wasti ng). 2 If IVI NaHCO 3 1mmol/kg/h given, distal reabsorption is overwhelmed and u-pH i >7. \200 d K + , with i distal Na + delivery and hyperaldosteronism l K + wasting. \200 d HC O 3 \200\223 (12 \200\223 20mmol/L), normal AG ( i Cl \200\223 ), negative u-AG (see below). Findings of Fanconi.